Stability Study

Paper910101
chap4,8
Basic concepts
Stability:basic concepts and objectives
GUIDED BY:
Dr. R.K.PARIKH
PRESENTED BY:
KALPESH G. VYAS M.PHARM -1 YEAR-2009-10 ROLL NO-10
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY

L.M.COLLEGE OF PHARMACY AHMEDABAD-09
Paper 910101 M.Pharm--2009-10
stability basic concepts & objectives KALPESH
ESSENTIAL DEFINITIONS ACCORDING TO ICH STABILITY STABILITY is officially defined as the time lapse(period) during which drug substance (API) or drug product (FPP) to retains the same properties and characteristics(i.e. Physical, Chemical, Microbiological, Therapeutic and Toxicological specifications to maintain its identity, strength, quality, and purity ) that it possessed at the time of manufacture. ACCELERATED STABILITY TESTING These are the studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programme. The data thus obtained, in addition to those derived from real time stability studies, may be used to assess longer term chemical effects under non-accelerated conditions and to evaluate the impact of short-term excursions outside the label storage conditions, as might occur during shipping. The results of accelerated testing studies are not always predictive of physical changes. LONG-TERM STABILITY STUDIES Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of an API or FPP, during and beyond the expected shelf-life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the re-test period or the shelf-life, to confirm the projected re-test period and shelf-life, and to recommend storage conditions. ONGOING STABILITY STUDY The study carried out by the manufacturer on production batches according to a predetermined schedule in order to monitor, confirm and extend the projected re-test period (or shelf-life) of the API, or confirm or extend the shelf-life of the FPP. STRESS TESTINGFORCED DEGRADATION (API) Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. To identify potential degradants (degradation pathways) of the API and assess if they can be formed during mfg. or storage of the FPP (Finished Pharmaceutical Product )
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 2
Paper 910101 M.Pharm--2009-10
STRESS TESTINGFORCED DEGRADATION (FPP) Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photostability testing (see ICH Q1B) and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development. MEAN KINETIC TEMPERATURE (MKT): MKT, as defined by the USP, is a single calculated temperature at which the total amount of degradation over a particular period is equal to the sum of the individual degradations that would occur at various temperatures RE-TEST PERIOD The period of time during which the API should be examined to ensure that the material is still in compliance with the specification and, thus suitable for use in the manufacture of a given FPP,when stored under the defined conditions. SHELF LIFE ( Expiration dating period, conformance period): The time period during which an API or a FPP is expected to remain within the approved shelf-life specification, if stored under recommended conditions. SPECIFICATION - RELEASE The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release. SPECIFICATION - SHELF LIFE The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of an API throughout its retest period, or that an FPP should meet throughout its shelf life. PRIMARY BATCH (called also exhibit batch) A batch of an API or FPP used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life, respectively. A primary batch of an API should be at least a pilot scale batch. For a FPP, two of the three batches should be at least pilot scale batch, and the third batch a production batch. PRODUCTION (SCALE) BATCH A batch of an API or FPP manufactured at production scale by using production equipment in a production facility as specified in the application.
Paper 910101 M.Pharm--2009-10
SUPPORTING DATA Data, other than those from formal stability studies, that support the analytical procedures, the proposed re-test period or shelf life, and the label storage statements. Such data include (1) stability data on early synthetic route batches of API, small-scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing; (2) information regarding test results on containers; and (3) other scientific rationales. TYPES OF STABILITY Mainly Five types of Stability are generally recognized Type of Stability Chemical Condition Maintained throughout the shelf life of drug product Each active ingredient retains its chemical integrity and labeled potency within the specified limit Physical The original Physical properties including appearance palatability, uniformity, dissolution and suspendability are retained. Microbiological Sterility or resistance to microbial growth is retained according to specified requirement. Therapeutic Therapeutic effect remains unchanged Toxicological No significant increase in toxicity occurs
What happens due to Instability ? 1) Increse in the concentration of API :For some products, loss of vehicle, can result in an increase in the concentration of active drug. For example, Some lidocaine gels exhibit this behaviour, perfusion bags sometimes allow solvent to escape and evaporate so that the product within the bags show an increase in the concentration. 2) Loss of content uniformity :-
Paper 910101 M.Pharm--2009-10
Suspensions are the drug delivery system most likely to show a loss of content uniformity as a function of time. For such systems, determination of ease of redispersion or sedimentation volume may be included in a stability protocol. 3) Decline of microbiological status :The microbiological status of a pharmaceutical product can change significantly with time . First, micro organisms present in the product at the time of manufacture may reproduce and thus increase the number of viable microorganisms. Drug assayed for the bioburden at the time of manufacture , is within limits ,ay when tested after say 6 months storage, exceed the maximum permitted limits. 4) Formation of toxic degradation products :If a drug degrades to a molecular species that is toxic, there must be a special attention given to the quantity of such products. E.g. Conversion of p-amino salicylic acid to p-amino phenol (Toxic). OBJECTIVES OF STABILITY TESTING:(1) Our concerns for patients welfare :Obviously , our primary reason for stability testing should be our concern for the well-being of the patients who will use our products. Sometimes in the mad rush to comply with other requirements, this important fundamental may be discounted or forgotten .Indeed , sometimes one gains the impression that is some quarters stability is regarded as having clinical revelance. Certainly , if a product that does not degrade to toxic decomposition products and that is characterized by a narrow therapeutic ratio is present on the market at only 85% of label claim , one would not expect patients to be dropping dead in the streets because of this deficiency instability . However , this is not to say that stability problems can never have serious clinical consequences. For example , in the early 1980s a packaging stability problem with nitroglycerine tablets unfortunately resulted in some tablets have 10% of label claim. Since nitroglycerine is used for the emergency treatment of a most serious cardiac conditions, angina, there is unfortunately strong cause for concern that some patients may have died as a result of this stability problem. (2) To protect the reputation of the producer. We should be jealous for the reputation that the stability of our pharmaceutical products compounded or manufactured enjoys. Thus a most important reason for conducting a stability testing program is to assure ourselves the our products will indeed retain fitness for the use with respect to all functionally relevant attributes for as long as they are on the market.
Paper 910101 M.Pharm--2009-10
(3) Requirements of regulatory agencies In many parts of the world, there are legal requirements that certain types of stability tests, as required by regulatory agencies, must be perfomed. Obviously, the law must be obeyed. However, it is wrong to abdicate from all scientific judgement and only conduct those stability tests that a regulatory agency is perceived as requiring. Indeed, there are occasions when any manufacturer with a true dedication to quality will perform stability tests that are over and above those required by regulation. (4) To provide a database that may be of value in the formulation of other products. Data obtained in the stability evaluation of product X in 1999 may prove to be of value when, in 2003, we start developing product Y. There may be occasions, although they are probably rare, when it will worthwhile to continue stability testing on an R&D formulation that we know will never be marketed just because we are interested in the stability of a new excipient that we have included in the formulation. (5) Shelf-life & storage condition and labeling specification :By carrying out stability testing we can find out the shelf life and expiry date can be calculated . We ca have information about best storage condition at which drug will contain its characteristic for long time. And if there is any specification that we can write it on the label. (6) Adequate formulation & container closer systems. We can have idea about the formulation which will be more stable. And if during stability testing we find any specification of container. e.g. menadione injection is packed in amber colour ampoule to protect from photo degradation. (7) How quality of drug substance or product varies with the time under the influence of various factors. (8) Degradation product & possible degradation pathway (9) Development & validation of stability indicating methodology (10) Prevent great loss by recalling the batch due to stability. If any difficulty is found during storage and in marketed product , than industry has to recall all the drugs of that batch which is not economical . But if stability studies are carried out than we may over come those problems.
Paper 910101 M.Pharm--2009-10
(11) To verify that no changes have been introduced in the formulatn or manufacturing process that can adversely affect the stability of the product (12) Providing evidence on how quality of drug substance or product varies with the time under the influence of various factors like temp, humidity and light. (13) Loss/increase in concentration of API (14) Modification of any attribute of functional relevance, e.g., alteration of dissolution time/profile or bioavailability (15) Loss of pharmaceutical elegance and patient acceptability Stability study requirement and guidance regarding this is covered in 1. International Conference on Harmonization(ICH) of technical requirements or registration of pharmaceutical for humane use. 2. ASEAN(Association of South-East Asian Nations) guideline for stability of drug products. 3. WHO guideline for stability of pharmaceutical products. 4. USFDA guideline 5. SUPAC guideline
TYPE OF STABILITY STUDIES:1. 2. 3. 4. 5. 6. 7. Accelerated stability testing intermediate testing Long term testing Stress testing forced degradation testing Photo stability testing Thermal analytical techniques for stability testing (DSC,microcalorimetry)
Paper 910101 M.Pharm--2009-10
Overview of ICH guideline for stability testing Q1A (R2) Q1B Stability Q1C Q1D Stability Testing in New Drugs and Products (Revised guideline) Photo-Stability Testing Stability testing: New Dosage Forms Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products Evaluation of Stability Data Stability Data Package for Registration in Climatic Zones III and IV
Q1E Q1F
STRESS TESTING Stress testing of the drug substance can help identify the likely degradation products, which can in turn help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved. Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10C increments (e.g., 50C, 60C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photostability testing should be an integral part of stress testing. Perform essentially during Preformulation study. Done on single batch same composition & quality as marketing batch including packaging. Conducted for period of 6 months . Stress testing of FPPs in solid state
Paper 910101 M.Pharm--2009-10
Stress testing of API in solution
STABILITY PROGRAMME If a manufacturer wants to apply for the registration of a new drug, i.e. if he is applying for a (1) Investigative New Drug Application (IND) or (2) New Drug Application (NDA) or(ANDA) then he has to assure the FDA regarding the drugs/drug products safety, quality and efficacy. For this he has to carry out stability tests and submit stability data specified by Q1A (R2). An API is considered as stable if it is within the defined/regulatory specifications when stored at 302oC and 655% RH for 2 years and at 402oC and 755%RH for 6 months.
Paper 910101 M.Pharm--2009-10
These guidelines divide the world into four zones and specify the temperature and relative humidity conditions to be maintained by each zone for stability studies. CLIMATIC ZONE The zones into which the world is divided based on the prevailing annual climatic conditions International Climatic Zones and Climatic Conditions Zone I Zone II Zone III Zone IV Temperate Mediterranean Hot/dry or Very (sub-tropical) Hot/moderate hot/humid RH 20.5-24C >24C >24C Mean Annual < 20C Temperature Kinetic Mean 21C Temperature (Virtual temperature) Mean Annual 45% Relative Humidity 26C 31C 31C Climatic Condition
60%
40%
70%
Few countries of various zones Zone I : Britain, North Europe, Russia, Canada Zone II : U.S.A, Japan , South Europe Zone III : Iran, Iraq, Sudan Zone IV :Brazil, Ghana, Indonesia, Phillipines INDIA COMES IN III AND IV ZONE
Paper 910101 M.Pharm--2009-10
DESIGNING STEPS 1) 2) 3) 4) 5) 6) 7) 8) SELECTION OF BATCHES TEST PROCEDURES AND TEST CRITERIA SPECIFICATIONS STORAGE TEST CONDITIONS TESTING FREQUENCY PACKAGING MATERIAL EVALUATION STATEMENTS AND LABELLING.
Selection of batches Stability information from accelerated & long term testing should be provided on batches of same formulation & dosage form in the container & closure proposed for marketing. Stability data on three primary batches are to be provided. The composition, batch size, batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached. Expected that atleast 1st two batches manufactured should be tested for long term stability studies. Testing frequency According to ICH STABILITY TESTING Real time testing (Q1 & CPMP-QWP/556/96) Accelerated testing (Q1A(R) Intermediate (Q1A ( R )) TESTING INTERVALS 0,3,6,9,12,15,24 months 0, 3 & 6 months 0,6,9 & 12 months
For accelerated testing , FDA guidelines suggest 0,2,4 & 6 months WHO guidelines 0,1,2,3, & 6 months FDA,CPMP & WHO guidelines dont suggest for intermediate testing
Paper 910101 M.Pharm--2009-10
Storage test conditions Zone I AND II Long term study Intermediate study Accelerated study Zone III AND IV Long term study Accelerated study ACCORDING WITH ICH Q1A AND Q1F TEMPERATURE RELATIVE HUMIDITY 250C 2 300C 2 400C 2 TEMPERATURE 300C 2 400C 2 60% 5 RH 65% 5 RH 75% 5 RH RELATIVE HUMIDITY 65% 5 RH 75% 5 RH
Acceptance Criteria : Significant change for a drug substance is defined as failure to meet its specification 1. A 5% potency loss from the initial assay value of a batch. 2. Any specified degradants exceeding its specified limit. 3. The product exceeding its pH limits. 4. Dissolution exceeding the specified limits for 12 capsules or tablets. 5. Failure to meet specifications for appearance and physical properties (e.g., color, phase separation, resuspendability, delivery per actuation, caking, hardness). 6. 5% loss in water from its initial value ,from packaged in a semipermeable container Specification - Release The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage. Shelf-life acceptance criteria should be derived from consideration of all available stability information. E.g :Release and shelf-life dissolution acceptance criteria (Q and t) must be the same
Paper 910101 M.Pharm--2009-10
Stability Commitment For confirmation of provisional (tentative) shelf-life, real-time data are required When available long term stability data on the primary batches donot cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish shelf life First 3 production batches on stability Follow up stability testing (FUST) one batch per year Evaluation 1. Tabulate and plot stability data on all attributes at all storage conditions and evaluate each attribute separately. 2. No significant change at accelerated conditions within six (6) months. 3. Long-term data show little or no variability and little or no change over time. labeling The use of terms such as ambient temperature or room temperature is unacceptable. Where applicable ,specific requirement should be stated eg protect from light ,protect from freezing . The use of precautionary statements should not be a substituted After the stability of the product has been evaluated, - store under normal storage conditions; - store between 2 and 8oC (under refrigeration, no freezing); - store below 8 oC (under refrigeration); - store between -5 and -20oC(in a freezer); - store below -18oC(in a deep freezer). Normal storage conditions have been defined by WHO as : storage in dry, well-ventilated premises at temperatures of 15-25 oC or, depending on climatic conditions, upto 30oC. Extraneous odours, contamination, and intense light have to be excluded. STABILITY PROTOCOL AND REPORT Batches tested General information Container/closure system Literature and supporting data
1. 2. 3. 4.
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5. Stability-indicating analytical methods 6. Testing plan 7. Test parameters 8. Test results 9. Other requirements (post-approval commitments) 10.Conclusions Result sheets must bear date and responsible person signature / QA approval
REQUIREMENT OF TEMPERATURE DEPEND ON TYPE OF TESTING TYPE OF STUDY Long term Intermediate Accelerated TEMPERATURE 25C 2C 30C 2C 40C 2C/ RELATIVE HUMIDITY /60% RH 5% RH /65% RH 5% RH 75% RH 5% RH TIME DURATION 12 months 6 months 6 months
DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON TYPE OF DOSAGE FORMS FOR DISTINCT PRODUCTS Solid oral DF, solids for reconstitution, dry &lyophilized powders in glass vials Liquids in glass bottles ,vials, sealed glass ampoules which provide an impermeable barrier to water loss AST 40C 2C 75 % 5%RH TYPE OF STUDY IST 40C2C 75 % 5% RH 30C2C Ambient humidity LST 40C2C 75 % 5% RH
40C 2C Ambient Humidity
25C2C Ambient Humidity
Paper 910101 M.Pharm--2009-10
Drug products in semipermeable containers
40C 2C NMT 25 % RH
30C2C 65 % 5% RH
25C2C 40 % 5% RH Or 30C2C 35 % 5% RH
Stages where stability studies carried out Stability testing is done in five different occasion when an NDA is being contemplated. 1. Preformulation and compatibility 2. Preclinical formulation 3. Clinical and NDA formulation 4. Commitment and product monitoring 5. Post NDA change of formulation Preformulation and compatibility In the early stage of drug designing, studies are done to find out what sort of decomposition is possible, what is the mechanism, sensitivity to moisture and oxygen interaction probabilities (compatibilities) optimum pH and polymorphic information. Drug excipient interactions physical as well as chemical are extensively studied. Preclinical formulation Keeping the data from the preformulation studies in mind formulations are designed and manufactured for use in Phase-I trails. More than the one or two formulations being used in Phase-I studies are manufactured and started on stability studies. This is because even a supposedly stable formulation may while in Phase-I use fail with respect to some stability issue, then you must have something to fall back upon. Clinical and NDA formulation When a product has passed Phase-I, its dosage level, interactions and stability profile are known to some degree and armed with this knowledge the Clinical manufacturing group of the company manufactures several batches of the product and keeps some products from every batch for stability. The required stability aspects of clinical are simply to ascertain that each batch is within specifications during the length of the trail. Late Clinical and First Pilot Batch
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The ICH stability guidelines require that three substantial batches, made in the same type production equipment intended for the final product, be made and that at least 12 months stability be in place at the time of NDA submittal. Marketed product stability At the time the NDA is filed, the large clinical and scate-up batches are only about a year old, and the stability data on them is not yet complete. So at this time, the company asks for an expiry date based on extrapolation of the existing stability data. The FDI will take all facts into consideration and grant an expiry date based on a commitment form the company that the company will continue to do stability studies on different batches. The storage requirements and the sampling times are very clearly specified by the ICH guidelines.
RECENT ADVANCES IN STABILITY TESTING 1) Stability Testing of Herbal Products Abstract:Since last one decade India has seen tremendous growth in herbal drug market, which has resulted in development of numerous proprietary herbal drug formulations by various manufacturers, majority of them comprising of polyherbal formulations. With the advancement of knowledge in the field of phytochemistry it has now been observed that many of these constituents present in the drug may react with each other raising the serious concern about the stability of such formulations. This is the area, which needs to be addressed in order to determine the efficacy of the formulation. This article is aimed to give some guidelines for undertaking stability studies for herbal products. Stability testing of herbal products is a challenging task, because the entire herb or herbal product is regarded as the active substance, regardless of whether constituents with defined therapeutic activity are known. The objective of a stability testing is to provide evidence on how the quality of the herbal products varies with the time under the influence of environmental factors such as temperature, light, oxygen, moisture, other ingredient or excipient in the dosage form, particle size of drug, microbial contamination, trace metal contamination, leaching from the container, etc. and to establish a recommended storage condition, retest period and shelf-life. Therefore evaluation of the parameters based upon chemical, physical, microbiological, therapeutic and toxicological studies can serve as an important tool in stability studies .
Paper 910101 M.Pharm--2009-10
2) Recent Developments on Long-Term Stability Test Conditions Abstract: Stability testing is the only way to demonstrate that the pharmaceutical product would meet the laid-down specifications within acceptance criteria throughout its lifetime. It is also required to gain the regulatory approval. The birth of International Conference on Harmonization (ICH) in 1991 and finalization of the guideline Q1A in 1993 led to harmonization of the stability test requirements for new drug applications, and was instrumental in development of a series of ICH and other National and regional stability guidelines, both for the new and existing drugs. There have been some recent developments, especially with respect to defining of storage condition for long-term stability testing. This note traces the new developments.
REFERENCES:1) Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes (Marcel Dekker, Inc., New York, 2000) 2) Modern Pharmaceutics.- Drugs and the Pharmaceutical Science by G S. Banker and C T. Rhodes. 3) I.C.H. guidelines. 4) THE PHARMA REVIEW (APRIL - MAY, 2008) 5) THE PHARMA REVIEW (DECEMBER, 2006) 6)JPS ,VOL 51,1962-solid state stability,100 7)JPS,VOL 51,1962,prediction of stability of drugs &pharmaceutical preparation ,811 8)www.pharmainfotech.com
Paper-910101
Chapter-4
Stability Studies By: Sanjay C. Modi
Seminar on Order of reaction And their applications in predicting shelf life of pharmaceutical formulations (Under stability study)
GUIDED BY: Dr. R. K. PARIKH PREPARED BY:SANJAY C. MODI M.PHARM PART- I (2009-10) ROLL NO 07. DEPT. OF PHARMACEUTICS AND TECHNOLOGY L.M.COLLEGE OF PHARMACY AHMEDABAD-09.
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Chapter-4
LIST OF CONTENTS:No. 1 2 3 4 5 6 7 8 9 10 CONTENT KINETIC OF REACTION ZERO ORDER OF REACTION FIRST ORDER OF REACTION SECOND ORDER OF REACTION COMPLEX REACTIONS COMPARISON OF REACTION DETERMINATION OF ORDER OF REACTION PREDICTION OF SHELF LIFE & OVERAGES QUESTION BANK REFERENCES
KINETICS Kinetics is the study of the rate at which processes occur. It is useful in providing information that: Gives an insight into the mechanisms of changes involved,and Allows a prediction of the degree of the change that will occur after a given time has elapsed. ORDER OF REACTION This is the number of concentration terms that determine the rate. Consider the reaction: A + B C + D The rate of the reaction is proportional to the concentration of A to the power of x, [A]x and also the rate may be proportional to the concentration of B to the power of y, [B]y.
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Chapter-4
The overall equation is, Rate = k [A]x [B]y The overall order of reaction is x+y RATE CONSTANT A rate constant is a proportionality constant that appears in a rate law. For example, k is the rate constant in the rate law d[A]/dt = k[A]. Rate constants are independent of concentration but depend on other factors, most notably temperature. ZERO ORDER REACTION When the reaction rate is independent of concentration of the reacting substance, it depends on the zero power of the reactant and therefore is zero order reaction. In this type of reaction, the limiting factor is something other than concentration, for example, solubility or absorption of light in certain photochemical reactions. The rate of decomposition can be described mathematically as: Rate of concentration decrease = -dCx = K.(1) dt Integrating the equation yields X= Kt + constant(2) A plot of X vs time results in straight line with slope equal to K. The value of K indicate the amount of drug that is degraded per unit time, and intercept of line at time zero is equal to constant in equation (2).
The unit of K is conc time-1, with typical units of mole L-1 s-1. Half-life is given by equation t1/2 = Co/2k. Examples: -Vitamin A acetate to anhydrous vitamin A. Photolysis of cefotaxime. Loss in color of multi sulfa product. Intravenous infusion, Drug released from TDDS.
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concentration time
SLOPE=K
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Chapter-4
FIRST ORDER REACTION When the reaction rate depends on the first power of concentration of a single reactant, it is considered to be first order. Example are Absorption,distribution,elimination rates. Microbial death kinetics. Thus the rate of reaction is directly proportional to the concentration of reacting substance and can be expressed as follows: Rate of concentration decrease = -dCX = KCx.(3) dt If concentration of reactant X is a at beginning of reaction when t = 0, & if amount that has reacted after time t is denoted by x then amount of X remaining at time t will be (a-x). Therefore equation (3) can be rewritten as: -dCX = K (a-x) dt dCX = -K dt---------------------------(4) (a-x) Integrating equation (4) between time limit 0 to t
a
a-x
dCX dt
= -K 0t
dt
ln (a-x) ln a = -Kt log (a-x) log a = -kt/2.303 log (a-x) = log a Kt/2.303 -----------(5) Equation (5) is like y = mx + c (linear relationship) If first order law is obeyed then a graph of log (a-x) v/s time t will give straight line with slope of K/2.303 and an intercept of log a at t = 0.
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Chapter-4
SLOPE = -K 2.303
Log (a-x)
Time Rearranging equation (5) we have K = 2.303 log (a/a-x) -----------------------------(6) t Unit of K for first order is time-1 i.e. SI unit is (sec)-1 because K is inversely proportional to t. The half-life, t1/2, of a drug is the time required for 50% of drug to degrade and can be calculated as follows: t1/2 = 2.303 log C0 = 2.303 log 100 k C k 50 =2.303 log 2 = 0.693 k k t1/2 = 0.693..(7) k
therefore,
In pharmaceutical field , the time required for 10% of the drug to degrade is an important value to know, since it represents a reasonable limit of degradation of active ingredients. The t10% value can be calculated as t10% = 2.303 log 100 = 0.104 k 90 k t10% = 0.104 (8) k or t10% = 0.152 t1/2 SECOND ORDER REACTION Rate of change in conc. of product and reactant is dependent on second power of conc. of single reactant or to first powers of the conc. of two reactants.
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Chapter-4
-dCX = K [X] [Y]-------------------------------------(9) dt or -dCX = K [X]2-----------------------------------------(10) dt Let us discuss - dCX = K [X] [Y] in detail dt Here decrease in conc. of Y is similar to X. If conc. of X and Y at time t = 0 are a and b respectively, and conc. of each substance that has reacted after time t is equal to x then conc. of X and Y remaining will be (a-x) & (b-x) respectively. In case when (a b) -dx = K (a-x) (b-x)----------------------------------------(11) dt Where -dx = rate of decrease in conc. of X or Y dt Integrating equation (11) we get Kt = 2.303 log b(a-x)---------------------------------(12) (a-b) a(b-x) Rearranging equation (12) we get log (a-x) = (a-b) Kt + log a----------------------------(13) (b-x) 2.303 b So, if second order reaction is observed then graph of log (a-x) vs t (b-x) gives straight line with slope (a-b) K and 2.303 intercept log a/b at t =0.
i.e.
Log (a-x) (b-x)
SLOPE = (a-b) K 2.303
Time
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Chapter-4
In case when (a=b) -dCX = K [X] 2 dt Integration gives, Kt = x ------------------------------------(14) a(a-x) Rearrangement of equation (14) gives us Kt = 1 - 1 -----------------------------(15) a-x a So if second order reaction is observed then graph of 1/a-x vs t gives straight line with slope K and intercept 1/a at t = 0. Unit of second order reaction is conc.-1 time-1 and SI unit is mol-1 sec1.
Half-life in this case is t1/2 = 1/ak. THIRD ORDER REACTION & HIGHER Rate of change in conc. is proportional to three concentration terms. However such reactions are rare and their analysis is complex. Reaction of even higher order is unlikely to occur. Rate eqn third order reaction is as follows: K = 1/2t [1/(a-x) 2 -1/a2] PSEUDO-ZERO ORDER REACTION In solid state, may drug decomposes by pseudo zero order i.e. reaction between drug and moisture in solid dosage form. The system behaves like suspensions and because of the presence of excess solid drug; the first order rate actually becomes pseudo zero order. Equation for it is similar to zero order except K is replaced by K. How suspension degradation follows pseudo zero order reaction? Suspension is the case of zero order kinetics in which the concentration in solution depends on the drugs solubility. As the drug decomposes in solution, more drug is released from the suspended particles so that the concentration remains constant. This concentration is of course the drugs equilibrium solubility in a particular solvent at a particular temperature. The important point is that the amount of the drug in the solution remains constant despite its decomposition with time.
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Chapter-4
The reservoir of solid drug in suspension is responsible for this constancy. It follows zero order kinetics because the suspended drug reservoir that ensures constant concentration. Once all the suspended particles have been converted into drug in solution the system changes to a first order reaction. PSEUDO-FIRST ORDER REACTION Here a second order or bimolecular reaction is made to behave like first order. This is found in the case in which one reacting material is present in great excess or is maintained at constant concentration as compared with other substance. Here reaction rate is determined by one reactant even though two are present. EXAMPLES: Decomposition of ascorbic acid tablet. Aspirin hydrolysis. COMPLEX REACTION Although most degradative reactions in pharmaceutical systems can be treated by simple zero order, first order and pseudo-first order kinetics, there are certain pharmaceutical formulations that exhibit more complicated reactions. These have opposing, consecutive and side reactions alongwith main reaction. They are as follows:
1. OPPOSING REACTION (REVERSIBLE)
The simplest case is in which both reactions are of first order
K K K
A somewhat more complicated reaction is when forward is first order type and reverse reaction is second order type.
K
A
K
B+C
Example: Epimerization of tetracycline.

1. CONSECUTIVE REACTIONS
k1 k2
C 25
Simplest is one where both the reaction is of first order.
Paper-910101
Chapter-4
If K2 > K1 then B can be considered as unstable intermediate and rate determining step for overall reaction would be conversion of A to B. Examples: Radioactive series \ Isotopic decay that follows first order, but it is a consecutive reaction. Degradation of chlorbenzodiazepine by hydrolysis to lactum form and further to benzophenone.
2. SIDE REACTIONS (PARALLEL)
Here the reacting substance can be removed by two or more reactions occurring simultaneously, as depicted
K1
A
K2
EXAMPLES: Purified insulin degrades by two mechanisms- deamidation and polymerization. The relative rates of deamidation and polymerization are pH and temperature dependent. KNOWN FACTS: There is no detectable difference between first order and zero order at less than 15% decomposition. Many companies take the attitude of plotting by first order in situation where the order is unknown. Establishing the true order of reaction can often be difficult, due to the fact that strength chances at 25c are small and that unitto unit and assay variation make such a distinction difficult. SUMMARY OF PARAMETERS:Order 0 1 2 (a = b) Integrate rate equation X = Kt log (a/a-x) = Kt/2.303 X/a(a-x) = Kt t1/2 = a/2K = 0.693/K = 1/aK Linear Graph Ordinate Abscissa Slope Intercept X t K 0 log(a-x) t -K/2.303 log a 1/a-x t K 1/a 26
Paper-910101
Chapter-4
Order of reaction Unit of K Zero First Second M L-1Sec-1 Sec-1 M-1Sec-1
COMPARISON OF FIRST, SECOND & ZERO ORDER REACTION A tablet decomposes after one year to 75% of its initial concentration.In the following table the data of rate constant and half-life is given for particular order.
PARAMETERS K (Per Year) HALF LIFE 1ST 1.38 0.50 2ND 0.03 0.33 ZERO 75% 0.66
Initially speed of reaction: 2nd order >1st order > Zero order Because in 2nd order reaction, two molecules of reactants collide faster than one. Ideally if every collision between molecules led to product, a second order reaction would be twice as fast as first order. But in our case this is not true as half-life of first order is not twice as that of second order. This indicates that not every collision between molecules lead to reaction. After two years, Order of reaction Zero First Second Drug remaining -50% 6.76% 20% This shows that in 2nd year the speed of reaction reverses and 2nd order reaction becomes slowest as it is dependent upon the concentration of reactants and the concentration of reactants gets depleted as the reaction progresses so the % of drug remaining is more in case of 2nd order reaction while in zero order all the drug got decomposed before two years.
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Paper-910101
Chapter-4
METHODS TO DETERMINE ORDER OF REACTION 1. SUBSTITUTION METHOD 2. INITIAL RATE METHOD 3. DATA PLOTTING METHOD 4. HALF-LIFE DETERMINATION METHOD
SUBSTITUTION METHOD:
The data accumulated in a kinetic study may be substituted in the integrated form of the equations which describes the various orders. When the equation is found in which the calculated k values remain constant the reaction is considered to be of that order.
INITIAL RATE METHOD:
Graphs are plotted of rate of reaction against concentration and the initial rate determined from the gradient at time = 0. If it is a straight line the reaction is first order. If a curve is obtained then we can say it is 2nd order reaction. A reaction which is independent on concentration is zero order.
Fig. Curves for different types of order DATA PLOTTING METHOD:
Plot of conc. against time is if linear then it is zero order reaction. Plot of 1/c against time is linear then second order. Plot of ln c against time is linear then first order reaction.
HALF-LIFE DETERMINATION METHOD:
The relationship in general between half-life of a reaction in which the concentrations of all reactants are identical, is t1/2 1/an-1 where n is the order of reaction.
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Paper-910101
Chapter-4
Thus if two reactions are run at different initial concentrations, a1 & a2 with their respective half-lives and putting them in above equation in logarithmic form we finally get n = log (t1/2(1)/t1/2(2)) + 1 log (a2/a1)
Determination of t10% by Arrhenius equation

o Temperature influences rate and order of reaction. So shelf life of product can be obtained under exaggerated condition. o It is said that for every 10 0C rise, rate of reaction increases by 2-3 times. o For this Arrhenius equation is used i.e. K = Ae-a/RT Where A= frequency factor, R= gas constant, K = rate constant, a = energy of activation Therefore, Log K = log A a 2.303RT o Graph of log K v/s 1/T gives straight line with slope a & intercept at t = 0. 2.303R o a represents energy required by molecule to react and undergo reaction. Higher is value of a higher is dependency on temperature. o a = 2-3 k-cal/mole ------Photolysis o a = 10-30 k-cal/mole ---Hydrolysis-Solvolysis o a = very high abt 50-70 k-cal/mole-----Pyrolysis o Rate constant at different temperature can be obtained by log (K2/K1) = a (T2-T1) R (T2*T1) o With help of K at different temperature we can predict T10% t 10% = 0.105 / k (For first order only) t 10% = C0/ 10*k (for zero order only)
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Paper-910101
Chapter-4
Disadvantages of Arrhenius equation: 1. At higher temperature evaporation of solvent takes place and thus changes in concentration. 2. At higher temperature change in solubility and humidity (decreases) which cannot be correlated with room temperature. 3. For disperse systems at higher temperature viscosity decreases which can change physical characteristics resulting in potentially large errors in prediction of stability. 4. Different degradation mechanisms may predominate at different temperatures thus making stability prediction difficult.
METHOD TO DETERMINE OVERAGES

