Vikesh Kumar

i
F FO OR RM MU UL LA AT TI IO ON N A AN ND D E EV VA AL LU UA AT TI IO ON N O OF F S SO OL LI ID D
O OR RA AL L D DO OS SA AG GE E F FO OR RM M ( (T TA AB BL LE ET TS S) ) O OF F
S SE EL LE EC CT TE ED D A AN NT TI I- -T TU UB BE ER RC CU UL LA AR R A AG GE EN NT TS S . .
By
Mr. VIKESH KUMAR SHUKLA
M.PHARM.
Thesis
Submitted to KLE University, Belgaum,
Karnataka, in partial fulfillment of the
requirements for the degree of
Doctor of Philosophy
in
Pharmacy

Under the guidance of
Prof. (Dr.) F.V. Manvi
M.Pharm. Ph.D, FIPA
DEPARTMENT OF PHARMACEUTICS
K.L.E.UNIVERSITYs COLLEGE OF PHARMACY,
BELGAUM-590010, KARNATAKA, INDIA.
MARCH 2011
ii
K KL LE E U UN NI IV VE ER RS SI IT TY Y
B BE EL LG GA AU UM M- -5 59 90 00 01 10 0, , K KA AR RN NA AT TA AK KA A, , I IN ND DI IA A
[Established under Section 3 of the UGC Act,1956 vide Government
of India Notification No. F.9-19/2000-U3 (A)]

Declaration by the Candidate
I I h he er re eb by y d de ec cl la ar re e t th ha at t t th hi is s t th he es si is s e en nt ti it tl le ed d F FO OR RM MU UL LA AT TI IO ON N
A AN ND D E EV VA AL LU UA AT TI IO ON N O OF F S SO OL LI ID D O OR RA AL L D DO OS SA AG GE E F FO OR RM M
( (T TA AB BL LE ET TS S) ) O OF F S SE EL LE EC CT TE ED D A AN NT TI I- -T TU UB BR RE ER RC CU UL LA AR R A AG GE EN NT TS S i is s a a
b bo on na af fi id de e a an nd d g ge en nu ui in ne e r re es se ea ar rc ch h w wo or rk k c ca ar rr ri ie ed d o ou ut t b by y m me e u un nd de er r t th he e
g gu ui id da an nc ce e o of f P Pr ro of f. . ( (D Dr r. .) ) F F. . V V. . M MA AN NV VI I, , D De ep pa ar rt tm me en nt t o of f
P Ph ha ar rm ma ac ce eu ut ti ic cs s, , K K. .L L. .E E. . U Un ni iv ve er rs si it ty y s s C Co ol ll le eg ge e o of f P Ph ha ar rm ma ac cy y, , B Be el lg ga au um m.
P Pl la ac ce e: : B Be el lg ga au um m
D Da at te e: :
M Mr r. . V VI IK KE ES SH H K KU UM MA AR R S SH HU UK KL LA A. .
M M. .P Ph ha ar rm m
D De ep pa ar rt tm me en nt t o of f P Ph ha ar rm ma ac ce eu ut ti ic cs s, ,
K K. .L L. .E E. . U Un ni iv ve er rs si it ty y s s C Co ol ll le eg ge e o of f P Ph ha ar rm ma ac cy y, ,
B Be el lg ga au um m 5 59 90 0 0 01 10 0. .
K Ka ar rn na at ta ak ka a
iii
[Established under Section 3 of the UGC Act,1956 vide Government of India
Notification No. F.9-19/2000-U3(A)]
Certificate by the Guide
b bo on na af fi id de e r re es se ea ar rc ch h w wo or rk k d do on ne e b by y M Mr r. . V VI IK KE ES SH H K KU UM MA AR R S SH HU UK KL LA A, , i in n
p pa ar rt ti ia al l f fu ul lf fi il ll lm me en nt t o of f t th he e r re eq qu ui ir re em me en nt t f fo or r t th he e D De eg gr re ee e o of f D DO OC CT TO OR R
O OF F P PH HI IL LO OS SO OP PH HY Y I IN N P PH HA AR RM MA AC CY Y ( (P PH HA AR RM MA AC CE EU UT TI IC CS S) ). .
D Da at te e: :
D Dr r. . F F. .V V. . M MA AN NV VI I
M M. .P Ph ha ar rm m. ., ,P Ph h. .D D. .
P Pr ri in nc ci ip pa al l a an nd d H He ea ad d, ,
K K. .L L. .E E. . U Un ni iv ve er rs si it ty y s s C Co ol ll le eg ge e o of f
P Ph ha ar rm ma ac cy y, , B Be el lg ga au um m 5 59 90 0 0 01 10 0. .
iv
ENDORSEMENT BY THE PRINCIPAL/ HEAD OF
THE INSTITUTION
b bo on na af fi id de e r re es se ea ar rc ch h w wo or rk k d do on ne e b by y M Mr r. . V VI IK KE ES SH H K KU UM MA AR R S SH HU UK KL LA A, ,
u un nd de er r m my y g gu ui id da an nc ce e a an nd d d di ir re ec ct t s su up pe er rv vi is si io on n. .

D Dr r. . F F. .V V. . M MA AN NV VI I
M M. .P Ph ha ar rm m. ., , P Ph h. .D D. .
H He ea ad d a an nd d P Pr ri in nc ci ip pa al l
K K. .L L. .E E. . U Un ni iv ve er rs si it ty y s s C Co ol ll le eg ge e o of f
P Ph ha ar rm ma ac cy y, , B Be el lg ga au um m 5 59 90 0 0 01 10 0. .
v
Copyright
Declaration by the Candidate
I I h he er re eb by y d de ec cl la ar re e t th ha at t t th he e K KL LE E U UN NI IV VE ER RS SI IT TY Y, ,
N NE EH HR RU U N NA AG GA AR R, , B BE EL LG GA AU UM M, , K KA AR RN NA AT TA AK KA A s sh ha al ll l
h ha av ve e t th he e r ri ig gh ht ts s t to o p pr re es se er rv ve e, , u us se e a an nd d d di is ss se em mi in na at te e t th hi is s
d di is ss se er rt ta at ti io on n i in n p pr ri in nt t o or r e el le ec ct tr ro on ni ic c f fo or rm ma at t f fo or r a ac ca ad de em mi ic c / /
r re es se ea ar rc ch h p pu ur rp po os se e. .
D Da at te e: :
KLE UNIVERSITY, NEHRU NAGAR, BELGAUM, KARNATAKA
M Mr r. . V VI IK KE ES SH H K KU UM MA AR R S SH HU UK KL LA A. .
M M. .P Ph ha ar rm m
D De ep pt t. . o of f P Ph ha ar rm ma ac ce eu ut ti ic cs s, ,
K K. .L L. .E E. .U Un ni iv ve er rs si it ty y s s C Co ol ll le eg ge e o of f P Ph ha ar rm ma ac cy y, ,
B Be el lg ga au um m 5 59 90 0 0 01 10 0. .
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Acknowledgements
The completion of this dissertation is not only fulfillment of my dreams but also the dreams of
my Parents, Grand parents, Big B and my sweet sister who have taken lots of pain for me in
completion of my higher studies.
I take this privilege and pleasure to acknowledge the contributions of many individuals who
have been inspirational and supportive throughout my work undertaken and endowed me with the
most precious knowledge to see success in my endeavor. My work bears the imprint of all those people
I am grateful to.
With grate pleasure and profound sense of gratitude, I express my most cordial and humble
thanks to my eminent, respected teacher and guide Prof. (Dr.) F. V. Manvi, Principal
Department of Pharmaceutics, K.L.E. University's College of Pharmacy, Belgaum and Co-ordinator
KLE University, Belgaum for his valuable guidance, keen interest, inspiration, unflinching
encouragement and moral support throughout my dissertation work. His strict discipline, urge for
hard work, principle, simplicity and provision of fearless work environment will cherish me in all
walks of life. I am immensely thankful to Prof. A. D. Taranalli, Vice-Principal and Head,
Department of Pharmacology, K.L.E. University's College of Pharmacy, Belgaum, for providing
necessary facilities and help in carrying out this work.
It is my privilege and honor to extend my gratitude to Dr. A. R. Bhat, Professor &
HOD Department of Pharma. Chemistry, K.L.E. University's College of Pharmacy, Belgaum, for
their valuable guidance and useful suggestions during the progress of my study.
I shall extend my gratitude to Dr. B.K. Nanjawade, Professor, Department of
Pharmaceutics, K.L.E. University, Belgaum for their timely help, guidance, and valuable suggestions
throughout the course.
I am also thankful to Dr. Ravish, Dr. Supriya, Mrs. Manvi mam and Dr. V. S.
Mastiholimath for their valuable guidance throughout the work.
It is with deep gratitude and humbleness, I express my indebtedness to Dr. Jalalpura,
Shri Ganachary, Dr. P. M. Dandagi, Smt. R. S. Masareddy Professor and Shri
Bolmal, Dr. Kunnur, Dr. Chandrashekhar Asst. Professor, K.L.E. University's College
of Pharmacy, Belgaum, for their guidance and help in instrumental analysis.
I also owe my sincere thanks to senior research scholars Dr. C. R. Patil, Dr.
Thippeswamy, Dr. M. N. Noolvi, Dr. Bongade, Talat mam, Palkar Sir for their
valuable suggestions, ever willing help and moral support during my dissertation work.
I wish to express my thanks to Prof. K. G. Bhat, Department of Microbiology, M.M.
Dental College and Research Centre, Belgaum, for actively engaging in microbiological screening of my
formulations.
I very special thanks to my best friend Kalpana, NIPER for her valuable suggestions, ever
willing help and moral support during my research work.
I also wish to express my thanks to Manager- R&D Centre, Macloads Pharma.
Pvt. Ltd., Mumbai for providing me necessary facility and pure INH and Rifampicin samples for
my research work.
I express my sincere thanks to all teaching and non-teaching staff members, especially Shri.
Deepshetty Lab. Technician, Department of Pharmsceutics, Shri. P. V. Kardi Lab.
Technician, Department of Pharmacognosy and Phytochemistry, Shri M. C. Hirremath Lab.
Technician, Department of Pharma. Chemistry and Store-In charge, Shri Kuri, Shri Prakash,
Shri Baganna, Shri Bijay and Shri Mudgappa, K.L.E.S's College of Pharmacy, Belgaum,
for their timely help and co-operation during my thesis work.
"Friends are in need are friends indeed", I am really thankful to my friends Mrs.
Sushma Bhabhi, Dr. Anand, Dr. Saurabh, Punia Sir (Ranbaxy labs), Md.
Salahuddin, Ravi, Praful, Amber, Vishwanath and Rupesh for their invaluable
suggestions, constant encouragement, moral support throughout my dissertation work and comfortable
stay in Belgaum.
I also express my thanks to my juniors Laxmi, Ravi Birari, Ansu, Kuntal,
Sandeep, Kaushik, Vijay and Lokesh for their help and cooperation.
How can I forget my best friends Deepak, Chimpi, Rajat, Yogi, Mayank, Ravi,
Boma, Ramesh, Ansuman, Vishal, Durga, Deepak, Prashant, Atul, Suraj,
Tanaji, Anand and All friends of Parampitta Hostel for their suggestions and
encouragement.
I often wonder, if one gets to see God in the moral life they might be like Parents who
showers their best fortunes always on me. From the deepest depth of my heart to express my thanks,
I bow my head to the feet of my beloved parents whose uncompromising life principles, love, affection,
has been always unshared and showered upon me at all stages of life and giving me more than what I
deserved in my life.
Last but not the least, I thank my internal belief God who always flowers his blessing on
me.
Thanks to one and all