STEP I: - Perform the experiment and find out concentration of drug
remaining at different time intervals at different temperature including room temperature. Plot the graph of concentration vs time for different temp. As shown in the figure measure the slope and from that get rate Constant K.
STEP II: - After measuring the K at different temperature find value of K25
from the graph as shown in the figure.
K25 Log K
25 C TEMP 30
Paper-910101
Chapter-4
STEP III: - The value of K25 is substituted into eq. K = 2.303/t * log (a / a-x) And get the value of t10 %, t20% t 90%. STEP IV: - Calculation for overages Plot the graph of time (Days) Vs conc. remaining. Extrapolate line from Y- axis, at 90% to the X- axis. The intersect point will give shelf life. To maintain or increase the shelf life as per need (from a to b as shown in fig.) draw a parallel line from Y to that of X, the intersect point at Y- axis will give the value of overages per 100 unit. As shown in the figure, The value of overages is 20%. So need to add 20 unit drugs to preexisting formulation. As per European guidelines the maximum amount of overages is 30%.
STEP V: - Expiration period Prime goal of stability testing is to establish an exp. Date. The terms defined in lines 82-90 of guidelines as The date placed on the immediate container label of a drug product that designates the date through which the product is expected to remain within specification. If the expiration date includes only a month and year, it is expected that the product meet specification through the last day of the month.
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Paper-910101
Chapter-4
Estimation of the Shelf Life (Expiration Period) of Drug Products :Shelf life is best defined as the time span over which the quality of a product remains within specifications. That is, it is the time period over which the efficacy, safety, and esthetics of the product can be assured. When the degradation of the essential components cannot be adequately described by a rate expression, shelf life cannot be easily estimated or projected. When a quality-indicating parameter changes with time via complex kinetics that cannot be adequately explained or predicted, one must determine stability solely from experimental observations. Many physical degradation processes exhibit this kind of behavior. In contrast, estimation of shelf life is often possible when the shelf life is governed by a degradation process that can be adequately described by a rate expression (like many chemical degradation processes). Estimation of product shelf life is done by two methodsestimation from data obtained under the same conditions as those that the final product is expected to withstand and estimation from tests conducted under accelerated conditions. This section describes these two methods for estimating the shelf life of pharmaceuticals when chemical degradation is the major contributor to the degradation process and the degradation can be adequately described by a rate expression. DIFFERENT METHODS: A} Extrapolation from Real-Time Data B} Shelf-Life Estimation from Temperature-Accelerated Studies C} Estimation of Shelf Life under Temperature-Fluctuating Conditions
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Paper-910101
Chapter-4
FREQUENTLY ASKED QUESTIONS :1. Compare the zero ,first,second order of reaction with suitable numerical data(LM-05) 2. How chemical kinetics is useful in studying order of reaction ? (LM-06) 3. Explain different type of order of reaction & enlist the method to determined it .Explain one of them with suitable example(LM-05;06) 4. Define pharmacokinetics & bio pharmaceutics (2006;LM-06;07) 5. Short note on order of reaction and its utility in stability studies(2006) STUDY QUESTIONS 1. What is kinetics? 2. What is order of reaction? Describe different methods to determine order of reaction. 3. Discuss first order drug degradation in detail. 4. How one can predict shelf life of suspension and ascorbic acid tablet? 5. Compare first, zero, second order of degradation. 6. Discuss complex reactions. REFERENCES 1. Biopharmaceutics and Pharmacokinetics A treatise by D. M. Brahmankar Sunil B. Jaiswal. Page no. 215-220. 2. Stability of drugs and dosage forms by Yoshioka and Stella (2002) 3. Remingtons pharmaceutical Science, Mack Publishing Company, 15th edition 1975, 275-283. 4. Physical; pharmacy by Alfred martin, second edition , 355-377. 5. The theory and practice of industrial pharmacy by Lachman, 760.
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Paper code-910101/ Chapter 4/ Importance of Accelerated stability study
Importance Of Accelerated Stability Study
Guided by Dr. R. K. Parikh
Prepared by Himaxi Rajput M.Pharm I (2009-2010) Roll no.9
Department Of Pharmaceutics and Pharmaceutical Technology

L.M.College of Pharmacy Ahmedabad 9.
Department Of Pharmaceutics and Pharmaceutical Technology L.M.C.P. Ahmedabad 9
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Accelerated stability testing

All medicinal products decompose with time. Paradoxically, when this decomposition is being assessed the skilled formulator becomes a victim of his own expertise, as a good formulation will take a long time to decompose. Instability in modern formulations is often detectable only after considerable storage periods under normal conditions. To assess the stability of a formulated product it is usual to expose it to high stress, i.e. condition of temperature, humidity and light intensity that cause break down. High stress conditions enhance the deterioration of the product and so reduce the time required for testing. Thus these are the studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programme. This enables more data to be gathered in shorter time, which in turn will allow unsatisfactory formulation to be eliminated early in a study and will also reduce the time for a successful product to reach a market. It must be emphasized that extrapolation to normal storage condition must be made with care, the formulator must be sure that such extrapolation are valid. The results of accelerated testing studies are not always predictive of physical changes.
Significant change occurs due to accelerated testing

Significant change at the accelerated conditions is defined as: A 5% potency loss from the initial assay value of a batch. Any specified degradants exceeding its specified limit. The product exceeding its pH limits. Dissolution exceeding the specified limits for 12 capsules or tablets. Physical Changes under Accelerated conditions of Temperature & Humidity 1. Under Light, both Primary and Secondary packaging affected, and fading of container color, and the print is fading. 2. Effervescent Tablet : Gain of moisture, loss of integrity 3. Capsule: Color fading in Blister and Sticking in a Glass bottle. 4. Powder : Spread within strip pockets 5. Suppositories : Softening 6. Change in Viscosity of a Gel, Jelly, Cream & Ointment 7. Lozenges : melting 8. Emulsions : Phase separation
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Objective
1. Main aim of accelerated stability study to predict the stability profile of a drug product that prediction of self life of the product before launching into market. 2. The rapid detection of deterioration different initial formulations of the same product. This is of use in selecting the best formulation from a series of possible choices 3. Prediction of shelf life, which is the time a product will remain satisfactory when stored under expected or directed storage condition. 4. The provision of rapid mean of quality control, which ensures that no unexpected change has occurred in the stored product. Good formulation will invariably break down more slowly than poor ones. When the perceived optimal formulation is decided, attempts can be made to predict its likely stability at proposed storage conditions. These may be at 250C for ambient room temperature (or 3000C for use in hot climates), or 0-400C for a refrigerator. The amount of decomposition that is acceptable in fixing an expiry date depends on the particular drug. This will be small if therapeutic index is low or if the decomposition products are toxic.
Stability Profiles: Accelerated stability study

Storage Condition Controlled room temperature 20-250C Refrigerated condition 2-80C Freezer condition -20 to -100C Testing Condition 400C and 75% RH for 6 months 250C and 60% RH for 6 months 50C for 6 months
Prediction of shelf life from accelerated stability data

Based on the principle of chemical kinetics demonstrated by Garret and Carper method Free and Blythe method
Shelf Life Determination Based on Arrhenius Plot (Garret and Carper method)
The mathematical prediction of shelf life is based on the application of the arrhenious equation, which indicates the effect of temperature on the rate constant, k, of a chemical reaction of thermodynamic temperature, 1/T, is a straight line. If the slope of this line is determined from the results of temperature by extrapolation, the k value obtained. And this k value is substituted in appropriate
36
Paper code-910101/ Chapter 4/ Importance of Accelerated stability study order of reaction allows the amount of decomposition after a given time. Preliminary experiments are there for necessary to determine this order. K=Ae-Ea/RT Log K=Log A - Ea/2.303*RT Where, K= rate constant R= gas constant =1.987 cal/mole T = absolute temperature A = frequency factor Ea = energy of activation T10% = (2.303/K)*(log100/90) T90% = (2.303/K)*(log100/10)
Garret and Carper method)

1. Keep several samples of the drug product at atleast three temperatures, such as 40oC, 50 oC and 60 oC. 2. Determine the drug content at all three storage points by taking a number of samples and take the mean drug content. We do this for a few weeks. 3. At each temperature we plot a graph between time and log percent drug remaining. If the decomposition is first order this gives a straight line. If it is zero order, percent drug remaining versus time will give a straight line. 4. Next we take the log K or log of reaction constant on Y axis and 1/T x 10-3 on X axis and draw a best fit line. This line is the Arrhenius Plot, extrapolate this line to get k at 25 oC and from this we calculate the shelf-life.
Arrhenius plot for predicting drug stability at room temp.
37
If the reaction is following zero-order Expiration date at 25 oC = Initial potency minimum potency / reaction rate at 25 C tx =Yo - Yx/ Ko If the reaction is following first order Expiration date at 25 oC (tx) = Log initial potency log minimum potency/reaction rate at 25 tx =log Yo log Yx / K1 Where Yo = initial potency Yx = final potency Ko = zero order constant K1 = first order constant
Limitation of arrhenious relationship for stability prediction:

There are varieties of situation in which arrhenious equation can be erroneous or invalid. Higher temperature may evaporate solvents thus producing unequal moisture concentration at different temperature. At higher temperature stability for drugs sensitive to the presence of moisture and oxygen. For dispersive systems viscosity decrease as a temperature increases and physical characteristic may alter and resulting in potentially large errors in predicting of stability. In spite of these difficulties the application of accelerated testing to pharmaceutical product is often useful, and predicted shelf lives are sufficiently accurate.
38
SHELF LIFE DETERMINATION Based on t90 values (Free and Blythe /method)
In this method the fraction life period is plotted against a reciprocal temp. and the time in days required for drug to decompose to some fraction of its original potency at room temp. this approach clearly illustrate in below fig.
the log% of drug remaining is plotted against time and days and the time for the loss line at several temp. to reach 90% of the theoretical potency is noted by the doted line. Shelf life and expiration date are estimated in this way.
The log time to 90% is then plotted against 1/T and the time for 10% loss of potency at room temp. can be obtain from the resulting straight line by extrapolation to 250C
39
Limitation of accelerated stability studies

Accelerated stability studies are valid only when the breakdown depends on temperature. Accelerated stability studies are valid only the energy of activation is about 10 to 30 kcal / mol. In solution phase most reaction has heat of activation in the range of 10 to 30 k.cal / mole. if energy of activation is less than 10 kcal / mol its rate would be fast at room temperature .in such cases elevated temperature has little influence on the decomposition .if energy of activation is higher than 30 kcal / mol very high temperature are required to enhance the degradation . Reaction at such high temperature may not have any relevance, because they do not reflect ambient storage condition. The result obtained for one set of condition for a preparation cannot be applied to other preparation of same drug. Stability prediction at elevated temperature is of little use when degradation is due to diffusion, microbial contamination, and photo-chemical reaction. Stability studies are meaningless when the product looses its physical integrity at higher temperature like coagulation of suspending agent, denaturation of proteins. Prediction will become erroneous when the order changes at elevated temperatures, as in case of suspension (zero order) which at higher temperature get converted to solution which follow 1st order.
SHELF LIFE DETERMINATION BASED ON REAL TIME TESTING

Another method which involves real time testing and statistical analysis, followed for determinng shelf life. 1. Keep three batches for stability study at least for 1 year at one fixed temperature. 2. Test them at 0, 1, 3, 6, 9, and 12 months for drug content. At each testing time test a number of samples, so that you have a mean and a standard deviation value of the result. 3. Now plot the graph of % drug content on Y axis and time on X axis along with confidence intervals. Where the lower 95% confidence curve intersects minimum potency, there you fix the shelf life. As an example we can see the data and figure given in Tablets, Volume 3, by Hebet A Lieberman and Leon Lachman. Vitamin Tablets Stability Confidence Intervals at 40oC
40
Fig: Plot of In potency against time showing 95% confidence limit line Table: Vitamin Tablets Stability Confidence Intervals at 40oC Time (Months) Results (mg/tablet) Lower limit Upper Limit
0 1 3 6 9 12
100.0 91.2 83.1 75.8 69.1 63.0
95.2 88.7 79.3 69.8 61.2 53.6
104.9 93.8 87.3 82.5 78.2 74.0
Where estimate of the standard error of regression(s)
y1 = predicted value at t1 n = sample size Sy = standard error of the line = 0.1 two-sided 0.05 One-sided This method also helps formulation scientists in fixing the amount of overages to be added to vitamin products.
41
Q10 method for Shelf life estimation.

Q10 approach taken by Simonelli & Dresback Q10 is the factor by which the rate constant increases for a 100C temp. increase. It is the ratio of two different reaction rate constants. Commonly used Q values OF 2, 3 & 4 relate to the energy of activation of reaction for temperature for room temperature (25C)
For an Arbitrary temp. change T
As is evident from this relationship, an increase in T will decrease the shelf life and a decrease in T will increase shelf life.
Scientists has found out that Activation energy (Ea) of all chemical decomposition reaction usually fall in the range 12 to 24 Kcal/mol. With a typical value of 19 to 20 Kcal/mol.
42
Ea ( K cal/mol. ) 12.2 19.4 24.5
Q10 ( 300 to 200C) 2.0 3.0 4.0
Q10 = 4 provides the higher estimate for the increase in rate with increasing temp., where as Q10 = 2 provides the lower estimate for the decrease in rate with decreasing temp. Q10 = 4 will estimate the maximum likely decrease in shelf life with increasing temp. and Q10 = 2 will provide the most conservative estimate of the increase in shelf life with decreasing temp. The value Q10 = 3 gives our most likely estimate.
T= T2-T1, T2= T1+ T
Where, t90 (T2) is the estimated shelf life, t90 (T1) is the given shelf life at given temp., and T is the difference in the temp. T1 and T2 Note : the estimate of t90(T2) is independent of the reaction order.
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Example: An antibiotic solution has a shelf life of 48 hrs. in the refrigerator (5 0C). What is its estimated shelf life at room temp.(250C)?using a Q10 value of 3.
Importance of Q10 method in shelf life estimation

It solves many problems like one t90 (T1) is the given shelf life at given temp., to determine the shelf life at another temp. t90 (T2). Some specific examples are. The expiration date is given for room temp. What is the expected extension of the shelf life in a refrigerator? The expiration date is given for refrigeration condition. How long the product may be left at room temp.? The expiration date is given for room temp. And it is desired to heat the product, what percent decomposition can be expected at higher temp.? The expiration date is given for refrigeration condition; the product is stored for a period of time at room temp. And is then returned to the refrigerator. What will be the corrected expiration date?
Overages
The excess quantity of drug that must be added to the preparation to maintain at least 100% of labeled amount during the expected self life of drug can be easily calculated and added to the preparation at the time of manufacture. The international pharmaceutical federation has recommended that overage be limited to a maximum of 30% over the labeled potency of an ingredient. While adding over-age safety and toxicity should also be considered. By convention overage to the of 10 % of excess dose of drug is added to the product at the time of manufacture. This is to ensure that the product contain 100 % labeled amount during the shelf life period. In other word at the end of one shelf period the concentration of drug of about 100 %. The same product will now take one more shelf life period in order to decrease the drug content to 90 % of labeled amount. Thus product will now take twice the shelf life as an expiry date.
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Stress testing
Stress testing to elucidate the intrinsic stability of the drug substance is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. The testing typically includes the effects of temperature (in 10oC increments (e.g. 50oC to 60oC) above that accelerated testing), humidity (e.g. 75%relative humidity or greater) where appropriate oxidation and photolysis on the drug substance. Stress testing of the drug product is undertaken to assess the effect of severe condition of the products. Such studies include photo stability testing and specific testing of the certain products.
Common high stresses or challenges

Temperature challenge
An increase in temperature causes an increase in the rate of chemical reactions. The products are therefore stored at temperature higher than room temperature. Sample is removed at various time intervals and the extent of decomposition is determined by analysis. Sensitive analytical methods are used in all stability tests of this nature, as small change can be detected after very short storage periods. The effects caused by high temperature should not confuse with those that arise from the effect of low humidity. Such confusion is possible because the relative humidity inside the high temperature in storage cabinet is lower than that of room temperature. This low humidity causes loss of moisture, which leads to apparent increase in the concentration of ingredients. If these concentration changes are not allowed for in subsequent analyses decomposition may be unsuspected.
LIMITATION:
The arrhenious equation involve only one rate constant and therefore applies to a simple(single step) decomposition mechanism. It cannot be used for complex reactions (consecutive, parallel etc.) or heterogeneous process involving the phase boundaries. The higher temperature may reduce the moisture content of the product, thus slowing the hydrolysis, gelatin may soften or melt, and tablet coating may split. The effects of temperature on photochemical and microbiological destruction are not predictable.
Humidity challenge
Storage of the product in atmosphere in high humidity will accelerate decomposition that result from hydrolysis. Marked acceleration will be obtained if the naked product (i.e. not enclosed in a container) is subjected to these tests, which usually indicate the minimum humidity tolerated by the product without undue decomposition, and therefore useful in determining the degree of protection that should be afforded by a container.
Light challenge
The source of artificial light used to accelerate the effect of sunlight or skylight. Day light fluorescent lamp provides a satisfactory source, and banks of such lamps may be used
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Paper code-910101/ Chapter 4/ Importance of Accelerated stability study to accelerate the effect of light. To reduce the heating effect of this lamp, glass plates used. Otherwise it is difficult to separate the accelerated decomposition cause by light from that caused by increase temperature. Objective Use
To select adequate (from the view of Development of product stability) formulation and container closure system. To determine shelf life and storage Development of the product and of the condition registration dossier To verify no changes have been introduce Quality assurance in general, including in the formulation or manufacturing that can quality control adversely affect the stability of the product
References 1. Aulton M. E, Pharmaceutics the science of dosage form design, Kinetics and stability testing. 2. Carstensen, J.T., Stability and Dating of Solid Dosage Forms Pharmaceutics of Solids and Solid Dosage Forms, Wiley-Interscience, 182-185, 1977 3. ICH Q1E Evaluation of stability data 4. Haynes, J.D., Worldwide Virtual Temperatures for Product Stability Testing, J. Pharm. Sci., Vol. 60, No. 6, 927 (June 1971). 5. the theory and practice of industrial pharmacy leon lachman, Herbert liberman joseph kanig third edition.
QUESTIONS:
1. How is accelerated storage stability carried out? (University 2006) 2. outline of accelerated stability study as per ICH guidelines.(lm 04,07) 3. How is accelerated stability carried out? What are current perspectives in stability testing from view point of regulatory agencies (university 2004, 2007?) 4. Elaborate on the stability testing frequency of pharmaceuticals 5. Explain shelf life determination based on arrehenius equation 6. what is Q10 method & its importance in shelf life estimation( LM 06) 7. Define stress testing .why stress testing should be carried out? 8. How accelerated stability test differ from stress testing? (lm 05) 9. explain method of predicting shelf life & overages ?(LM 05)
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PAPER-910101
CHAPTER-4
STABILITY STUDIES NITU
EFFECT OF VARIOUS ENVIRONMENTAL / PROCESSING FACTORS ON STABILITY OF THE FORMULATION AND TECHNIQUES FOR STABILIZATION OF PRODUCTS AGAINST THE SAME. PREPARED BY, Nitu Changoiwala Roll No:- 04 M-Pharm Sem-I GUIDED BY, Dr. R.K Parikh
DEPARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY. L.M.COLLEGE OF PHARMACY AHMEDABAD -09
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PAPER-910101
CHAPTER-4
PROCESSING FACTORS:BLENDING:It is most important step for manufacturing of solution dosage form. High speed of mixing may introduce air into the product and slow mixing may not form a satisfactory product. For mixing step, both mixing time and speed should be evaluated for API and Excipients. Mixing might produce particle size reduction or polymorphic conversion During mixing some other factors like type of agitator, temperature or vaccum etc. can affect the stability. Say for example, if during mixing, vacuum is not applied than air bubble will present into the product that might produce oxidation of product.
WAYS FOR STABILIZATION:-
Use of optimum time and rate of mixing. Use of optimum and controlled temperature. Application of vacuum. Use of closed system.
FOR SOLID DOSAGE FORM:During pharmaceutical powder blending process in case of solid dosage form, electrostatic charges generate due to particle-particle & particle wall collision. The effect of electrostatic charging on pharmaceutical powder homogeneity was investigated on 2 binary blending system:LACTOSE as an excipient with CAFFEINE as an API & MCC as an excipient with CAFFEINE as an API 3 different blending procedures were conducted 1. Conventional without charge control. 2. Blending with simultaneous charge neutralization. 3. Blending combined with corona(apparatus) charging process It was found that presence of uncontrolled electrostatic charges has an adverse effect on powder blend uniformity. Elimination of charges also appears to have negative impact on blend uniformity. In contrast blending of negatively charged excipient & positively charged API leads to better blend uniformity. (JPS,VOL-98,NO-7,JULY,2009)
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FREEZE-DRYING PROCESS:Freeze-drying process also affects the stability of product & there are various substances used for the process of freeze-drying which also leads to either increase or decrease in the stability. o A method to produce physically stable formulation. o Applicable for multivitamin preparation, antibiotics, hormones and Proteins formulation. o Cryoprotectant is added in formulation when product is lyophilized. o To act successfully as a protectant, it should have, -- A high glass transition temperature (Tg), -- A poor hygroscopicity, -- A low crystallization rate, -- Contain no reducing groups. Eg:Freeze drying was found to have destructive effect on the ordered structure of starch & this effect varied with respect to preparation condition. (JPS,VOL-98, NO-10,OCT 2009, pg no-3387) Surfactants & sugars possess synergistic effects on the lipoplex stability during freeze drying. (JPS,VOL-98,NO-9,SEPT.2009,Pg no-3319) Impact of bulking agents was studied on the stability of monoclonal antibody.it was found that sucrose acts as a primary stabilizer but when glycine was added, glycine leads to increase in the stability & when mannitol was added instead of glcine again there was increase in the stability though to a lesser extent as compared to glycine. (CA,VOL-151, NO-14, NOV 2009,321346z,Pg no-1954)
POLYMERIC FILM COATING PROCESS:The key to a successful application of an aqueous film coat to solid dosage forms is a full understanding of the important processing factors influencing the application process. Here we will enlist processing factors that contribute to product performance, since slight variation in processing conditions will impact the properties and therapeutic response of a film-coated drug delivery system.
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CHAPTER-4
List of processing factors influencing the properties of polymeric film coatings:-
WAYS FOR STABILIZATION:
Use of optimum processing condition for film coating. Identification and use of excipients which increased stability of film coated product. Interactions during Aqueous film coating of Ibuprofen with Aquacoat ECD. During the development of a coated ibuprofen formulation a sticking tendency occurred when applying Aquacoat ECD. The compatibility of the components of Aquacoat ECD with ibuprofen was investigated by differential scanning calorimetry. Cetyl alcohol, a stabilizing excipient in Aquacoat, was found to form a eutectic system with ibuprofen. It was characterized by the construction of a phase diagram with 33 mol% ibuprofen and an onset temperature of 40.5 C.
MILLING
The milling process results in a reduction in the particle size of a given material and can be conducted using the mildest conditions possible to render a sample homogeneous, or can use more rigorous milling to reduce the primary particle size. The formation of a high energy amorphous material is usually undesirable and given the opportunity, will spontaneously transfer either to a crystalline hydrate or anhydrate.
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PAPER-910101
CHAPTER-4
These physical changes in the state of the drug substance can alter the stability, dissolution characteristics and possibly even the bioavailability of the drug.
WAYS FOR STABILIZATION:
Use of moderate condition of milling. Optimum time of milling. Eg:1. The phase transformation of chloramphenicol palmitate associated with grinding and the effect of seed crystals
40 min. (1%Form B)
16 min.
150 min.
Form A
Form B
Form C
30 min. (1% Form A)
Thus, as we know that with increase in the concentration of form A of chloramphenicol palmitate the blood level are found to decrease and there is a detection test for presence of form A in Pharmacopoeias, so while grinding no impurity of form A should be present and grinding time should not exceed 150 minutes (to prevent conversion of form B to form A). 2) Formation of physically stable amorphous drug by milling. DRUGS NEUSILIN (KETOPROFEN, INDOMETHACIN, (AMOR. MAGNESIUM NAPROXAN, PROGESTERON) ALUMINUM SILLICATE)
Ball Milling
AMORPHIZATION OF DRUG
Storage
NO CONVERSION
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CHAPTER-4
CONCLUSION: - The amorphous form formed was studied for stability and
found that this form is much more stable than normal amorphous form. AND Similar studies were done on Salbutamol Sulphate & PVP.Experiment was done to improve the stability of SS as SS gets easily coverted from amorphous form to agglomerated particles.stability was induced by the method of co-milling.co-milling of SS with excipients like pvp was done..
EFFECT OF COMPRESSION:It is generally assumed that overall amount of energy input into a formulation during compression is not sufficient to induce a phase transformation and for many substances this situation is certainly true.There are numerous examples, for which changes in phase composition do accompany a compression step. Carbamazepine is a drug which shows differences in the dissolution rates that are associated with production of different polymorphs by tablet mfg process. It has 3 different crystalline form , and Dihydrate form. Manufacturing process is Grinding (ball mill for 15 and 60 min) Compression (single punch machine) It was found that Dihydrate - good compressibility but not stable - best stability but sticking - best stability . The effects of milling and compression on the solid-state Maillard reaction between metoclopramide hydrochloride and lactose were investigated. Anhydrous metoclopramide hydrochloride was milled for various times, and then mixed with amorphous lactose. The mixtures were stored at 105C and 0% RH. The reactivity of metoclopramide hydrochloride towards the Maillard reaction increased with milling time, as the result of increased surface area, formation of amorphous content, and creation of defects. Metoclopramide hydrochloride anhydrate and lactose were mixed and the mixtures were compressed into tablets under pressure varied from 70 to 350 MPa. Both tablets and mixtures were stored at 105C and 0% RH for 9 days. For all three types of lactose used, spray-dried anhydrous lactose, spray-dried lactose monohydrate, and amorphous lactose, tablets exhibited higher reaction rate toward the Maillard
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reaction than the powder mixtures. Tablets containing metoclopramide hydrochloride and amorphous lactose prepared at higher pressure showed higher reaction rates than those prepared at lower pressure.
(JPS, , VOL. 94 , sept 2005)
EFFECT OF LOCAL MOBILITY:Local mobility in amorphous forms of pharmaceuticals can lead to changes in their glass transition temperature effect of which is such that amorphous form converts to crystalline form. (JPS,VOL-98,NO-9,SEPT 2009,Pg no-2935)
WET GRANULATION:Wet granulation process, the both wetting phase solvent and drying phase conditions can cause a suitable environment for the transformation to alternate crystalline forms.
API molecule Polymorph 1 Polymorph 2
Polymorphic transformations during wet granulation can be divided to 1) Conversion of a metastable form to the stable form; 2) Conversion of the stable form to a metastable form; or 3) Conversion of an unsolvate form to a solvate form. WAYS FOR STABILIZATION: Use of granulating liquid which will not produce polymorphic conversion. Moderate/Optimum condition for drying. The preparation of tablets by THE MELT GRANULATION PROCESS was investigated to enhance chemical stability of a highly water-soluble drug substance, dipeptidylpeptidase IV (DPP-IV) inhibitor (Compound I), that is susceptible to degradation in presence of moisture. Melt granulation with a lipophilic binder (hydrogenated castor oil) improved the stability of the drug, while still maintaining immediate53
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release characteristics of the drug product.With higher binder levels, the sensitivity of the drug to degradation under humidity conditions decreased. It is postulated that the lipophilic binder coated drug particles at the surface protecting them from the influence of moisture. The granules had good flow properties and good compressibility and tablets prepared from them exhibited low weight variation and low friability. (IJPS, oct 2009, Vol 381, Pg.56-61) The effect of some processing and formulation variables on the stability of tablets containing a crystalline salt of a triazine derivative was studied. The salt has a relatively low melting point and a low microenvironmental pH due to the weakly basic nature of the parent compound (pKa = 4.0). This compound decomposes through acid-catalyzed hydrolysis. A full factorial design was used to study the effect of three variables on tablet stability: aqueous wet granulation, ball milling of the salt and filler prior to manufacturing, and the inclusion of sodium carbonate in the formulation as a pH modifier. In addition to the factorial design experiments, a batch of tablets was prepared by wet granulation, using sodium bicarbonate as the pH modifier. Stability of tablets was adversely affected by wet granulation. However, stability was greatly improved by wet granulation in the presence of sodium carbonate.The use of sodium bicarbonate as a pH modifier resulted in only marginal enhancement of tablet stability, suggesting that a higher microenvironmental pH than that provided by sodium bicarbonate is needed to maximize stability.Milling was found to have no effect.
EFFECT OF ADDITIVES:The amorphous character is common in the polymeric molecules used as excipients. For example, sugars usually exist in the amorphous state e.g. as a result of milling, spray drying or freeze drying. Amorphous sugars are highly hygroscopic and at high RHs they may sorb large amounts of water causing crystallization of that sugar. This process can have significant consequences for the stability of pharmaceutical formulations, because the presence of only small amounts of amorphous material can affect the interaction between the powder and other components of a formulation. Optimizing the selection of excipients in the formulation could reduce transformation during manufacturing and storage of final dosage forms.
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INSTABILITY of APIs and excipients may be broadly classified as: CHEMICAL INSTABILITY (like Hydrolysis, Oxidation and Deamidation) or PHYSICAL INSTABILITY (like Polymorphism, Pseudopolymorphism or Crystallization). WAYS FOR STABILIZATION: Avoid use of excipients which produce instability. Minimum numbers of excipients should be used. Use of excipient with multiple action.
Eg:SURFACTANTS: Presence of surfactants may either increase or decrease the stability.LIKE presence of micelles of CETYL TRIETHYLAMMONIUM BROMIDE & CETYL PYRIDINIUM CHLORIDE inhibits degradation of aspirin by hydrolysis which is acid catalyzed reaction in contrast increase the degradation of base catalzsed reaction. COMPLEXING AGENTS: Complexing agents increase the stability.Aromatic esters like benzocaine,procaine & tetracaine can be stabilised in solution form by the addition of 1-5% caffiene because of formation of complex. ANTIOXIDANTS & CHELATING AGENTS: These agents generally increase stability by decreasing the rate of reaction.
EFFECT ON STABILITY IN PRESENCE OF OTHER DRUGS:Sometimes presence of one drug affects either physical or chemical stability of other drug. Eg:1. Yuxingcao injection when mixed with 6 drugs at temp. 25c & analysed using uv following observation done:YUXINGCAO + PENICILLIN = PRECIPITATION YUXINGCAO + GANCYCLOVIR= PRECIPITATION YUXINGCAO + OFLOXACIN = NO CHANGE YUXINGCAO + RIBAVIRIN = NO CHANGE YUXINGCAO + CEPHRADIN = NO CHANGE FOR 2 HRS & DECREASE IN CONTENT WITHIN 24 HRS.
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YUXINGCAO + ACYCLOVIR = DECREASE IN CONTENT WAS OBSERVED. (CA,VOL-151,5th OCT 2009,Pg no-1970,321538p) 2. When fosfomycin sodium & gatifloxacin were mixed & analysed by UV spectroscopy it was found that content & spectra of UV spectra changed significantly. (CA,VOL-151,5th OCT 2009,Pg no-1970,321539q) 3. Stability of cefotiam in moxifloxacin injection. Stable for 8hrs at 25 C & 37C. (CA, VOL-151,12th OCT 2009,Pg no-1906,344130p)
RADIATIONS:Not common variable. Employed in the sterilization of pharmaceutical product so, its effect on stability of drug should be considered. WAYS FOR STABILIZATION: Avoid irradiation if sterilization by other ways is possible. Formation of various products on irradiation of diazepam in a methanolic solution was inhibited by ascorbic acid. - Irradiation Effects on Stability of Poly(lactide-co-glycolide) Microspheres Containing Clonazepam. The influence of CLO on PLGA radiolysis mechanisms and the identification of possible irradiation markers were investigated. Microspheres were prepared by means of a spray-drying method. Radiolysis mechanisms were investigated paramagnetic resonance (EPR) analysis. by using electronic
Polymer/CLO spin transfer reactions suggest that CLO had radiostabilising effect on the polymeric matrix.
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ENVIRONMENTAL FACTORS:TEMPERATURE:Study of decomposition of the product at elevated temperature should be done to know the temperature dependency of reaction. It helps in predicting the stability of the product at ordinary shelf temperature. Rate of reaction is denoted for each 10 c rise in temperature accelerated study is done to decrease the time period for stability study. At 37 c it takes 100 days for degradation & for 80 c it takes 25 days for degradation. Temperature is one of the primary factors affecting the drug stability. As temperature increases a greater available free energy leads to a more rapid reaction and typically a 10 C increase in temperature produces a two to five fold increase in decay. It catalyses hydrolysis, oxidation & thermal reaction follows just after initiation of photolytic reaction. The most satisfactory method for expressing the influence of temperature on reaction velocity or rate is the quantitative relation proposed by Arrhenius: K = A * e-Ea/RT Where, K = specific rate of degradation A = Frequency Factor Ea = Arrhenius Activation Energy R = Gas Constant T = Absolute Temprature Logarithmically it can be expressed as: Log K = log A - Ea/ 2.303 RT
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From the graph of K
1/T one can determine Ea from slope and A from intercept.
LOG K
SLOPE = -Ea/2.303R
INTERCEPT = LOG A
1/T Limitations of Arrhenius relationship for prediction of stability of products: 1. At higher temp., there is less relative humidity & O2 solubility , thus hindering the predictability of RT stability of drug sensitive to presence of moisture and oxygen. 2. For dispersed systems, viscosity is decreased as temp. is increased and physical characteristics may be altered, resulting in potentially large errors in prediction of stability . 3. Different degradation mechanisms may predominate at different temperatures, thus making stability prediction marginal at best. WAYS FOR STABILIZATION: Pharmaceutical product should be stored within the temperature range in which they are stable. They should not be exposed to extremes of temperature. Usually they should be stored at low temperature if they lack sufficient stability at room temperature. There are few drugs on which freezing has an adverse effect, so freezing should be avoided unless until it is stable at such temperatures.
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HUMIDITY: Higher humidity may lead to moisture adsorption. As relative humidity is increased stability is decreased for drusgs which are highly sensitive to hydrolysis. Higher humidity increases ageing process through interaction of drugs with excipients. It can affect the stability of pharmaceuticals by, Hydrolytic degradation Isomerization Crystallization Affecting flow and compaction properties etc.
Figure: Water vapour adsorption and deliquescence of a water soluble solid particle. EFFECT OF MOISTURE CONTENT ON THE STORAGE STABILITY OF LIPOPLEX FORMULATIONS CONTAINING THIOBARBITURIC ACID DERIVATIVES WAS FOUND. TEMPERATURE CHOOSEN WERE RT,40C & 60 C FOR 3 MONTHS. RESULTS:AT ROOM TEMPERATURE CONCENTRATION WAS MAINTAINED . AT HIGHER MOISTURE CONTENT 1.93 LOWER TBA DERIVATIVES. AT LOWER MOISTURE CONTENT LITTLE HIGHER TBA DERIVATIVES. (JPS,VOL-98,NO-9,SEPT 2009,Pg no-3301)
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WAYS FOR STABILIZATION: Maintenance of controlled humidity condition Moisture proof packaging.
OXIDATION:LIGHT:BOTH ARE SAME AS DISCUSSED IN PREFORMULATION (PHYSICO-CHEMICAL FACTORS).
pH
The change of more than 10 fold in rate constants result in just shift of 1 pH unit. So, before formulating the drug in solution , K versus pH should be studied & optimum pH at lowest value of rate constant is to be found out. Hydrogen ion catalysis occurs at lower pH & hydroxyl at higher Ph.
MAXIMUM STABILITY AT THIS pH
pH
WAY FOR STABILIZATION:
Maintenance of stable pH by use of appropriate buffer salts.

The effect of salt form on the stability of an ester prodrug of a IIb/IIIa receptor antagonist was investigated. The pH of maximum stability for the ester prodrug is approximately 4. The mesylate salt is thought to provide lower microenvironment pH, closer to the pH of maximum stability, than the acetate salt. Stability of drug
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product manufactured using the mesylate salt (DMP 755) was studied and compared with that for the acetate salt (DMP 754). Formulations contained disodium citrate as a pH modifier to control formulation pH, since solid state stability for this compound is dependent on the microenvironment pH. The pH modifier was not able to achieve adequate microenvironment pH control for the DMP 754 drug product when added using a dry manufacturing process. While DMP 754 required the use of a pH modifier added in solution during wet granulation in order to improve drug product stability, DMP 755 was able to achieve similar results using the dry granulation process. Stability of DMP 755 drug product was independent of effectiveness of the pH modifier. This study showed that the choice of the salt form may provide an alternative for maximizing drug product stability.
EFFECT OF SOLUBILITY:Applicable to drugs in solution form.
Eg:Penicillins are very unstable in aqueous solution because of hydrolysis of lactam ring. WAYS FOR STABILIZATION: Stabilised by using insoluble salts of API. Formulate the drug in suspension dosage form.
EFFECT OF IONIC STRENGTH:The rate of reaction can be influenced by the ionic strength of the solution in accordance with the following equation: log k = log k0 + 1.02ZA ZB Where, ZA & ZB - charges carried by the reacting species in solution U- the ionic strength K- rate constant at infinite dilution. & Where, 2 U=
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ZA,ZB = +ve ZA,ZB = 0

logk-logk0
ZA,ZB = -ve
Drugs with positive charge undergoes H+ion catalysis & in this increase in ionic strength caused by the addition of salt increases rate of reaction. If the drug is neutral change in ionic strength will have no effect. Drugs with negative charge undergoes OH- ion catalysis & in this increase in ionic strength caused by the addition of salt decreases rate of reaction.
EFFECT OF PACKAGING COMPONENTS: Most commonly employed are CONTAINERS: Glass, Plastic, Metal CLOSURES:Rubber CONTAINERS: 1) GLASS PROBLEMS: a) Release of alkali b) Release of Insoluble flake
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REMEDY FOR PREVENTION OF RELEASE OF ALKALI: By decreasing soda content Siliconization of surface. By replacing sodium oxide with other oxides. Surface treatment by sulphur-di-oxide in presence of water-vapour & heat. REMEDY FOR PREVENTION OF RELEASE OF INSOLUBLE FLAKE: Flake formation can be prevented by using borosilicate glass Pretreatment of the container with dilute acid.
2) PLASTIC HIGH MOLECULAR WEIGHT POLYMERS LIKE POLYETHYLENE, POLYPROPYLENE, POLYSTYRENE, PVC ETC PROBLEMS: a) Permeation of moisture b) Leaching c) ADSORPTION OR ABSORPTION d) CHEMICAL/PHYSICAL REACTION OF CONTENTS OF CONTAINERS WITH PRODUCTS. REMEDY: Lining of the container with an epoxy resin eliminates this problem but has to be evaluated separately for each product . (epoxy lining doesnot prevent sorption of phenyl mercuric nirate). Stablity of FENTANYL 5g/ml diluted with 0.9% sodium chloride injection & was stored in polypropylene syringes. It was found that above solution was stable for 90 days in controlled ambient conditions when stored protected from light.. (CA, 5th Oct, 2009,vol-151,pg no-1973,321560q) 3) METALS Metals commonly used are tin , plastic coated tin , tin-coated lead , aluminum and coated aluminum . PROBLEMS: a) Reactivity 1. TIN + CHLORIDE ERROSION 2. ALUMINUM + FATTY ALCHOL WHITE
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ENCRUSTATION REMEDY: Application of an epoxy lining to internal surfaces of aluminum tubes was found to make them more resistant to attack .
CLOSURES:a) RUBBER PROBLEMS: a) Sorption of API into rubber. b) Extraction of one or more components of rubber into vial solution . Leached extractive in the solution can cause:a. Interference with chemical analysis of drug. b. Affects toxicity & pyrogenicity of injectables. c. Can cause drug inactivation. d. Can cause physical instability so,to prevent such intereferences. REMEDY: Epoxy lining applied to rubber stoppers - reduction results in amount of extractive leached from stopper but no effect on sorption of preservative from solution . - However use of Teflon Coated rubber stoppers essentially prevents sorption and leaching of the rubber stopper .
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NEW STABILIZATION TECHNIQUE:SUPERCRITICAL FLUID:-
Near the critical points, supercritical fluids possess liquid like densities and gas like transport properties. CO2 -choice for pharmaceutical application Dry powders of Stable Protein Formulations from aqueous solutions Prepared using Supercritical CO(2)-assisted Aerosolization Use of a new supercritical carbon dioxide-assisted aerosolization coupled with bubble drying technology. Two model proteins, lysozyme and lactate dehydrogenase (LDH). In the absence of excipients, lysozyme was observed to undergo perturbations of secondary structure observed by solid-state infrared spectroscopy. In the presence of sucrose, this unfolding was minimized. The more labile LDH suffered irrecoverable loss of activity on reconstituting in the absence of carbohydrate stabilizers. LDH could be stabilized through with the addition of sucrose, and almost complete preservation of activity was achieved with the further addition of a surface active agent, such as Tween 20.
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PRIOR STUDY QUESTIONS:1. Enlist various processing factors affecting stability of formulation ? 2. Describe effect of particle size reduction (or milling) on stability of formulation product and stabilization against the same? 3. Describe effect of radiation on stability of formulation product and stabilization against the same? 4. Effect of RH on stability and stabilization against the same? 5. What is process induced transformation? Discuss the effect of wet granulation, compression and excipients on the stability? 6. Discuss the effect of temperature, light and RH on the stability and stabilization against the same? 7. Note on the influence of packaging components on the dosage form stability? NEW STUDY QUESTIONS:1. What is the effect of pH & ionic strength on the stability of drug? 2. Write a note on effect of blending on solid as well as liquid dosage form? 3. Explain the effect of freeze drying on the stability? 4. What are the effects of polymeric film coating & amorphous mobility on the stability of drug? 5. Note on effect of additives on stability? 6. Note on effect of presence of other drugs? 7. Explain the effect of solubility on stability with examples & stabilization techniques? 8. Write a note on various stabilization techniques employed for the stability of pharmaceutical dosage form?
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REFERENCES
1. THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY BY LEON LACHMAN, HIBERT A. LIBERMAN AND JOSEPH L. KANIG. 2. PHYSICAL PHARMACY BY ALFRED MARTIN. 3. MODERN PHARMACEUTICS BY MARCEL DEKKER, CH-6. 4. www.drugdeliverytech.com 5. www.sciencedirect.com 6. www.informaworld.com 7. JPS,VOL-98,NO-7,JULY,2009,pg no-2936 8. IJPS, oct 2009, Vol 381, Pg.56-61 9. JPS,VOL-98, NO-10,OCT 2009, pg no-3387 10.JPS,VOL-98,NO-9,SEPT.2009,Pg no-3319 11.CA,VOL-151, NO-14, NOV 2009, Pg no-1954, 321346z 12.JPS,VOL-98,NO-9,SEPT 2009,Pg no-2935 13. CA,VOL-151,5th OCT 2009,Pg no-1970,321538p 14. CA,VOL-151,5th OCT 2009,Pg no-1970,321539q 15. CA, VOL-151,12th OCT 2009,Pg no-1906,344130p 16.JPS,VOL-98,NO-9,SEPT 2009,Pg no-3301 17.JPS, , VOL. 94 , SEPT 2005 18. CA, VOL-151,5th Oct, 2009, pg no-1973,321560q aiche.confex.com/aiche/2008/techprogram/P124994.HTML
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SEMINAR on
Regulatory requirement related to stability testing
PREPARED BY: MANAVADRIYA HIMANSHU GUIDED BY: Dr R.K PARIKH M.PHARM: I ROLL NO: 02 DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L. M. COLLEGE OF PHARMACY, AHMEDABAD- 09
Paper 910101 M.Pharm--2009-10
regulatory requirement related to stability testing HIMANSHU
List of Contents:
Contents
Introduction Over view of ICH guidelines Climate zones SUPAC guidelines Photo stability testing of new drug substance & products Bracketing and metrixing of new drug substance & products Impurity profile References
Department of pharmaceutics and pharmaceutical technology,LMCP Page 69
Paper 910101 M.Pharm--2009-10
STABILITY[2,3,4]: The capacity of a drug product to remain within specifications established to ensure its identity, strength, quality and purity.
PURPOSE OF STABILITY STUDY[2,3,4]: To provide evidence of how the quality of drug substances or products varies with time under the influence of environmental factors. (temperature, humidity and light) To establish a re-test period for the drug substances or the shelf-life for the drug products and recommended storage conditions. To ensure that drug products retain their full efficacy until the end of their expiration date. Most important guidelines are Food and Drug Administration (FDA) International Conference on Harmonization (ICH) European Union Guidelines (EU) Japanese Guidelines (MHW) World Health Organization (WHO) Guidelines
[2,3,4]
Currently ICH guidelines are most commonly accepted which provides information on stability testing within the areas of European Union (EU), Japan, and United States.
Stability
Overview of ICH guideline for stability testing Stability Testing in New Drugs and Q1A Products (Revised guideline) (R2) Photo-Stability Testing Q1B Stability testing: New Dosage Forms Q1C Q1D Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products Evaluation of Stability Data Stability Data Package for Registration in Climatic Zones III and IV Definitions and Terminology Methodology Impurity Testing in New Drug Substances Impurities in Dosage Forms: Addendum to the Guideline on Impurities in New Drug Substances Impurities: Residual Solvents
Page 70
Q1E Q1F
Analytical validation Impurities
Q2A Q2B Q3A Q3B
Q3C
Department of pharmaceutics and pharmaceutical technology,LMCP
Paper 910101 M.Pharm--2009-10
Pharmacopeias Biotechnology Quality
Q4 Q5A Q5B Q5C Q5D
Pharmacopeial harmonization Viral Safety Evaluation Genetic Stability Stability of Biotechnology Products Cell Substrates Specifications, Test Procedures, and Acceptance Criteria for New Drug Substances and Products Biotechnological substance GMP for active pharmaceutical ingredients Pharmaceutical development Quality Risk Management
Specification
Q6A
Q6B GMP Development Management Q7A Q8 Q9
STABILITY GUIDELINE
S1(A)
S1(B) S1(C) S2A
S2B S(3A) S(3B)
S4 S5
Guidelines on The Need For Carcinogenicity studies of pharmaceuticals Testing for carcinogenicity of pharmaceuticals Dose selection for carcinogecity studies of pharmaceuticals Guidance on specific aspect of regulatory genotoxicity test for pharmaceuticals Standard for genotoxicity testing for pharmaceuticals Note for guidance on Toxicokinetics Pharmacokinetic:- Guidance for repeated dose tissue distribution studies Duration of Chronic Toxicity testing in Animals Detection of Toxicity To Reproduction for Medicinal product
Page 71
Paper 910101 M.Pharm--2009-10
S6
S7 S8
and toxicity to male fertility Preclinical Safety Evaluation Of Biotechnology derived Pharmaceuticals Safety Pharmacology studies for Human Pharmaceuticals Immunotoxicity studies for Human Pharmaceuticals The Extent of Population Exposure to Assess clinical Safety Clinical safety Data management Implementation working group Clinical safety Data management :periodic safety update reports & marketed drugs Post aproval safety data manegemant :- Definations and Standards for expedited reporting Pharmacovigillance Planning Development safety update report Structure and content of clinical study reports Dose response Information to support drug regisitration Ethnic factors in the acceptability of foreign clinical data Guideline for Good Clinical Practice Studies in support of Specific Population General Consideration For Clinical Trials Stastical Principles For Clinical Trials Clinical Investigation of medicinal products In The Pediatric population Principles Of Clinical Evaluation of New Anti-hypertensive drugs
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EFFICACY GUIDELINES
E1 E2(A) E2(B) E2C
E2(D)
E2(E) E2(F) E3 E4 E5 E6 E7 E8 E9 E10
E11
Paper 910101 M.Pharm--2009-10
E12
E13
MULTIDISCIP M1 LINEGUIDELINES M2
M3
The Clinical Evaluation of proarrythmic potential for NonAntiarrythmic drugs Definations of genomic biomarkers, pharmacoecononomics, pharmacogenetics, Genomic DATA & sample coding categories Maintenance of The ICH Guideline on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals Electronic Transmission of Individual Case Safety Reports Message Specification Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use
INTERNATIONAL CONDITIONS[1,2,3,4]
CLIMATIC
ZONES
AND
CLIMATIC
Climatic Zone I Zone II Zone III Zone IV Condition Temperate Mediterranean Hot/dry or Very (sub-tropical) Hot/moderate hot/humid RH < 20C 20.5-24C >24C >24C Mean Annual Temperature 26C 31C 31C Kinetic 21C Mean Temperature (Virtual temperature) 45% 60% 40% 70% Mean Annual Relative Humidity
Paper 910101 M.Pharm--2009-10
REQUIREMENT OF TEMPERATURE DEPENDED ON TYPE OF TESTING TYPE OF STUDY Long term Intermediate Accelerated TEMPERATURE 25C 2C 30C 2C 40C 2C/ RELATIVE HUMIDITY /60% RH 5% RH /65% RH 5% RH 75% RH 5% RH TIME DURATION 12 months 6 months 6 months
DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON TYPE OF DOSAGE FORMS FOR DISTINCT PRODUCTS Solid oral DF, solids for reconstitution, dry &lyophilized powders in glass vials Liquids in glass bottles ,vials, sealed glass ampoules which provide an impermeable barrier to water loss Drug products in semipermeable TYPE OF STUDY AST 40C 2C 75 % 5%RH IST 40C2C 75 % 5% RH LST 40C2C 75 % 5% RH
40C 2C Ambient Humidity
30C2C Ambient humidity
25C2C Ambient Humidity
40C 2C NMT 25 % RH
30C2C 65 % 5% RH
25C2C 40 % 5% RH Or 30C2C
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containers
35 % 5% RH
SUPAC GUIDELINES[1,2,3,4]
1) Stability Testing for New Drug Applications(NDA) A. Drug Substance B. Drug Product
2) Stability Testing for Abbreviated New Drug Applications(ANDA)

A. Drug Substance Stability Data Submission Supporting information may be provided directly to the drug product ANDA or by reference to an appropriately referenced drug master file (DMF). For ANDA bulk drug substances- on a minimum of one pilot-scale batch. ANDA bulk drug substances produced by fermentation- on three production batches, at least two of which should be generated from different starter cultures. B. Drug Substance Testing A program for stability assessment may include storage at accelerated, long-term, and, if applicable, intermediate stability study storage conditions (refer to IV.G. of the ICH Q1A Guidance and Section II.A. of this guidance). C. Drug Product As per ICH Q1 A [Section II.B.] D. ANDA Data Package Recommendations Accelerated stability data at 0, 1, 2, and 3 months. A tentative expiration dating period of upto 24 months will be granted based on satisfactory accelerated stability data unless not supported by the available long-term stability data. Long-term stability data Additional stability studies accelerated stability study. E. Stability Study Acceptance
3) Stability Testing For Investigational New Drug Applications

The amount of information needed to achieve that assurance will vary with o The phase of the investigation, o The proposed duration of the investigation, o The dosage form. A. General Supportive stability data for changes to an approved drug application (i.e. post approval changes) required . If change does not alter the stability of the drug product, the previously approved expiration dating period can be used. But now SUPAC-IR, MR , SS guidance are followed for stability studies . Provides 5 stability data package types . B. Change in Manufacturing Process of the Drug Substance
Paper 910101 M.Pharm--2009-10
Carried out at approved manufacturing site . Should be supported by the submission of sufficient data to show that such change does not compromise the quality , purity , or stability of the drug substance and the resulting drug product Special concerns are there for biological products.
C. Change in Manufacturing Site Site changes consists of change in location site of : Manufacture Packaging operations Analytical testing laboratory both of company owned and contract manufacturing. Sufficient data to show that such a change does not alter the characteristics or compromise the quality, purity, or stability of the drug substance or drug product may be necessary. The data should include a side-by-side comparison of all attributes to demonstrate comparability and equivalency of the drug substance or drug product manufactured at the two facilities. New manufacturing locations should have a satisfactory cGMP inspection. D. Change in Formulation of the Drug Product Historically, all changes in drug product formulation were grouped together and required extensive stability documentation, usually submitted as a prior-approval supplement. An exception was the detection of a color from a product that could be reported in an annual report without supporting stability data E. Addition of a New Strength for the Drug Product The addition of a new strength for an approved drug product will generally require the submission of a prior-approval supplement. Demonstration of equivalent stability between the approved drug product and the new strength will allow extension of the approved drug product expiration dating to the new strength. New strengths intermediate to those of an approved drug product may be supported by bracketing/Matrixing studies (See Section VII.G. and VII.H.). F. Change in Manufacturing Process and/or Equipment for the Drug Product Can be supported by the submission of sufficient data to show that such a change does not alter the characteristics or compromise the stability of the drug product. The standard stability commitment to conduct and/or complete the stability studies on the first three production batches produced by the revised manufacturing process in accordance with the approved stability protocol is necessary. If the data are found acceptable, the approved expiration dating period may be retained. G. Change in Batch Size of the Drug Product A key question : whether the change involves a change in equipment or its mode of operation, or other manufacturing parameters described for the approved batch size. Table 19 presents the recommended stability data packages for a variety of batch size situations not involving equipment or mode of operation changes.
Paper 910101 M.Pharm--2009-10
If an equipment change is part of the batch size change, please refer to Change in Manufacturing Process of the Drug Product (Section IX.F.). H. Reprocessing of a Drug Product Stability data submitted should take into account the nature of the reprocessing procedure and any specific impact that might have upon the existing stability profile of the drug. The expiration dating period for a reprocessed batch should not exceed that of the parent batch, and the expiration date should be calculated from the original date of manufacture of the oldest batch. Reprocessing range from repackaging to regrinding and recompressing tablets. Any batch of the drug product that is reprocessed should be placed on accelerated and long-term stability studies using the approved protocol to generate a Type 2 stability data package.
I. Change in Container and Closure of the Drug Product

The first factor used in determining the stability data package recommendation is whether or not the protective properties of the container/closure system are affected by the proposed change. Protective properties of the container/closure system include, moisture permeability, oxygen permeability, light transmission. Changes that may affect these properties should be supported by a greater amount of data to support the change. The second factor is the nature of the dosage form itself. A solid dosage form will generally be less affected by a container change than a liquid dosage form
Paper 910101 M.Pharm--2009-10
PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS[1,4]

1. GENERAL The ICH Harmonized Tripartite Guideline covering the Stability Testing of New Drug Substances and Products notes that light testing should be an integral part of stress testing.
A. Preamble
The intrinsic photostability characteristics of new drug substances and products should be evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable change. Normally, photostability testing is carried out on a single batch of material. Under some circumstances these studies should be repeated if certain variations and changes are made to the product (e.g., formulation, packaging). The guideline primarily addresses the generation of photostability information for submission in Registration Applications for new molecular entities and associated drug products. The guideline does not cover the photostability of drugs after administration (i.e. under conditions of use). A systematic approach to photostability testing is recommended covering, as appropriate, studies such as:
i) Tests on the drug substance; ii) Tests on the exposed drug product outside of the immediate pack; and if necessary ; iii) Tests on the drug product in the immediate pack; and if necessary ; iv) Tests on the drug product in the marketing pack.
The formal labeling requirements for photolabile drug substances and drug products are established by national/regional requirements.
B. Light Sources
The light sources described below may be used for photostability testing. The applicant should maintain an appropriate control of temperature to minimize the effect of localized temperature changes.
Option 1
Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. D65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard. For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.
Option 2
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For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp. 1. A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) ; and 2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.
C. Procedure
For confirmatory studies, samples should be exposed to light providing an overall

illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product.
DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS
2. DRUG SUBSTANCE For drug substances, photostability testing should consist of two parts: forced degradation testing and confirmatory testing. The purpose of forced degradation testing studies is to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation.
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This testing may involve the drug substance alone and/or in simple solutions/suspensions to validate the analytical procedures. In these studies, the samples should be in chemically inert and transparent containers. In these forced degradation studies, a variety of exposure conditions may be used, depending on the photosensitivity of the drug substance involved and the intensity of the light sources used. For development and validation purposes it is appropriate to limit exposure and end the studies if extensive decomposition occurs. For photostable materials, studies may be terminated after an appropriate exposure level has been used. Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies. Confirmatory studies should then be undertaken to provide the information necessary for handling, packaging, and labeling. Normally, only one batch of drug substance is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch if the drug is clearly photostable or photolabile. If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted. Samples should be selected as described in the Parent Guideline.
A. Presentation of Samples
Care should be taken to ensure that the physical characteristics of the samples under test are taken into account and efforts should be made, such as cooling and/or placing the samples in sealed containers, to ensure that the effects of the changes in physical states such as sublimation, evaporation or melting are minimized. All such precautions should be chosen to provide minimal interference with the exposure of samples under test. Possible interactions between the samples and any material used for containers or for general protection of the sample, should also be considered and eliminated wherever not relevant to the test being carried out. As a direct challenge for samples of solid drug substances, an appropriate amount of sample should be taken and placed in a suitable glass or plastic dish and protected with a suitable transparent cover if considered necessary. Solid drug substances should be spread across the container to give a thickness of typically not more than 3 millimeters. Drug substances that are liquids should be exposed in chemically inert and transparent containers.
B. Analysis of Samples
At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity, or color of solution) and for assay and degradants by a method suitably validated for products likely to arise from photochemical degradation processes. Where solid drug substance samples are involved, sampling should ensure that a representative portion is used in individual tests. Similar sampling considerations, such as homogenization of the entire sample, apply to other materials that may not be homogeneous after exposure. The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test.
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C. Judgement of Results
The forced degradation studies should be designed to provide suitable information to develop and validate test methods for the confirmatory studies. These test methods should be capable of resolving and detecting photolytic degradants that appear during the confirmatory studies. When evaluating the results of these studies, it is important to recognize that they form part of the stress testing and are not therefore designed to establish qualitative or quantitative limits for change. The confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product, and if light resistant packaging is needed. When evaluating the results of confirmatory studies to determine whether change due to exposure to light is acceptable, it is important to consider the results from other formal stability studies in order to assure that the drug will be within justified limits at time of use (see the relevant ICH Stability and Impurity Guidelines). 3. DRUG PRODUCT (It is same as that described in drug substances) 4. ANNEX
A. Quinine Chemical Actinometry
The following provides details of an actinometric procedure for monitoring exposure to a near UV fluorescent lamp (based on FDA/National Institute of Standards and Technology study). For other light sources/actinometric systems, the same approach may be used, but each actinometric system should be calibrated for the light source used. Prepare a sufficient quantity of a 2 per cent weight/volume aqueous solution of quinine monohydrochloride dihydrate (if necessary, dissolve by heating). Option 1: Use 20 ml colourless ampoules (seal hermetically).
Shape and Dimensions for ampoule specifications. Option 2: Use 1 cm quartz cell. For both the options, prepare sample and control wrap in aluminum foil to protect completely from light, and measure their absorbance At and Ao respectively at 400nm using 1cm path length. Measure the change in absorbance.
The length of exposure should be sufficient to ensure a change in absorbance of at least 0.9.
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BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS[1,4]
1. GUIDELINES
1.1 General
A full study design is one in which samples for every combination of all design factors are tested at all time points. A reduced design is one in which samples for every factor combination are not all tested at all time points. A reduced design can be a suitable alternative to a full design when multiple design factors are involved. Any reduced design should have the ability to adequately predict the retest period or shelf life. During the course of a reduced design study, a change to full testing or to a less reduced design can be considered if a justification is provided and the principles of full designs and reduced designs are followed.
1.2 Applicability of Reduced Designs
Reduced designs can be applied to the formal stability study of most types of drug products, although additional justification should be provided for certain complex drug delivery systems where there are a large number of potential drug-device interactions. Whether bracketing or matrixing can be applied depends on the circumstances. Data variability and product stability, as shown by supporting data, should be considered when a matrixing design is applied. Bracketing and matrixing are reduced designs based on different principles. Therefore, careful consideration and scientific justification should precede the use of bracketing and matrixing together in one design.
1.3 Bracketing
Bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills selected for testing are indeed the extremes.
1.3.1 Design Factors
Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a study design for their effect on product stability.
1.3.1.1 Strength
Bracketing can be applied to studies with multiple strengths of identical or closely related formulations. Examples
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(1) capsules of different strengths made with different fill plug sizes from the same powder blend, (2) tablets of different strengths manufactured by compressing varying amounts of the same granulation, and (3) oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants, flavourings). In cases where different excipients are used among strengths, bracketing generally should not be applied.
1.3.1.2 Container Closure Sizes and/or Fills
Bracketing can be applied to studies of the same container closure system where either container size or fill varies while the other remains constant. The characteristics such as container wall thickness, closure geometry, surface area to volume ratio, headspace to volume ratio, water vapour permeation rate or oxygen permeation rate per dosage unit or unit fill volume should be compared to select the extremes which may affect the product stability. With justification, bracketing can be applied to studies for the same container when the closure varies. Justification could include a discussion of the relative permeation rates of the bracketed container closure systems.
1.3.2 Design Considerations and Potential Risks
If, after starting the studies, one of the extremes is no longer expected to be marketed, the study design can be maintained to support the bracketed intermediates. Before a bracketing design is applied, its effect on the retest period or shelf life estimation should be assessed. If the stability of the extremes is shown to be different, the intermediates should be considered no more stable than the least stable extreme (i.e., the shelf life for the intermediates should not exceed that for the least stable extreme).
1.3.3 Design Example
An example of a bracketing design is given in Table 1. This example is based on a product available in three strengths and three container sizes. In this example, it should be demonstrated that the 15 ml and 500 ml high-density polyethylene container sizes truly represent the extremes. The batches for each selected combination should be tested at each time point as in a full design.
Table 1: Example of a Bracketing Design
Strength Batch Container size 15 ml 100 ml 500 ml

1.4 Matrixing
50 mg 1 T T 2 T T 3 T T 1
75 mg 2 3 1 T T
100 mg 2 T T 3 T T
Key: T = Sample tested Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point.
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At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly, in some cases, different container closure systems. When a secondary packaging system contributes to the stability of the drug product, matrixing can be performed across the packaging systems. Each storage condition should be treated separately under its own matrixing design.
1.4.1 Design Factors
Matrixing designs can be applied to strengths with identical or closely related formulations. Examples (same as bracketing). With justification, matrixing designs can be applied, for example, to different strengths where the relative amounts of drug substance and excipients change or where different excipients are used or to different container closure systems.
1.4.2 Design Considerations
A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission. However, due to the recommended full testing at certain time points, it may be difficult to achieve a complete balance in a design where time points are matrixed. In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point. If full long-term data for the proposed shelf life will not be available for review before approval, all selected combinations of batch, strength, container size, and fill, among other things, should also be tested at 12 months or at the last time point prior to submission. In addition, data from at least three time points, including initial, should be available for each selected combination through the first 12 months of the study. For matrixing at an accelerated or intermediate storage condition, care should be taken to ensure testing occurs at a minimum of three time points, including initial and final, for each selected combination of factors.
1.4.3 Design Examples
Examples of matrixing designs on time points for a product in two strengths (S1 and S2) are shown in Table 2. The terms one-half reduction and one-third reduction refer to the reduction strategy initially applied to the full study design. For example, a one-half reduction initially eliminates one in every two time points from the full study design and a one-third reduction initially removes one in every three. In the examples shown in Table 2, the reductions are less than one-half and one-third due to the inclusion of full testing of all factor combinations at some time points as discussed in section 2.4.2. These examples include full testing at the initial, final, and 12-month time points. The ultimate reduction is therefore less than one-half (24/48) or one-third (16/48), and is actually 15/48 or 10/48, respectively.
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Table 2: Examples of Matrixing Designs on Time Points for a Product withTwo Strengths
One-Half Reduction Time point (months) S t r e n g t h S1 Batch 1 Batch 2 Batch 3 S2 Batch 1 Batch 2 Batch 3 0 T T T T T T T T 3 T T T T T 6 9 T T 12 T T T T T T T T T T T 18 24 T 36 T T T T T T
Key: T = Sample tested One-Third Reduction Time point (months) S t r e n g t h S1 Batch 1 Batch 2 Batch 3 S2 Batch 1 Batch 2 Batch 3 0 T T T T T T T T T 3 T T T T T T T T 6 9 T 12 T T T T T T T T T T T T T 18 24 T 36 T T T T T T
Key: T = Sample tested
Additional examples of matrixing designs for a product with three strengths and three container sizes are given in Tables 3a and 3b. Table 3a shows a design with matrixing on time points only and Table 3b depicts a design with matrixing on time points and factors. In Table 3a, all combinations of batch, strength, and container size are tested, while in Table 3b, certain combinations of batch, strength and container size are not tested.
Tables 3a and 3b: Examples of Matrixing Designs for a Product with Three Strengths and Three Container Sizes 3a Matrixing on Time Points
Strength Container size Batch 1 Batch 2 Batch 3 A T1 T2 T3
S1 B T2 T3 T1 C T3 T1 T2 A T2 T3 T1
S2 B T3 T1 T2 C T1 T2 T3 A T3 T1 T2
S3 B T1 T2 T3 C T2 T3 T1
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Strength Container size Batch 1 Batch 2 Batch 3
3b Matrixing on Time Points and Factors S1 S2 A T1 T3 B T2 T3 T1 T2 C A T2 T3 T1 T2 B C T1 T3 T1 T2 A
S3 B T1 T3 C T2 T3
Time-point (months) T1 T2 T3
0 T T T
6 T
9 T T
12 T T T
18 T T
24 T T
36 T T T
T T
S1, S2, and S3 are different strengths. A, B, and C are different container sizes.
1.4.4 Applicability and Degree of Reduction
The following should be considered when a matrixing design is contemplated: knowledge of data variability expected stability of the product availability of supporting data stability differences in the product within a factor or among factors number of factor combinations in the study In general, a matrixing design is applicable if the supporting data indicate predictable product stability and also when the supporting data exhibit only small variability. However, where the supporting data exhibit moderate variability, a matrixing design should be statistically justified. If the supportive data show large variability, a matrixing design should not be applied.
1.4.5 Potential Risk
Due to the reduced amount of data collected, a matrixing design on factors other than time points generally has less precision in shelf life estimation and yields a shorter shelf life than the corresponding full design. In addition, such a matrixing design may have insufficient power to detect certain main or interaction effects, thus leading to incorrect pooling of data from different design factors during shelf life estimation. If there is an excessive reduction in the number of factor combinations tested and data from the tested factor combinations cannot be pooled to establish a single shelf life, it may be impossible to estimate the shelf lives for the missing factor combinations. A study design that matrixes on time points only would often have similar ability to that of a full design to detect differences in rates of change among factors and to establish a reliable shelf life.
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This feature exists because linearity is assumed and because full testing of all factor combinations would still be performed at both the initial time point and the last time point prior to submission.
2.5 Data Evaluation
Stability data from studies in a reduced design should be treated in the same manner as data from full design studies.
IMPURITY PROFILE[1,4] ICH guidelines: Impurities Q3A Q3B Impurity Testing in New Drug Substances Impurities in Dosage Forms: Addendum to the Guideline on Impurities in New Drug Substances Impurities: Residual Solvents
Q3C
IMPURITIES IN NEW DRUG SUBSTANCES