Date: SHUKLA
Place: B Be el lg ga au um m. .
Vikesh Shukla et. al. Department of Pharmaceutics, KLE University, Belgaum
i
CONTENTS
S. No. Particulars Page No.
1. INTRODUCTION 1 17
2. NEED AND OBJECTIVES 18 21
3. REVIEW OF LITERATURE 22 46
4. MATERIALS AND METHODS 47 72
5. RESULTS AND DISCUSSION 73 211
6. SUMMARY 212 - 215
7. CONCLUSION 216 218
8. BIBLIOGRAPHY 219 234
9. ANNEXURE 235 237
ii
LIST OF PLATES
PLATE
NO.
TITLE
PAGE
NO.
1. Fast disintegrating Tablets of Isoniazid 93
2. Disintegration of Tablet in 60 sec 93
3. Anti-Tubercular Activity-Formulations 94
4. In-vivo Bioavailability study 95
5. Scanning Electron Microscopy of Formulation F1 96
iii
LIST OF FTIR SAMPLES
FIG.
NO.
TITLE
PAGE
NO.
1.
Pure Isoniazid. 108
2.
Pure Rifampicin. 109
3.
Pure Avisol pH102 110
4.
Pure Ac-Di-Sol 111
5.
Pure Poly Plastadone XL 112
6.
Pure Sodiun Starch Glycolate 113
7.
Pure Kollidon CL 114
8.
FTIR study of Formulation F1 115
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
iv
LIST OF X-RAY POWDER DIFFRACTION SAMPLES
FIG.
NO.
TITLE
PAGE
NO.
1.
Pure Isoniazid. 127
2.
Pure Rifampicin. 128
3.
Pure Avisol pH102. 129
4.
Pure Ac-Di-Sol. 130
5.
Pure Poly Plastadone Xl. 131
6.
Pure Sodiun Starch Glycolate(SSG). 132
7.
Pure Kollidon Cl 133
8.
X-ray Powder study of Formulation F1 134
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
v
LIST OF TABLES
TABLE
NO.
TITLE
PAGE
NO.
1. Composition of fast-disintegrating formulations 146
2.
Standard Calibration Curve of Isoniazid and Rifampicin at 261 nm and
333nm in PB 6.8
147
3.
Pre-compression parameters of formulations: Angle of Repose, Loose
Bulk Density, Tapped Bulk Density, Carr's Compressibility Index
148
4.
Post compression tablet Parameters: Uniformity of thickness, Hardness,
Weight, Drug content uniformity, Friability, Test of dispersion.
149
5.
Post compression tablet Parameters: Wetting Time, Water Absorption
Ratio
150
6.
Post compression tablet Parameters: In vitro Disintegration Time, In
vivo Disintegration Time, Mouth Feel
151
7. In vitro Dissolution Profile of the pure Isoniazid 152
8. In vitro Dissolution Profile of the Isoniazid Marketed formulation 153
9. In vitro Dissolution Profile of the Formulations F1, 154
10. In vitro Dissolution Profile of the Formulations F2 155
13. In vitro Dissolution Profile of the Pure Rifampicin 158
14. In vitro Dissolution Profile of the Marketed Rifampicin 159
vi
19. In vitro Dissolution Profile of the Formulations F9-INH Release 164
23. In vitro Dissolution Profile of the Formulations F9-RIFA Release 168
27.
Kinetic values obtained from in-vitro release data of different
dispersible formulations. Model fitting of the release profile using two
different models
172
28.
dispersible formulations. Model fitting of the release profile using three
different models
173
29.
dispersible formulations: n value, k value, order of reaction
174
30.
Anti-Tubercular Activity of Isoniazid, Rifampicin and Combination
Dispersible Formulations.
175
31.
In-vivo pharmacokinetic studies of Isoniazid from dispersible
formulation (F-1) and free drug in blood
176
32.
In-vivo pharmacokinetic studies of Rifampicin from dispersible
formulation (F-5) and free drug in blood
177
33.
In-vivo pharmacokinetic studies of Isoniazid and Rifampicin from
dispersible formulation (F-9) and free drug in blood
178
34.
In-vivo pharmacoki netic studies of all t he selected formulations
(F-1, F-5 and F-9)
179
35.
Stability studies- shelf life determination at 40c
180
36.
Stability studies- shelf life determination at 25c
181
vii
LIST OF FIGURES
TABLE
NO.
TITLE
PAGE
NO.
1. Standard Calibration Curve of Isoniazid at 261 nm in PB 6.8 182
2. In vitro Dissolution Profile of the pure Isoniazid 183
3. In vitro Dissolution Profile of the Isoniazid Marketed formulation 184
4. In vitro Dissolution Profile of the Isoniazid Formulations F1 to F4
(Zero Order plot)
185
(First Order plot)
186
(Higuchi Matrix plot)
187
(Peppas plot)
188
(Hixson Crowell plot)
189
9. In vitro Dissolution Profile of the pure Rifampicin 190
10. In vitro Dissolution Profile of the Rifampicin Marketed formulation 191
11. In vitro Dissolution Profile of the Rifampicin Formulations F5 to F8
(Zero Order plot)
192
(First Order plot)
193
13. In vitro Dissolution Profile of the Rifampicin Formulations F5 to
F8(Higuchi Matrix plot)
194
(Peppas plot)
195
196
(Zero Order plot)
197
(First Order plot)
198
viii
(Higuchi Matrix plot)
199
(Peppas plot)
200
201
F12 (Zero Order plot)
202
22. In vitro Dissolution Profile of the Rifampicin F9 to F12 (First Order
plot)
203
23. In vitro Dissolution Profile of the Rifampicin F9 to F12 (Higuchi
Matrix plot)
204
F12 (Peppas plot)
205
F12 (Hixson Crowell plot)
206
(Zero Order plot)
207
27. Pharmacokinetic Rel ease Profile for Formulation F-1 208
30. Stabili t y studies of f ormulation 1 (F-1), formul ation 2
(F-5) and formulation 3 (F-9) at 40c and 25c
211
ix
LIST OF ABBREVIATIONS
INH Isoniazid
RIFA Rifampicin
FDT Fast disintegrating tablet
DDS Drug delivery system
FDT Fast disintegrating tablet
FDC Fixed dose combination
MDT Mouth dissolving tablet
UV Ultra violet Spectroscopy
et. al Co-author
ODT Oral dispersible tablets
MR Modified release
SEM Scanning electron microscopy
ICH International Conference on Harmonization
Chapter I Introduction
1
INTRODUCTION
Due to a society that is becoming increasingly aged, the development of an
appropriate dosage form for the elderly is most desirable. Because the changes in various
physiological functions associated with aging including difficulty in swallowing, current
dosage like capsule, are impractical.
1
DISPERSIBLE DOSAGE FORMS:
Oral drug delivery is most widely utilized route of administration among all the
routes due to ease of ingestion, pain avoidance, versatility (to accommodate various types
of drug candidates) and most importantly patient compliance.
2
One of the added
advantage of solid oral delivery system does not require sterile conditions and are
therefore less expensive to manufacture. Such type of oral drug delivery is most widely
utilized route of administration among all the routes that have been explored for systemic
delivery of drugs via pharmaceutical products of different of dosage form. The most
popular solid dosage forms being tablets and capsules, one important drawback of these
dosage forms for patient is the difficulty to swallow, especially the elderly and
pediatrics.
3
Difficulty in swallowing (dysphasia) is a common problem of all age group,
especially the elderly and pediatrics because of the physiological changes associated with
these groups.
4
Other categories that experience problems using conventional oral dosage
forms are the psychiatric, uncooperative and nauseated patients, those with condition of
motion sickness, sudden episodes of allergic attack or coughing. Sometimes, it may be
difficult to swallow conventional products due to unavailability of water. These problems
led to the development of novel type of solid oral dosage forms called fast-dispersible
tablets, which disintegrate and dissolve rapidly in saliva without the need of drinking
water. They are known as fast dispersible tablets, melt-in-mouth tablets, rapimelts,
2
porous tablets, mouth dissolving tablets, quick dissolving or rapidly disintegrating
tablets.
5-6
When kept on tongue, upon ingestion, the saliva serves to rapidly dissolve the
dosage form. The saliva containing the dissolved or dispersed medicament is then
swallowed and the drug is absorbed. As the tablet, which disintegrates in the mouth, this
could enhance the clinical effect of the drug through pre-gastric absorption from the
mouth, pharynx and oesophagus as the saliva passes down in to the stomach. In such
cases, bioavailability of drug is significantly greater than those observed from
conventional tablet dosage form by avoiding first pass liver metabolism.
7

The advantages of mouth dissolving dosage forms are increasingly being
recognized in both, industry and academia. Their growing importance was underlined
recently when European pharmacopoeia adopted the oro-dispersible tablet as a tablet to
be placed in the mouth where it disperses rapidly before swallowing. Despite
disadvantages, novel technologies with improved performance, patient compliance, and
enhanced quality have emerged in the recent past. Oral mouth dissolving dosage forms,
three-dimensional printing (3DP) and electrostatic coating are a few examples of a few
existing technologies with the potential to accommodate various physico-chemical,
pharmacokinetic and pharmacodynamic characteristics of drugs.
8
The reasons that the oral route achieved such popularity may be in part attributed to
its ease of administration as well as the traditional belief that by oral administration the
drug is as well absorbed as the food stuffs that are ingested daily. In fact, the
development of a pharmaceutical product for oral delivery, irrespective of its physical
form involves varying extent of optimization of dosage form characteristics within the
inherent constraints of gastrointestinal physiology. Therefore, fundamental
understandings of various disciplines, including gastrointestinal physiology,
pharmacokinetic, pharmacodynamic and formulation design are essential to achieve a
systemic approach to the successful development of an oral pharmaceutical dosage form.
3
The more sophisticated a delivery system, the greater is the complexity of these
various disciplines involved in the design and optimization of the system. In any case, the
scientific framework required for the successful development of an oral drug delivery
system consists of a basic understanding of the following three aspects.
9-15
1. Physicochemical, pharmacokinetic and pharmacodynamic characteristic of drug
2. The anatomic and physiologic characteristics of the GIT
3. Physicochemical characteristics and the drug delivery mode of the dosage form to
be designed
7
Desired criteria for mouth disintegrating drug delivery system:
16-19
Fast-dispersible tablet should have characteristics such as:
- Do not require water to swallow, but it should dissolve or disintegrate in the
mouth in the matter of seconds
- Should have a pleasing mouth feel, Be compatible with taste masking
- Be portable without fragility concern
- Leave minimal or no residue in the mouth after oral administration
- Exhibit low sensitivity to environmental condition i.e. humidity and temperature
- Allow the manufacturer of tablet using conventional processing and packing
should be at low cost
Salient features of Fast-dispersible tablet:
- Ease of administration to patients who refuse to swallow a tablet such as,
pediatric, geriatric and psychiatric patients
- Convenience of administration and accurate dosing as compared to liquids
- No need of water to swallow the dosage form, which is highly convenient
especially for patients who are traveling and do not have immediate access to
water
4
- Good mouth feels property of MDDS helps to change the basic view of
medication as bitter pill, particularly for pediatric patients
- Rapid dissolution and absorption of drugs, which may produce quick onset of
action
- Some drugs will absorbs from mouth, pharynx and oesophagus as the saliva
passes down in to the stomach; in such cases bioavailability of drugs is
increased
- Ability to provide advantages of liquid medication in the form of solid form
- Pre-gastric absorption can result in improved bioavailability and as a result of
reduced dosage, improved clinical performance through a reduction of
unwanted effects
Mechanism of action of oral dispersible tablets