1. PREAMBLE This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substances used during the clinical research stage of development. The following types of drug substances are not covered in this guideline: biological/biotechnological peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin. Impurities in new drug substances are addressed from two perspectives:
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Chemistry Aspects include classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and Safety Aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies.
2. CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following categories:

Organic impurities (process- and drug-related) Inorganic impurities Residual solvents
Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include:
Starting materials By-products Intermediates Degradation products Reagents, ligands and catalysts
Inorganic impurities can result from the manufacturing process. They are normally known and identified and include:
Reagents, ligands and catalysts Heavy metals or other residual metals Inorganic salts Other materials (e.g., filter aids, charcoal)
Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished.
IMPURITIES IN NEW DRUG PRODUCTS

INTRODUCTION 1.1 Objective of the guideline
This document provides guidance for registration applications on the content and qualification of impurities in new drug products produced from chemically synthesised new drug substances not previously registered in a region or member state.
1.2 Scope of the guideline
This guideline addresses only those impurities in new drug products classified as degradation products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container closure system. Impurities arising from excipients present in the new drug product or extracted or leached from the container closure system are not covered by this guideline.
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This guideline also does not apply to new drug products used during the clinical research stages of development. The following types of products are not covered in this guideline: biological/biotechnological products Peptides Oligonucleotides Radiopharmaceuticals fermentation products and semi-synthetic products derived therefrom herbal products, and crude products of animal or plant origin.
2. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION PRODUCTS
The applicant should summarise the degradation products observed during manufacture and/or stability studies of the new drug product. This summary should be based on impurities arising from the interaction with excipients and/or the immediate container closure system. In addition, the applicant should summarise any laboratory studies conducted to detect degradation products in the new drug product.
3. ANALYTICAL PROCEDURES
The registration application should include documented evidence that the analytical procedures have been validated and are suitable for the detection and quantitation of degradation products. In particular, analytical procedures should be validated to demonstrate specificity for the specified and unspecified degradation products. As appropriate, this validation should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation. The quantitation limit for the analytical procedure should be not more than ( ) the reporting threshold. Degradation product levels can be measured by a variety of techniques, including those that compare an analytical response for a degradation product to that of an appropriate reference standard or to the response of the new drug substance itself. Reference standards used in the analytical procedures for control of degradation products should be evaluated and characterised according to their intended uses. The drug substance can be used to estimate the levels of degradation products.
4. REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES
Analytical results should be provided in the registration application for all relevant batches of the new drug product used for clinical, safety, and stability testing, as well as batches that are representative of the proposed commercial process. Quantitative results should be presented numerically. For each batch of the new drug product described in the registration application, the documentation should include: Batch identity, strength, and size Date of manufacture Site of manufacture Manufacturing process Immediate container closure
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Degradation product content, individual and total Use of batch (e.g., clinical studies, stability studies) Reference to analytical procedure used Batch number of the drug substance used in the new drug product Storage conditions for stability studies
5. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS
The specification for a new drug product should include a list of degradation products expected to occur during manufacture of the commercial product and under recommended storage conditions. Stability studies, knowledge of degradation pathways, product development studies, and laboratory studies should be used to characterise the degradation profile. The selection of degradation products in the new drug product specification should be based on the degradation products found in batches manufactured by the proposed commercial process. Those individual degradation products with specific acceptance criteria included in the specification for the new drug product are referred to as "specified degradation products" in this guideline. Specified degradation products can be identified or unidentified. A rationale for the inclusion or exclusion of degradation products in the specification should be presented. This rationale should include a discussion of the degradation profiles observed in the safety and clinical development batches and in stability studies, together with a consideration of the degradation profile of batches manufactured by the proposed commercial process. In summary, the new drug product specification should include, where applicable, the following list of degradation products: Each specified identified degradation product Each specified unidentified degradation product Any unspecified degradation product with an acceptance criterion of not more than ( ) the identification threshold Total degradation products.
6. QUALIFICATION OF DEGRADATION PRODUCTS
Qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the level(s) specified. The level of any degradation product present in a new drug product that has been adequately tested in safety and/or clinical studies would be considered qualified. Therefore, it is useful to include any available information on the actual content of degradation products in the relevant batches at the time of use in safety and/or clinical studies. Degradation products that are also significant metabolites present in animal and/or human studies are generally considered qualified. Degradation products could be considered qualified at levels higher than those administered in safety studies based on a comparison between actual doses given in the safety studies and the intended dose of the new drug product.
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Justification of such higher levels should include consideration of factors such as: (1) the amount of degradation product administered in previous safety and/or clinical studies and found to be safe; (2) the increase in the amount of the degradation product; and (3) other safety factors, as appropriate.
REFERENCE:
1. ICH HARMONISED TRIPARTITIE GUIDELINES www.ich.org 2. Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes; chapter-13 & 17. 3. Remington, The Science and Practice of Pharmacy; 21st Edition, volume-1, chapter4. Stability of drugs and dosage forms by Sumie yoshika & valentio stella; chapter- 6; page no- 205 5. 17. Food and Drug Administration for immediate release consumer media: 888-InfoFDA. May 6, 1998. 6. Chemical Works of Gedeon Richter Ltd., P.O.B. 27, H-1475 Budapest, Hungary(Talanta 44 (1997) 1517-1526)
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STABILITY STUDIES SHWETA IYER
APPLICATIONS
OF MICROCALORIMETRY IN STABILITY STUDIES
GUIDED BY: Dr.R.K.PARIKH
PREPARED BY:
SHWETA IYER M-PHARM SEM-I ROLL NO-8 2009-2010
DEPARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY
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INTRODUCTION:
Calorimetry is the science of heat. It is concerned with how a given material responds to temperature changes on both the atomic and macroscopic level. This varies widely from substance to substance, and reveals important information about the arrangement and interaction of the atoms. Calorimetry or Microcalorimetry is the measurement of the heat evolved or absorbed by a chemical or physical process. Since heat evolved or absorbed is directly proportional to the rate of the process, it serves to study rate & extent of reactions. Microcalorimetry is the calorimetry of small samples, specifically microgram samples (or thereabouts). These are much more challenging to study than big mass of material because (1) The time scale for changing the temperature is much faster and (2) The probes you attach to the sample to measure it takes away a greater proportion of the heat involved. Therefore, MICROCALORIMETRY is an advanced form of Calorimetry. Calorimetry of microgram of Sample. Power detection limit for microcalorimeter approaches a few microwatt. It is 10,000 times more sensitive than DSC.
PRINCIPLE OF MICROCALORIMETRY:
Microcalorimetry works on the principle that all physical and chemical processes are accompanied by a heat exchange with their surroundings. So when a reaction occurs a temperature gradient is formed between the sample and its surroundings. The resulting heat flow between the sample and its surroundings, is measured as a function of time. When any reaction takes place, heat will be generated or absorbed by the molecules reacting. In isothermal microcalorimetry heat input in sample cell adjusted to keep T constant. So, Exothermic reaction will result in negative peaks (less heat is needed while the reaction proceeds) Endothermic reactions will result in positive peaks (more heat is needed while the reaction proceeds)
CALORIMETERS:
A calorimeter is a device used for calorimetry, the science of measuring the heat of chemical reactions or physical changes as well as heat capacity. The word calorimeter is derived from the Latin word calor, meaning heat.
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Differential scanning calorimeters, isothermal microcalorimeters, titration calorimeters and accelerated rate calorimeters are among the most common types. A simple calorimeter just consists of a thermometer attached to a metal container full of water suspended above a combustion chamber.
WORKING:
To find the enthalpy change per mole of a substance A in a reaction between two substances A and B, the substances are added to a calorimeter and the initial and final temperatures(before the reaction started and after it has finished) are noted. Multiplying the temperature change by the mass and specific heat capacities of the substances gives a value for the energy given off or absorbed during the reaction. Dividing the energy change by how many moles of A were present gives its enthalpy change of reaction. This method does not account for the heat loss through the container or the heat capacity of the thermometer and container itself. In addition, the object placed inside the calorimeter show that the objects transferred their heat to the calorimeter and into the liquid, and the heat absorbed by the calorimeter and the liquid is equal to the heat given off by the metals.
SCHEMATIC DIAGRAM OF MICROCALORIMETER
In its most basic form a microcalorimeter consists of three parts: a thermal mass that absorbs the x-ray and converts the energy to heat, a thermometer to measure the temperature rise of the thermal mass, and a thermal link to a heat sink to allow the absorbed energy to escape from the thermal massThe energy resolution of a microcalorimeter is limited by fluctuations in its thermal energy content; a simple thermodynamic analysis gives the energy resolution as: 94 M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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dE = (kT2C)1/2 where k is the Boltzmann constant, T is the heat sink temperature, and C is the heat capacity of the detector. In a more detailed analysis of a microcalorimeter with a resistive thermometer, the resolution given above is modified by a multiplicative factor of order one that depends primarily on the temperature sensitivity of the thermometer. Energy, E, are incident upon a thermal mass of heat capacity C. A thermometer measures the temperature rise of the thermal mass. A thermal link with conductance, G, connects the thermal mass to a heat sink allowing the absorbed energy to leak away with a time constant equal to C/G.
TYPES OF CALORIMETERS:
1. ADIABATIC CALORIMETER: No heat exchange takes place between the calorimetric vessel and its surroundings. The amount of heat that is evolved or absorbed in an ideal adiabatic calorimeter is equal to the product of the measured temperature change and the heat capacity of the vessel, including its content. No adiabatic calorimeter is truly adiabatic some heat will be lost by the sample to the sample holder. Examples of adiabatic calorimeters are:
THT EV-Accelerating Rate Calorimeter HEL Phi-Tec A simple Dewar flask Systag FlexyTSC a successor of their SIKAREX unit - the electronics of which could be used to apply a feedback system to heat the sample holder to give a result closer to true adiabaticy, however as the sample holder is an open ended glass tube, one soon loses the sample as a great deal of smoke. 2. REACTION CALORIMETERS:
A reaction calorimeter is a calorimeter in which a chemical reaction is initiated within a closed insulated container. Reaction heats are measured and the total heat is obtained by integrating heatflow versus time. This is the standard used in industry to measure heats since industrial processes are engineered to run at constant temperatures. Reaction calorimetry can also be used to determine maximum heat release rate for chemical process engineering and for tracking the global kinetics of reactions. There are four main methods for measuring the heat in reaction calorimeter : a) Heat flow calorimetry:
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STABILITY STUDIES SHWETA IYER The cooling/heating jacket controls either the temperature of the process or the temperature of the jacket. Heat is measured by monitoring the temperature difference between heat transfer fluid and the process fluid. In addition fill volumes (i.e. wetted area), specific heat, heat transfer coefficient have to be determined to arrive at a correct value. It is possible with this type of calorimeter to do reactions at reflux, although the accuracy is not as good. b) Heat balance calorimetry The cooling/heating jacket controls the temperature of the process. Heat is measured by monitoring the heat gained or lost by the heat transfer fluid. c) Power compensation The thermal power from an exothermic process is balanced by a known cooling power (usually Peltier effect cooling), alternatively by a decrease of heating power. Endothermic processes are balanced by a known thermal power released in a heater or by reversing the Peltier effect current. Power compensation uses a heater placed within the vessel to maintain a constant temperature. The energy supplied to this heater can be varied as reactions require and the calorimetry signal is purely derived from this electrical power. d) Constant flux Constant flux calorimetry (or COFLUX as it is often termed) is derived from heat balance calorimetry and uses specialized control mechanisms to maintain a constant heat flow (or flux) across the vessel wall. 3. BOMB CALORIMETERS: A bomb calorimeter is a type of constant-volume calorimeter used in measuring the heat of combustion of a particular reaction. Bomb calorimeters have to withstand the large pressure within the calorimeter as the reaction is being measured. Electrical energy is used to ignite the fuel; as the fuel is burning, it will heat up the surrounding air, which expands and escapes through a tube that leads the air out of the calorimeter. When the air is escaping through the copper tube it will also heat up the water outside the tube. The temperature of the water allows for calculating calorie content of the fuel. In more recent calorimeter designs, the whole bomb, pressurized with excess pure oxygen (typically at 30atm) and containing a known mass of sample (typically 1-1.5 g) and a small fixed amount of water (to absorb produced acid gases), is submerged under a known volume of water (ca. 2000 ml) before the charge is (again 96 M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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electrically) ignited. The bomb, with sample and oxygen, form a closed system - no air escapes during the reaction. The energy released by the combustion raises the temperature of the steel bomb, its contents, and the surrounding water jacket. The temperature change in the water is then accurately measured. This temperature rise, along with a bomb factor (which is dependent on the heat capacity of the metal bomb parts) is used to calculate the energy given out by the sample burn. A small correction is made to account for the electrical energy input, the burning fuse, and acid production (by titration of the residual liquid). After the temperature rise has been measured, the excess pressure in the bomb is released.
4. CONSTANT PRESSURE CALORIMETER: A constant-pressure calorimeter measures the change in enthalpy of a reaction occurring in solution during which the atmospheric pressure remains constant. An example is a coffee-cup calorimeter, which is constructed from two nested Styrofoam cups having holes through which a thermometer and a stirring rod can be inserted. The inner cup holds the solution in which of the reaction occurs, and the outer cup provides insulation. Then
where Cp = Specific heat at constant pressure H = Enthalpy of solution T = Change in temperature W = mass of solute M = molecular mass of solute 5. DIFFERENTIAL SCANNING CALORIMETER: In a differential scanning calorimeter (DSC), heat flow into a sampleusually contained in a small aluminium capsule or 'pan'is measured differentially, i.e., by comparing it to the flow into an empty reference pan. 97 M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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In a heat flux DSC, both pans sit on a small slab of material with a known (calibrated) heat resistance K. The temperature of the calorimeter is raised linearly with time (scanned), i.e., the heating rate dT/dt = is kept constant. This time linearity requires good design and good (computerized) temperature control. Of course, controlled cooling and isothermal experiments are also possible. Heat flows into the two pans by conduction. The flow of heat into the sample is larger because of its heat capacity Cp. The difference in flow dq/dt induces a small temperature difference T across the slab. This temperature difference is measured using a thermocouple. A modulated temperature differential scanning calorimeter (MTDSC) is a type of DSC in which a small oscillation is imposed upon the otherwise linear heating rate. This has a number of advantages. It facilitates the direct measurement of the heat capacity in one measurement, even in (quasi-)isothermal conditions. It permits the simultaneous measurement of heat effects that are reversible and not reversible at the timescale of the oscillation (reversing and non-reversing heat flow, respectively). It increases the sensitivity of the heat capacity measurement, allowing for scans at a slow underlying heating rate. 6. ISOTHERMAL TITRATION MICROCALORIMETER: In an isothermal titration calorimeter, the heat of reaction is used to follow a titration experiment. This permits determination of the mid point (N) of a reaction as well as its enthalpy (delta H), entropy (delta S) and of primary concern the binding affinity (Ka) The technique is gaining in importance particularly in the field of biochemistry, because it facilitates determination of substrate binding to enzymes. The technique is commonly used in the pharmaceutical industry to characterize potential drug candidates 7. X-RAY MICROCALORIMETER: In 1982, a new approach to non-dispersive X-ray spectroscopy, based on the measurement of heat rather than charge, was proposed by Moseley et al. (1984). The detector, and X-ray microcalorimeter, works by sensing the heat pulses generated by X-rayphotons when they are absorbed and thermalized. The temperature increase is directly proportional to photon energy. This invention combines high detector efficiency with high energy resolution, mainly achievable because of the low temperature of operation. Microcalorimeters have a low-heatcapacity mass that absorbs incident X-ray (UV, visible, or near IR) photons, a weak link to a lowtemperature heat sink which provides the thermal isolation needed for a temperature rise to occur, and a 98 M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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thermometer to measure change in temperature. Following these ideas, a large development effort started. The first astronomical spacecraft that was designed, built and launched with embarqued cryogenic microcalorimeters was Astro-E2. NASA as well as ESA have plans for future missions (e.g.,IXO) that will use some sort of micro-calorimeters. 8. HEAT LOSS CALORIMETER: The heat developed inside the cell is collected by the inner copper cup. Then, it flows through the siliconerubber which serves as a thermal resistor and the outer copper cup, to the flowing water surrounding the outer copper cup. 9. HIGH ENERGY PARTICLE CALORIMETER: It is a component of a detector that measures the energy of entering particles. 10. THERMAL MICROCALORIMETER: A thermal detector in principle is a very sensitive calorimeter which measures the energy deposited by a single interacting particle through the corresponding temperature rise. For this mechanism to be really effective the detector must have a very small heat capacity: this is accomplished by using suitable materials (dielectrics, superconductors below the phase transition, ...) and by running the detector at low temperatures (usualluy below 100 mK) in a refrigerator (we use dilution refrigerators).
Precautions to be taken for efficient working:

1. The materials used on the device must not react with each other. 2. The membrane must be robust enough to survive deposition of thin films. 3. The leads going off the membrane must be made of a material and be of a size which compromises between low electrical resistance and low thermal conductance (so they don't carry away too much heat), and the thermal conductivity should have a weak temperature dependence. 4. Care should be taken when positioning features on the chip to avoid capacitance between elements of the circuit.
There are many commercial types of equipment available; few of them are as under 1. TRONAC solution calorimeter 2. LKB Thermal Activity Monitor 3. Thermometric 2277 Thermal Activity Monitor
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Applications of Microcalorimetry
Microcalorimetry is highly useful in following fields, 1. Stability testing. 2. Studies of powder wettability (by immersion and adsorption). 3. Sorption reactions 4. Crystal properties. 5. Dissolution of tablets and powders. 6. Excipient compatibility. 7. Direct in vitro studies of biological response. 8. To monitor rate and extent of physical and chemical processes. 9. To study powder surface energetics. 10. As a useful tool for solving shelf life problems in the food and pharmaceutical industry. 11. Rapid screening of excipients. 12. Microorganism Drug interaction 13. Food Drug interaction. 14. Lymphoma cell drug interaction. 15. Cyclodextrin drug interaction. 16. Water Excipient interaction 17. Drug Excipient interaction. 18. In identification of polymorphs.
APPLICATIONS IN STABILITY STUDIES:

CONVENTIONAL METHODS FOR STABILITY STUDY At present, the standard method used for stability analysis of a solid state pharmaceutical product is HPLC. In summary, the concentration of parent compound and/or the concentration of any daughter compounds produced are determined as a function of storage time. The method has certain drawbacks. Often not very sensitive to small changes in concentration. It requires a certain degree of method development to establish a sample preparation and analysis protocol It relies on the dissolution of the solid product. This last drawback can cause distortions in an assay as a result of rapid acceleration of decomposition when a compound is in a solvated state. Because of the poor sensitivity of the technique, it is necessary to perform the experiment over an extended time frame to allow sufficient reaction to take place. Hence, samples are stored under elevated temperature and humidity after preparation to accelerate the potential decomposition. 100 M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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STABILITY STUDIES SHWETA IYER The samples are then assayed over a period of time that can range from a few weeks to many months to give reaction snapshots along the decomposition profile. For each storage condition, a rate constant, (k), is calculated. By plotting lnk against 1/T using the Arrhenius relationship, it is possible to extrapolate back to ambient temperature and hence determine the rate constant at that temperature.
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where k is the rate constant, A is the Arrhenius factor or pre-exponential constant, Ea is the activation energy, R is the gas constant, and T is the temperature. This technique for the determination of stability has been accepted as normal practice for many years. LIMITATIONS OF ARRHENIUS EQUATION It does, however, rely on some assumptions that are not necessarily true in all cases. It is assumed that the Arrhenius plot gives a linear relationship. This may not be true for many reasons. If there are two competing reactions occurring simultaneously, then they will both have an associated activation energy leading to an incorrect extrapolation & thus a major error in calculating the ambient rate constant. Finally, if the reaction does not go by a first order reaction, it is necessary to determine a different rate equation that gives an improved understanding of the system under study. This is not always straightforward, and, for solid state reactions, can be very complex. The rate of decomposition at room temperature may be too slow to asses accurately the rate of disappearance of the drug substance or appearance of a decomposition product. A useful approach is often to study the rate of decomposition at higher temperature and to assume that the rate of decomposition at storage temperature may be extrapolated from the high-temperature data by using the Arrhenius equation. The high-temperature stability testing may not be feasible each time and thus stability study at room temperature is must. The rate of any decomposition reaction is very slow and difficult to measure so long term study is must. Microcalorimetry can measure heat changes at microwatt levels and thus can be used for stability testing at room temperature. EXAMPLES: Few drugs for which stability study can be performed using microcalorimetry are Aspirin, PAS, and some -lactam antibiotics Microcalorimetry is applied to study the thermodynamic stability of Proteins present in the pool water of some reverse micelles (Lysozyme, Cytochrome-c and Ribonuclease). By using Microcalorimetry, stability study of ampicillin in aqueous Solutions as a function of conc. of ampicillin, pH & temperature was carried out Determination of decomposition mechanism of lovastatin by measuring rate of heat production at different temperature & time was carried out by microcalorimetry. 101 M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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STABILITY STUDIES SHWETA IYER - Lovastatin degraded by an auto-catalytic mechanism in presence of oxygen. Microcalorimetry is used to correlate the decomposition rate of several Cephalosporins in solids & aqueous solution states. The activation energy, determined by Microcalorimetry & a degradation rate Determined at a single elevated temperature by HPLC. Testing of physical stability of drug:Microcalorimetry has proved to be an effective analytical technique for characterizing micronised compounds. It can be used to detect the presence of metastable regions not detectable by X-ray diffraction. Furthermore, the kinetic of recrystalisation of these regions can be studied, making a prediction of physical stability possible. Thus the application of Microcalorimetry in the pharmaceutical development has a great potential. Determination of amorphous contents or crystallinity of pharmaceutical drugs and excipients: The amorphous regions can alter the physical properties of the material, which may have an impact on further pharmaceutical processes or the quality of the material. Microcalorimetry is a very sensitive way to measure amorphous contents well below 1%. The heat of recrystallization of the amorphous parts can be measured and by a suitable calibration the amorphous content can be determined. Solution calorimetry is able to measure directly the heat change caused by the dissolution of a crystalline or partially crystalline powders. The observed heat of solution is a function of the variability in crystallinity displayed. The quantification of amorphous contents, however, requires the availability of pure amorphous and pure crystalline standards. Amorphous content of lactose (hydrophilic) and Erythromycin (lypophilic) was assessed by isothermal microcalorimetry. Temperature was fixed at 22C and humidity at 40% RH
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Microcalorimetric spectra of Erythromycin in Chloroform
Microcalorimetric spectra of Erythromycin in Benzene
Amorphous-crystal transition behavior of erythromycin
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Identification of Stable & Metastable forms: Example: Microcalorimetric specra of Tripalmitin
In the case of Tripalmitin, the first heating run shows the sample as received is in the stable form. On cooling, a metastable modification crystallizes out, whose melting point lies lower than that of the thermodynamically stable form. In the second heating run, the metastable modification first melts and then immediately begins recrystallization into the stable modification, which melts again at the higher temperature. The lower onset temperature and slightly lower heat of fusion observed for the stable form in the second heating experiment are caused by incomplete crystallization. To study the thermal stability of antibodies: DSC was used to study the thermal stability of antibodies that were being engineered for improved potency. In this study, we demonstrated a correlation between decreased thermal stability based on DSC data, and greater aggregation formation during accelerated stability studies (at 60C). The SEC-HPLC stability data agree quite well with the stability predicted by DSC, suggesting that the thermal stability data obtained from DSC correlates with protein stability. Information derived from DSC can indicate potential long-term stability issues, thus making the technique a useful tool in the screening and selection of engineered proteins. Monitoring the stability of heat sensitive substances: Example: Vitamin A is very sensitive to chemical degradation caused by oxygen, light, heat, and other stress factors. If light and oxygen are excluded, the dominant degradation reaction for vitamin A derivatives is heatinduced formation of kitols, that is, dimers or higher oligomers. The vitamin A stability of a given sample can easily be predicted from the initial heat flow in a simple microcalorimetry experiment. Compared to conventional stability tests, this offers savings of money and time.
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A new technique Microcalorimetry has been developed to determine stability of low molecular weight materials in both aqueous and non-aqueous solvents. Its primary application areas include drug formulation and stability. Estimates of product stability are often made using accelerated thermal decomposition studies at high temperatures followed by extrapolation of the data to the temperature of interest. When the temperature range under investigation is much higher than the temperature of interest, the extrapolation of results is less certain, since the mechanism of decomposition can be different at different temperatures. Identifying optimal pH conditions to stabilize pharmaceutical proteins in solution formulations: The utility of microcalorimetry as a rapid screening tool for assessing the solution stability of high molecular weight pharmaceutical proteins was evaluated by using model recombinant antibodies, Protein I and Protein II. Changes in the transition midpoint, Tm, were monitored as a function of pH and/or in the presence of excipients, and results were compared with traditional accelerated stability data from samples that were analyzed by size exclusion chromatography (SEC). The data from microcalorimetry were well correlated with those from SEC for predicting both optimal solution pH as well as excipient effects on solution stability. Identification of compatible exipient to stabilize drug molecule: Microcalorimetry is a power full and easy to use tool for rapid screening of excipients for formulation development. If the sum of the heat out put of the compound and the excipient alone is not equal to the heat output of a binary blend then there is a potential compatibility issue. Example 1 Long-term stabilization potential of PVP for amorphous lactose in spray-dried composites. Study was done to investigate the potential of PVP to inhibit the crystallization of amorphous lactose during storage of the composites up to 6 months. Short-term stability was assessed by microcalorimetry over 10 days and long-term stability by storage in desiccators with different relative humidities for 3 and 6 months. Example 2 Microcalorimetry was used to study the effect of menadione & prednisone on the stability of the microemulsions. The stability was not changed in the presence of drugs. Example 3 Chemical & physical processes accompanying Cyclodextrin-drug interactions are usually endothermic or exothermic in nature so they can be studied by microcalorimetry.
Determination of Biomaterials Stability: Used to study stability of implants. 105 M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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STABILITY STUDIES SHWETA IYER Stability of UHMWPE, CaSO4 bone void filler, and buffered saline was studied using microcalorimeter. One major finding was that radiation sterilization increases the oxidation rate of UHMWPE 7X-10X compared to EtO, and the rate difference persists after 9 years of post-sterilization shelf storage and/or clinical TJA implantation. Oxidation embrittles UHMWPE. Direct information on the stability and biological activity of immobilized proteins: Give insight on the thermodynamic consequences of the immobilization in most experimental conditions, ranging from multipoint covalent attachment to simple absorption. assess the effects of the immobilization, support environment, and the type of entrapment on the active site reflected as differences in the binding capacity of specific ligands. Determination of Oxidation of Polymers: The deterioration of polymeric materials is often caused by oxidation and typically manifested by gradually increasing yellowing and embrittlement.This cause instability of polymers which can be efficiently detected by microcalorimeters. Example: study of oxidation of polyamide 6 film. Measurement of the Kinetics of Slow Reactions: Processes degrading or otherwise changing the properties of materials often occur too slowly to be readily measured by conventional chemical analyses but can be measured in a relatively short period of time by heat conduction calorimetry. Determination of critical moisture content in hygroscopic substances: Presence of moisture & amount of moicture determines the stability of the sample. Example: Two extremely water-soluble substances (flupentixol,2HCl and Lu 25109, water solubility over 1000 mg/ml) and a hydrophobic substance (sertindole, approximately 10 g/ml) were examined for critical moisture content by microcalorimetry. The values determined by isothermal microcalorimetry showed results similar to various weighing methods. This is known as characterization of hygroscopic property of API. Determination of surface energetic of crystal: Isothermal microcalorimetry gas flow vapour sorption experiments can be used to assess the surface energetics of crystals, the formation and/or loss of hydrates as a function of humidity and the onset of deliquescence, and to identify the presence of amorphous content in powders. This directly or indirectly gives idea about the stability of the crystal substance.
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Characterisation of adsorption & absorption into powders: Adsorption of gases, liquids or solids onto solid surfaces can cause change in physical properties & can affect stability of the substance. This can be effectively determined by microcalorimetry as surface properties changes the heat properties. Example: Adsorption isotherms were constructed from the cumulative heat as a function of humidity using a perfusion microcalorimetry. It was possible to differentiate among different samples of .ALPHA.-lactose monohydrate. Characterisation of browning reaction: An isothermal microcalorimeter can be utilized to characterize a model solid-state interaction. Example:The degradation of the HIV protease inhibitor, DMP 450, in a binary mixture with hydrous lactose was followed in the presence of 5% additional water. Heat produced in the microcalorimeter sample vessel from either chemical or physical change (Browning reaction) is channeled through extremely sensitive thermopile blankets and is measured as it flows into infinite heat sinks. Identification of stable polymorph: The polymorphic behavior of organic substances is driven by thermodynamic and kinetic factors. Therefore several solid phases may coexist. Example: Polymorphic behavior of Donepezil Hydrochloride Three polymorphs were identified (II, III and V) by DSC curves and thermodynamically stable form III was determined (the highest: melting point, enthalpy and true density).
DSC curves of amorphous and polymorphic forms II, III and V.
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INTERPRETATION AND TREATMENT OF MICROCALORIMETRIC DATA It is difficult to determine rate constants, order of reaction and enthalpy of reaction from the microcalorimetric output data. Recently Willson has described a general procedure for the determination of both thermodynamic and kinetic parameters from microcalorimetric output data. The procedure takes a kinetic equation for a particular reaction, and modifies it such that it applies directly to microcalorimetric data. This is achieved by recognition of the fact that the total heat evolved during the course of a reaction (Q) is equal to the total number of moles of material reacted (Ao) multiplied by the change in molar enthalpy for that reaction ( H). Q = A0 H ..(1) Similarly, the heat evolved at time t (q) is equal to the number of moles of material reacted (x) at time t multiplied by the change in molar enthalpy for that reaction. q = x H (2) Eq. (2) may be substituted into a general rate expression of the form dx/dt to give an expression of the form dq/dt (or power). For example, the general rate expression for a simple, first-order, A B process is given by Eq. (3). (3) Substitution of Eq. (2) into Eq. (3) yields, . (4) This modified rate expression may be used to fit powertime data recorded using the microcalorimeter.
INNOVATIONS: o MULTI-CHANNEL "CHIP CALORIMETERS" that operate in the Nano range (watts, material concentration) with high throughput potential. Drug studied is Benzoyl Peroxide.
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REFERENCE: Wikipedia Encyclopedia Vol. 02 Page no. 247.,239 JPS 91,2, 2002 Page no. 417-422) Microsc Microanal 11(Suppl 2), 2005 Meas. Sci. Technol. 1 (1990) 680-686. Pure Appl. Chem., Vol. 73, No. 10, pp. 16251639, 2001. D. A. Wollman, K. D. Irwin, G. C. Hilton, L. L. Dulcie, N. F. Bergren, Dale E. Newbury, and John M. Martinis, internet article. . Drug stability by carstensen pg. 09 www.acta.chemsoc.si/pdf www.sciencedirect.com www.springerprotocols.com www.pubs.acs.org www.ecmjournal.org www.informahealth.com www.ingentaconnect.com www.springerjournal.com JPS, VOL-97, July 2007 Int.JPS 117(1995) 253-256
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CHAPTER- 4 STABILITY STUDY
COSMETIC AND DENTALPRODUCTS BY: JIGNASHA R. BHURIA
FORMULATION AND EVALUATION OF VARIOUS COSMETIC AND DENTAL PRODUCT
GUIDED BY: Dr.R. K. Parikh
PRESENTED BY:Jignasha R. Bhuria M. Pharm Sem-1 Batch:-2009-2010 Roll no:-05
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY, 2009-2010
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COSMETIC PRODUCT
LIST OF CONTENTS:CONTENTS
DEFINITION CLASSIFICATION INGREDIENTS OF COSMETICS FORMULATION QUALITY CONTROL COSMOCEUTICALS
1) DEFINITION:The term cosmetics have been derived from the term COSMETIKOS which means the skill to decorate. Thus cosmetics is the art of decorating yourself to look beautiful. According to D & C Act:Cosmetics mean any articles meant to be rubbed, poured, sprinkled or sprayed on or introduced into or otherwise applied to any part of the human body for cleansing, beautifying, promoting attractiveness or altering appearance and include any article intended for use as a component of cosmetic. Soap is not covered under cosmetic product.
2) CLASSIFICATION OF COSMETICS:-
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3) INGREDIENTS OF COSMETICS:1. 2. 3. 4. 5. 6. 7. 8. Water Oils, Fats, Waxes Humectants Surfactants Preservatives Perfumes And Colors Herbal Or Plant Material Functional Raw Materials
1. WATER: - It is the main ingredient of cosmetics formulation. Thus stability and

quality of final product is dependant on the purity of water used so pure water should be used in manufacturing of cosmetics. Pure water on large scale can be manufactured by any of the methods mentioned below. Ion exchange system Distillation Reverse osmosis
2.OIL, FATS and WAXES:-
These are used in preparation of creams, lotions, brilliantine, hair oil, lipsticks etc. The source of oil, fat & wax can be mineral source & animal source. The source and example is given below. Source:-1) Mineral source -mineral oil -paraffin and petroleum jelly 2) Animal source -wool fat -bees wax, Spermaceti
OILS:Name of oil Use in cosmetics (Vegetable) Almond Creams (emollient) Arachis Castor Olive Hair oil, Brilliantines Lip stick, hair oil cream ,lotion Bath oils ,creams lotions
Type of mineral oil Use in cosmetics product Light liquid In bath oil, hair paraffin oil,lotions,creams,brilliantine Heavy liquid In bath oil, paraffin oil,lotions,creams,brilliantine (emollient) hair
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waxes:- The commonly used waxes in preparation of cosmetics Include bees

wax, spermaceti,ceresin,ozokerite wax
3. HUMECTANTS:- This is added to prevent drying out of cosmetics

(e.g. o/w creams)
Type of Humectant
Examples
1.Inorganic
Calcium chloride (not used now due to compatibility problems) Sodium lactate (used in sunscreen lotions) Polyethylene glycol, Propylene glycerol, sorbitol, mannitol, glucose glycol,
2.Metal organic 3.Organic
4. SURFACTANTS: - Surfactants lower one or more boundary tensions at interface

in the system. one common feature of surfactant is that they all are amphipathic molecules containing a hydrophobic part & a hydrophilic part. Used in cosmetics to impart following functions. DETERGENCY, WETTING, FOAMING, EMULSIFICATION, SOLUBILIZATION Surfactants on basis of their ionic behavior can be divided into following 4 types:Type surfactant 1.Anionic of Examples Fatty acid soaps, alkyl sulphates, alkyl sulphonates, polyethylene glycol ester,alkyl ether sulphates taurines,sarcosinates etc. Alkyl trimethyl ammonium salts, Dialkyl dimethyl ammonium salts alkyl pyridinium salts, quaternised diamine salts. Alkanolamides,alkyl polyglycol ether, thioethers, alkyl polyethyleneimine amides. Betains, alkylimidazolines, acyl peptides,etc.
2.Cationic 3. Non ionic
4.Ampholytic
5. PRESERVATIVES:- Used to prevent spoilage which occurs due to

1) Oxidation of oils 2) Microbial growth Unused cosmetics are usually contaminated wit PSEUDOMONAS but used cosmetics are contaminated with STAPHYLOCOCCI,FUNGI,YEAST Types of preservatives :1) Anti microbial agents:- e.g. .Benzoic acid, formaldehyde, cresol, phenol, thiomersol,phenyl mercuric salts. Etc. 113
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2) Antioxidants :- Gallic acid, methyl gallate,BHA,BHT,Tocopherol, citric acid,Ethanolamine,lecithin,ascorbic acid, sodium sulphite, Sodium metabisulphite 3) Antioxidant synergists: - Enhance the efficacy of antioxidants. examples include:-ascorbic acid, citric acid, phosphoric acid 4) UV absorbers:-These are mainly used in products which are vulnerable to visible or UV light. By incorporating UV absorbers colorless containers can be used if deterioration is due to UV light only.
6. PERFUMES:- The word perfume has been derived from per means through
and fumum means smoke. It suggests that early perfumes were pleasant smells obtained by burning wood and grass etc.
Source of perfume
Natural (Animal source) Natural (Plant source) Aroma chemical Floral base Woody base
Example
Musk ,civet, Ambergris, Castroreum etc. Rose ,jasmine, lemon, lavender etc. Eugenol, Farnesal, Rose oxide, Citral ,Limonene Rose base, Jasmine base Citrus base(in colognes),spice base, oriental base, fruity base ,etc
7. COLORS: - It defined as visual sensation caused by a definite wavelength by an

object by one/more phenomenon of emission, reflection, refraction, transmission. Colors can be classified into three classes:a) Natural colors:- Plant source :- e.g. Saffron, turmeric Animal source:-e.g. Cochineal (red) b) Inorganic colors:- e.g. Iron oxides, chromium oxides, carbon black, titanium dioxide, zinc oxide etc. c) Coal tar colors:-Tartrazine, amaranth, Erythrosine, Indigocarmine. etc.
8.HERBAL OR PLANT MATERIAL:-These herbal or plant materials are used in

different cosmetics preparations. NAME USE IN COSMETICS Almond Azadiracta Comfrey Tulsi Cucumber Henna Facial and body scrubs Tooth paste and skin care Creams and lotions Skin cream and lotions Masks, toner, cleanser Dyeing of hair
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Amla Jasmine Lemon Apricot
Shampoo Hair oil Skin tonic, cleansers Facial and body scrubs
9.
FUNCTIONAL RAW MATERIALS:- These agents contribute towards
some functional property .
TYPE VITAMINS
EXAMPLE & USE Vit C (antioxidant in emulsion),vit A, Vit E (skin beautification)
AMINO ACIDS AV HILL MP TT (all essential amino acids) ANTI Allantoin (hand cream & lotion) Cade INFLAMMATORY oil(eczema& psoriasis),Calamine AGENTS SUNSCREEN PABA, Vitamin C, Quinine salts AGENTS Coumarin derivatives ANTIDANDRUFF Selenium, cadmium sulphide, ZPTO
(4) FORMULATION
COSMETICS FOR SKIN
Function:1) To provide decoration 2) To supplement natural functions of skin
Type of cosmetics used for skin:1. 2. 3. 4. 5. 6. 7. Skin cream Lotion Face powder & Compacts Skin colorants Body powder Face pack & Masks Bath Preparations (bath salt,oil,powder,foam)
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8. Astringents &Skin tonics (antiperspirants, astringent lotion, preshave & after shave lotion, colognes)
1. CREAMS: - These
TYPES OF CREAMS: A. Cleansing cream B. Massage creams C. Night creams D. Moisturizing creams E. Foundation creams F. Vanishing creams G. All purpose creams
are the solid or semisolid preparation which is either a o/w or w/o type emulsion.
A) CLEANSING CREAM:- Cleansing cream is required for removal of facial make up, surface grime, oil, water and oil soluble soil efficiently mainly from the face & throat. Characteristic of a good cleansing cream:1) Be able to effectively remove oil soluble & water soluble soil, surface oil from skin. 2) Should be stable &have good appearance. 3) Should melt or soften on application to the skin 4) Should spread easily without too much of drag. 5) Its physical action on skin & pore openings should be that of flushing rather than absorption Type of cleansing cream:I.) Anhydrous type:- It contains mixture of hydrocarbon, oils and waxes. It also contains cetyl alcohol, spermaceti, cocoa butter, fatty acid esters etc. Not popular. Mineral oil-80 gm, Petroleum jelly 15gm Ozokerite wax -5 gm Preservative and perfumes q.s Note :- Formation crusty surface is avoided by adding Ozokerite & petrolatum (prevent bleeding of mineral oils.) Opaque character obtained by adding Zno, mg.stearate, Tio2 II.) Emulsified type:- They can be either o/w or w/o type. Common Ingredients:Oil phase..Spread easily Waxes..Give appropriate thixotropy Emollient materiallikes cetyl alcohol, spermaceti, lanolin Water phase with preservative Different types:(1) Cold Cream:Cooling effect is produced due to slow evaporation of the water contained in the formulation. These are w/o type.
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(2) Beeswax Borax type:- These contain high percentage of mineral oil. These are o/w type. This cream contains high amount of mineral oil for cleansing action. Basically these are o/w type emulsion. After the cream is being rubbed into the skin sufficient quantity of water evaporates to impart a phase inversion to the w/o type. The solvent action of the oil as external phase imparts cleansing property. In this type of cream borax reacts with free fatty acids present in the bees wax and produces soft soap which acts as the emulsifying agent and emulsifies the oil phase .
A typical formulation:Bees wax -2 gm Almond oil -50 gm Lanolin 0.5gm Borax-2 gm Rose water 35.5 gm preservative and perfume q.s
B) NIGHT & MASSAGE CREAM:These are generally applied on the skin and left for several hours say overnight and assist in the repair of skin which has been damaged by exposure to various elements or exposure to detergent solution or soap. The mostly have a moisturizing & a nourishing effect of affected skin. These also contain vitamins and hormones basing on the application. This cream give better look to the skin and prevent dryness. A typical formulation Mineral oil-38gm Borax 1gm Petroleum jelly-8gm Water 35gm White bees wax-15gm Perfume & preservative q.s Paraffin wax 1.0gm Lanolin 2gm C) VANISHING CREAM:- These are named so as they seem to vanish when applied to the skin. High quantity of stearic acid as oil phase used.This provides an oil phase which melts above body temp, and crystsllises in a suitable form, so as to invisible in use and give a non greasy film. Main component is emollient esters ,stearic acids Part of stearic acid is saponified with an alkali & rest of stearic acid is emulsified this soap in large quantity of water. The quality of cream depends on the amount of acid saponified & nature of alkali used. NaoH makes harder cream than koH. Borax makes cream very white but product has tendency to grain. Pearliness can be attained using liq.paraffin, cocoa butter, starch, castor oil, almond oil. Ammonia solution has a tendency to discolor creams made with it after some time. Cetyl alcohol improves texture and stability at low temperature without affecting sheen. A typical formulation 117
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Stearic acid 15gm KOH 0.5 gm NaOH 0.18 gm Cetyl alcohol 0.50 gm Propylene glycol 3.0gm
Glycerin 5gm water 75.82 gm preservative &perfume q.s
Stearic acid has whiteness like snow so some times the preparation is called as SNOW.
D) FOUNDATION CREAM: Applied to skin to provide a smooth emollient base or foundation for the application of face powder & other make up preparations. They help the powder to adhere to skin. They are almost o/w type. Types: 1) Pigmented 2) Unpigmented
A typical formulation Lanolin 2 gm Cetyl alcohol 0.50 gm Stearic acid 10gm KoH 0.40 gm Propylene glycol 8gm water 79.10 gm Perfume &preservative q.s
E) HAND & BODY CREAM: The repeated or constant contact with soap and detergent damages & removes film of sebum thus this cream is used to impart following functions to the skin. The function of these creams are - Replace/reduce water loss. - Provide oily film to protect the skin. - Keep the skin soft, smooth but not greasy. Type:a) Liquid cream:-consistency is of liquid nature b) Solid creams:- Consistency is higher c) Nonaqueous type:-Not containing any aqueous medium. A typical formulation a.) Isopropyl myristate - 4 gm Mineral oil -- 2 gm Stearic acid 3.gm Emulsifying wax - .275 gm Lanolin - 2.5 gm b.) Glycerin -3.0 gm
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Triethanolamine 1 gm Water -84.225 gm Perfume and Preservative -q.s (F) ALL PURPOSE CREAMS:- All purpose means it is suitable for hands, face and body. They are w/o types. Formula:- Oil phase Water phase Mineral oil 18% Water 61.3% Lanolin 2% Glycerol 5% Petroleum jelly 2% Magnesium sulphate 0.2% Ozokerite 7 % Perfume, preservative q.s Paraffin wax 3%
2) LOTIONS :(I) Cleansing lotion

A typical formulation Mineral oil 38%, Bees wax 2%, Triethanolamine stearate 8%, Water to make 100% Preservative & Perfumes q.s Note :- Triethanolamine discolors on standing so it should be made in situ using calculated amount of stearic acid and Triethanolamine. O/W lotion have tendency to increase in viscosity with ageing (this is prevented by using ethoxylated cholesterol)
(II) Sunscreen lotions :- These lotion has property of protecting the skin from
sun burning. An ideal sunscreen agent should have following properties. Absorb light over the range of 200-400 nm. Be stable to heat, light & perspiration Be nontoxic & nonirritant Not be rapidly absorbed Be neutral Be readily soluble in suitable vehicles. US dept of health has recommended following ingredients to be used as sunscreen agents. They absorb U.V radiation. CYCLOFORM MONOGLYCERYL PARA AMINO BENZOATE DIGALLOYL TRIOLEATE BENZYL SALICYLATE BENZYL CINNAMATE And few others are PABA, cinnamic acid derivatives, coumarin derivatives, Quinine salts, uric acid derivatives. A typical formulation Glyceryl p-amino benzoate 3.0 % Glycerin 5.0 % Alcohol 10 % 119
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Methyl cellulose Perfume Water to make 100 %
0.5 % q.s
3.POWDERS:These are categorized as face powder, body powder, and Compacts. The powders should have following properties: Must have good covering power so can hide skin blemishes. Should adhere perfectly to the skin & not blow off easily. Must have absorbent property. Must have sufficient slip to enable the powder to spread on the skin by the puff . The finish given to the skin must be preferably of a matt or peach like character.
The raw materials used to manufacture of various powders are classified with example as follows:RAW MATERIAL FOR EXAMPLE POWDER IMPARTING Covering prop Titanium dioxide,zno,kaolin,zn stearate Adhesion prop Mg.stearate,talc,mg & ca salt of myristic acid Zn/mg undecanate,aluminium hydrosilicate Starch, colloidal kaolin,bentonite,pptd chalk Rice starch,silica,powdered silk Guanine, bismuth oxychloride,mica,Zn,Al Iron oxides
Slip & Softness Absorbency prop Peach like finish Frosted look Color & perfumes
FACE POWDER:Types of Face Powders:A. Loose face powder B. Compact face powder C. Talcum powder D. Baby powder A) LOOSE FACE POWDER :The essential feature of a good face powder includes Covering power, slip, Adhesiveness, Absorbency, Bloom, Coloring, Perfuming. 120
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Type:b) Light type c) Medium type d) Heavy type Type of powder LIGHT face purpose & composition Dry skin, contains large amount of talc
MEDIUM
Normal or moderately oily skins, lesser talc & zinc oxide Extremely oily skins ,low talc but higher amount of Zinc oxide
HEAVY
TYPICAL FORMULATION OF FACE POWDERS:LIGHT POWDER Talc ---------63gm Kaolin --------20 gm Cal. carbonate(l) 5 gm Zinc oxide ---5.0gm Zinc stearate-5.0gm Mg.carbonate1.0gm Color ------0.5gm MEDIUM POWDER Talc---------39.7gm Kaolin-------39.5 gm Cal. carbonate(l) 5 gm Zinc oxide ---7.0gm Zinc stearate-7.0gm Mg.carbonate1.0gm Color ------0.2gm HEAVY POWDER Talc---------20.0gm Kaolin(light)-20 0gm . Cal. carbonate(l) 39 g Zinc oxide ---15.0gm Mg.stearate5.0gm Color ------0.5gm
Perfume------0.5gm
Perfume------0.5gm
Perfume------0.6gm
B) COMPACT FACE POWDER:It is a dry powder which has been compressed into a cake. The pressure for compaction is very important. The powder must come off easily when rubbed with puff.
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Type of binder
1) Dry binder 2) Oil binder repellant )
Examples
Zn/Mg.stearate
(water Mineral oil, isopropyl myristate, Lanolin derivative PVP, CMC, Tragacanth Cellulose, Acacia,
3) Water soluble binder 5) Emulsion binder
Triethanolamine stearate, Glycerol monostearate
(C) TALCUM POWDER:- It is used as an adsorbent for making the skin from the excess moisture. Light magnesium carbonate added to mix perfume. Formula:- Zinc oxide . .. 50 Zinc stearate 50
Chlorhexidine diacetate 3 Light magnesium carbonate.100 Talc .797 Perfume.0.2

D) BODY POWDER:It consists of mainly talc, with small portion of a metallic stearate, precipitated chalk, magnesium carbonate(light). Talcum/body powders containing antiseptic substances are also used for prickly heat, and fungus infections. Boric acid act as antiseptic. A typical formulation Talc - 75 gm Aluminum stearate 4 gm Colloidal Kaolin 10 gm Boric acid 0.3 gm Colloidal silica--- 5 gm Perfume --- 0.7 gm Magnesium Carbonate- 5 gm
3. SKIN COLORANTS:It includes a) Lipsticks b) Rouge a) LIPSTICK:-These are basically dispersions of coloring matter in a base consisting of a suitable blend of oils, fats, waxes, suitably perfumed and flavored, moulded in the form of a stick. Ideal character of lipstick includes: Should cover the lips adequately with some gloss and last for long time. It should make the lips soft. The film must adhere firmly to the lips without being brittle.& tachy.
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Should have high retention of color intensity without any change in shade. Should be completely free from grittiness & free from drying. Nonirritating to the lips. Desirable degree of plasticity & have a pleasant odor and flavor. Classification of raw materials:1) Wax mixtures (bees, candeilla, carnauba, ceresin, Ozokerite wax) 2) Oil mixtures (castor, paraffin, THFA, isopropyl myristate) 3) Bromo mixture 4) Colors 5) Preservatives Types of lipsticks 1) Transparent lipstick 2) Liquid lipstick 3) Lip rouge 4) Lip jelly 5) Lip salve 6) Lip glosses A typical formulation of lipstick. Castor oil 54 gm Lanolin (anhydrous) 11 gm Candeilla wax Isopropyl myristate White beeswax Carnauba wax Ozokerite wax Eosin Lakes Rose flavor Antioxidant Preservative 9 gm 8 gm 5 gm 3 gm 3 gm 2 gm 5 gm q.s q.s q.s
b) SKIN ROUGE: - These are the cosmetics preparations used to apply a color to
the cheeks. The color may vary from the palest of pinks to the deep blue reds .The tint or color may be achieved using water insoluble colors such as iron oxides and certain organic pigments or by using water soluble organic colors which actually stain the skin. Types : Powder rouges Wax based rouges (Stick rouge) Emulsion cream rouges Liquid rouges
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Powder Rouges Talc.40 Zinc oxide..10 Magnesium carbonate.20 Pigment..14 Lanolin...30 Perfume..2
Stick rouge Carnauba wax3 Candelilla6 Ozokerite1.5 Bees wax1.5 Hexadecyl stearate10 Isopropyl myristate.8 Castor oil.65 BHA..0.02 Color5 Liquid rouge (A) Iso stearic acid.0.02 Mineral oil.30 Iso propyl myristate..5 Colloidal silica..1 Color...3 (B) Water..48.3 Triethanolamine4 Perfume.0.2
Emulsion cream rouge (vanishing type) Stearic acid.15 Potassium hydroxide.0.5 Sod. Hydroxide..0.18 Glycerin..8 Water..76 Pigment, Perfume & Preserativeq.s
(4) ANTIPERSPIRANTS & DEODORANTS:Anti perspirants:- Aluminium chlorhydrate used which has antibacterial and astringent action. Aluminium chloride and Zirconium compounds are also used as antiperspirants. Deodorants:--11 ( Hexachlorophene) - TMTD (Tetra methyl triuram disulphide) - Bithionol - Bromosalicylanilide - Diaphene - Neomycin ( Antibiotic) - Ion-exchange resin used like Amberlite - Metal chelates like 1,3 Diketones used which chelate copper, aluminium, Mg compounds.
COSMETICS FOR HAIR:Includes following type of preparations:1. Shampoo 2. Hair tonics & Conditioners 3. Hair colorants and hair color remover 4. Hair grooming preparations 5. Depilatory & Epilatory 6. Shaving soaps & creams 7. Hair wave sets & lacquers ,rinses
1. SHAMPOO
Ideal characters of a shampoo: Should effectively and completely remove the dust, excessive sebum.
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Should effectively wash hair. Should produce a good amount of foam The shampoo should be easily removed by rinsing with water. Should leave the hair non dry ,soft, lustrous with good, manageability. Should impart a pleasant fragrance to the hair,. Should not make the hand rough and chapped. Should not have any side effects or cause irritation to skin or eye.
Composition of shampoo:1) Principal surfactant (anionic type) Non ionic surfactant has sufficient cleansing property but have low foaming power. Cationic are toxic. So anionic are preferred. 2) Secondary surfactant (anionic or ampholytic detergent) They modify detergent and surfactant properties of principal surfactant. 3) Antidandruff agents (selenium, cadmium sulfide, ZPTO) 4) Conditioning agent (lanolin, oil, herbal extract, egg, amino acids) 5) Pearlescent agents (substituted 4 methyl coumarins) 6) Sequestrants (EDTA) Added because Ca, Mg salts are present in hard water. Soaps cause dullness by deposition of Ca, Mg soaps on hair shaft. This prevented by EDTA. 7) Thickening agents (alginates, PVA, MC) 8) Colors, perfumes and preservatives
Types of shampoo:1) Liquid cream shampoo 2) Solid cream and gel shampoo 3) Powder shampoo 4) Antidandruff shampoo 5) Aerosol foam shampoo Formulation of shampoo:-
Liquid Cream shampoo SLS 30% PEG 400 Distearate Mag. Stearate Dist. Water Ninol AB 21 Oleyl alcohol Perfume PEG 400 distearate and Mg stearate used to convert clear liquid shampoo to liquid cream shampoo. Ninol AB 21- Thickening agent Oleyl alcohol- Conditioning agent
Solid cream and Gel Shampoo SLS20% Coconut monoethanolamide.1% Propylene glycol monostearate..2% Stearic acid.5% Sodium hydroxide0.75% Water, perfume, Colour.100
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1) Powder shampoo Henna powder 5 gm Borax .15 gm Sod. carbonate 25 gm Pot. Carbonate .. 5 gm Soap powder.. 50 gm Perfume . q.s.
2) Antidandruff shampoo Selenium disulphide 2.5 gm Bentonite ...... 5 gm Sod. Lauryl Sulphates ... 40 g Water 52.5 gm Perfume q.s.
Aerosol Shampoo:- SLS.30% Triethanolamine lauryl stearate..5% Polyethylene glycol stearate3% Perfume..0.3% Water100 90 parts of above packed with 2 parts of propellant 12 and 8 parts of propellant 14.
2) CONDITIONERS:- These are the preparations used after shampooing to render

the hair more lustrous, easy to comb, and free from static electricity when dry. Conditioners are usually based on cationic detergents and fatty materials like lanolin, or mineral oil.
3) HAIR COLORANTS:-These are used either to hide gray hair or to change the
color of the hair . An ideal hair dye should have following properties: Should be nontoxic to the skin or hair, should not impair natural gloss and texture. Should not be a dermatitic sensitizer. The color imparted must be stable to air, light, water, shampoo. Should be easy to apply. Hair dyes are divided into 1) Vegetable Example is Henna 2) Metallic Example:- Lead dyes, Bismuth dyes, Silver dyes, Copper, nickel, cobalt salts Formula:- (Lead dyes) Precipitated sulphur.1.3% Lead acetate..1.6% Glycerine.9.6% Rose water.87.5% 3) Synthetic organic dyes They are of two types. a) Semipermanent dye. b) Permanent dyes Thyoglycolic acid50% Paraphenylene diamne dye NH3 solution(PH 9.2)100%
HAIR DYE REMOVER:Formula:- Formamidine sulfinic acid.1.5% PVP5% 126
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Ethylene glycol monobutyl ether..5% Ammonium carbonate1% Ammonia..0.5% CMC..2.5% Water up to .1oo Formamidine sulfinic acid is acting as hair dye remover.
4) HAIR GROOMING AIDS :-These are important group of cosmetics which are
used both by men and women to keep their hair in order for good looking, &enhance overall appearance. Types:1. 2. 3. 4. Brilliantines & Hair oils Hair setting lotions Hair creams Hair lacquers or sprays
5) DEPILATORIES: These are the preparations that remove superfluous hair by chemical breakdown. This removes hair at the neck of the hair follicle and thus has advantage over razor shaver which removes hair on a level with the surface of epidermis. Desirable Characters of an ideal depilatory preparation are: Selective in action Efficient and rapid action in few minutes. Non toxic and non allergic to the skin. Odorless Easy to apply Stable Non staining INGREDIENTS :- includes Inorganic sulphates (Sod,calcium,barium sulphide,Strontium sulphide) Thioglycollates: - (Calcium.thioglycollate & Lithium thioglycollate) Stannites: - sodium stannite Enzymes:-Keratinase (3-4%) Humectant: - Glycerol,Sorbitol ,Propylene glycol
1. 2. 3. 4. 5.
FORMULATION
Name of ingredient 1.Strontium sulphide 2.Talc 3.Methyl cellulose 4.Glycerin 5.Water 6.Perfume 7. Preservative Amount 20.0 gm 20.0gm 3.0 gm 15.0 gm 42.0 gm q.s q.s 127
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6) EPILATORIES:Epilation is longer lasting or even can be of permanent nature. This is achieved by plucking the hair out and removing the root either by tweezers, threading,or by waxing. it is a permanent or long lasting effect (done by plucking the hair out, removing the root) Camphor-impart cooling effect to reduce discomfort of hair pulling. Local Anaesthetics:- overcomes discomfort and pain FORMULATION Rosin Bees wax Ozokerite Perfume 70 gm 20 gm 10 gm q.s
7) SHAVING PREPARATIONS: - These are preparations used to carryout shaving. Type a) Ued before shaving b) Used after shaving Preparations before shaving includes 1) Lather shaving creams 2) Brushless shaving cream 3) Shaving soaps (solid, cream) 4) Aerosol preparation Preparation after shaving is Aftershave lotion SOAP BAR SOAP CREAM I Ingredients A amount I Ingredients A Amount S Stearic acid C Coconut oil 49 gm 1 13 gm 22 gm 12 gm A. A. 1. Stearic acid 2. Coconut oil 3. Palm kernel oil 05 gm 30 gm 10 gm
C Caustic potash C Caustic soda W Water
1.25 gm B. B. 1. Pot. hydroxide 07 gm 2. Sod. hydroxide 3. Water 4. Perfume 1.5 gm 36.5 gm q.s
S Sodium dioxy stStearate (50%) o.75 gm S Sorbital liquid 1.25 gm G Glycerol P Perfume 0.75 gm q.s
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P Preservative
q.s
5. Preservative
q.s
1) BRUSHLESS SHAVING CREAM Here Lathering with shaving brush is avoided. Formulation of brushless shaving cream INGREDIENTS AMOUNT 1. Stearic acid 2. Mineral oil 3. Spermaceti 4. Glycerin 5. Dil .ammonia solution 6. Water 7. Perfume 8. Preservative 16 gm 14 gm 2 gm 6 gm 2 gm 6 gm q.s q.s
2) LATHER SHAVING CREAM:Lathering with shaving brush is required. INGREDIENTS A AMOUNT (%) Stearic acid Coconut oil Palm oil Pot. hydroxide Sod. hydroxide Glycerin Perfume Preservative Water to make 28 12 5 6.5 1.5 10 q.s q.s 100
AFTER SHAVE PREPARATION:Main purpose of shave preparation is to confer a pleasant feeling of comfort and well being after shaving. This is achieved by giving slight coolness, anaesthesia, tautness or emolliency to skin. At the same time it should be aseptic also. Formula:-( Antiseptic after shave lotion) Hyamine..0.25% Alcohol.40% 129
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Menthol0.005% Benzocaine.0.025% Water59.72% Perfumeq.s
COSMETICS FOR NAILS:Includes 1. 2. 3. 4. 5. Nail polishes Nail lacquers & removers Nail bleaches & Stain removers Cuticle remover & softener Fingernail elongations
1 ) NAIL POLISHES:A distinction between nail polishes and lacquer is that in nail polish exert the abrasive action. Due to friction it draw the blood to numerous capillaries of nail bed and increasing blood supply, and exert stimulating effect to growth of nail. Examples are stannic oxide, talc, precipitated chalk. Silica exert abrasive action. Formula:- Stannic oxide90% Powdered silica.8% Butyl stearate2% Pigment & Perfume.. ..q.s
2) NAIL LACQUERS : These are the preparations that cover the nail with a water and air impermeable layer which normally remains for days. A good Nail lacquer should fulfill the following characters:1) 2) 3) 4) Must be innocuous to the nail & the skin Must be easy and inconvenient to apply Product should be stable on storage The product should produce a good &satisfactory film.
COMPOSITION:-
1) Film former:-Nitro cellulose, Cellulose nitrate (mostly used), Cellulose acetate, cellulose acetobutyrate, Ethyl. Cellulose. 2) Resins :- Give film more body, gloss, depth, adhesion Natural - Gum damar, Benzoic acid, Gum copal, Shellac Synthetic - Sulphonamide Formaldehyde Resins 3) Solvents:-Mix of solvent is preferred, Mixing middle b.p solvents like alcohols, acetates,and aromatic solvents rate of evaporation can be retarded. 4) Diluents:5) Plasticizers :- Dibutyl phthalate, Castor oil ,n-butyl stearate, castor oil 6) pearlescent material :-Guanine crystals (R.I-1.8), mica flakes, Ti02, Platelets coated with bismuth oxychloride. 130
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7) colors and perfumes Formulation (Nail Lacquer) INGREDIENT Nitrocellulose Resin plasticizer Solvent Color Perfume AMOUNT 16 gm 9 gm 4.8 gm 60.5 gm 0.5 gm q.s
b) LACQUER REMOVERS:These are also called as nail cleansers which is applied to remove nail lacquers. FORMULATION OF LACQUER REMOVERS Ingredients Butyl acetate Ethylene glycol monoethyl ether Propylene glycol ricinoleate Perfume Amount 15 gm 80 gm 05 gm q.s
c) CUTICLE REMOVERS AND SOFTENERS:Cuticle preparations either soften or remove the cuticles.
COSMETICS FOR EYES:Includes following preparations 1. Eye shadow 2. Mascara 3. Eyebrow pencil 4. Eye cream 5. Eye liners 6. Kajal
1) EYE SHADOW: Give a back ground of color to the eye Formulated as cream, liquid, powder or stick. Ultramarine(20 part)& Ti02 --- (BLUE) Iron oxide(30 part) &Ti02 (5 part)-- (BROWN)
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Ingredients petroleum jelly Liquid lanolin Bees wax Micro crystalline wax Isopropyl myristate
Amount 47.5 gm 4.5 gm 4.5 gm 8.5 gm 35 gm
2) EYE LINER:Types 1) Pencil type 2) Liquid type (suspension in a base containing film forming material) 3) Cake eye liners Formulation of Cake type eyeliner Kaolin Zn Stearate Ppted Caco3 Pigment Talc to make 5% 12% 7% 10% 100 %
3) EYE BROW PENCIL: Contain high proportion of wax to increase M.P so that these can be moulded into sticks.
Ingredient Bees wax Ozokerite Butyl stearate Lanolin Castor oil Mineral oil Perfume
Amount 25% 25% 8% 2% 25% 15% q.s 132
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Antioxidant
q.s
4) MASCARA: Black pigmented preparation for applying to eye lashes or eye brows ,it darkens the eye lashes & gives an illusion of their density and length. Type:- Cake , Cream , Liquid
Formulation:Carbon black Coconut oil sodium soap Palm oil sodium soap 55 % 25% 22.5%
7) QUALITY CONTROL OF COSMETICS :We all know that Price of a product is quickly forgotten but the quality is remembered so quality control plays a vital role regarding monitoring different parameters that may affect quality &also helps in producing quality product every time. Includes :1) RAW MATERIAL CONTROL 2) INTERMEDIATE PRODUCT CONTROL 3) FINISHED PRODUCT CONTROL 4) PACKAGING MATERIAL CONTROL
1) Q.C OF RAW MATERIAL: Done by determination of Bioburden The bacterias that are monitored in raw materials include:Enterobacteriaceae E.Coli Salmonella Pseudomonas aeruginosa Staphylococcus aureus
2) Q.C OF INTERMEDIATES AND BULK FINISHED PRODUCT:Basing on the type of product few typical processing parameters are continuously to ensure quality final product. few of them have been enlisted here. a) CREAMS & LOTIONS: Mechanics, perfume addition temp addition of phases Viscosity Temp of filling 133
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rate of cooling b) FACE POWDER Uniformity of mixing Apparent density Shade ,color Compression pressure (compacts) c) LIPSTICKS Color match Texture Softening point Breaking point test d) SHAMPOO: -Foam & foam stability -Detergency & coloring action -Wetting action -Eye irritation -Oral toxicity e) NAIL LACQUER: Color match, Drying rate, Non volatile content, Smoothness, Gloss, Hardness, abrasion resistance, adhesion etc.
Sampling size for final Q.C:No of packaging Up to 3 4-50 51-150 151-300 301-500 >500 No of packing selected Each 03 04 05 06 07
8) COSMOCEUTICALS: disease fighting property
These are cosmetics with therapeutic &
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The following substances are now recognized having cosmoceutical potentials 1) Polysacharides :-Fom Tamarind extract and skin beneficial acids from Coriander extract provide moisture-lipid balance preventing dryness and itching 2 2) Wheat Germ Oil guard skin against free radical damage. 3) Moringa Extract protects your skin against dust and harmful pollutants. 4) Galanga Oil * protects skin from harmful UV rays and fights pimple in acne prone skin. Skin beneficial fatty acids from Coriander boost the deposition of skin proteins, enhancing tissue repair 5) Cococin provides wholesome freshness and nourishment of natural tender coconut water. Natural growth promoters like kinetin and amino acids in Cococin impart natural conditioning, suppleness and glow to the skin. 6) Ubiquinone(CO.Q.10) rejuvenates and increases the oxygen uptake into the cells. 7) Tetrahydrocurcuminoids, patented molecule from turmeric in combination with potent antioxidants - Alpha lipolic acid and Ubiquinone reduces fine lines, wrinkles, crow's feet, minimizes the UV induced signs of photo aging and pigmentation, leaving behind blemish-free, youthful skin. 8) Isoflavons from Soy impart luster and brightness to the skin by improving skin thickness, skin blood circulation, increased desquamation resulting in excellent surface texture and softness. 9) Tetrahydropiperine as Cosmoperine from Pepper improves the dermal penetration of the actives,
MISCELLANEOUS ISSUES:SKIN TESTING:-
Type of cosmetic Preparation