Tablet
Disintegration into
ordered units
Units adhere to the
sublingual mucosa
Carrier particle dissolve
and release the active
drug, which dissolve and
is absorbed over the
mucosa
Biopharmaceutical consideration:
20,21
Elderly do not respond to the drug therapy in the same manner as young adult.
Several age related changes in the gastrointestinal tract have the potential effect to alter
the drug absorption, which effect overall drug absorption hence the drug efficacy.
Pharmacokinetics: The altered drug binding to serum albumin has been extensively
studied in geriatric patients. A decrease in lean body mass and total body water is
expected to result in decrease volume of distribution (Vd), of lipid soluble drugs. The
decrease in liver volume and regional blood flow to the liver reduces the
5
biotransformation of drugs through oxidation, reduction and hydrolysis. The drug
excreted by renal clearance is slowed, thus half-life of renal excreted drugs increased.
Pharmacodynamic: Drug receptor interaction are impaired in elderly as well as in
young ones due to the under development of organs.
22
- Decreased ability of the body to respond baroreflexive stimuli, cardiac output,
and orthostatic hypotension may seen in taking antihypertensive like prazocin
- Decreased sensitivity of the CVS to |-adrenergic agonist and antagonist
- Immunity is less and taken into consideration while administered antibiotics
- Altered response to drug therapy- elderly show diminished bronchodilator
effect of theophylline shows increased sensitivity to barbiturates
- Concomitant illnesses are often present in elderly, which is also taken into
consideration, while multi-drug therapy is prescribed
- The incidence of diabetes and glucose tolerance is well documented and hence
every attempt is made to avoid sugar-containing excipients
Increasing the number of medication results in more complex dosing interval,
dosage regimen and difficulties in dosage form design.
Difficulties with existing oral dosage form:
23-24
The elderly patients exhibit not only a change in pharmacokinetics and pharmaco-
dynamics but also deterioration in their vision, hearing, memory, taste, smell and
physical abilities. All this affects elderly patients ability to differentiate various dosage
forms and accurately self-administration of medication.
- In multiple disease state or polypharmacy, where two or more drugs prescribed are
different dosage form, with different dosing interval and also different mode of
administration
6
- Patient may suffer from tremors therefore they have difficulty to take powder and
liquids. In dysphagia physical obstacles and adherence to esophagus may cause
gastro-intestinal ulceration
- Liquid medicaments (suspension, emulsion) are packed in multi-dose container;
therefore achievement of uniformity in the content of each dose may be difficult
- Buccal and sublingual formulations may cause irritation to oral mucosa, so patient
refuses to use such medication
- Cost of the product is main factor as parentral formulations are more costly
- In transdermal drug delivery systems, there is an increase in rate of permeation
through aging skin but the permeated drug substances have slower rate of clearance
into general circulation which may lead to incomplete drug distribution
Formulation of Fast-dispersible tablets:
For rapid dissolution of dosage, water must rapidly penetrate into tablet matrix to
cause quick disintegration and instantaneous dissolution of tablet. Several techniques are
used to achieve these fundamentals to formulate Fast-dispersible tablet; like table
moulding, freeze-drying, spray drying, sublimation, and addition of disintegrating agents.
Direct compression:
25
Conventional equipment, commonly available excipients and a limited number of
processing steps are involved in direct compression. Disintegrant efficiency is strongly
affected by tablet size and hardness. Large and hard tablet have disintegration time more
than that usually required. As a consequence, product with optimal disintegration
properties often have medium to small size and/or high friability and low hardness.
Disintegrants have major role in disintegration and dissolution of mouth dissolving
tablets made by direct compression. Disintegration efficiency is based on force
equivalent concept, which is combined measurement of swelling force development and
7
amount of water absorption. The simultaneous presence of disintegrant with high
swelling force called disintegrating agent and substances with low swelling agent are
claimed to be key factor for rapid disintegration of tablet; which also offer physical
resistance.
Sublimation:
26-28
Low porosity prolonged dissolution even tablets containing highly water soluble
ingredients, inert solid ingredients that volatilize readily (camphor, ammonium
bicarbonate, ammonium carbonate, ammonium acetate, urea, urethane, naphthalene)
were mixed with other ingredients and then mixture compressed into tablets. Volatile
material is removed by subliming, which tends to produce porous structure. Compressed
tablets containing mannitol and camphor have been prepared by sublimation technique.
The tablets exhibit sufficient mechanical strength for practical use.
Tablet Moulding:
29,30
By using water-soluble ingredients, moulded tablets are prepared. Powder is
moistened with the help of hydroalcoholic solvent and then moulded in to tablets under
pressure less than conventional dosage form. Removal of solvent is done by air drying.
Moulded tablets possess porous structure, which facilitate easy dissolution passing a
powder blend through very fine screen increasing dissolution rate. To increase
mechanical strength sucrose, acacia or polyvinyl pyrolidone are added. Moulded tablet
shows poor taste masking characteristics, to overcome this problem the taste masked
discrete particles of active ingredient were prepared by subjecting a molten mixture of
hydrogenated cotton seed oil, sodium bicarbonate, lecithin, peg, lecithin and active
ingredients to spray congealing process. Recently, moulded forms also have been
prepared directly from the molten matrix in which the drug is dissolved or dispersed (heat
molding or by evaporating the solvent from the suspension at standard pressure.
8
Freeze drying:
31-36