CREAMS DEODORANT DEPILATORIES HAIR DYE COLD WAVE LOTIONS
Suspected agent to cause harm

Mercurial & Salicylic acid Phenolic antimicrobials, Aluminium.chloride Sulphides of alkali (R.A) Ammonia solution Thioglycollates
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LIPSTICK HAIR & BATH Prep
Bromofluorescein dye ( cause Cheilitis) Agent which cause eye irritation
4) TEN SYNTHETIC COSMETIC INGREDIENTS TO AVOID:Organic consumers association has given the following list of chemicals that are to be avoided in preparation of cosmetics. 1. Imidazolidinyl Urea and Diazolidinyl Urea 2. Methyl and Propyl and Butyl and Ethyl Paraben 3. Petrolatum 4. Propylene Glycol 5. PVP/VA Copolymer 6. Sodium Lauryl Sulfate 7. Stearalkonium Chloride 8. Synthetic Colors Example: FD&C Red No. 6 / D&C Green No. 6 9. Synthetic Fragrances 10. Triethanolamine
Newer approaches
Hair Growth-accelerating preparation containing chlorogenic acid or its isomer for treating androgenic alopecia and its formulation. Cosmetic composition contain in caffeine ,acetic acid and sodium hyaluronate for preventing alopecia.
(chemical abstract-151-2009)
DENTAL PRODUCTS
LIST OF CONTENTS
1) 2) 3) 4) 5) 6) Introduction The teeth and common problem Causes of oral health problems Classification Formulation of dentifrices Type of dentifrices 1. Tooth pastes 2. Tooth powders 3. Solid blocks 4. Liquid preparations 5. Mouth wash 7) Topical anesthetics 8) Tartar reducing product 9) Mechanical method for plaque control 10) Safety 11) Dental care product 12) Newer approaches 136
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INTRODUCTION
dentifrice a preparation for cleansing and polishing the teeth; it may contain a therapeutic agent, such as fluoride, to inhibit dental caries. A substance, such as a paste or powder, for cleaning the teeth. Etymology: L, dens + fricare, to rub a pharmaceutic compound used with a toothbrush for cleaning and polishing the teeth. It typically contains a mild abrasive, detergent, flavoring agent, fluoride, and binder. Other common ingredients are deodorants, humectants, desensitizers, and various medications to prevent dental caries. Also called toothpaste. dentifrice (toothpaste) n a pharmaceutical compound used in conjunction with the toothbrush to clean and polish the teeth. Contains a mild abrasive, a detergent, a flavoring agent, a binder, and occasionally deodorants and various medicaments designed as caries preventives (e.g., antiseptics). Two type of Dentifrice 1. Simple cleansing dentifrices 2. Therapeutics dentifrices: Therapeutic dentifrices may contain the bactericidal, bacteriostatic, enzyme inhibiting or acid neutralizing qualities of the drugs or chemicals.
The teeth and common problem

1. Bad Breath If you suffer from bad breath, you are not alone. Bad breath, also called halitosis, can be downright embarrassing. According to dental studies, about 85% of people with persistent bad breath have a dental condition that is to blame. Gum disease, cavities, oral cancer, dry mouth and bacteria on the tongue are some of the dental problems that can cause bad breath. Using mouthwash to cover up bad breath when a dental problem is present will only mask the odor and not cure it. If you suffer from chronic bad breath, visit your dentist to rule out any of these problems. 2. Tooth Decay Did you know tooth decay, also known as cavities, is the second most prevalent disease in the United States (the common cold is first). Tooth decay occurs when plague, the sticky substance that forms on teeth, combines with the sugars and / or starches of the food we eat. This combination produces acids that attack tooth enamel. The best way to prevent tooth decay is by brushing twice a day, flossing daily and going to your regular dental check ups. Eating healthy foods and avoiding snacks and drinks that are high in sugar are also ways to prevent decay. 3. Gum (Periodontal) Disease Studies have shown that periodontal disease, also known as gum disease, is linked to heart attacks and strokes. Gum disease is an infection in the gums surrounding the 137
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teeth. Gum disease is also one of the main causes of tooth loss among adults. There are two major stages of gum disease: gingivitis and periodontitis. Regular dental check ups along with brushing at least twice a day and flossing daily play an important role in preventing gum disease. 4. Oral Cancer Oral cancer is a serious and deadly disease that affects millions of people. In fact, the Oral Cancer Foundation estimates that someone in the United States dies every hour of every day from oral cancer. Over 300,000 new cases of oral cancer are diagnosed every year, worldwide. This serious dental disease, which pertains to the mouth, lips or throat, is often highly curable if diagnosed and treated in the early stages. 5. Mouth Sores There are several different types of mouth sores and they can be pesky and bothersome. Unless a mouth sore lasts more than two weeks, it is usually nothing to worry about and will disappear on its own. Common mouth sores are canker sores, fever blisters, cold sores, ulcers and thrush. 6. Tooth Erosion Tooth erosion is the loss of tooth structure and is caused by acid attacking the enamel. Tooth erosion signs and symptoms can range from sensitivity to more severe problems such as cracking. Tooth erosion is more common than people might think, but it can also be easily prevented. 7. Tooth Sensitivity Tooth sensitivity is a common problem that affects millions of people. Basically, tooth sensitivity means experiencing pain or discomfort to your teeth from sweets, cold air, hot drinks, cold drinks or ice cream. Some people with sensitive teeth even experience discomfort from brushing and flossing. The good news is that sensitive teeth can be treated. 8. Toothaches and Dental Emergencies I can't think of much worse than suffering from a toothache. While many toothaches and dental emergencies can be easily avoided just by regular visits to the dentist, we all know that accidents can and do happen. Having a dental emergency can be very painful and scary. Fortunately, you can do several things until you are able to see your dentist. 9. Unattractive Smile While an unattractive smile is not technically a "dental problem," it is considered a dental problem by people who are unhappy with their smile and it's also a major reason that many patients seek dental treatment. An unattractive smile can really lower a person's self-esteem. Luckily, with today's technologies and developments, anyone can have a beautiful smile. Whether it's teeth whitening, dental implants, orthodontics or other cosmetic dental work, chances are that your dentist can give you the smile of your dreams.
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Causes of oral health problems

1)Pellicle The pellicle is rapidly formed on all freshly cleaned tooth surfaces by the deposition and absorption of some salivary proteins. It is less than 0.1 mm thick and is invisible to the naked eye. 2)Plaque Following the deposition of pellicle on a freshly cleaned tooth surface, plaque forms rapidly. Plaque is an invisible sticky film of bacteria, salivary proteins, and polysaccharides that accumulates on everyone's teeth. It is not washed away by the saliva, and the composition of bacteria depends upon the host, the site in the mouth and the age of the plaque layer. In the event of poor oral hygiene, plaque ages and there is a shift in bacterial population to more harmful organisms as the plaque age. 3)Dental calculus (tartar) Dental plaque may itself become mineralized and this hard deposit is called calculus. It accumulates on the tooth surface mainly at the gingival margin opposite the salivary ducts. It is a hard mineral deposit, containing predominantly calcium and phosphate, very tightly bound to the tooth surface. Once it has formed, it is virtually impossible to remove it except by a dental hygienist.
CLASSIFICATION OF DENTAL PRODUCTS

Dental preparations are classified as followsClassification depending on Dental Problems. I. Products for carries control. a. Systemic fluoride b. Topical fluoride i. Dentifrices ii. Gel iii. Rinses iv. Miscellaneous II. Products for plaque control. a. Chemical agents i. Dentifrices ii. Mouth washes b. Mechanical products i. Tooth brushes ii. Dental floss iii. Other aids to plaque removal. III. Products for tooth surface hypersensitivity. IV. Topical anesthetic. V. Halitosis
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TOOTHPASTE INGREDIENTS AND MANUFACTURE

Requirements of a toothpaste/dentifrice
The major requirements of oral preparations, especially toothpastes, have been summarized on many occasions in the past. For a toothpaste, these requirements were: 1. When used properly, with an efficient toothbrush, it should clean the teeth adequately, that is, remove food debris, plaque and stains. 2. It should leave the mouth with a fresh, clean sensation. 3. Its cost should be such as to encourage regular and frequent use by all. 4. It should be harmless, pleasant and convenient to use. (It should conform to the EC Cosmetics Directive in that it is 'not liable to cause damage to human health when applied under normal usage conditions'.) 5. It should be capable of being packed economically and should be stable in storage during its commercial shelf-life. 6. It should conform to accepted standards in terms of its abrasivity to enamel and dentine. 7.Claims should be substantiated by properly conducted clinical trials. These requirements remain valid today, with perhaps only the priority and emphasis placed on any individual point being changed. To achieve this it is necessary to have a high solid suspension in a stable viscous form and therefore gelling agents or thickening polymers have to be incorporated. To prevent it from drying out it also becomes necessary to add humectants to the system. Finally, colours (if desired), and preservatives (if necessary), are also added, creating a complex matrix of ingredients which can be classified as a 'simple' cosmetic toothpaste, i.e. 1. Cleaning and polishing agents (abrasives). 2. Surfactant (cleaning and foaming). 3. Humectants. 4. Binding (gelling) agents. 5. Sweetener. 6. Flavouring agents. 7. Minor ingredients (colours, whitening agents, preservatives). In such a complex system many interactions can take place depending upon internal and external factors. Even the 'simple' formulations require extensive stability testing, over a range of temperatures and time, in order to be confident that the product quality does not change upon storage. Only in this way can the manufacturer have a high degree of confidence that the product seen by the consumer is of premium quality. 'A dentifrice should be no more abrasive than is necessary to keep the teeth clean - that is free of accessible plaque, debris and superficial stain'. (American Dental Association, 1970.) Thus, considerable performance testing on the final formulation is necessary.
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Ingredients used in toothpastes

All ingredients generally have specifications approved for use in foodstuffs or are special grades available for dental preparations, especially abrasives. 1. Cleaning and polishing agents (abrasives) Clearly the main purpose of the cleaning and polishing agent is to remove any adherent layer on the teeth, and the materials normally considered are given below. (a) Dental grade silicas (SiO2)n. In a relatively short period of time silica has generally become the abrasive of choice because it offers great flexibility to the formulator. It can be produced to a high state of purity giving excellent compatibility with therapeutic additives and flavours. Varying the particle size can alter the finished product abrasivity. Clear gels can be formulated by carefully matching the refractive indices of silica used with the liquid phase of the toothpaste. Silica can also give additional thickening properties to the dental cream if extremely fine particle sizes are used (silica thickeners). When used in toothpastes, silica is generally incorporated at levels between 10 and 30%. (b) Dicalcium phosphate dihydrate (DCPD) CaHPO4-2H2O. DCPD is one of the most commonly used dental cream abrasives, perhaps because it gives good flavour stability. It is normally white in colour and gives toothpaste which generally does not require additional whitening agents. The main drawback is that it is only fully compatible with sodium monofluorophosphate as the fluoride source because of the presence of free calcium ions. Formulating with other therapeutic fluoride sources does not appear to have been successful. The abrasive is usually formulated at levels between 40% and 50% to give relatively dense toothpaste. (c) Calcium carbonate CaCO3. Calcium carbonate is probably one of the most commonly used dental cream abrasives. Precipitated calcium carbonate (chalk) is available with a white or off-white colour and both particle size and crystalline form can be varied, depending upon its conditions of manufacture. As a result of its structure and calcium content, precipitated calcium carbonate is incompatible with sodium fluoride, but is stable with the less reactive sodium monofluorophosphate. Calcium carbonate is also used at levels between 30% and 50% to give a relatively dense paste. (d) Sodium bicarbonate (or baking soda NaHCO3). Sodium bicarbonate has a unique 'salty' mouth-feel that tends to polarize consumers, many finding it attractive possibly due to its heritage as a cleaner/deodorizer. It is a very mild abrasive, usually used at a 5-30% level, in combination with other abrasives such as silica or calcium carbonate to achieve the required cleaning action. (e) Hydrated alumina Al2O3 3H2O or Al(OH)3.
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Hydrated alumina is relatively inert, cost-effective, and available as a white amorphous solid. It has good compatibility with sodium monofluorophosphate and other ingredients added to give a therapeutic benefit. The abrasive is usually formulated at levels between 40% and 50% to give a relatively dense paste. (f) Other abrasives. Insoluble sodium metaphosphate (IMP) (NaPO3)x, is available as a free-flowing white powder, with moderate abrasivity and good compatibility with flavour oils, sodium monofluorophosphate and ionic fluoride sources (stannous and sodium fluorides). it is now only used in extremely limited amounts. Calcium pyrophosphate (CPP), Ca2P2O7, was the original abrasive purposely developed for its compatibility with stannous fluoride to give the first commercially available therapeutic dentifrice containing fluoride (America Dental Association, Council on Dental Therapeutics, 1960). 2. Surfactants Surfactants are used in the toothpaste to aid in the penetration of the surface film on the tooth by lowering the surface tension. They also provide the secondary benefits of providing foam to suspend and remove the debris, and the subjective perception of toothpaste performance. They often have better foaming properties, and are more compatible with other ingredients since their pH range is essentially neutral. They are also available with a higher degree of purity that can eliminate some of the bitter flavour components that affect taste. In general, surfactants are used at a concentration of around 1-2% by weight in the dental cream. (a) Sodium lauryl sulphate (SLS) This has been the main surfactant of choice, used in nearly all toothpaste brands. However, while alternative surfactants have been considered, and will continue to be looked at and developed, none is in widespread use since all have some disadvantages compared to SLS. 3. Humectants Humectants are used to prevent the paste from drying out and hardening to an unacceptable level. At the same time they give shine and some plasticity to the paste. Generally only two major humectants are considered for use in toothpaste, often in combination with small amounts of additional minor humectants. (a) Glycerin, CH2OHCHOHCH2OH. Glycerin is still the humectant used in greatest bulk quantity in toothpaste. It is one of the best humectants, producing a shiny, glossy product. It is stable, non-toxic, available from both synthetic and natural sources, and provides a useful sweetening function to the paste. (b) Sorbitol, CH2OH(CHOH)4CH2OH. Sorbitol syrup (approximately 70%) is also extensively used throughout the industry and is sometimes considered superior to glycerin depending upon the formulation. It also imparts sweetness, and is a stable humectant.
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(c) Propylene Glycol, CH3CHOHCH2OH and Polyethylene Glycol, CH2OH(CHOH)nCH2OH. Propylene glycol and polyethylene glycol are not normally used as the sole humectant in a paste since they are more expensive and, in the case of propylene glycol, can impart a slightly bitter taste. They are more generally used in relatively small amounts in combination with either glycerin or sorbitol. The amount of humectant in any formula obviously has to be adjusted depending upon the other constituents of the formula (especially abrasive nature), but generally the total humectant loading is in the range 10-30% by weight. (d) Xylitol (CH2OH(CHOH)3CH2OH). Xylitol is a polyol equivalent of sorbitol, but with a five-carbon chain instead of six. Like sorbitol it is a naturally occurring material with a relative sweetness equal to sugar. Currently its high cost and limited availability restrict its use. 4. Gelling agents Gelling or binding agents are hydrophilic (water-loving) colloids which disperse and swell in the water phase of the toothpaste and are necessary to maintain the integral stability of the paste and prevent separation into component phases. They are probably the most widely variable components of toothpaste and the choice of gelling agent can greatly influence the dispersibility of the paste in the mouth, the generation of foam and, above all, the release of the flavor components. Some formulations have combinations of gelling agents in order to achieve the desired consumer preferences. (a) Sodium Carboxymethyl Cellulose CMC. Carboxymethyl cellulose is one of the preferred gelling agents for use in toothpaste. It can be manufactured to a high state of purity, and tailor-made for an individual requirement by varying the degree of substitution on the cellulose chain. This can give flexibility in terms of solubility, elasticity and some increased stability in the presence of electrolytes. (b) Carrageenan. It is a purified colloid, consisting of a mixture of sulfated polysaccharides and, as with all natural products, it can be of variable quality, which could cause a problem for any formulator. Therefore, it is standardized either by repeated blending, or dilution with variable amounts of inert material. Some flexibility in the gelling properties of carrageenan can be achieved by controlling the cations present by ion exchange. (c) Miscellaneous gelling agents Xanthan - this is a polysaccharide produced by fermentation technology. It offers excellent properties for use in toothpaste since it gives a highly structured gel, relatively easily broken down when sheared, but which recovers rapidly.
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It is relatively insensitive to electrolytes and heat, but unfortunately it is generally incompatible with cellulosic materials because of contaminating enzymes that degrade cellulose. Hydroxy ethyl cellulose HEC - this is occasionally used as an alternative to carboxymethyl cellulose (CMC), especially when a greater electrolyte tolerance is required. Synthetic polymers - crosslinked acrylic acid polymers have become more intensively used in the past decade because of their useful thickening and suspending properties combined with their inertness and their stability to heat and ageing. Clays - colloidal clays, either natural processed bentonites or synthetic clays, have been used as binding agents because of their thixotropic properties. Depending upon the rest of the formula components (e.g. abrasive, amount of free water), the level of gelling agent added to a paste can vary from 0.5% to 2.0% by weight. 5. Sweetening agents These are important for product acceptance, since the final product must be neither too sweet nor too bitter. These ingredients must always be considered in partnership with the flavour because of their combined impact. (a) Sodium saccharin. This is the sweetening agent in widest commercial use, and is generally used at a level between 0.05% and 0.5% by weight. 6. Flavours Flavours are probably the most crucial part of toothpaste because of consumer preferences. The flavour is a blend of many suitable oils, with peppermint and spearmint being the major base components. These are nearly always fortified with other components such as thymol, anethole, menthol (to give a pleasant cooling effect), eugenol (clove oil), cinnamon, eucalyptol, aniseed, and wintergreen (to give a medicinal effect). In addition, because the flavour is a mixture of sparingly soluble organic oils, its interactions with the other dentifrice components are often unpredictable and unexpected. Taste and stability can be influenced greatly by both the other components of the dental cream, e.g. free water content, or absorption by the abrasive (perhaps to the surface), and also by the physical properties of the dental cream, e.g. pH, viscosity etc., Depending upon the formulation, e.g. the abrasive nature and level, the gelling agent used and the presence of therapeutic ingredients which may impact taste perception, the flavour level may vary from around 0.5% to 1.5% by weight. 7. Minor ingredients (a) Titanium Dioxide TiO2- Titanium dioxide may be added to give additional whiteness and brilliance to the paste. (b) Colours. Colours can be an integral part of the aspect of any toothpaste that may influence consumer preference and purchase intent. The EEC Cosmetics Directive (Annex IV) lists the permitted colours and only a small amount is necessary to create a large impact, <0.01% by weight. 144
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(c) pH regulators. Occasionally buffering systems need to be added to the dental cream to adjust the pH of the final finished product. (d) Sparkles. A recent introduction in the marketplace is the addition of small reflective mica particles to coloured transparent gel products. This gives toothpaste the appearance of containing 'sparkles' and is especially aimed at younger children. 8.Fluoride and other 'active' ingredients The earliest fluoride dentifrices contained sodium fluoride. However, the fluoride was biologically unavailable because the calcium in the dentifrice abrasive bound the fluoride and thus inactivated it. Although a number of dentifrices containing fluoride are on the market, not all provide available fluoride because the abrasive systems that some dentifrices contain inactivate the fluoride. Therefore, the product may contain as much fluoride as any other dentifrice but it is not available. Also, if the product has a short shelf life, it will be ineffective if poor marketing gets it to the consumer too late. For these reasons, only dentifrices approved by the Council on Scientific Affairs of the American Dental. Various topical fluoride preparations are available as given in the table. Form of fluoride Acidulated phosphate fluoride Preparations Topical solution Topical gel Mouth rinse Paste Dentifrices Mouth rinse Topical solution Mouth rinse Dentifrice Dentifrices Topical solution Mouth rinse Paste Gel Dentifrices Concentration of fluoride 1.23 % in 1 % phosphoric acid 1.23 % in 1 % phosphoric acid 0.02-0.04 % 1.2 % 1.6 % 2.5 % 2% 2.5 % 0.2 % (weekly) 0.76 0.8 % 8% 0.1 % 8% 0.4 % 0.4 %
Amine fluoride Sodium fluoride
Sodium monofuorophosphate Stannous fluoride
Currently accepted dentifrices contain sodium monofluorophosphate,sodium fluoride, or, less frequently,stannous fluoride, all of which reduce caries by approximately 25% when used daily. The composition of some popular tooth pastes is given in table. Brand Fluoride Abrasive Sweetener Foaming agent
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Aim
0.8 % Na.MFP
10 % Hydrated silica xerogel 19 % Hydrated silica
67 % sorbitol
1.5 % SLS
Aim extra strength Aqua fresh
1.2 % Na.MFP 0.76 % Na.MFP 0.76 % Na.MFP
Colgate
12.6 % calcium carbonate 12 % silica 48.76 % dicalcium phosphate
52.8 % sorbitol 22 % glycerin
1.15 % SLS 1.2 % SLS
stannous fluoride dentifrices stained teeth, particularly in pits and fissures. This stain is related to the tin in this compound, which adheres to plaque. The significance of this staining and its esthetic problems have resulted in a decreased usage in dentifrices. Stannous fluoride dentifrices are marketed in a plastic container because a reaction of stannous ions at an acid pH occurs when conventional soft metal tubes are used. Dentifrices containing stannous fluoride as an active ingredient are no longer widely marketed; however,these formulations were the first to be evaluated for caries-reducing properties. Effectiveness in caries reduction varied from 23 to 34%. Amine fluoride amine fluorides also have strong plaque-reducing properties. However, although the amine fluorides may be more effective for caries reduction than other forms of fluoride, the FDA has not allowed these products to be extensively tested in this country. Sodium fluoride Recent studies of sodium fluoride dentifrices formulated to ensure ready availability of fluoride ions have shown anticaries benefits similar to those obtained in clinical caries trials with dentifrices containing stannous fluoride and sodium monofluorophosphate. Clinical caries trials conducted under wellcontrolled, daily supervised brushing conditions have reported reductions in dental caries of approximately 2548%. Sodium monofluorophosphate A number of clinical studies have been conducted with dentifrices containing 0.76% monofluorophosphate (MFP). The data from these controlled clinical studies of sodium MFP dentifrices have indicated reductions in dental caries ranging from approximately 17 42%. Therapeutic effects of fluoride Caries control M/A: fluoride ion can replace the hydroxyl ion in hydroxyapatite the major crystalline structure of enamel.
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The substituted crystals called fluorapatite is more resistant to acid, such as those produced by plaque bacteria. As fluoride is also an antienzyme. It may inhibit enzymatic acid production by plaque bacteria. Dental plaque control Mainly stannous fluoride is used for this purpose. M/A: related to an alteration of bacterial aggregation and metabolism. Caries sites 1. Pit-and-fissure caries develop initially in the fissures of the teeth, but can spread into the dentine 2. Smooth-surface caries are most common on interdental surfaces, but can occur on any smooth surface of the tooth 3. Root caries attack the cementum and dentine, which becomes exposed as gums recede
Sources of fluoride Topical agents Fluoridated water Other ingested source
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Fluoride effect on remineralization and demineralization of ename Promote remineralization1
Reduce demineralization2,3
Inhibitacid generation from plaque bacteria4
MECHANICAL PRODUCTS FOR PLAQUE CONTROL

Toothbrush Toothpaste Dental Floss Tongue Scraper 1. Toothbrush The toothbrush is the primary dental hygiene product you need to take care of your teeth. First, the regular toothbrush alone provides a plethora of options. Toothbrushes come in various sizes and styles. Various brushes differ from the handle to the bristles. Thats why buying a toothbrush can be a confusing task. In choosing a brush, most dentists recommends soft-bristled brushes more because these can best remove plaque and traces of food that gets stuck in the teeth. You should also choose a brush that does not have a big head. Small148
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headed brushes can reach the back areas of the mouth for thorough and complete mouth cleaning. You can also choose from squared heads or tapered ones. As for the handle, you should go for brushes that provide good grip. The shape of the handles themselves differs a lot. But the most important part of the brush is the bristles. There are many forms of bristles, such as rippled, flat, trimmed, or domed ones. All these different types of bristles provide specific benefits that may help meet your needs. Aside from regular brushes, however, you can also use power brushes, which is very popular among younger users. These powered brushes help clean the teeth better than children usually can. 2. Toothpaste Another important choice you have to make is what toothpaste to use to go with that perfect brush. The toothpaste aisle in the supermarket is highly congested, and the different brands and kinds often differ in ways that are vague to consumers. Thats why it is even harder to choose a toothpaste than a toothbrush. The trick, however, is to follow the fluoride arrow. Look for a toothpaste that contains fluoride, and the brand usually doesnt matter much. Fluoride is an essential ingredient that can provide strengthening for your teeth. Fluoride works by keeping cavities away and also by polishing tooth enamel. Another clue to look for is the seal of approval by the American Dental Association, which will help lead you to safe and effective products that have passed clinical scrutiny. You can also consider your specific tastes, such as desensitizing toothpaste for sensitive teeth, whitening toothpaste for yellowing teeth, and tar-tar control toothpaste for those dealing with tar-tar problems. 3. Dental Floss Another important dental hygiene product is dental floss, which is often neglected by a lot of people. Flossing should be done at least once daily, and benefits are far ranging. Flossing can help clean teeth and in between teeth to make sure no food debris are left. It can help you easily get rid of the food stuck irritatingly between your teeth, which can lead to tooth decay, gum disease, and accumulation of bacteria in the long run. Also, bacteria can lead to bad breath, so dental floss can help keep bad breath away. 4. Tongue Scraper Another less popular product is the tongue scraper or tongue cleaner, which cleans the surface of the tongue to remove bacteria, food debris, fungi, and dead cells. The tongue is vulnerable to bacteria and fungi that can cause bad
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breath, oral problems and even medical conditions. Tongue cleaners come in a general form, but one thing to note is that it should be used before brushing your teeth, since brushing might cause the stuff on your tongue to recede into the throat.
Tartar (Calculus)-Reducing Products

A number of products, both dentifrices and mouthrinses,are available for reduction of supragingival calculus (tartar) in dental patients. Calculus reduction has been shown with dentifrices containing pyrophosphates, zinc salts, triclosan, and papain. The incidence of calculus formation ranges from 45 to 66%, with some variation between males and females and different age groups. Although supragingival calculus is not a major etiologic agent for gingivitis or periodontitis, its surface porosity provides an environment for plaque formation. In addition, it serves as a plaque-delivery system by holding plaque against gingival tissues. Although plaque formation has been well correlated with gingivitis and periodontitis, a similar correlation for calculus has not been reported. For this reason, the ADA does not offer an acceptance program for products that reduce calculus formation because this is considered to be a cosmetic issue, rather than an issue of disease. The mechanism of action of the calculus-reducing chemicals is related to the latters ability to inhibit crystal growth and interrupt the transformation of calcium phosphate (found in foods and saliva) into dental calculus. This effect may occur as follows: 1. The agents complex on the tooth surface to block receptor sites for calcium phosphate that precipitates from saliva and chemically absorbs to initiate calculus formation. 2. This same receptor site blockage also occurs in the calculus matrix as it begins to form. 3. The pyrophosphate complexes combine with free calcium in saliva to inhibit the attachment at the tooth surface (probably a secondary mechanism).
TYPE OF DENTIFRICES (A) Pastes form Tooth paste (B) Powder form Tooth powder (C) Solid blocks (D) liquids (A) TOOTH PASTES Tooth pastes are most popular valuable and widely used preparations for cleansing the teeth. It has largest share of dental cleansing and care preparations. Tooth pastes are preferred over other dental preparations because of following reasons. Easy to take and spread on the tooth brush 150
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No spillage or wastage Attractive consistency Proper distribution in mouth Available in wide varieties A good tooth paste should have following characteristics It must clean the dental surface properly without any scratches. Consistency should be such that it can be easily squeezed out of the tube to spread on the brush, but should not penetrate in to the brush. The consistency should remain constant in wide range of temperature during shelf life. It should be non toxic and should not sensitize buccal membrane. It should not interact with the container material. It should have pleasant taste and odour. It should have good appearance. Formulation: Method: - 1 The binder, prewetted with the humectant, it is disperse in liquid portion containing the saccharin and preservative and allow swelling to form a homogeneous gel. The swelling may be accelerated by heat and agitation. The solid abrasive is added slowly to homogeneous gel and mixed in mixer until a paste formed. The flavour and detergent are added last and distributed uniformly. Excessive, aeration, particularly in the presence of detergent, should be avoided. The paste can then be milled, deairated and tubed. Method: - 2 The binder is premixed with solid abrasive, which is then mixed with the liquid phase, containing humectant, preservative and sweetener into a mixer. After formation of homogeneous paste, the flavour and detergent are added, mixed, milled deairated and tubed. (A) TOOTH POWDERS Tooth powders are oldest and simplest preparations. Over the years their market share has been reduced due to popularity of pastes, but steel they have a considerable market share. The main problems encountered with powders areFloating of powder in air during manufacturing. Formation of cake on storage Uneven distribution in mouth Composition Tooth powders contain the following ingredientsAbrasives Surfactants or detergents Sweetening agents Flavours Colours Abrasives are used in manufacturing of tooth powders are similar to that of tooth pastes. Though lighter calcium carbonate is used in tooth paste but in tooth powders heavier grade calcium carbonate is used. 151
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Other ingredients are similar to that of tooth paste.
General procedure for manufacture This is done by simple mixing First ingredients of small quantity are premixed and then mixed with other ingredients. Ribbon type or agitator type of mixer are used. Flavour can be sprayed on to the bulk or can be premixed with part of some abrasive. (3) SOLID BLOCKS Solid dentifrice is like a soap preparation. Basically they consist of tooth powder suspended in a base of soap powder, water, and humectant. Solid detifrices provide a convenient and handy from of cleaning for the teeth. Formulation The soap first dissolved in a mixture of glycerin and water with the aid of heat. The powder (abrasive) is then mixed until soft mass formed. Mass is dried on trays, cut into blocks.
EVALUATION OF SOLID DENTAL PRODUCTS

Identification of ingredients and estimation of their contents are essential components of overall quality control and evaluation of dental care products. The products, tooth pastes and tooth powders, can be basically classified into foam forming and non-foam forming. Some other special evaluation tests are as follows: Abrasiveness Various tests have been designed and reported over the year, mostly on the set of extracted teeth. The teeth were mechanically brushed with pastes or powders and then the effects were studied by observation, mechanical or other means. Abrasive character normally depended on the particle size. So, study of particle size can also give such idea. Particle size This can be determined by microscopic study of the particles or by sieving or other means. Cleansing property This is studied by measuring the change in the reflectance character of a lacquer coating on the polyester film caused by brushing with a tooth cleanser (paste or powder). Also an in vivo test has been suggested in which teeth were brushed for two weeks and condition of teeth was assessed before and after use with the help of photo graphs. Consistency 152
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it is important that the product , paste, should maintain the consistency to enable the product press out from the container. Study of viscosity is essential for this. Rheology of powders is also important for proper flow of the powder from the container. PH of the product PH of the dispersion of 10 % of the product in water is determined by P H meter. Foaming character This test is specially required for foam forming tooth pastes or tooth powders. Specific amount of product can be mixed with specific amount of water and to be shaken. The foam thus formed is studied for its nature, stability, washability. Limit test for arsenic and lead This is very important as these are highly toxic metals. Specific tests are there to estimate these two metals; products may not have excess of such metals. Volatile matters and moisture A specific amount of the product required to be taken in a dish and drying is to be done till constant weight. Loss of weight will indicate percentage of moisture and volatile matters. Effect of special ingredients Special test should be done for the special ingredients if any, like antiseptics, enzymes, etc. for each one special and specific test are to be done. (4) LIQUID DENTAL PREPARATIONS Use of liquid dentifrices are comparatively less than solid one. They are basically aqueous or hydroalcoholic solutions of surfactants with additional components like Thickening agent Sweeteners Flavours etc. They do not contain any abrasive as they will sediment Action of this preparation on dental surface is less but the cleansing effect is more. Manufacturing process is making solution of all ingredients. Formulations Formula :1 4.0 gm 4.0 gm 0.1 gm 0.3 gm 5.0 gm 10.0 gm 85.4 gm
Sodium myristate sulphate Methyl cellulose Saccharine sodium Flavouring oil Glycerin Alcohol Water
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HALITOSIS
Local factors, systemic factors, or a combination of both can cause halitosis. It is estimated that 80% of all mouth odors are caused by local factors within the oral cavity, and these odors are most often associated with caries, gingivitis, and periodontitis. Oral malodors occur because of the action of various microorganisms on proteinaceous substances, such as, exfoliated oral epithelium, salivary proteins, food debris, and blood. Studies have shown that saliva from individuals who are free of dental disease produces malodor less rapidly than saliva from patients with dental disease. It has also been observed that after prolonged periods of decreased salivary flow and abstinence from food and liquid malodors tend to be most severe. Various oral bacteria produce products that are degraded to a number of compounds, foremost of which are sulfides and mucoproteins. These compounds have been most often associated with oral malodor. Specifically, it appears that oral malodor usually results from the bacterialmediated degradative processes of methyl mercaptan and hydrogen sulfide in oral air. Ammonia is also produced but does not appear to contribute significantly to halitosis. It has even been suggested that ammonia production may improve the odor of mouth air. However, for many patients, systemic or local factors cannot be identified. Tongue scraping has been shown to reduce malodor in some patients. Mouthwashes and dentifrices can serve an esthetic function by reducing halitosis. They can accomplish this by masking malodors, acting as antimicrobial agents, or both. There are no ADA-accepted products to reduce halitosis at this time.
Safety
While dentifrice products have a long history of safety, there is an ongoing concern associated with dental fluorosis due to fluoride ingestion in children under age six. Studies have shown that for children 13 years, 3075% of the dentifrice is ingested, and for children 47 years 1448% is ingested. As with any OTC drug product, precautions need to be taken to prevent overdose. The FDA requires labeling of all fluoride dentifrice products to include a statement "to minimize swallowing use a pea-size amount in children under six." Making childproof caps available on fluoride dentifrice products intended for use by children has been recommended. Another approach would be to provide metered dentifrice delivery systems for children under age six, which could be set to dispense the correct amount of fluoride depending on the body weight of the child.
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Dental care products
Effervescent Polident Denture Cleansers Non abrasive cleaning and antibacterial action in a soaking solution with oxidizing agents and detergents to remove food particles, stains and bacteria. Cleaning action is available in variants for 3 minutes, overnight and stain removing whitening and for partials.
Polident Fresh Cleanse Denture Foam Denture Cleansing foam provides non abrasive mechanical cleaning and antibacterial action and stain removal with detergents and a long lasting flavor
Polident Dentu-Paste and Dentu- Gel Denture Cleansers Mechanical cleaning with a brush using these denture cleansers containing detergents and oxidizing agents
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Super Poligrip Denture Adhesive Cream Poly(methylvinylether/maleic polymer cross linking salts to provide adhesion between denture and the alveolar ridge and the palate. The denture adhesive cream fills gaps between gum and denture for a strong hold and sealing out food particles
Super Poligrip Denture Adhesive Powder Poly(methylvinylether/maleic polymer cross linking salts to provide adhesion between a denture and the alveolar ridge and the palate. The denture adhesive powder forms a strong, thin seal to keep out food particles
Super Poligrip Denture Adhesive Strips Extruded strip with a Polyox/Carboxymethylcellulose system. The denture adhesive strips are pre cut to control the amount of the application.
Texas Dental Firm Offers Novel Tooth-Whitening Product Line

Ultra-White Products, Inc., a tooth whitening product manufacturer in Texas, now offers an attractive alternative to marginally effective over-the-counter tooth whitening product lines and costly dental treatments. The companys novel tooth whitening product affords users the ability to obtain custom application trays and whitening gels at a fraction of the cost normally associated with professional cosmetic dentistry and are far more effective than over-the-counter solutions.
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The company has a worldwide following with over 30,000 clients and is owned an managed by a practicing dentist.
NEWER FORMULATIONS OF DENTIFRICE FROM CHEMICAL ABSTRACTS

Functional toothpaste containing nano sized silver. High Fluoride ion recovery dentifrice compositions. Stable Suspensions of composite material s for use as dentifrices containing an antimicrobial organic acid salt. Application of water soluble chitosan in toothpaste & mouthwash. Dentifrice containing silica microparticles as the sole abrasives. Dentifrice compositions comprising alkyl galactoside derivatives +nonionic disinfectants or +protein naturants or +vit- E gives strong coaggregation-inhibitory effect & antibacterial effect against Fusobacterial & other dental caries & periodontal disease- causing bacteria.
QUESTIONS:1) Define cosmetics? Put some light on its origin and development through different ages. 2) Describe in brief the cosmetics products for skin? 3) Define shampoo? Write note about it? 4) Write a note on skin colorants? 5) Classify cosmetics with examples? 6) Define cosmoceutical? how it differs from cosmetics products? explain 7) Describe different nail preparations? 8) Write in detail about quality control of cosmetics including sampling size? 9) What is powder? classify powers ? Give formulation of any one type? 10) Classify raw materials of cosmetics? Write in brief about each with example?
REFERENCES:1. Harrys Cosmeticology, by Ralph.G.Harry, and Leonard Hill books and intertex publisher. 6th edition. 2. 1) Cosmetics : Science and Technology : Edward Sagarin 3. 2) Cosmetic Science and Technology Series : Volume 19 : Novel Cosmetic Delivery System : Shlomo Magdassi ,Elka Touitou 4. Cosmetics: formulation, Manufacturing, Q.C:P.P SHARMA 5. A Handbook of cosmetics: B.M MITTAL, R.N SAHA 6. COSMETICS & TOILETORIES Journal 7. www.mydenturecare.com 8. www.ultracosmetics.com 9. www.health.howstuffworks.com 10. Encyclopedia of pharmaceutical sciences Vol.3 157
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11. Hand book of cosmetics by Mitthal Cosmetics Formulations, manufacturing & quality control P.P.Sharma 12. Cosmetics formulation by Poucher. 13. Chemical abstract vol-147.No 23 2007. 14. Chemical abstract vol-147.No 5 2007. 15. Chemical abstract vol-151,No 2009.
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Chapter-8
KRUPA MEHTA
FORMULATION AND EVALUATION OF THE HERBAL INGREDIENTS AND OFFICIAL HERBAL DRUGS
Guided By: DR.R.K.PARIKH Prepared By: KRUPA MEHTA SAURABH PATEL M.PHARM(SEM-1)
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Classification of the ingredients

1)Solid 2)Semi solid 3)Liquid or Oil herbal Solid Herbal Ingredients: Senna,Digitalis,Cinchona,ipecacuanha,Ginger etc. Semi solid Herbal:Aloes,Acacia,Tragacanth,Guar gum etc Liquid or Oil Herbal:Castor oil,Almond oil,Cedar oil all types of oil include in the Oil herbal..
FORMULATION OF HERBAL INGREDIENTS For the Solid preparation: Drugs are cleaned and dried. They are coarsely powederd, weighed as per formula, and then mix well.. For the Semi solid preparation: the preparation generally have liquids, sugar or sugar candy, powders or certain drugs, oil and honey.. Sugar or sugar candy dissolved in the liquid and strained to remove the foreign particles. This solution boiled over a moderate fire.when pressed between two figers or when it sinks in water without getting easily dissolved, it should be removed from the fire. Fine powders of drugs are then added in small quantities and stirred continuously and vigorously to form a homogenous mixture. Oil is mentioned is added while the preparation is still hot and
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mixed well. Honey , if mentioned is added when the preparation is cool and miwed well.. For the Liquid preparation: for this preparation generally steam distillation method is used. The drugs are cleaned and coarsely powdered. Some quantity of water is added to the drugs for soaking and kept over-night. This makes the drugs soft and when boiled releases the essential volatile principle easily. The vapour is condensed and collected in a receiver. In the beginning, the vapour consists of only steam and may not contain the essential principles of the drugs. It should therefore be discarded. The last portion also may not contain therapeutically essential substance and should be discarded. The aliquots collected in between contain the active ingredients and may be mixed together to ensure uniformity of the product..
SUGGESTED EVALUATION METHODS