A process in which water is sublimated from the product after freezing is called
freeze drying. Freeze dried forms offer more rapid dissolution than other available solid
products. The lyophilization process imparts glossy amorphous structure to the bulking
agent and some times to the drug, thereby enhancing the dissolution characteristics of the
formulation. However the use of freeze drying is limited due to high cost of the
equipment and processing. Other major disadvantages of the final dosage forms include
lack of physical resistance in standard blister packs.
The freeze-drying process consists of three phases.
1. Freezing to bring the material below its eutectic zone
2. Sublimation drying or primary drying to reduce moisture to around 4% w/w
of dry product
3. Desorption or secondary drying to reduce bound moisture to the required final
value
Spray drying:
37-41
Spray drying can be used to prepare rapidly dissolving tablets. This technique is
based upon a particulate support matrix that is prepared by spray drying and aqueous
composition containing support matrix and other components to form a highly porous
and fine powder. This is then mixed with active ingredients and compressed into tablet.
The mouth dissolving tablets prepared form spray drying technique disintegrated within
20 seconds.
Mass extrusion:
16
The technology involves softening the active blend using the solvent mixture of
water soluble polyethylene glycol, using menthol and expulsion of softened mass through
the extruder or syringe to get a cylinder of the product into even segments using heated
9
blade to form tablets. The dried cylinder can also be used to coat granules of bitter tasting
drugs and thereby masking their bitter taste.
Patented technologies for mouth dissolving tablets:
Zydis technology:
18
Zydis formulation is a unique freeze dried tablet in which drug is physically
entrapped or dissolved within the matrix of fast dissolving carrier material. When Zydis
units are put into the mouth, the freeze-dried structure disintegrates instantaneously and
does not require water to aid swallowing. The Zydis matrix is composed of many
materials designed to achieve a number of objectives. To impart strength and resilience
during handling, polymers such as gelatin, dextran or alginates are incorporated. These
form a glossy amorphous structure, which impart strength to obtain crystallinity,
elegance and hardness; saccharides such as mannitol or sorbitol are incorporated. Water
is used in the manufacturing process to ensure production of porous units to achieve rapid
disintegration. Various gums are used to prevent sedimentation of dispersed drug
particles in the manufacturing process. Collapse protectants such as glycine prevent
shrinkage of Zydis units during freeze drying process or long term storage. Zydis
products are packed in blister packs to protect the formulation from moisture in the
environment.
Durasolve technology:
37
Durasolve is the patented technology of CIMA labs. The tablets made by this
technology consist of drug, fillers and a lubricant. Tablets are prepared by using
conventional packaging system like blisters. Durasolve is an appropriate technology for
products requiring low amounts of active ingredients.
10
Orasolve technology:
37
Orasolve technology has been developed by CIMA labs. In this system active
medicament is taste masked. It also contain effervescent disintegrating agent. Tablets are
made by direct compression technique at low compression force in order to minimize
oral dissolution time, conventional blenders and tablet machine is used to produce the
tablets. The tablets produce are soft, friable and packed in specially designed pack and
place system.
Flashdose (fluisz technologies ltd.):
37
Fluisz technologies has three oral drug delivery systems that are related to fast
dissolution, the first two generations of quick dissolving tablets, soft chew and floss
chew, require some chewing. This technology utilized a unique spinning mechanism to
produce floss like crystalline structure, much like cotton candy. This crystalline sugar can
then incorporate the active drug and can be compressed in to a tablet.
FLASHTAB (propharm group):
37
The FLASHTAB technology is yet another fast dissolving/disintegrating tablet
formulation; it utilizes most of the same excipients as in conventional compressed tablets.
A disintegrating agent and a swelling agent are used in combination with coated drug
particles in this formulation to produce tablets that disintegrates in the mouth in less than
one minute.
WOWTAB technology:
37
WOWTAB technology is patented by yamanouchi pharmaceutical company.
Wow means without water. In this process, combination of low mouldability
sacccharides and high mouldability sacccharides is used to obtain a rapidly melting
tablet. The active ingredient is mixed with low mouldability saccharide and granulated
with a high mouldability saccharide and compressed into tablet.
11
Oraquick (kv pharmaceutical company inc.):
37
The Oraquick mouth dissolving tablet formulation utilized a patented taste
masking technology. KV pharmaceutical claims its microsphere technology, known as
micromask, has superior mouthfeel over taste masking alternatives. The taste masking
process does not utilize solvents of any kind, and therefore leads to faster and more
efficient production. Also lower heat of production than alternative fast dissolving
technologies make oraquick appropriate for heat sensitive drugs. Oraquick claims quick
dissolution in a matter of seconds, with good taste masking.
Shearform technology:
42-44
The Shearform technology is based on preparation of floss that is also known as
shearform matrix, which is produced by subjecting a feedstock containing sugar carrier to
flash heat processing. In this process, the sugar is simultaneously subjected to create an
internal flow condition, which permits part of it to move with respect of the mass. The
flowing mass exits through the spinning head that flings the floss, the floss so produced is
amorphous in nature, which is further chopped and re-crystallized by various techniques
to provide uniform flow properties and thus facilitate blending.
The crystallized matrix is then blended with other tablet excipients and an active
ingredient and other excipients can be blended with floss before carrying out re-
crystallisation. The shearform floss, when blended with the coated or uncoated
microsphere, is compressed into tablets on standard tabletting equipment.
Ceform technology:
46-48
In Ceform technology microsphere containing active drug ingredient are
prepared. The essence of ceform microsphere manufacturing process involves placing a
drug powder, containing substantially pure drug material or a special blend of drug
material plus other pharmaceutical compounds and excipients into precision engineered,
12
and rapidly spinning machine. The centrifugal force of the rotating head of ceform
machine throws the drug blend at high speed through small, heated openings. The
carefully controlled temperature of the resultant microburst of heat liquefies the blend to
form a sphere without adversely affecting drug stability. The microsphere are then
blended and/or compressed into the pre-selected oral delivery dosage form. The ability to
simultaneously process both the drug and excipients generates a unique
microenvironment in which materials can be incorporated into the microsphere that can
alter the characteristics of the drug substance, such as enhancing solubility and stability.
The microsphere can be incorporated into a wide range of fast dissolving dosage forms
such as EZ chew, spoon dose as well as conventional tablets.
ROLE OF DISINTEGRANT:
49
For tablets, it is necessary to overcome the cohesive strength introduced into the
mass by compression. Therefore, it is usual practice to incorporate excipients called
disintegrant, which will include during formulation. Tablets containing a disintegrant
break up rapidly in the water because of the sudden and immediate application of the
stress. However, when a tablet containing such disintegrant is exposed to water stress is
built up slowly and tablet absorbs some of the strain. For most tablets the most important
step is the breakdown of the tablet into the smaller particles or granules, this step is
known as disintegration.
Type of Disintegrants:
I) Disintegrants that propagate capillary effects:
There is evidence to suggest that water uptake caused by capillary force is the
crucial factor in the disintegration process of many formulations. In such systems the
pore structure of the tablet is prime importance, and many inherent hydrophilicity of the
tablet mass will adversely affect it. Therefore, disintegrant is in this group must be able to
13
maintain a porous structure in the compressed tablet and show a low interfacial tension
based towards aqueous fluids. Rapid penetration by water throughout the entire tablet
matrix to facilitate its breakup is thus achieved. Concentrations of the disintegrants that
ensure a continuous matrix of disintegrant are desirable, and levels of between 5 to 20%
are common.
II) Disintegrants that swell:
One general problem with group of disintegrats is that on swelling, many
disintegrant produce a sticky or gelatinous mass that resist break up of the tablet, making
it particularly important to optimize the concentration present. Although untreated
starches do not swell sufficiently, certain modified forms, such as Sodium starch
glycolate, do swell in cold water and are better as disintegrant.
Some powdered gums, such as agar, karaya or Tragacenth swell considerable
when wet, but their pronounced adhesiveness limits their value as disintegrant and
restricts the maximum concentration at which they can be effectively used to
approximately 5% of the tablet weight.
III) Gas Producing Disintegrants:
Gas producing disintegrants are used when extra rapid disintegrantion or a rapidly
soluble formulation is required. They have also been a value when poor disintegration
characteristics have also been a value when poor disintegration characteristics have
resisted other methods of improvement. Their main drawback is the need for more
stringent control over environmental conditions during the manufecture of tablets made
with the materials.
IV) Enzymes:
When tablets are not naturally very cohesive and have thus been manufactured by
a wet granulation process involving on of the binders (Acacia, PVP, Tragacanth
14
mucilage) addition of small quantity of appropriate enzyme may be sufficient to produce
rapid disintegration.
Mechanism of action:
50-51
Water Uptake:
Water uptake has been implicated as a mechanism of action for tablet disintegrats.
The ability of particles to draw water into the porous network of a tablet (wicking) was
essential for efficient disintegration. If wetting of the disintegrant particle showed,
disintegration of the tablet showed, thus extent of water uptake are both critically
important for a number of tablet disintegrants.
Swelling:
Perhaps the more widely accepted general mechanism of action for tablet
disintegration is swelling. Almost all disintegrants swell to some extent. And swelling
has been reported quite universally in the literature.
Deformation:
Plastic deformation under the stress of tableting has been reported for many years.
The deformed particles returned to their normal shapes, when exposed to water. The
swelling capacity of starch granules was improved when the granules were extensively
deformed during compression.
Heat of wetting:
Starch granules exhibit slight exothermic properties when wetted and reported
that this was the cause of localized stress resulting from capillary air expansion.
This explanation, however, is limited to only a few types of disintegrants and can
not describe the action of most modern disintegrating agents. A significant heat of
wetting is generated during disintegration. However, there is not always a corresponding
decrease in disintegration time.
15
Particle Repulsion Theory:
Theory of the tablet disintegration attempt to explain the swelling of tablets made
with a non-swellable starch. A particle repulsion theory based on the observation that
particle do seem to swell but still disintegrate tablets was proposed. It was revealed that,
alteration in the dielectric constant of disintegrating media an effort to identify electric
repulsive forces as the mechanism of disintegration was successful, and the water was
required for tablet disintegration. Hence, repulsion is secondary to wicking, as the
primary mechanism of action for all tablet disintegrants.
Particle Size:
Physical characteristics of disintegrants, such as particle size, also have some
bearing on the mechanism of disintegration. (eg. Swelling and water uptake). Several
attempts have related the particle size of disintegrants to their efficiency. The effect of
particle size of starch grains on the ability to disintegrate tablets. Starch grains with
relatively large particles size were more efficient disintegrants then the finer grades.
Particle size plays a key role in the overall efficiency.
TUBERCULOSIS:
Tuberculosis is a chronic granulomatous disease and a major health problem in
developing countries. About 1/3
rd
of the worlds population is infected with
Mycobacterium tuberculosis and Mycobacterium. bovis. As per WHO estimate, 9 million
people globally developing active Tuberculosis and 1.7 million die of it annually. In
India, it is estimated that 2 million people develop active disease every year and about
0.5 million die from it.
52

Tuberculosis has been described as king of disease in the vedas and was
mentioned by Charaka and sushruta about 600 B.C. with the discovery of tubercle
bacillus, the causative organism, by Robert Koch in 1882, the disease become known as
16
tuberculosis.
53
M. Tuberculosis is a slender, or slightly curved bacillus, ranging from 1-4
m length, they are acid-fast bacilli.
54
The therapeutic potential of Rifampicin in tuberculosis is well recognized due to
its unique ability to kill semi dormant tubercule bacilli (M. Tuberculosis). It is
categorized amongst first line agents including Isoniazid, Pyrazinamide, Ethanbutol and
Streptomycin which are used in combination as effective therapy for all forms of diseases
caused by M. Tuberculosis. WHO recommends a six month regimen comprising
Rifampicin, Isoniazid, Pyrazinamide and Ethanbutol which are given together for the first
two month followed by Rifampicin and Isoniazid therapy for the next four months.
Rifampicin is mainly eliminated in bile and then reabsorbed, hence enterohepatic
circulation ensues. During this time the drug is progressively deacylated into its
microbiologically active metabolite, 25-desacetyl Rifampicin which is less absorbable as
compared to the parent drug.
55

Tuberculosis has a definitive affinity for the lungs causing primary disease.
However, any part of the body can be affected, including the mouth and normally these
lesions are secondary to lung disease.
Oral tuberculosis:
Oral tuberculous lesion may be either primary or secondary, secondary lesions are
more common. Primary form of tuberculosis oral lesions is more commonly found in
children and aldolesescents then in adults, usually affecting gingival and mucobuccal
folds and associated with cervical lymphadenopathy. The primary lesion remains painless
in the majority of cases. The secondary lesions, on the contrary, are more common and
are seen mostly in older persons. The lesions are seen as superficial ulcers, patches
indurated soft tissue lesions, or even a lesion in the jaws that may be in the form of
tuberculous osteomyelitis, or simple bony radiolucencies. Of all these oral lesions, the
17
ulcerative form is the most common and is often painful with no associated caseation of
the dependent lymph nodes.
56
Reports have shown that oral lesions occur in 0.05-5% of the patients with
tuberculosis and frequently are secondary affecting more usually elderly patient. On the
other hand, the primary form more uncommon and more usually affects young patients.
57
An attempt has been made, in the present work, to develop dispersible tablet of
Isoniazid, Rifampicin and their combination by direct compression methods, to increase
the bioavailability of the anti tubercular agents as well to provide the local delivery in the
case of oral tuberculosis. The formulations are prepared by using a bland of
superdisintegrants such as Ac-di-sol, Sodium Starch Glycolate, Polyplastadone XL and
Kollidon CL. The main objectives of the study were to investigate the performance of
superdisintegrants and effect of other process variables on the characteristics of the
Isoniazid, Rifampicin and their combination dispersible formulations, as well as evaluate
the in-vitro and in vivo performance of the formulations.
Chapter II Need and Objectives
18
NEED AND OBJECTIVES
NEED
Fast disintegrating tablets are drug delivery systems with high acceptance and
compliance. The major advantage of fast disintegrating tablet is drug administration at
any time without water, self medication and stability compared to parenterals which
increased patient compliance.
58
Due to disintegration of formulation in the mouth,
elimination of bitterness is important criteria in product formulation of mouth dissolving
tablets.
59
Rifampicin, Isoniazid, Pyrazinamide and Ethambutol are the drugs of choice for
treating tuberculosis. Fixed dose combination of two, three or four drugs is a preferred
dosage form for efficient reduction in viable bacterial population and minimizing
development of resistance to anti-tubercular drugs.
60
Isoniazid is a widely used antimycobacterial agent for first line therapy of
Tuberculosis (TB). The drug is characterized by a short half-life ranging from 1 h to 4 h,
depending on the rate of metabolism. INH is inactivated in liver, mainly by acetylation
and dehydration; the rate of acetylation is genetically determined and subjected to
individual variation. Long term continuous therapy with INH leads to heapatotoxicity
and peripheral neuritis.
61
Rifampicin is the semi-synthetic hydrazine derivative of Rifampicin B.
Rifampicin is the first line drug recommended by WHO in the treatment of tuberculosis.
Relatively high doses of the drug are required to maintain therapeutic concentration for
longer periods, which leads to several side effects. Due to its high cost and adverse side
effects it is used mainly in intermitted therapy. The biological half-life varies from 1.5 to
5 hours. The prolong treatment of tuberculosis with conventional chemotherapy of
Rifampicin and its adverse effects promoted the development of dispersible delivery
19
systems. However, bioavailability of Rifampicin is significantly impaired when it is
administered along with Isoniazid as a Fixed Dose Combination (FDC).
62-63
Difficulty in swallowing (dysphasia) is a common problem of all age groups,
especially the elderly and pediatrics because of the physiological changes associated
with these groups.
4
Other categories that experience problems using conventional oral
dosage forms are the mentally ill, uncooperative and nauseated patients, those with
condition of motion sickness, sudden episodes of allergic attack or coughing.
Sometimes, it may be difficult to swallow conventional products due to unavailability of
water. These problems led to the development of novel type of solid oral dosage forms
called fast-dispersible tablets, which disintegrate and dissolve rapidly in saliva without
the need of drinking water. They are known as fast dispersible tablets, melt-in-mouth
tablets, rapimelts, porous tablets, mouth dissolving tablets, quick dissolving or rapidly
disintegrating tablets.
4-5
The most desirable formulation to use by the elderly is one that is easy to swallow
and easily to handle. Oral dispersible formulation of the anti-tubercular drug, increase the
bioavailability of the anti-tubercular agents as well to provides the local delivery in the
case of oral tuberculosis. Taking these requirements into consideration, attempts have
been made to develop a fast disintegrating tablet. Since, such a tablet can disintegrate in
the small amount of water in the oral cavity. It is easy to take for any age patient,
regardless of time or place. It can be taken anywhere at anytime by anyone who do not
have easy excess to water. It is also easy to dose the aged bed ridden patients or infants
who have problems swallowing tablets and capsules.
20
OBJECTIVES
The study has been designed to develop the fast disintegrating formulations of
Isoniazid, Rifampicin and its combination which would enhance absorption and
bioavailability of the drugs. It includes selection and optimization of the suitable
excipients such as superdisintegrants for development of fast disintegrating tablet for the
treatment of the tuberculosis. Following specific aims were set to achieve the above
stated objective.
1) Preparation of standard calibration curve for Isoniazid and Rifampicin
2) Formulation development of fast disintegrating tablet by direct compression method
3) Characterization and evaluation of the formulations
I. Pre-compression parameter:
a. Drug excipient compatibility studies: Comparison of drugs and its
combination with various polymers by FTIR
b. Evaluation of powder: Angle of repose, compressibility index
II. Post-compression parameters:
a. Appearance and its dimension measurements
b. Weight variation test
c. Drug content uniformity
d. Wetting time
e. Water absorption ratio
f. Hardness test
g. Friability test
h. Surface morphology studies using scanning electron microscopy (SEM)
i. Powder X-ray diffraction studies
21
4) In vitro evaluation of formulations
a. In vitro dispersion studies
b. In vitro disintegration studies
c. In vitro dissolution studies and curve fitting analysis
d. Microbiological screening of formulations
e. Stability studies and shelf life determination of the selected formulations
5) In vivo studies
a. In vivo pharmacokinetic studies for selected formulations
b. In vitro-In vivo correlations (IVIVC)
Chapter III Review of Literature
22
REVIEW OF LITERATURE
Drug Review:
Isoniazid
Isonicotinylhydrazid; INH
N
CONHNH
2
C6H7N3O Mol. Wt. 137.14
Isoniazide is Isonicotinohydrazide.
Category: Antitubercular
Dose: 300mg daily or up to 1g twice weekly.
Description: Colourless crystals or white, crystalline powder; odourless.
Solubility: Freely soluble in water; sparingly soluble in ethanol (95%); slightly
soluble in chloroform; very slightly soluble in ether.
Storage:

Store in well-closed, light- resistant containers.
Absorption and Fate: Isoniazid is readily absorbed from the GIT. Peak concentration of
about 3 to 8 g per ml appears in blood after a fasting dose of 300 mg by mouth. The rate
and extent of absorption of Isoniazide is reduced by food. Isoniazide is not considered to
be bound appreciably to plasma proteins and diffuses into all body fluids, including the
CHF . It appears in fetal blood if given during pregnancy and in breast milk. The plasma
half-life for Isoniazid ranges from about 1 to 6 hours, those who are fast acetylators
having shorter half- lives.
Uses and administration: Isoniazid is a hydrazide derivative that is the mainstay of the
primary treatment of pulmonary and extrapulmonary tuberculosis.
23
Isoniazid given in the initial and continuation phase of short- course tuberculosis
regimens. The usual adult dose is 300 mg daily by mouth on an empty stomach.
Childrens dose varies between 5 mg per body-weight daily. All with the maximum of
300 mg daily.
Similar doses to those used orally may be given by Intramuscular injection when
Isoniazid cannot be taken by mouth; it may be also given by Intravenous injection.
Isoniazid has also given Intrathecally and Intrapeleurally.
In tuberculosis prophylaxis, daily doses of 300 mg are given at least 6 months and
sometimes for up to 1 year. Alternatively it may be given with Rifampicin for 3 months.
Doses of 5 to 10mg per kg Isoniazid daily to a maximum of 300mg daily have been
suggested for prophylaxis in children in the UK.
Preparations:
BP 1998: Isoniazid injection, Isoniazid Tablets;
USP 23: Isoniazid injection, Isoniazid Tablets, Isoniazid Syrup, Rifampicin and
Isoniazid capsules.
61, 64, 65
Past work done on Isoniazid:
Rastogi R, et al, Designed the spherical microspheres able to prolong the release
of INH by a modified emulsification method, using sodium alginate as the hydrophilic
carrier. The shape and surface characteristics of placebo and drug loaded formulations
measured by SEM using gold sputter technique and particle distribution was determined
by optical microscope. The DSC determined the physical state of the drug in the
formulation, and release profiles of INH from microspheres were examined in stimulated
gastric fluid (SGF pH 1.2) and stimulated intestinal fluid (SIF pH 7.4). They carried
gamma-scintigraphic studies to determine the location of microspheres on oral
administration and the extent of transit through the GIT. They found that microspheres
had a smoother surface and discreet and spherical in shape. The particle was
24
heterogeneous with the maximum particle of an average size of 3.719m. They conclude
that the mean particle size of the microspheres increased with an increase in the
concentration of polymer and the cross-linker as well as the cross- linking time.
66
Maria SM and Angnes L proposed a new, fast and precise method to analyze
Isoniazid based on the electrochemical oxidation of the analyte at glassy carbon electrode
in 0.1M NaOH, quantification was performed by utilizing Amperometry associated with
the batch injection analysis (BIA) technique. Fast sequential analysis in an unusually
wide dynamic range with high sensitivity and low limit of detection and quantification
was achieved. They concluded that such characteristics allied to a good reproducibility of
the current responses for the specific determination of Isoniazid in Isoniazid- Rifampicin
tablet.
67
Gursoy A, et al, Co-encapsulated the INH and RIF in the same liposome
formulation, INH was incorporated in the aqueous phase and RIF in the lipid layer;
separate liposome formulation of INH and RIF was also prepared. All the liposome
formulations were compared for their loading capacity, encapsulation percentage and
release properties, drug amounts in the liposomes were estimated using peak-to-peak first
order derivative UV spectroscopy. They concluded lipid and water-soluble drugs could
be successfully co- encapsulated in the same liposome formulation and derivative UV
spectroscopy is a sensitive method for direct and accurate quantification of these co-
encapsulated drugs.
68

Agrawal S, et al, Studied the comparative bioavailibility of Rifampicin, Isoniazid
and Pyrazinamide from a four drug fixed dose combination with separate formulation at
same dose levels, bioequivalence study of the four drug FDC tablet was conducted, by
using 22 healthy male volunteers according to WHO recommended protocol to determine
bioavailibility of Rifampicin, Isoniazid and Pyrazinamide compared to standard separate
combination at same dose level. Bioequivalence of the both Rifampicin and Isoniazid is
25
clinically insignificant. They concluded that FDC formulation is bioequivalent for
Rifampicin, Isoniazid and Pyrazinamide and ensure the successful treatment of TB
without compromising therapeutic efficacy of any of these components of anti-TB
therapy.
69

Singh S et al, Determined the behavior of moisture gain by four anti-tuberculosis
drugs, viz. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol, when exposed in pure
form and in combinations to accelerated conditions of 40C and 75% RH, in the absence
and the presence of light, weight gain was seen only in those samples that contained
Ethambutol, and this behavior was observed in both in dark and lighted chambers. They
observe decrease in moisture uptake with an increase in the number of drugs in the
mixture. They also observed that higher weight gain by the mixture of Ethambutol and
Isoniazid in a dark chamber, then either pure Ethambutol or drug combinations
containing Ethambutol. They concluded that an overall acceleration of weight gain in the
presence of light as compared with dark conditions.
70

Agarwal S and Punchagnula R developed a dissolution methodology to predict
in vivo performance of Rifampicin containing FDC (INH) products. Six FDC
formulations were used in this study, of which four passed bioequivalence while two
failed. The studies were conducted at agitation intensity of 30-40 rpm as a measure of
hydrodynamic stress and at pH media corresponding to gastric and intestinal conditions
71
.
26
RIFAMPICIN
Formula: C43H58N4O12 Mol. Wt. 822.95
Rifampicin is (12Z,14E,24E)-(2S,16S, 17S, 18R, 19R, 20R, 21S, 22R, 23S)- 1,2 dihdro-
5.6.9, 17, 19- heptamethyl-8-(4-methyl-peprazine-1-yliminomethyl)-1,11,13-
triemino)neptho[2,1-b] furan 21-yl acetate.
Category: Antitubercular.
Dose: for an adult, 450 to 600 mg (about 10mg per kg) daily preferably before breakfast.
For child, up to 20mg per kg daily to a maximum of 600 mg.
Description: Brick-red to reddish brown, crystalline powder; practically odourless.
Solubility: Soluble in chloroform and in methanol; slightly soluble in acetone, in
ethanol, in ether, in water.
Storage:

Store in well-closed, light- resistant containers.
Absorption and Fate: Rifampicin is readily absorbed from GIT and peak plasma
concentration of about 7 to 10 g per ml have been reported in 2 to 4 hrs after a dose of
600mg but may be considered individual variation. Food may reduce and delay
absorption. Rifampicin is approximately 80% bound to plasma protein. It is widely
distributed in body tissues and fluids and diffusion into the CSF is increased when the
meninges are inflamed. Rifampicin crosses the placenta and is distributed into breast
milk. Half life for Rifampicin has been reported to the range initially from 2 to 5 hours,
the longest elimination time occurs after largest dose. Rifampicin is mainly metabolized
27
in the liver mainly to active desacetylrefampicin; rifampicin and desacetylrefampicin are
excreated in the bile.
Uses and administration: Rifampicin belongs to the rifamycin group of
antimycobecterial and is used in the treatment of various infections due to mycobecteria
and other susceptible organisms. It is usually given combined with other antibacterial to
prevent the emergence of resistant organisms.
Preparations:
BP 1998: Rifampicin capsule, Rifampicin oral suspension.
USP 23: Rifampicin and Isoniazid capsule; Rifampicin capsule, Rifampicin or
injection; Rifampicin oral suspension.
62,72,73
Past work done on Rifampicin:
Singh S et al (2002) determine the behavior of moisture gain by four anti-
tubercular drugs, viz. Isonaizid, Rifampicin, Pyrazinamid, Ethambutol, when exposed to
the pure form and in combination to accelerated condition of 40Cand 75%RH, in
presence and absence of light. Weight gain was observed only in those samples that
contained ethambutol, and the behavior was observed both in dark and in lighted
chambers. The most interesting finding was an overall acceleration of weight gain in the
presence of light as compared with dark conditions.
74
Mariappan TT et al (2004) observe, when present in fixed-dose combination
(FDC) of anti -tubercular drugs, Rifampicin and Isoniazid interact with each other to
form Isonicotinyl hydrazone. The analysis of combinations of Rifampicin and
Isonicotinyl hydrazone revealed that Rifampicin could be overestimated to a miximum
extent 33%. The Study suggested any method devoid of interference of Isonicotinyl
hydrazone should be preferred for analysis of Rifampicin, whatever it is present along
with Isoniazid.
75
28
Panchagnula R et al investigate the effect of food on the bioavailability of
Rifampicin from anti-tubercular fixed dose combination formulations. They assessed the
effect of hydrodynamic stress in presence of food and meal composition on 2 Rifampicin
containing fixed dose combination formulations by carrying out dissolution at different
agitation rates (Simulation of fasted and fed state) as well as presence of different
percentage of oil (fatty food). Agitation intensity as well as presence oil did not had any
influence on Rifampicin release from formulation A. they concluded food may not has
have any effect on the release of Rifampicin from the formulation and subsequently on its
bioavailability if the formulation has excellent release profile( > 85% release in 10 min.),
further. Effect on food on the Rifampicin release was a function of dosage form
characteristics such as disintegration time and dissolution rate, which will subsequently
affect the release behavior of the formulation in presence of food.
76
Rao BS et al (2001) investigate the possibility to develop different levels of
correlation between in vitro dissolution parameters and in vivo pharmacokinetic
parameters for three Rifampicin formulations. A level A correlation of in-vitro
dissolution and in-vivo absorption could be obtained for individual plasma level data by
means of the Wagner Nelson method.
77
Past Work Done On Drug Delivery System
Literature reviews reveals the vast research in the area of development of
dispersible tablets.
Shimizu T, et al., (2003) formulated Lansoprazol fast disintegrating tablet, which
consists of enteric-coated microgranules and inactive agents, MCC, L-HPC, L-HPC33
(New type) and Crospovidine were used as binders and disintegrates. Rapid
disintegration time, in mouth (<30 secs) and dissolution behavior studied in acid stage
and buffer stage were evaluated and compared with current capsules.
78
29
Lalla JK, et al, (2004) prepared fast dissolving Rofecoxib tablets by forming
inclusion complexes between Rofecoxib and -cyclodextrin using ball mill technique and
evaluated by using DSC technique. Tablet disintegration times were in the range of 30-
40s. The dissolution study indicates either wet or dry granulation, which showed
complete release of drug. Rofecoxib tablets showed complete release in 12 min as
compared to 12% drug release from conventional marketed tablets during same period.
79
Kuchekar BS, et al., (2004) prepared Sumatriptan succinate mouth dissolving
tablets using disintegrates such as sodium starch glucolate, carboxy methylcellulose
sodium, and treated agar by direct compression method. The prepared tablets were
evaluated for various parameters. The tablet disintegration in-vitro and in-vivo was found
to be 10 to 16 sec respectively. The formulations containing combination of sodium
starch glycolate and carboxy methylcellulose was found to be giving best result.
80

Mukesh G, et al, (2004) Formulated, designed and optimized the mouth
dissolving tablets of Nimesulide using vacuum drying technique. Granules were prepared
by using camphor and crospovidone, and then exposed to vacuum for camphor
sublimation and compressed. Alternatively next tablets were first prepared and then
exposed to vacuum. In conclusion a 3
2
full factorial designed was used to investigate the
joint influenced of 2-formulation variable: amount of camphor and crospovidone. From
multiple linear regression and contour plot, sublimation of camphor from tablets resulted
superior tablets.
81
Yang S, et al, (2004) developed the FDT using poly (acrylic acid) superporous
hydrogels microparticals. Compression behavior of SPH micropartical, filler, tableting
pressure and each factor contained three levels on the disintegration time and tensile
strength of the prepared FDTS. SPH microparticals FDT showed fastest disintegration
time and higher tensile strength and thus concluded good superdisintegrant.
82
30
Fahum, et al, (2004) Invented orodispersible tablets containing Fexofenadine in
the form of coated granules and mixture of excipients comprising of at least one
disintegrating agent, a lubricant and organoleptic additives.the granules posses all
pharmaco-technical property.
83
Amin PD, et al, (2004) Prepared the fast disintegrating dosage form of Oflaxacin
and Metronidazole benzoate. They optimized the process of taste masking with respect to
parameters like time required for complexation, percentage loading and volume required.
They showed that the ion exchange resins could be successfully used, as both taste
masking agent and superdisintegrants.
84
Abdelbery G, et al, (2005) determined the in-vivo disintegration profile of
rapidly disintegration tablets and correlation with oral disintegration with the use of the
texture analyzer. They have shown in their study that the obtained time-distance profile
or disintegration profile and calculated values reflected the mechanism of disintegration
of different RDT and gave a qualitative measure of their mouth feel.
85
Patravale VB, et al, (2005) Focused on the quinine sulphate having bitterness
threshold of 0.0007% indicating its intense bitter taste. They developed the process for
preparing drug resonates was optimized with respect to parameters like drug and resin
ratio, volume of medium and taste of the complex. Ratio of 1:5 drugs to Indion 234 gave
a complete taste masked complex, which could be easily incorporated in a prototype
suspension formulation to give a palatable product. Indion 234 was found to be superior
in formulating taste masked suspension of Quinine sulphate.
86
Chaudhari PD, et al, (2004) Studied the bitter taste of Fomatidine was masked
using drug: Eudragit E-100 to 1:4 by time intensity method and prepared the fast
disintegrating tablets using different superdisintegrants with their varying concentrations.
The dissolution release rate from all the formulations were studied and to be 100% in 4
31
min in the case of formulation containing 3% and 5% of Ac-Di-Sol and polyplasdone
showed 91.89 %and 101% release respectively in 12 min.
87
Mahayana HS, et al, (2000) developed the rapidly disintegrating tablets for
elderly patients and they concluded that rapidly disintegrating tablets can be prepared by
conventional direct compression method using superdisintegrants which show rapid rate
of disintegration and alternate form of oral medication for elderly.
88
Mizumoto T et al, (2005) designed the formulation of novel fast disintegrating
tablets as a user-friendly dosage form for the aged using Acetaminophen as a model drug.
Mannitol and lactose were used as the low compressibility saccharide and maltose as the
high one and as the binder for granulation. Aspartame and Menthol flavor were used as a
taste masking for the bitter teste of Acetaminophen.
89
A new approach to prepare RDT with sufficient mechanical integrity was
proposed by Abdelbary A. et al (2004), involving the use of a hydrophilic waxy binder
(superpolystate) PEG-6- stearate). Superpolystate) PEG-6- stearate act as a binder and
increased the physical resistance of tablet but will also help the disintegration of tablets
as it melt in the mouth and solublises rapidly leaving no residues. Scanning electron
microscope (SEM) was used to examine their morphological characteristics. The
potential of intragranular addition of crosscarmellose sodium as a disintegrating agent
was also evaluated. An improvement in tablet hardness and friability was observed.
90
A rotatable central composite design was used by Barbal R. et al (1998) to
evaluate the effect of lubricant and compression force on the physical characteristics of
effervescent tablet. Effervescent tablets lubricated with a combination of spray dried L-
leucine and polyethylene glycol 6000 are prepared by direct compression and evaluated.
Residual force, crushing strength and disintegrating time are considered as response
variables and related to the L-leucine and polyethylene glycol concentration and to the
32
compression force. The calculation models are used to assess the crushing strength and
prolong tablet disintegration, the L-leucine concentration is kept at a low level.
91
Shicheng Y. et al (2004) used poly (acrylic acid) as a wicking agent to decrease
disintegration time of fast disintegrating tablets (FDTs). Compression behavior of poly
(acrylic acid) SPH microparticals was evaluated by Kawakita equation. They observe the
effect of various SPH microparticals size and a 19 run fractional factorial design. The
factorial design based on four factors consisting Ketoprofen, SPH, micropartical and
tableting pressure, and each factor contained three levels on the disintegration time and
tensile strength of the prepared FDTs. The compressibility of SPH microparticals
increased significantly as the microparticals size increased. They concluded poly (acrylic
acid) SPH microparticals could serve as a good Super-disintegrent decreasing the
disintegration time of FDTs.
92