As mentioned earlier that the expiratory date can not be used for the herbal formulations. This guidelines details out simple quality assessment parameters as a means of evaluating the best before use date EASIEST METHOD TO PREDICT DATE IS 1. To decide requisite condition and parameter to be monitored during Processing Packing Storage condition 2. Selection of packing material 3. Exposing packs to challenging conditions to study behavior of formulation in
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A. STEPS 1. Batch size of at least 5% of the regular production batch is taken for testing. 2. Samples from one to three batches are selected. 3. The properly closed selected packs with one or more intended packing material proposed for packing the formulation is recommended for such study. 4. Adequate numbers of sample are required. 5. If more than one packaging material are to be studied test for each packaging material is required with the same batch. B. CHALLEGING CONDITION FOR STORAGE OF PACKS FOR ACCELERATED
STUDIES
AT 45 2 0 C AT 40 2 0 C / 75% 5% RH For comparison purpose one set of sample to be stored in a refrigerator below 25 0C Samples are to be evaluated on pre decided parameter at 0, 1, 2, 3 and 6 months.
C. REAL TIME STUDY
Temperature = 30 0 C 2 0 C Relative humidity = 65% 5% For long period of time. Samples are evaluated at 0,3,6,12,18,and 24 months
D. PARAMETERS TO BE EVALUATED 1. 2. 3. 4. 5. 6. 7. Appearance Colour Odour Taste Particle size Flowability Viscosity 162
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8. Clarity 9. pH 10. Moisture content 11. Sedimentation 12. Flocculation 13. Emulsion breakage 14. Friability 15. Hardness 16. Extractive Values ( in selected solvents) 17. Volatile matter contents 18. Free fatty acids/ acidity 19. Peroxide values 20. Microbial parameters Total viable count (TPC) Yeast and mould count ( YMC) Coil form count and other pathogens 21. Specific parameters applicable to formulation
/ dosage form
E. HOW TO DETERMINE THE CRITICAL PARAMETER
Done by intentionally exposing the formulation to such conditions promoting their degradation and determining the critical parameter. eg. Churna have moisture content 3.5 % when it increase up to 7-10 % start to look different and can start degradation.
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Novel product Vijay Makwana
paper code:910201
SEMINAR ON
Novel products
GUIDED BY: Dr. R. K. PARIKH
PRESENTED BY: Vijay Makwana M.PHARM I ROLL NO. 01 YEAR:-2009-10
DEPARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY
. 164 PHARM PART I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD - 09
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CONTENTS Introduction Classification Cream Preparations Shaving Preparations Lipsticks Hair Products Cosmetics For Nail Deodarants Facewash & Facemask Dentifrices
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Introduction Definition: As per Drug and Cosmetic Act Cosmetic means Any article intended to be rubbed, poured, sprinkled, or sprayed on or introduced into or otherwise applied to the human body or over part there of for cleaning, beautifying, promoting attractiveness or altering the appearance. People use cosmetic for beautifying, promoting attractiveness, altering the appearance and for the care of body , eyes, teeth, hair, face, skin etc. Cosmetic are mainly for two purpose 1.Care of body parts 2.Enhancing personal appeal of body. Classification Cosmetics are classified under two groups. o Group-1.According to the part of the body on which they are used. o Group-2.According to their physical nature. Group-1 further subdivided as follow: A. For skin: e.g. Powder, Cream, Lotion, and Make up, Deodorant etc. B. For Hair: e.g. Shampoo, Hair dressing and Brilliantine,Depilatories etc C. For Nails: e.g. Nail polish and its remover D. For Teeth and Mouth: e.g. Dentifrices, Mouth wash
Group-2 further divided as follows: A: Aerosols: e.g. Perfume, Hair set etc.
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B: Cakes: e.g. Rouge, Toilet soap etc. C: Emulsion: e.g. Cold cream, Vanishing cream, Cleansing cream D: Jellies: Hand jelly, Brilliantine jelly etc. E: Mucilages: e.g. Hand lotion etc. F: Oils: e.g. Hair oils etc. G: Paste: e.g. Tooth paste, Deodorant paste etc. H: Powders: e.g. Face powder, Tooth powder, Talcum powder etc. I: Solution: e.g. Shampoos, After shave lotion etc. J: Sticks: e.g. Lipsticks, Deodorant sticks etc. K: Suspension: e.g. Lotion etc Cream Preparations Cosmetic cream are emulsions and can be available in either O/W or W/O form which may provide opportunity to choose the cream for oily or for dry skin respectively <A> Cold Creams It function is cooling effect on application due to evaporation of water separated by breaking of W/O emulsion. It is used as emollient creams. It is widely used in winter season. Most popular cold cream is water-in-oil emulsion. COMPOSITION OF COLD CREAM White bees wax Mineral oil Triethanolamine Glycerin
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Distilled water Perfume METHOD OF PREPARATION First melt waxes, fats, and oils together at temperature 70 C. Then take water, Glycerin and Triehanolamine in another beaker and heat up to 70C. Then add melted fat to triehtnolamine solution and stir continuously until cold and add perfume lastly. <B> Cleansing Cream Cleansing cream is water-in-oil emulsion used to clean the dirt, oil on skin. It also removes applied cosmetic such as face powder, cake make up etc. Cleansing cream possess following characteristics: 1. It should liquefy at body temperature. 2. It should have low viscosity. 3. It should leave the skin smooth, nongreasy and clean. 4. It should spread easily without dragging. COMPOSITION OF CLEANSING CREAM Beeswax Paraffin White petrolatum Mineral oil Borax
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Glycerin Water METHOD OF PREPARATION Same as cold cream. <C> Vanishing Cream It is oil-in-water emulsion. It is applied to skin to provide a smooth emollient base before the application of face powder and make up preparation. They help the powder to adhere to the skin and act as protective to prevent damaging effects by sun. They mainly used to provide fairness to the skin. The choice of alkali is an important criteria in preparing vanishing cream. COMPOSITION Stearic acid Cetyl alcohol Potassium hydroxide Glycerin Methyl parahydroxybenzoate Purified water Perfume The main ingredient of vanishing cream is excess stearic acid. METHOD OF PREPARATION Melt the stearic acid and cetyl alcohol in a beaker.
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Then dissolve potassium hydroxide and methyl parahydroxybenzoate in water in a separate beaker and add glycerin to it. Heat the above aqueous solution up to 70C and add to melted stearic acid and cetyl alcohol mixture. Perfume is added to the emulsified mass when the temperature cools down to 45C. Mix gently. <D> All Purpose Cream All purpose cream is a cream which combines the properties of specialized cream. It possesses function of foundation cream, cleansing cream, vanishing cream. All purpose cream is suitable for hand, face, and body. COMPOSITION Borax Bees wax Mineral oil Stearic acid Paraffin wax Glycerin Anti-oxidant Preservative Purified water perfume
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METHOD OF PREPARATION First mix all oily material and melt at 70C. Then mix all aqueous material and heat up to 70C temperature. Then mix oily phase and aqueous phase. Stir continuously. Then add perfume, preservative when temperature lowers to 40C. Shaving Preparation Shaving preparation is used for the shaving of beard hair. Most common problem associated with shaving is skin irritation. The lather should have resistant to rapid drying. It should rapid become softening properties. It should produce skin lubrication. It should produce sufficient foam and stable foam so shaving is done comfortably. Lather Shaving Cream Shaving cream normally contain 30-50% of soap. COMPOSITION Stearic acid Coconut oil Potassium hydroxide Sodium hydroxide Glycerol Water METHOD OF PREPARATION
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First melt stearic acid with coconut oil at 80C temperature. Mix potassium hydroxide and sodium hydroxide in glycerol and water mixture. Then mix both above mixture with continues stirring. Cool slowly.
Evaluation Of Shaving Preparation 1. Lathering capacity Stability Shaking with water. 2. Beard softening ability Definite amount taken and wetting effect seen and how much water required for hydration on skin. 3. Damage to skin (superficially) Aerosol Shaving Foam The aerosol can filled with a soap solution, the concentrate, together with liquid propellant under pressure. This foam applied to the pre-wetted beard, is sufficiently stable to last throughout the shaving process. COMPOSITION Stearic acid Lauryl or stearyl alcohol Sodium lauryl sulfate
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Glycerol Triethanolanime Water Perfume METHOD OF PREPARATION First melt fatty acid and alcohol together to 70 C temperature. Mix glycerol, sodium lauryl sulfate, triethanolamine and water and heat at 70C. Then mix above both mixture and stir continuously. Add perfume when mixture is below 40C. Then fill in aerosol. After Shave Product It is applied on the face after shaving. Its produce cooling effect. It refreshes the skin. It produces mild astringent effect. They protect it from bacterial infection while it recovers from the slight injury. After Shave Lotion COMPOSITION Ethanol Propylene glycol Water Fragrance
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Color METHOD OF PREPARATION Mix perfume, propylene glycol and dissolve in alcohol. Add water slowly with stirring. Add color. Then cool the mixture to 4C and filter through a fine filter to give a clear product.
Lipsticks Lipsticks is the lip cosmetic molded into sticks, are essentially dispersions of coloring matter in a base consisting of a suitable blend of oils, fats, and waxes. Lipstick is used to impart an attractive color and appearance to the lips. It provides an oily protective film to prevent chapping and drying out of the lips. Lipsticks possess following characteristics: An attractive appearance, a smooth surface of uniform color free from defects. Pharmacologically inert when applied topically. Easy to apply, giving a film on the lips that is neither greasy nor too dry. Its color is not permanent but easily washable. Typical Lipsticks Formulation Castor oil
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Carnauba wax Bees wax Candelilla wax Octyldecyl stearoyl stearate Lanolin oi Mineral oil Anti-oxidant Color Fragrance
Lipsticks Ingredient COLORING MATERIALS Color of lipsticks is one of the major selling points. The color is imparted to the lips in two ways: A. By staining the skin, which requires a dye in solution, capable of penetrating the outer surface of the lips. B. By covering the lips with a colored layer that serves to hide any surface roughness and give a smooth appearance. The color of lipsticks must be selected on the bases of Drug And Cosmetic Act. Typical proportion for color in lipsticks. PIGMENTS Both organic and inorganic pigments are used to create a full range of shade.
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Titanium dioxide produces pink color. IRON OXIDES These are used for matching the brown shades. Bismuth Oxychloride It is dense, white pigment. LIPID BASE MATERIAL Quality of the lipstick during manufacturing, storage, and use will be determined for the most part by the composition of the fatty base. In the mould it must set quickly with good surface and good release properties. In use the stick must soften sufficiently in contact with the lips.
CASTOR OIL It act as solvent for the waxes that give structure to lipsticks and yielding sticks that have a fine crystalline structure, good stability, and resistance to breakage. It is excellent vehicle for pigment. LIQUID FATTY ALCOHOL These are good solvents for polar waxes.it act as co-solvents between polar and nonpolar materials in formulation. E.g. Isocetyl, isostearyl and octyldodecyl. ESTERS Esters are of many type including linear and branched alkyl esters of mono, di, and tribasic fatty acid. Lactate esters impart a slipepery yet nongreasy.
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E.g. triisostearyl trilinoleate, triisocetyl citrate. MINERAL OIL It has been used to provide a glossy surface to the sticks. WAXES Waxes are included in lipstick bases to provide the high melting points or the hardness that are required to give satisfactory molding properties. Its ranges between 8% and 15% of the formulation. E.g. Carnauba wax Candelilla Microcrystalline waxes Beeswax
Manufacture Of Lipsticks It consists of two stages: (1)preparation of component blends Melt all waxes at 85-95C and mix oily material then add color grind. Blending of these intermediates used to form the lipstick mass. (2)Molding of the lipstick mass into sticks. The melted mass poured into mould sticks and lowers the temperature up to 20C. Evaluation Of Lipsticks MELTING POINT
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Determined by capillary tube method by keeping the size of capillary, lenth of fill and rate of heating constant. Melting point should be more than 50 for safe handling. BREAKING POINT This test is done to determine the strengh of the lipsticks. The lipsticks is held horizontally in a socket inch above the base and weight is applied on the lipstick.The weight is gradually inceased at iterval of 30 seconds. The weight at which lipstick breaks is considered as the breaking point. The test shoul done at specific temperature (25C). Hair Products Brilliantine Brillientines are employed to impart luster to the haiir and also keeping them in the proper place. They have to be applied to the dry hair after it has been waved. They are avaliable in liquid form or viscous form. Liqid form is liked by women because of ease of application on their long hair while men like viscous creamy form. LIQUID BRILLIANTINE COMPOSITION Olive oil Sweet almond oil Caster oil Parahydroxybenzoic acid ester Alcohol
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Perfume METHOD OF PREPARATION Mix olive oil, caster oils and add almond oil mixture to it. Dissolve the parahydroxybenzoic acid ester and perfume in alcohol. Mix above both mixture and filter it. Hair Straiteners These preparation which are used to take curl or kink out of the hair and and at the same time impart a sheen and perfume to the hair. They are applied on the hair with the help of hard brush. COMPOSITION Petrolatum Rosin Perfume METHOD OF PREPARATION Melt the rosin with petrolatum. Stir well. Cool slightly and add perfume at 45C. Depilatories These preparations are employed for temporarily removing any undesired hair above the outer surface of the skin. Women are the main user of such type of preparation. The action of depilatories is to dissolve the hair. Intially, it is softened, sweeled and disperesed by the action of the chemical. These chemical may have irritating effect on the epidermis.
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The user should be advised to do the sensitivity test on a part of arm which is devoid of hair, by applying a little deplilatory. Depilatory Powder COMPOSITION Titanium dioxide Barium sulfide Wheat starch Perfume METHOD OF PREPARATION Mix all powder geometrically and add the perfume in it. Cosmetics For Nails Nails are protective covering of the finger toes. The care of nails is referred to as manicuring. These preparetion used by women. Manicure preparation includes many preparations like nail polish, polish remover, and nail bleach, cte.
Nail Polish COMPOSITION Nitrocellulose Ethlyl acetate Butyl acetate Diethyl phthlate
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Camphor Color The color should be complying with the Drug and Cosmetic Act. METHOD OF PREPARATION Dissolve the nitrocellulose and the camphor in the ethyl acetate. Add the rest of ingredients along with color and perfume. Mix both the mixture. Nail Polish Remover COMPOSITION Butyl stearate Ethyl acetate METHOD OF PREPARATION Mix both preparations. USE Used for thr removal of polish on the nail.
Deodarant There is a problem of the body odor from men and women because of perspiration. There are two types of deodarants, one is employed to 1.Deodorize perspiration without restricting its flow.
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2. Deodorize and prevent decomposition through bacteria inhibiting action. Deodarants may be liquids, pastes, powders, sticks. Deodarant Liquid COMPOSITION Oxyquinoline sulphate Aluminium sulphate Magnesium sulphate Alcohol Purified water Perfume METHOD OF PREPARATION Mixall three salta in purified water. Dissolve perfume in alcohol. Mix both mixture.
FACE MASK Introduction Face pack are topically applied preparation particular to facial area, either in form of liquid or paste and allow to dry. With drying produce tightening effect and warmth is experienced. This produces stimulating sensation after removal. As such when they are removed, skin debris and blackheads may be removed along with them.
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They have cleansing effect. They also improve circulation. They also have healing power. This preparation are allow applied to face and allow to set. Ideal Properties of the Preparations. They should form a smooth paste and should have pleasant odour. When applied to a face, they should dry out rapidly to form an adherent coating on the face. However, the the coating should be such which can be removed either by peeling off the face or by gentle washing without causing pain. They should be capable of producing significant cleansing of the skin. They should application. produce sensation of tightening of the skin after
They should be non toxic to the skin. Types of The Face Mask High Viscosity Pastemasks They contain high percentage of colloidal clay, kaolin or other suitable solids dispersed in liquid vehicle. Law Viscosity or Liquid Masks They contain film forming hydrophilic colloids. They have less cleansing capacity, Cleansing action can be improved by inclusion of detergent. Formulation of Face Mask While formulating face mask they should be an effort to produce product which will have properties above mentioned. There are five basic system, these systems are based on: Waxes, Rubbers, Vinyl-resins, Hydrocolloids, Earths. Wax Base Formulations Usually wax based systems consists of paraffin wax , petroleum jelly and polar materials like stearyl alcohols. These products are solids and are required to
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melt before application. These may be applied with brush while hot. When waxes solidify, sensation of tightness is fill. Due to coating of wax profuse perspiration is produce. This may lead to cleansing of follicular penings of the skin by flushing out dirt and impurities. To facilitate application thixotropy is imparted to the preparations. Rubber Based Formulations They form continuous and elastic film on the skin. Resultant film is water impermeable , it interfere with skin respiration, and cause rise in temperature, and also increase blood circulation to the skin. Vinyl Resins Based Formulations Vinyl resins like polyvinyl alcohol or polyvinyl acetate can form continuous film.adsorbants are also added. Hydrocolloids Based Formulations They can be prepared in form of high viscosity solutions or in form of solid gels. For formulating such type of face masks variety of gums can be usued like gum acacia, gum tragacanth, guar gum, gelatine, carboxy methyl cellulose, polyvinyl pyrolidone etc. Hydrocolloids Based Formulations Solid gel is required to be melt before application. Viscosity of gel can be varied by changing the gum and its concentration. Plasticizer and humectants also have to use. They are easy to apply. Earths Based Formulations They contains high percentage of solids. They may be prepared either as powders or as pastes. Water is require before application, if mask is in form of powder. These masks, on drying, harden on the skin and contract giving a sensation of mechanical astringency. Absorbent clays produce cleaning effect. Hydrocolloids may be added to stabilize the suspention of solids humectants and plasticizers also added. Earths which are usued in the preparation include china clay, colloidal kaolin, fullers earth, bentonite etc.
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They also contain ingredients like astringents. Bleaching gents if required. An oxygenated face mask can be prepared by incorporating peroxide like magnesium peroxide. Oxygenated mask recommended for use by person having oily skin. In powder form peel off type alginates can also be used. Sodium alginate can also be used as gelling agent in powder form peel off packs. Sodium carbonate used as gelling regulator. Titanium dioxide and zinc oxide can be used as opacifier. Cellulose type thickeners used to modify plasticity. Manufacture of Face Mask If face mask are to be manufactured in powder form, all powders are blended in a blender like ribbon blander. The powder mixture is then transferred to filling machine. These may either be filled in bulk containers or in sachets. Manufacturing of high viscosity face mask as follows: Phase -A Kaoline Bentonite ZnO Sulpher Cetrimide Phase -B Phase - C Glycerile monostearate Menthol Emulsifying wax Alcohol Cetyl alcohol Mineral oil Glycerine Perfume water
Procedure Prepare cream from phase B by dispersing oily phase in water and glycerine at 70 C. Mix powders and micronized it then stir into the cream base. Gradually cool the mixture to 35 C. Finally mix menthol and perfume in alcohol and add to cream. Low viscosity or liquid mask They contains film forming hydrophilic colloids. They have less cleansing capacity. Cleansing action can be increased by inclusion of detergent.
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Rx Methocel, low viscosity Glycerin Water Color Perfume preservative Face mask for oily skin Frequent and effective cleansing is recommended for oily skin To reduce the amount of sebum left on the skin to minimum and To avoid the development of spots and pimps. Emulsion cleansers are avoided since they tend to leave layer of oil on the skin. Synthetic detergent can be used for cleansing of oily skin. This lotion cleanser may be applied with a cotton ball or impregnated into a wipe fabric a total product. Rx Isopropyle palmitate A Polysorbate Pyridoxine tripalmitate B Water Propelyne glycol Penthenol C Ethanol Eucalyptus Face mask and exfoliating lotion They are used for exfoliation of acne-prone skin rather than facial scrubs. The following formulation makes use of keratolytic properties of salicylic acid as exfoliating agent. Chamomile is used for its anti-inflammatory properties
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Rx Water Ethanol Propylene glycol Preservative Chamomile extract Salicylic acid Perfume Color Procedure: Dissolve preservative and propylene glycol. Blend all the ingredient add water slowly and mix well. Add perfume. Medicated clear cleansing gel Gel have become popular product for cleansing purpose. Carbopol gel is used in next formula where alcohol provides antiseptic and astringent effect, allantoin is added to as a soothing agent. Rx Carbopol-940 Water Alcohol Glycerine Allantoine Menthol
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Perfume
Procedure: Hydrate carbopol In water. Add remaining ingredients. When completely homogeneous, isopropanolamine soln Emulsion cleanser Emulsion based cleansers are recommended for people with dry skin. Cleansing creams, lotions and milk can be O/W or W/O emulsions which combines the solvency of water and to effective cleaning of the skin. In doing this they also leave a layer of emollient oil on the skin, leaving it feeling smooth, in contrast to the dry sensation often feel after the use of synthetic detergent system. neutralize to pH 6.5 with di-
FACE WASH Introduction Surfactant based face wash product have made significant impact on cleansing market. Face wash generally contain mixture of surfactant which works synergistically to produce foam. These preparations also contain moisturizing agent, opacifier, thickener, perfume and water and appearance of product enhanced by water soluble dyes. Ingredients
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Mixture of surfactant used to produce foam. In past anion surfactant system such as fatty alcohol other sulphates combined with fatty acid such as diethanolamides were popular but they cause adverse reactions. This resulted in move to use anionic or amphoteric surfactant such as alkyl betains, amido alkyl betains, sulphobetains and N-alkyl-amino propionates. Silicone derivative have increased in popularity because of their ability to impart smoothness. Example of silicone include dimethicone copolyol and diquaternary polydimethyl siloxane. Dimethicone copolyol also offer good skin feel. moisturizers: moisturizers help the skin to maintain moisture content of the skin; keeping it smooth and pliable. It include occlusive oils and wax like lanolin, paffin, patrolatum, long chain alcohols and humectants include glycerol, propylene glycol and ethoxylated sorbitol. Polysorbate 20 and PEG-40,castor oil are use as co-solubilizers. PEG distearate is thickening agent.
BMR
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It should be based on master formula record which is prepared by R&D dept. BMR required to maintain for each batch of product to be manufactured. Before any process begins, check should be made to ensure that all work station are clear of previous product. During processing information should be recorded, signed and dated by persons responsible for processing of operations.
Advances in skin care Delivery system have expand from emulsion to microcapsule, multiple emulsion, liposomes, cyclodextrin and polymeric systems. A) microcapsule: they composed of hollow vesicle containing an active ingredient. B) liposomes: they are microscopic spherical vesicle in which the membranes consist of a bilayer of amphiphilic molecules Because of lipophilicity and particle size, microcapsule and liposomes efficiently penetrates the skin, compared to classical emulsion Because of the presence of amphiphile, they represents a safe way of delivering actives such as moisturizers to deeper layer of skin. Following formula based on liposomes using lecithin and acrylates as a emulsifying agent. Alkyl acrylate cross polymer A Carbomer Capric triglycerides Octyle stearates Mineral oil B Water Glycerine C NaOH Lecithin
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Procedure: Combine the ingredients of Part-A in vessel. Mix the ingredients with rapid stirring to disperse the polymer. Combine the ingredients of Part-B in vessel. Add Part-B to Part-A slowly. Mix for about 20 mins. to swell the polymer. When emulsion is formed, add NaOH to maintain pH 7 Add preservative and mixed. Cyclodextrin They are starch derivative. They reduce skin penetration and so protect the skin from undesirable properties of the active material.
Porous polymeric system Release of active ingredient from skin surface by partitioning of the active ingredient between the polymer and skin surface.
Evaluation test Viscosity Viscosity is an important in process quality control test. Measurement of pH Visual examination It reveals the presence of any physical contaminants in product. Microscopy
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This examination give information about uniformity of a particle size, carried on regular basis. Spot test Specific reagent used to form colored complexes to detect, the presence of a range anions and cations, confirm the presence of additives or presence of contaminants. Identification of raw materials Analytical technique developed to identify raw materials Efficacy testing Foam testing Shade testing Pressure testing Breakage testing
SUN SCREEN LOTION Introduction Earths atmosphere absorbs all wavelengths of EMR below 295nm ;Of wavelengths of radiation which reach earths surface UV has highest energy. Photo biologist divide sub-region energy of UV spectrum in descending order of
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Far UV : UVC: UVB: UVB region:
100-200nm
200-280nm 280-320nm
It is primary initiator of sun burn; also responsible for certain Skin cancer, photodermatosis, premature skin aging and generation of melanin pigments. On positive note it is also responsible for synthesis of Vitamin D synthesis. UVA region: Long term effects of this rays on dermal layers of human skin shows aging of skin and capable of generating immediate skin pigmentation. SUNSCREEN AGENTS It must absorb UV light over a broad or specified part of UV spectrum. Chemically stable easy to formulate in to cosmetic vehicles and should be absorbed easily into the skin resistant to removal by water or sweat must not require too frequent re-application to be effective effective at law concentration non toxic, non irritant and non sensitizing Organic sunscreens All allowable screening materials are catagorised by both US FDA and EC in Europe. PABA and derivatives Cinnamates:octylmethoxycinnamates Salicylates:methylsalicylates
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Anthranilates:methylsalicylates Camphor derivatives. Benzophenones:2-hydroxy 4-methoxy benzophenone. Dibenzoyl methane:4 butyl 4methoxy dibenzoyl methane Octocrylene: Water soluble sunscreens They become more effective by virtue of their skin penetrating properties. 2 hydroxy 4 methoxy benzophenone 5 sulfonic acid 2 phenyl benzimidazole 5 sulfonic acid Inorganic sunscreens Inorganic compound which has radiation scattering and reflective properties due to its physical form. Natural minerals and pigments like talc, kaolin, metal oxides, TiO 2 but choice depends on cosmetic acceptability. ZnO has good light barrier properties Across both UV A and UVB range ;also to some extent visible spectrum. TiO2 has similar effects to ZnO. Metallic oxides where used in combination with organic filters; Also gives higher SPF products. Water proofing agent An important requirements of any sun screen products is that it should withstand water; It is desirable that products is not easily washed off. There are official test for standard of water resitance which improve in vitro SPF before and after immersion for fixed period of time. It should retain at least 50% of its SPF after immersing in water . W/O lotion are inherently water resistant. Law level of water present as dispersed phase are readily loss on application to skin to leave ; continuous oily phase spread over the surface to gives water repellant film .W/O lotion often have greasy fill. O/W lotion are cosmetically more elegant and have better skin effects. Silicon oils are extremely resistant to water penetration ;are easily spreadable and form continuous thin water repellant film on skin surface ;which is highly acceptable.
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Most widely used materials are dimethicone , cyclo methicone and trimethylsiloxy silicate. Recently polymeric film formers like PVP are excellent for imparting water resitant to a formulation.
Plant layout
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METHOD OF MANUFACTURING It involves heating the oily phase to dissolve oil soluble components material satisfactorily. Water phase heated similarly and both phases are then combined with mixing to form emulsion. pH is adjusted to gel the water phase. Perfumes are added slowly once emulsion cooled. Polymeric materials require careful addition and complete dissolution must be ensured. BMR (batch manufacturing record) BMR is required to maintain for each batch manufactured. It should be based on master formula records, which is prepared by R&D department. Before any process begins check should be made to ensure that all work-station are clear off previous products. During processing information listed below should be recorded, signed and dated by persons responsible for processing operations. Name of the product Batch number Date of commencement and completion of significant intermediate stage Name of person responsible for each stage product Batch number, quantity, quality control report number of each ingredient actually weighted Amount of any recovered material added In process control carried out their result and signature of persons who performed Theoretical yield and actual yield at appropriate stage of production BPR (batch packaging record)
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Batch packaging record proceed.
should be keep for each batch or part of batch
Before any packaging operation begins; check should be made and recorded that the equipment and work station are clear of previous product. It is a part of batch process record. Line clearance have to be obtained before carry out packaging operations. WHO guidelines require that following information should be recorded at time of each action. Name, batch number & quantity of bulk finished product to be packaged Theoretical yield, practical yield & reconciliation Date & time of packaging operation, Name of responsible person carrying out packaging IPQC check and check for identity and conformity with packaging instruction Evaluation of sunscreen lotion S.P.F. (sunscreen protection factor) Level of protection from sun burn afforded by sun product is described by sun protection factor. COLIPA SPF test method Individual is exposed to source of UV radiation and comparing very law dose of UV that is needed to produce reddening of human skin; 24 hour after exposure. SPF Ratio of dose of energy required to produce a MED(minimum erythamal dose) on protected skin to that required to produce MED on unprotected skin.
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SPF Testing in vivo In vivo testing is typically carried on the skin of human volunteers, exposing 1cm2 sites on skin to increasing dose of radiation from xenon arc solar stimulator; irradiated test sites are examined after 24 hour exposure. the sun product examined similarly. SPF testing also performed in vitro on research tool and also during early screening process. Standard for water resistance The official test standard for water resistance involve an in vivo SPF testing before and afterr immersing for a fixed period of time in a water. If product retain at least 50% of its SPF following moderate activity in water, a product is described to be described as water-resistant. - glucans - glucans are polysaccharides. In skin care sunscreen products - glucans found to reduce oxygen radical formation and stimulate the langerhans cells in UV radiated skin, also stimulate collagen synthesis, increase in epidermal turnover rate, reduction of fine wrinkles, reduction in skin damage caused by detergent.
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Dentifrices INTRODUCTION
Dental preparations are the preparation that is used for the cleansing of teeth. These preparations are able to maintain the health of the teeth and gum. Various dental care preparations or dentifrices are now a day available in the market for this purpose. As we know that the health of the teeth and gum is very important for the good general health, use of the dental care preparations or dentifrices is increased. The teeth are grinder for food what we eat. These food particle if not removed regularly may become pocket for the microbes to grow. So the removal of the food particle from the teeth is very important for good general health. This can be possible with the help of the dental and oral care preparation. Importance of cleaning the teeth was probably realized along with need for maintenance of body cleanliness. In ancient time chew sticks and sponges were used for the teeth cleaning purpose. Material were used as ingredients of dentifrices at that time were dried animal parts, herbs and plant parts, honey and minerals. Several items of the early ingredients were found to be harmful, destroying teeth, irritating oral mucosa. Some of these harmful substances were sulphuric acid, acetic acid, lead ores, and abrasive minerals. Over the period of time, various studies on these substances have helped to identify safe and useful dentifrices ingredients. Dental Care preparations (Dentifrices) are:
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Tooth pastes Tooth powders Solid and Liquid dental preparation Dentifrices may be a simple dentifrices or therapeutic dentifrices, later contain additionally a therapeutic ingredients for some special functions like decrease the occurrence of dental caries and help in control of periodontal disease. Therapeutic dentifrices containing stannous fluoride are widely used products. Tooth pastes and tooth powder are similar in composition except that tooth pastes are made pasty by addition of suitable solvents.
Functions of Dentifrices: Though the primary function of dentifrices is the cleaning of the accessible surface of the teeth, but it can have some other functions also. The expected functions of a dentifrices are as follows. 1. Cleaning the surface of teeth 2. Prevention of formation of dental plaque 3. Prevention of formation of calculus 4. Polishing of teeth 5. Reduction of occurrence of tooth decay 6. Reduction of periodontal diseases 7. Prevention of mouth odors 8. Freshening of breath
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Some commercial dentifrices may be performing all of the above functions and some may be fulfilling partial function.
TOOTH PASTES Tooth pastes are the most popular and widely used preparations for cleansing the teeth. These preparations are more expensive than the tooth powder but still they are more preferred. Advantages: Easy to take measured quantity Easy to spread on the tooth brush No spoilage or wastage Attractive consistency Proper distribution in the mouth
Ingredients: Various ingredients are added in the toothpastes for fulfill the requirements or the special function of the toothpastes in order to obtain the good product for the consumers. Common ingredients used in the toothpastes are listed below: 1. 2. 3. 4. 5. 6. 7. 8. Abrasive and polishing materials Detergents and foaming materials Humectants Binding agents Sweetening materials Flavors Preservatives Special ingredients e.g. Therapeutic agents Colors Whitening agents Bleaches Lubricants
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Abrasive and polishing materials: Abrasive and polishing materials are known as cleansing materials. They are the main constituents of the toothpaste and tooth powders. It is hard powder but it should not make scratches on the enamel of the teeth and gum. The abrasives and polishing materials are responsible for the removal of the food particle from the teeth. Abrasive and polishing material build up the half of the total weight of the tooth pastes. Materials that are used as abrasive and polishing materials are calcium carbonate, tricalcium phosphate, Dicalcium phosphate, aluminium phosphate, magnesium trisilicate. Calcium carbonate is available in different grade which are vary in density, particle size, crystal form. calcium carbonate in the toothpastes preparation is responsible for the alkalinity of the preparation. Dicalcium phosphate dehydrate impart neutral pH to the tooth pastes. Aluminum hydroxide is also act as abrasive materials and it is used with other abrasive materials. Dehydrate and anhydrous dicalcium phosphate, tricalcium phosphate and calcium pyrophosphate are important calcium salts used as abrasive in tooth pastes. Dicalcium phosphate dehydrate is mostly used among them. These substances are mild abrasives. Both dicalcium phosphates are odorless, tasteless and white. They are slightly soluble in water. Tricalcium phosphate is also a tasteless, odorless white amorphous powder and insoluble in water. It also impart mild abrasive and polishing effect.
Detergents and Foaming agents: These materials are added in the toothpastes for causing wetting and dispersion of the powdered materials in the toothpastes. Also detergents are responsible for the cleansing of the teeth by lowering the surface tension. These agents help to penetrate paste and abrasive in to the fine cracks and thus remove the food particles. Apart from this, these agents are responsible for producing foam. Though soaps are alkaline in nature but still they are used. Specially prepared dental soaps are available in the market for use in tooth pastes. As soaps may have odor or taste, tasteless or odorless soaps are to be added. Materials that are used as detergents and foaming agents are Sodium Lauryl sulphate, magnesium lauryl sulphate, diethyl sodium lauryl sulphosuccinate, sodium
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lauryl sarcosinate. Sodium laurylsarcosinate is also act as a bacteriostatic and anticariogenic agents. Humectants: Humectants are added in the toothpastes formulation for prevention of drying of the product and to impart the plasticity to the pastes. Humectant normally used in the toothpastes formulation is varies from 5 to 10 % w/w. Actual amount that is to be used in the formulation is depends on the specific gravity of the powder mass. Materials that are used as humectants are glycerin, Sorbitol, propylene glycol etc. amongst all glycerin is widely used in the toothpastes formulation as humectants. Sorbitol prevents the separation of the water from the pastes and also impart viscosity to the pastes. Binding agents: Binding agents are added in the toothpastes formulation to improve and maintain the consistency of the product. Also these binding agents help to prevent the separation of the toothpastes. Aqueous dispersion of the hydrocolloids are viscous. These hydrocolloids are used in the range of 1-2.5%. Though once liquid glucose and simple syrup were used but slowly they were replaced by mucilage of various gums. An amount that is to be used in the formulation is depends on the consistency wanted. Normally the gum is first mixed with sufficient quantity of glycerine, alcohol before adding water. This is done to prevent the formation of lumps. Materials that are used as binding agents are gum tragacanth, karaya gum, carboxy methyl cellulose, sodium alginate, carbopols, bentonite etc. Gum tragacanth is still a widely used binding agent.
Sweetening materials: Sweetening agents are added to impart good tastes to the product. Sodium saccharine is widely used sweetening agents in toothpastes formulation. Amount of the sweetener added is depends on the sweetness of the other ingredients. Flavors;
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Essentially the flavors are incorporated in the toothpastes for test and for long tern effect in the mouth. Flavors used are blending of suitable oils with the sweetening agents to produce smooth but distinct tastes in the product and also the pleasant smell in the mouth after use. Flavors used are peppermint oil, clove oil, cinnamon oil, cassia oil, menthol etc.
Preservatives: Toothpastes formulations are prone to microbial growth due to the presence of gums and water, preservatives are added to prevent the microbial growth in the product. Examples of preservatives: Methyl parahydroxy benzoate with propyl parahydroxy benzoate. Special Ingredients: Bleaches: Added in pastes to impart whitening effect to the pastes. Hey are basically oxidizing agents. Examples are sodium perborate, magnesium peroxide, stabilized hydrogen peroxide. Lubricants: Lubricants are sometimes added in the tooth pastes to give softness to the product that will help in the filling purpose or to facilitate the pastes to come out. Color : Added in the pastes to give good appearance and to attract the customer attention towards the products. General Method of preparation: First step in the preparation of toothpastes is to mix the gum with the humectants. Then binding agent is dispersed in the alcohol. If preservative is used it should be dissolved in the water or glycerin. Other powder ingredients are sifted together and added to mucilaginous mixture with continuous gentle stirring. Then the aqueous media is mixed and stirred to get the product.
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Flavor and detergents are added at the last.
TOOTH POWDERS Tooth powders are oldest, simplest and cheapest preparation used for the cleaning of the teeth. Over the years their market share has been reduced by popularity and advantages of tooth pastes. The oldest tooth powder is reported to be camphorated chalk. Disadvantages: Floating of powder in air during manufacturing Formation of cake on storage
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Uneven distribution in mouth Composition: Quantity (gm) Phenol 2.5 Kieselguhr 57.5 Calcium carbonate (heavy) 40.0 Flavor q.s. Color q.s. Calcium pyrophosphate Dicalcium phosphate Tricalcium phosphate Aluminum sulphate 2. Detergents or Surfactants 3. Sweetening materials 4. Flavors 5. Color (if required) Ingredients Basically, tooth powders contain the following ingredients. 1. Abrasive and polishing materials Abrasive used in the tooth powder is same as used in the tooth pastes. e.g. Calcium carbonate- heavier grade
Method of Preparation: Done by simple mixing First ingredients of small quantity are premixed and then mixed with other ingredients in ribbon type or agitator type of mixer. Flavor can be sprayed on the bulk or premixed with part of some abrasive and then mixed with the bulk. Finally sieve the bulk mass to get tooth powder
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EVALUATION OF DENTIFRICES: Identification of ingredients and estimation of their contents are essential components of overall quality control and Quantity Ingredients (gm) evaluation of dental care preparations. Calcium carbonate 92.5 Some special evaluation tests are as (heavy) follows: Dental soap powder 6.0 Flavoring oil 1.0 Saccharine sodium 0.2 Color q.s. Ingredients Quantity (gm) Abrasiveness: Calcium carbonate (heavy) 76.0 Various tests have been Kaolin 11.9 designated and reported over the SLS 2.0 years, mostly on the set of extracted Powdered pumice 10.0 teeth. Teeth were mechanically Saccharine sodium 0.1 Flavor q.s brushed with pastes or powders and Color q.s. then the effect were studied by observation, mechanical or other means. Abrasive character normally depends on the particle size. So, study of particle size can also give such idea. Particle size: This can be determined by microscopic study of the particles or by sieving or other means. Cleansing property: This is studied by measuring the changes in the reflectance character of a lacquer coating on a polyester film caused by brushing with a tooth cleanser (paste or powder). Also an in vivo test has been suggested in which teeth were brushed for 2 weeks and condition of teeth was assessed before and after use with the help of photographs. Consistency:
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It is important that the product, paste, should be maintain the consistency to enable the product press out from the container. Study of viscosity is essential for this. Rheology of powders is also important for proper flow of the powders from the container. pH of the product: pH of the dispersion of 10% of the product in water is determined by pH meter. Foaming character: This test is specially required for foam-forming tooth pastes or tooth powders. Specific amount of product can be mixed with specific amount of water and to be shaken. The foam thus formed is studied for its nature, stability and washability Limit test for arsenic and lead: This is very important as these are highly toxic metals. Specific tests are there to estimate these two metals. However, if the raw materials are tested for the limit of these two metals, product may not have excess of such metals. Volatile matters and moisture: A specific amount of the product required to be taken in a dish and drying is to be done till constant weight. Loss of weight will indicate percentage of moisture and volatile matters. Effect of special ingredients: Special tests should be done for the special ingredients if any, like antiseptic, enzymes, etc. For each one special tests and specific test are to be done.
DETAL GELS Dental gel is one type of dental care preparation that is used for the treatment of various dental diseases. Thus dental gels are therapeutic dentifrices that contain
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one or more therapeutic agent that has special function to prevent periodontal disease. The systemic use of antibiotics to prevent dental disease has several disadvantages. A prolonged administration of antibiotics increases the risk of problems like, such as like nausea, diarrhea and pseudomembranous colitis As a result of these unwanted reaction, studies focusing on the development of localized drug delivery systems for the release of antibiotics in the periodontal pockets are becoming more frequent. This approach leads to higher concentrations of the drug at the target sites, minimizing the potential systemic side effects. Dental gels provide local delivery of antimicrobials in periodontal pockets may be carried out with fibers, films, microparticles and gels made of biodegradable or nondegradable polymers and have been proposed as effective methods to administer antimicrobial agents in periodontal therapy .One class of hydrogels used for controlled release of drugs in many pharmaceutical applications is represented by the poloxamers, which are nonionic poly(ethylene oxide)-poly(propylene oxide)poly(ethylene oxide) triblock copolymers. Poloxamer 407 has been one of the most extensively used copolymers. It has low toxicity, is compatible with other chemicals and can solubilize drugs with different physicochemical properties. Additionally, aqueous solutions of Poloxamer 407, at concentrations of 20% and above, demonstrate a thermo reversible gelation behaviour, characterized by a critical temperature. At temperatures under the critical one, Poloxamer solution is in the form of a low-viscosity sol, while above it, when approaching body temperature, a viscous transparent gel is formed. Among the antimicrobials dental gels used for the treatment of periodontitis, metronidazole dental gel particularly suitable due to following advantages. Restricted spectrum of activity Limited side effects, compared to those of tetracycline. antibiotic resistance adverse drug reactions
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RECENT INNOVATION Metronidazole-containing dental gel for the treatment of periodontitis Fluoride Dental Gels for dental caries prevention Antimicrobial activity of dental gel on cariogenic bacteria Dental sealant Over the last few decades, several advancements have been made in caries prevention. Along with systemic and topical fluoride, he increased acceptance and use of pit and fissure sealants have without question had an impact on the prevention of caries. Fluorides have been found extremely effective in preventing caries on smooth surfaces of the teeth, but less effective on occlusal surfaces. Sealants protect the occlusal surfaces, inhibiting bacterial growth and providing a smooth surface that increases the probability that the surface will stay clean Advances in the treatment of root dentine sensitivity: Dentine hypersensitivity (DH) is characterized by pain derived from exposed dentine in response to chemical, thermal, tactile or osmotic stimuli which cannot be explained as arising from any other dental defect or pathology. A recent modification to this definition has been made to replace the term pathology with the word disease presumably with a view to avoid any confusion with other conditions such as atypical odontalgia. Traditionally, the term dentine hypersensitivity was used to describe this distinct clinical condition; however, several authors have also used the terms cervical dentine sensitivity (CDS) or cervical dentine hypersensitivity (CDH) or dentine sensitivity (DS), and root dentine sensitivity (RDS)/root dentine hypersensitivity (RDH).
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Algorithm for the treatment of Dentine Hypersensitivity/Root Dentine Sensitivity by Practitioners is shown here:
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REFERENCES
A handbook of cosmetics by B.M. Mithal & R.N. Saha J.B.Wilkinson, Harrys cosmeticology, Leonard Hill book, London, UK. P.P.Sharma, cosmetics. Formulation, manufacturing and quality control, Vandana publications, Delhi, India. W.A. Poucher, Modern cosmetics, Vol-I,II & III, B.I. Publications, New Delhi, India. D.G. GILLAM & R. ORCHARDSON. Advances in the treatment of root dentine sensitivity: mechanisms and treatment principles Endodontic Topics 2006, 13, 1333 Ndia Araci Bou-Chacra, Sandra Sayuri Gobi, Mitsuko Taba Ohara, Terezinha de Jesus Andreoli Pinto. Antimicrobial activity of four different dental gel formulas on cariogenic bacteria evaluated using the linear regression method . Revista Brasileira de Cincias Farmacuticas Brazilian Journal of Pharmaceutical Sciences vol. 41, n. 3, jul./set., 2005 Dental sealant . Access special supplemental issue, July 2001.
PAPER-910101
CHAPTER-8
OFFICIAL HERBALS KRUPA MEHTA
OFFICIAL HERBAL DRUGS

Guided by: Dr.r.k.parikh Prepared by: Krupa Mehta m.pharm(sem-I)
PAPER-910101
CHAPTER-8
OFFICIAL HERBALS KRUPA MEHTA
HERBAL DRUGS:
Herbal drugs are widely used now-a-days..due to TRADITION:used through out history COST: perceived as gentler and safer. ACCESS: no prescription is necessary. SYNERGISM: a view that multiple ingredients working together yield better results. BUTCASE AGAINST HERBAL DRUGS: -Lack of FDA Regulations -Lack of dose standardization -Potential for toxicity and drug interaction. Butstill herbal drugs are widely used..even as pharmaceutical aids. List of herbal drugs official in different pharmacopoeias are given here.. A look at the table indicates that IP has a long way to go to catch up, if one wishes to have high /comparable number of herbals as in other Pharmacopoeiae, covered with quality monographs for them.
Table 1. Recent Trend-Coverage of Herbal/Phytopharmaceuticals Monographs in recent editions of Pharmacopoeiae
Sl No. Category of monographs. In B.P 2005 In USP31/NF26[2nd suppl] In EP, 5th Edn2005. 80 25 54 14 In IP,2007.+IP addendum2008
1 2 3 4
Raw herbs Excipients [Naturals.] Processed herbs [extracts/V.oils /Essn.oils/Resins...] Finished Products [Tinctures/Waters/syrups/tablets/Capsules/ear drops] TOTAL
67 15 60 47
37 22 61 84
45 6 15 2
189
204
173
68
PAPER-910101 HERBAL DRUGS ABSORBENT COTTON ACACIA ADHATODA(VASAKA/ADULASA) AGAR ALLANTOIN ALMOND OIL ALOE AMALAKI/AMLA AMARA AMRITA(GUDUCHI/TINOSPORA/GILOE) ANISE OIL ARACHIS OIL (PEANUT/GROUNDNUT OIL) ARJUNA ARTIMISIA ASHWAGANDHA(INDIAN GINSENG/WITHANIA) BACOPA(BRAHMI) BALSAM OF TOLU BASIL(TULSI) BELLADONA BENZOIN BHOI AMLA(PHYLLANTHUS) BHRINGRAJ(ECLIPTA) BLACK CURRANT(Ribes nigrum) BLACK PEPPER(MARICHA) CAFFEINE CAMPHOR CAPSICUM CARAWAY CARDAMOM CASCARA CASTOR OIL CATECHU CEDAR OIL CHAMOMILE FLOWERS CHASTE TREE CHERRY CHOCOLATE CINCHONA BARK CINNAMON IP07
CHAPTER-8 BP93 VINCOBLASTINE, CRISTINE BARBADOS & CAPE (ANISEED) -
OFFICIAL HERBALS KRUPA MEHTA USPNF2006 (SYRUP) VINCRISTINE,BLASTINE, VINORELBINE -
(POWDER) BARBALOIN
(HERB,LEAF, POW, EXT) (TINCTURE) (ANHYDROUS) -
(HERB) (SUMATRA) (RACEMIC) (POW,OIL) (FRUIT,OIL) (POW) (POW) (POW) (POW,OIL)
(SYRUP) (LEAF,EXT, TAB,TINCTURE) (SPIRIT) (OLEORESIN) (OIL,SEED, TINC) (EXT) (EMUL.,CAP) (POW,EXT) (JUICE,SYRUP) (SYRUP) -
PAPER-910101 HERBAL DRUGS CLOVE CLOVER,RED COCAINE COCILLANA COCOA BUTTER COCONUT OIL CODEINE COLCHICINE COLEUS COLOPHONY CORIANDER CORN COTTONSEED OIL CRANBERRY CURCUMA(HARIDRA/HALDI) DIGITALIS
CHAPTER-8 IP07 (TAB) (CURCUMIN) (TAB,DIGOL, DIGOXIN INJ, PAEDIA.) (HCL,INJ) (ERGOTAMINE ,METRINE, NOVINE) (CAP,INJ) (POW,EXT, DR TAB) (HCL) (ANHY, HCL) BP93 (OIL,POW) (POW,OIL) -
OFFICIAL HERBALS KRUPA MEHTA USPNF2006 (OIL) (EXT,POW,TAB) (OIL) (OIL,STARCH) (LIQ PREP) (PAPER)
DILL OIL ECHINACEA ANGUSTIFOLIA (E.PALIDA,E.PURPUREA) EMETINE EPHEDRINE ERGOT
(LEAF,POW, DIGOXIN, DIGITOXIN)
(CAP,POW,TAB, DIGITOXIN, DIGOXIN) (HCL) (HCL,SO4 ) (NOVINE, TAMINE)
ETOPOSIDE EUCALYPTUS OIL EUGENOL FENNEL OIL FRANGULA BARK FRIERS BALSAM GARCINIA(VILAYATI IMLI) GARLIC(ALLIEUM SATIVUM) GENTIAN GINGER GINKGO GINSENG GOKHRU
(POW) (POW) -
(POW,CAP,TINC) (AMERICAN, ASIAN) -
PAPER-910101 HERBAL DRUGS GUAR GUM GUDMAR(GYMNEMA) GUGGUL(COMMIFORA) HAWTHORN LEAF WITH FLOWER HORSE CHESTNUT HYOSCYAMUS INDIAN SQUILL IPECACUANHA ISPAGHULA(PLANTAGO) KALMEGH(ANDROGRAPHIS) KUNDURU(SALAKI GUM/ GUM OF BOSWELIA) LEMON OIL LINALOOL LINSEED LIQUORICE(MULETHI/YASTI/JETHIMADH) LOBELIA POWDER LONG PEPPER(CATKINS-BIG/SMALL) MAIZE MALT EXTRACT MANDUKPARNI(CENTELLA/GOTUKOLA) MANGO MANJISTHA(INDIAN MADDAR/ Rubia cordifolia) MARITINE PINE MATRICARIA FLOWERS MATTO GROSSO IPECAC MENTHA OIL MILK THISTLE MINT OIL-DEMENTHOLISED MYROBALAN -BELLIRIC/BHIBHITAKI -CHEBULIC/HARAD/HARITAKI/ TERMINALIA MYRRH NETTLE STNGING NUTMEG OIL
CHAPTER-8 IP07 (LIPID) (HUSK) BP93 (POW) (POW,PREP) (BARK)
OFFICIAL HERBALS KRUPA MEHTA USPNF2006 (POW,EXT) (SEED) -
(TERPENELESS, PEEL) (POW,OIL) (POW) (OIL,STARCH) -
(TINC) (POW,EXT)
(POW,EXT,TAB, CAP) (TOPICAL SOLU) (POW)
PAPER-910101 HERBAL DRUGS OLIVE OIL OPIUM(PAPAVER) ORANGE IP07 -
CHAPTER-8
OFFICIAL HERBALS KRUPA MEHTA BP93 (RAW,TINC) (OIL,PEEL,TINC, SYRUP,SPIRIT) USPNF2006 (POW,TINC) (MORPHINE) (OIL,PEEL,TINC, SYRUP,SPIRIT) (OIL,WATER, SPIRIT) (RESIN) (HUSK,SUSP) (POW) (RESERPINE) (POW) (POW) (TINNEVELLY) (POTATO) (OIL,OINTMENT) (POW,EXT)
PACLITAXEL PALM-KERNAL OIL PAPAIN PEPPERMINT OIL PHYSOSTIGMINE PICRORRHIZA(KUTKI) PIPERIDINE PODOPHYLLUM PSEUDOEPHEDRINE PSYLLIUM PUNARNAVA(HOGWEED/BORREHWIA) PURPUREA PYGEUM PYRETHRUM QUILLIA RAPESEED OIL RAWOLFIA(SARPGANDHA) RHATONY ROOT RHUBARB ROSE SAFFLOWER OIL SATAVARI(ASPARAGUS) SATI(HEDYCHIUM) SAW PALMETTO SENNA(CASSIA) SESAME OIL SHELLAC(LAC) SOYA OIL SOYBEAN OIL SPEARMINT OIL SQUILL ST. JOHNS WART STARCH STERCULIA LEAF STRAMONIUM LEAF SUNFLOWER OIL
(LEAF,POW) -
(LEAF,SPIRIT) -
PAPER-910101 HERBAL DRUGS SUNTHI(SONTH) TURPENTINE OIL THEOBROMA OIL THEOPHYLLINE THIO TEPA TOMATO TRAGACANTH VALERIAN VANILLA WHEAT WINTERGREEN OIL IP07 -
CHAPTER-8 BP93 (VANILLINE)
OFFICIAL HERBALS KRUPA MEHTA USPNF2006 (TINC) -
REFERENCES:
1.Indian pharmacopoeia,2007 2.British Pharmacopoeia,1993 3.USPNF,2006 4.www.expresspharmaonline.com

Stability Study

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Stability Study

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Paper910101

Stability:basic concepts and objectives

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 4

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 7

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 8

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Stress testing of API in solution

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 9

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 10

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 11

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 13

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

40C 2C Ambient Humidity

25C2C Ambient Humidity

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 14

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Drug products in semipermeable containers

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

Paper 910101 M.Pharm--2009-10

stability basic concepts & objectives KALPESH

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 17

Stability Studies By: Sanjay C. Modi

Stability Studies By: Sanjay C. Modi

Stability Studies By: Sanjay C. Modi

Stability Studies By: Sanjay C. Modi

Stability Studies By: Sanjay C. Modi

Stability Studies By: Sanjay C. Modi

Log (a-x) (b-x)

SLOPE = (a-b) K 2.303

Stability Studies By: Sanjay C. Modi

Stability Studies By: Sanjay C. Modi

The simplest case is in which both reactions are of first order

Example: Epimerization of tetracycline.

Simplest is one where both the reaction is of first order.

Stability Studies By: Sanjay C. Modi

Stability Studies By: Sanjay C. Modi