Panday VP et al (2007) formulated dispersible tablets of Solbutamol sulphate as
paediatric dose. They used dry granulation method for the formulation of Solbutamol
dispersible tablets and evaluate other pharmacopoeial and non- Pharmacopoeial
specifications. They concluded that the formulated tablets are stable, safe and patient
compliance.
93
Belgamwar AV et al (2007) prepared fast releasing Carbamazepine tablets for
kids by using the solid dispersion process. The tablets were prepared by melt granulation
method and evaluate the tablets for official parameters. They found that the tablets are
fulfilled all the official parameters and formulation prepared with crosprovidine gave rise
to ameliorate of the disintegration and dissolution performance and proved best for
kids
94
.
Shukla V. et al (2007) formulated Piroxicam dispersible tablets with natural
disintegrants by direct compression and wet granulation method using starch paste as a
binder. The formulated tablets were evaluated for official parameters. They concluded
33
that formulated formulations fulfill all official requirements and gave fast and rapid
dissolution of drug.
95
Madukar AR et al (2007) studied the efficiency of Indion 414 and Amberlite
IRP 88 as superdisintegrent in mouth dissolve tablets. The Nimuslide dispersible tablets
with Indion 414 and Amberlite IRP 88 were prepared and evaluated for disintegration
effect. The concluded that Indion 414 was found to be better superdisintegrants.
96
Chebli C and Cartilier L (1998) evaluated properties of a new tablet
binding/disintegrating agent, cross-linked cellulose (CLC) in comparision with other
binding/disintegrating agents widely used in tablet manufacturing such as Avicel PH101
and Avicel PH 102, as well as with superdisintegrents known for their high efficiency
such as Ac-di sol and Explotab. CLC C25 was obtained y simple reaction of cellulose
with epichlorohydrin in strong basic medium. The effect of CLC-C25 concentration on
particle properties of direct compression tablets was also studied. CLC-C25 demonstrated
good binding/disintegrating agents
97
.
A rapidly disintegrating tablet in oral cavity was prepared using glycine as a
disintegrant by Fukami J et al (2006). They determine the effect of disintegrant on the
disintegration behavior of the tablet in the oral cavity. The wetting time prepared from
carboxymethylcellulose (NS-300) having hardness of 4 kg was 3 second. Tablet
containing NS-300Showed fastest disintegration compared to other formulations
98
.
Malke S et al (2007) formulated and evaluate Oxcarbazine fast-dissolve tablet for
the treatment of convulsion in adults and childrens. The tablets were prepared containing
Avicel PH102 as a diluent and Ac-di-sol as a superdintegrents by wet granulation
process. All the formulation was evaluated for characteristics of dispersible tablets. They
conclude formulated Oxcarbazine fast-dissolve tablet were suitable for the treatment of
convulsion in adults and childrens
99
.
34
Patel MM and Patel DM(2006) prepared and evaluated Valdecoxib Fast
dissolving tablets containing solid dispersion of Valdecoxib. Solid dispersion of
Valdecoxib with mannitol, polyethylene glycol 4000, and polyvinylpyrrolidone K-12
were prepared with a view to increase its water solubility. The formulation was found to
be stable for 4 weeks at 45, with insignificant change in the hardness, disintegration time
and in vitro drug release pattern
100
.
Adamo F et al (2008) developed fast dispersible and slow release Ibuprofen
tablets. To prevent bitter test and side effect of the drug, the drug is associated with
Phosphophlipon 80H, a saturated lecithin by wet granulation. The granules were then
formulated with sweetener (Aspartame), a mannitol-based diluent( pearlitol SD200) and
Kollidon CL(1-4K) were added as added as superdisintegrants and compacted under low
compression force. They concluded an appropriate combination of excipients it is
possible to obtain orally disintegarating tablets and a delayed release of ibuprofen using
simple and conventional technique
101
.
Chandrashekhar R et al (2009) evaluated the role of formulation excipients in
the development of lyophilized fast-disintegrating tablets, using a progressive three-stage
approach. A series of hardness, fracturability and disintegration time test were performed
on the formulations at each stage. During stage 1, tablets were prepared in concentrations
between 2% and 5%w/w, and were formulated at each concentration as single and
combinational bloom strength gelatin using 75 and 225BSGs. They concluded hardness
and disintegration time increased with an increase in gelatin concentration
102
.
Sekar V and Chellan VR (2008) formulated and evaluated the immediate release
tablets of Telmisartan using Polyplastadone XL superdisintegrants. The prepared
granules and tablets evaluated for their physiological properties and in-vitro dissolution
study. They concluded immediate release tablets with proper hardness, disintegration
time and with increase rate of dissolution can be made using Polyplastadone XL
103
.
35
Shukla V et al (2008) prepared and evaluated Clozapine dispersible tablets, using
different superdisintegrants such as Ac-di-Sol, Polyplastadone XL, Explotab for the
effective management of Schizopherenia. The tablets were prepared by direct
compression and sublimation method. The prepared formulations showed acceptable
pharmaco-technical properties. They concluded the mouth dissolving tablets could be a
promising drug delivery system for Clozapine with good mouth feel and improved drug
availability with better patients compliance
104
.
Balasubramanium J et al (2008) studied the effect of selected superdisintegrants
on the dissolution behavior of several cationic drugs with varying water solubility. All
formulations were made with fixed disintegrant concentration and equal drug load using
a model formulation. Tablets were formulated by direct compression and were
compressed to equal hardness. They conclude crospovidone can be effectively used as a
tablet disintegrant to improve the dissolution of either soluble or poorly soluble cationic
drugs
105
.
Seong HJ and Park K (2008) studied the complex formation between drugs and
ion change resin and the effect of coating by various aqueous polymeric dispersions on
the complex were evaluated for developing new sustain release fast-disintegrating tablets.
Complexes of ion change resin and Dextromethorphen, a model drug, were using
different particle sizes of the resin. Aqueous colloidal dispersion of ethyl cellulose and
poly (vinyl acetate) were used for fluid-bed coating. Drug release profiles and SEM
pictures were compared before and after the manufacturing process. They conclude as the
particle size increase, the drug loading and release rate decrease due to the reduced
effective diffusion coefficient and surface area, higher coating level decrease the release
rate further
106
.
Anisul Q and Kotlar K (2006) conducted a comparative study of different
superdisintegrants. The compared various superdisintegrants (Ac-di sol, Primogel,
36
Polyplastadone XL, Kollidon CL) in term of physiological properties and use in direct
compression and wet granulation. They conclude particle size distribution of
Polyplastadone XL is broader, and the swelling volume is bigger then those of Kollidon
CL. Kollidon F and SF grades had a substantially smaller particle size then Kollidone
CL and Polyplastadone XL and showed higher swelling volumes and hydration
capacities
107
.
Profile of polymer and excipients used
MICROCRYSTALLINE CELLULOSE (Avicel PH 102) :
108
Nonproperietary Name:
NF : Microcrystalline cellulose.
USP : Microcrystalline cellulose.
Functional Category: Tablet and capsule diluent, tablet disintegrant, suspending
and/or viscosity increasing agent.
Synonyms: Cellulose gel, Crystalline cellulose, Avicel PH 101,102,
Chemical names: Cellulose
CAS Registry Number: 9004-34-6
Empirical formula: (C
6
H
10
O
5
)n n=220
Molecular weight: 36,000(approx)
Structure:
O O
H
O
CH
2
OH
H
OH
H
H
OH
H
CH
2
OH
H
O
OH
H
OH
H
H
H
H H
O
O H
H
OH
H
CH
2
OH
O
H
OH
H
CH
2
OH
H
O
H
OH
OH
H
OH
H
Microcrystalline Cellulose
37
Description: Purified, partially depolymerized cellulose occurs as a white, odorless,
tasteless, crystalline powder composed of porous particles.
Density:
Apparent density- 0.28g/cm
3
Tap density- 0.43g/cm
3
Solubility: Insoluble in water, dilute acids and most organic solvents, slightly soluble in
5% w/v NaOH solution.
Stability and Storage Conditions: Stable and hygroscopic. Store in a well closed
container.
Incompatibilities: None cited in the literature.
Safety: Generally regarded as safe.
Applications:
Tablet binder/diluent (wet or dry granulation) 5 to 20%
Tablet disintegrant 5 to 15%
Tablet glidant 5 to 15%
Antiadherent 5 to 20%
CROSSCARMELLOSE SODIUM (Ac-di-sol, Cellosol):
109
Nonproprietary names:
USP: Carmellose sodium
BP: Carmellose sodium
Functional category: As a superdisintegrant.
Synonyms: Ac-di-sol, Carmellose sodium.
CAS Registry Numbers: [9050-32-4]
Molecular weight: 608.18
38
Description: Cross linked sodium carboxymethylcellulose White, free flowing powder
with high absorption capacity. Contains no sugar or starch.
Solubility: Easily Dispersed in Water
Stability and storage conditions: Crosscarmellose sodium is a stable though
hygroscopic material. Crosscarmellose sodium should be stored in a well-closed
container in a cool, dry, place.
Safety: It is inert and nontoxic.
Applications in pharmaceutical formulation: Crosscarmellose sodium is used in oral
pharmaceutical formulations as a disintegrant for Capsules, Tablets and Granules. In
tablet formulations, Crosscarmellose sodium may be used in both direct-compression and
wet-granulation processes.
CROSSPOVIDONE (Polyplasdone XL):
108
USP: Povidone
BP: Povidone
Functional category: Superdisintegrant, tablet binder, suspending or viscosity
increasing agent, sweetening agent
Synonyms: Kollidon, plasdone, polyvinylylpyrrolidone.
Chemical name: 2-pyrrolidinone, 1-ethenyl-, homopolymer 1-Vinyl-2-
pyrrolidinone-polymer
6
H
9
NO)n
Molecular weight: 10,000 to 7,00,000
Description: It is white to creamy white, odorless or almost odorless, hygroscopic
powder.
39
Solubility: Readily soluble in water up to 60%. Freely soluble in many organic solvents.
Storage conditions: Store in a moisture-proof, tight container to prevent decomposition
Applications in pharmaceutical formulation: As a superdisintegrant, carrier for drugs,
dispersing agent, tablet binder and as a diluents.
SODIUM STARCH GLYCOLATE (Explotab):
108
Non-Proprietary Name:
NF: Sodium starch glycolate
BP: Sodium starch glycollate
Functional Category: Tablet disintegrant, Tablet and capsule disintegrant
Synonyms: Sodium carboxy methyl starch; Explotab; Primojel
Chemical Names: Starch carboxymethyl ether, Sodium Salt
Structural Formula:
O O O
H
CH
2
OH
O
H
O
H
H
OH
H
H
OH
CH
2
O-CH
2
COONa
OH
H
H
OH
H
O
H
CH
2
OH
OH
H
H
OH
H
O
SODIUM STARCH GLYCOLLATE
H
Description: White to off-white, odourless, tasteless, free-flowing powder.
Microscopic: Oval or spherical granules, 30-100 m in diameter with some less-spherical
granules ranging from 10-35 m in diameter.
Solubility: Soluble in water and insoluble in organic solvents
Stability and Storage Conditions: Stable, store in a well-closed container, variations in
humidity and temperature that may cause caking. It has long shelf-life stability.
40
Incompatibilities: No citations found.
Applications in Pharmaceutical Formulation or Technology: It is used in
tablet/capsule as disintegrant (wet granulation or direct compression) in concentration
range 2-10%
KOLLIDON CL
110
USP: Kollidon 12
BP: Kollidon 12
Functional category: As a superdisintegrant, Tablet binder, suspending or
viscosity increasing agent, sweetening agent
Synonyms: Povidonum, Povidon(e).
Chemical name: Polyvinylpyrrolidone, povidone
CAS Registration No: 9003-39-8
6
H
9
NO)n
Molecular weight: 2,000 to 15,00,000.
Structural formula:

Description: It is white to creamy white, odorless or almost odorless, hygroscopic
powder.
Solubility: Kollidon CL is insoluble in all the usual solvents.
Storage conditions: Store under ordinary conditions in a moisture-proof, tight container.
41
Applications in pharmaceutical formulation: The main function is as super-
disintegrant in tablets to fasten disintegration and dissolution. Like the soluble products
crospovidone improves the bioavailability of some hardly soluble actives.
CAMPHOR:
109
Synonyms: Gum Camphor
CAS Registration No: 76-22-2
Molecular Weight: 152.24
Chemical Formula: C
10
H
16
O
Chemical name: Bicyclo [2,2,1] heptan 2-one, 1,7,7-trimethyl-camphor 2-
bornanone
Structure:
CH
3
C H
3
C H
3 O
Handling and Storage:
Keep in a tightly closed container. Store in a cool, dry, ventilated area away from
sources of heat or ignition. Protect against physical damage. Store separately from
reactive or combustible materials, and out of direct sunlight. Isolate from incompatible
substances. Containers of this material may be hazardous when empty since they retain
product residues (dust, solids); observe all warnings and precautions listed for the
product.
Description: Colorless or white crystalline solid, fragrant penetrating odor.
Solubility: 1 in 10 solution in Hexone is clear.
42
Melting point: 176 to 180 C
Application: As a rubefacient, as a plasticizer for cellulose esters and ethers, explosives
and pyrotechnics, as a moth repellent, as a preservative in pharmaceuticals and
cosmetics.
MANNITOL:
108
USP: Mannitol
BP : Mannitol
Functional category: Tablet and capsule diluent, sweetening agent, tonicity
agent, vehicle (bulking agent) for lyophilized preparations.
Synonyms: Mannite; manna sugar; manita.
Chemical name: 1,2,3,4,5,6 Hexanehexol.
CAS Registry Number : 69-65-8.
Empirical formula: C
6
H
14
O
6
Structural Formula:
CH
2
OH
C
C
C
C
H
H
OH
OH
O H
O H
H
H
CH
2
OH
Mannitol
Description: White, odorless, crystalline powder, or free flowing granules. One half as
sweet as sucrose and about as sweet as glucose.
Density:
Particle : 1.48 g/cm
3
43
Bulk : 0.401 g/cm
3
Tapped : 0.58 g/cm
3
Solubility: Freely soluble in water, practically insoluble in ether.
Stability and Storage conditions: Mannitol is stable in dry state and in aqueous
solutions. In solution it is not attacked by cold, dilute acids or alkalies, not by
atmospheric oxygen in the absence of catalysts. No special storage conditions are
required. Store in a well closed container.
Incompatibilities: None reported in dry state. Mannitol is incompatible with a xylitol
infusion and forms complexes with metals like Fe, Al and Cu
Safety: When consumed orally in large quantities laxative effects may occur. Daily
ingestion of over 20 G is foreseeable.
Applications: As a diluent in tablets (10-90% w/w). It is not hygroscopic and can be
used with moisture sensitive active ingredients. In the manufacture of chewable tablet it
is used because of its negative heat of solution, sweetness and mouth-feel.
SACCHARIN SODIUM:
108
USP: Saccharin sodium
BP: Saccharin sodium
Functional category: Sweetening agent
Synonyms: Soluble saccharin, sodium o-benxosulfimide.
Chemical names: 1,2-Benzisothiazol-3(2H)-one-1,1-dioxide, sodium salt
7
H
4
NNaO
3
S
Molecular formula: 205.16
44
Structural formula:
S
N
O
O
O
-
Na
+
Description:
It is white, odorless or faintly aromatic, crystalline powder with an intensely
sweet taste.
Solubility: soluble in water and ethanol.
Stability and storage conditions: Store in an airtight container
Safety: estimated acceptable temporary daily intake up to 2.5 mg kg of body weight.
Applications in pharmaceutical formulation: As a sweetening agent, as a sugar
substitute in preparations for diabetics
MAGNESIUM STEARATE:
108
NF : Magnesium stearate.
BP/EP: Magnesium stearate.
Synonyms: Metallic stearic; Magnesium salt.
Functional category: Tablet and capsule lubricant.
Chemical names: Octadecanoic acid; Magnesium salt; Magnesium stearate
CAS Registry number: 557-04-0
36
H
70
MgO
4
Structural Formula:
Magnesium Stearate
CH
3
(CH
2
)
16
COO
CH
3
(CH
2
)
16
COO
Mg
45
Description: It is a fine, white, precipitated or milled, impalpable powder of low bulk
density, having a faint characteristic odor and taste. The powder is greasy to touch and
readily adheres to the skin.
Density (He) : 1.03-1.08 g/Cm
3
Bulk volume : 3.0-8.4 ml/g
Tapped volume: 2.5-6.2 ml/g
Solubility: Practically insoluble in ethanol, ethanol (95%), ether and water, slightly
soluble in benzene and warm ethanol (95%).
Stability and Storage Conditions: Stable, non-self polymerizable. Store in a cool, dry
place in a well closed container.
Incompatibilities: Incompatible with strong acids, alkalies, iron salts and with strong
oxidizing materials.
Safety: Described as inert or nuisance dust. OSHA has adopted limits of 15mg/m
3
for
the total dust and 5mg/m
3
for the respirable fraction. Dust clouds of magnesium stearate
may be explosive. However, oral consumption of large quantities may result in some
laxative effect or mucosal irritation.
Applications: Tablet and capsule lubricant, glidant and antiadherent in the concentration
range of 0.25 to 2.0%.
TALC:
108
USP : Talc
BP/EP : Purifeid talc.
Synonyms: French chalk; purified chalk; talcum: soapstone; steatite.
Functional category: Tablet and capsule lubricant;glidant; talc dusting powder;
antiadhesives.
46
Chemical names: Hydrous magnesium silicate.
CAS Registry number: 14807-96-6
Empirical formula: Mg
6
(Si
2
O
5
)
4
(OH)
4
Description: A very fine, white to greyish white, impalpable, odorless crystalline
powder, unctuous; adheres readily to skin; soft in touch free from grittiness.
Density:
Loose, CTFA-C8-1 : 19-24 lb/ft
3
Tapped, CTFA-C7-1 : 48-62.5 lb/ft
3
pH (1:5 dilution) : 6.5-10
Solubility: Insoluble in water, Organic solvents, cold acids and dilute alkalis.
Stability and Storage Conditions: Stable. Preserve in a well closed container.
Incompatibilities: Quaternary ammonium compounds
Safety: Should not be applied to open wounds or used on surgical gloves. Prolonged and
intense exposure to talc may produce pneumoconiosis. Talc should not be inhaled.
Applications:
Lubricant in tablet and capsule - 1-4%
Filler for tablets - 5-30%

Chapter IV Materials and Methods
47
MATERIALS AND METHODS
MATERIALS:
The following materials that were either AR/LR grade or the best possible pharma
grade available were used as supplied by the manufacturer.
S. No. MATERIALS GRADE Manufacturer
1. Isoniazid IP Macloads Pharma. Ltd, Mumbai,
India
2. Rifampicin IP Macloads Pharma. Ltd, Mumbai,
India
3. Avicel pH 102 (MCC) Pharma Signet chemical, Mumbai
4. Kollidon CL Pharma Gujarat Microwax Ltd, Indore
5. Ac-di-sol Crosscarmellose) Pharma FMC biopolymer, USA
6. Cellosol (Crosscarmellose) Pharma Gujarat Microwax Ltd, Indore
7. Polyplasdone XL
(Crosspovidone)
Pharma Sun pharma, Mumbai
8. Explotab (SSG) Pharma Forum bioscience, England (U.K.)
9. Camphor L.R. S.D. Fine-Chem Ltd., Mumbai,
India
10. Ammonium bicarbonate L.R. Ranbaxy Fine-Chem. Ltd, Delhi
11. Ammonium carbonate L.R. S.D. Fine-Chem Ltd., Mumbai,
India
12. Mannitol L.R. Ranbaxy Fine-Chem. Ltd, Delhi
13. Sodium saccharin L.R. Genuine chemical corporation,
Mumbai
14. Magnesium Stearate L.R. Loba Chemie Pvt. Ltd., Mumbai,
India
15. Talc L.R. S.D. Fine-Chem Ltd., Mumbai,
India
16. Hydrochloric Acid L.R. S.D. Fine-Chem Ltd., Mumbai
48
S. No. MATERIALS GRADE Manufacturer
17. Potassium dihydrogen
orthophosphate
L.R. Ranbaxy Fine Chemicals Ltd., New
Delhi, India
18. Di-potassium hydrogen
orthophosphate anhydrous
L.R. S.D. Fine-Chem Ltd., Mumbai,
India
19. Acetone L.R. S.D. Fine-Chem Ltd., Mumbai,
India
20. Potassium bromide (KBr) L.R. S.D. Fine-Chem. Ltd., Mumbai
EQUIPMENTS AND ACCESSORIES:
S. No. Name Manufacturer
1.
Afcoset Electronic Balance The Bombay Burmah Trading Corp. Ltd.,
Bombay, India
2.
Hydraulic / Pellet Press Type-
WT
Kimaya engineers, Pokharan Road-I,
Upwan, Thane-400606, India
3. Monsanto Hardness tester Campbell electronic, Bombay
4. Friability Test Apparatus Campbell Electronics, Bombay, India.
5. Dial Caliper Mututoyo, Japan
6. Disintegration test apparatus Electrolab
7. Dissolution Apparatus USPXXIII Electrolab-Tablet Dissolution Tester
8. FTIR 200 Spectrometer Thermo Nicolet
9. Hot Air Oven P.S.M. Industries, Bangalore, India
10.
Distillation Assembly Model
No.MOD2PQ
Bhanu Scientific Instruments Co. Pvt.
Ltd., Bangalore, India
11.
Jasco-/V/-/5/3/0/-U.V./ Vis
Spectrophotometer (Model V-
530)
Jasco Corporation, Japan
49
METHODS:
1) Preparation of Standard Calibration Curve:
Drug 1 Isoniazid
Standard Curve for Isoniazid:
111
The standard curves for Isoniazid were prepared in distilled water, phosphate
buffer (pH 6.8) and methanol. Accurately 100 mg of Isoniazid were dissolved in 100 ml
of three different solvents such as distilled water, phosphate buffer (pH 6.8) and
methanol respectively. 1 ml of each of these solutions was diluted to 100 ml with distilled
water, phosphate buffer pH 6.8 and methanol respectively. The resulting stock solutions
were diluted to 10 ml with their respective solvents to give Isoniazid solution of 2, 4, 6,
8, 10 g/ml concentration. The absorbance of prepared solutions of Isoniazid in distilled
water, phosphate buffer (pH 6.8) and methanol were measured individually at
max
263
nm, 261 nm and 267 nm respectively, in UV Shimadzu spectrophotometer against the
respective medium as blank.
The absorbance data for standard curves are given in Tablet no. 2. Standard curve
follow the Lambert-Beers Law in concentration range of 1-10 g/ml. All the readings
were taken in triplicate.
Drug 2 Rifampicin
Standard Curve for Rifampicin:
112
The standard curves for Rifampicin were also prepared in distilled water,
phosphate buffer (pH 6.8) and methanol. Accurately 100 mg of Rifampicin was dissolved
in 100 ml of distilled water, phosphate buffer (pH 6.8) and methanol respectively. 1 ml of
each of these solutions was diluted to 100 ml with distilled water, phosphate buffer (pH
6.8) and methanol respectively. The resulting stock solutions were diluted to 10 ml with
50
their respective solvents to give Rifampicin solution of 2, 4, 6, 8, 10 g/ml concentration.
The absorbance of prepared solutions of Rifampicin in distilled water, phosphate buffer
(pH 6.8) and methanol were measured at
max
256 nm, 333 nm and 244 nm respectively,
in UV Shimadzu spectrophotometer against the respective medium as blank.
The absorbance data for standard curves were given in Tablet no. 2. Standard
curve follow the Lambert-Beers Law in concentration range of 1-10 g/ml. All the
readings were taken in triplicate.
2) Formulation Development of Fast Disintegrating Tablets:
Direct Compression Technique:
113-114
The vast majority of medicinal agents are rarely so easy to tablet, however in
addition, the compression of a single substance may produce that do not disintegrate. If
disintegration is the problem, other component are needed, which in turn may interfere
with the compressibility of the active ingredient and thus minimize the usefulness of the
method. Most materials posses relatively weak intermolecular attraction or are covered
with films of adsorbed gases that tend to hinder compaction. Thus, most large-dose drugs
do not lend themselves to this process. With many other drugs having small doses,
uniform blends of the drug and coarser direct compression diluents can not be achieved,
which make this process impractical. However, the use of compressible diluents with
many moderate dose drugs makes this process the most streamlined method of tablet
manufacture.
A directly compressible diluent is an inert substance that may be compacted with
little difficulty and may be compressed even when quantities of drugs are mixed with it.
Compression capacity is still maintained when other tablet material necessary to flow,
disintegration, and so forth are blend in direct compression materials, in addition to
possessing good flow and compressibility, must be inert, tasteless, reworkable, able to
51
disintegrate, and inexpensive. Even through direct compression has some important
advantage there are some limitations to the technique.
1. Differences in particle size and bulk density between the drug and diluent may
lead to stratification within the granules. The stratification may then result in poor
content uniformity of the drug in the compressed tablet. The stratification and
resultant content uniformity are problems of special concern with low dose drugs.
2. A large dose drug may present problems with direct compression if it is not easily
compressible by itself. To facilitate compression, non-compressible large dose
drugs, which are usually restrict to about 30% of a direct compression formula,
could require an amount of diluent so large that the resultant tablet is costly and
difficult to swallow.
3. In some instances, the direct compression diluent may interact with the drug. A
good example of such a reaction is that which occurs between amine compounds
and spray dried lactose, as evidenced by a yellow discoloration.
4. Because of the dry nature of direct compression, static charge build up can occur
on the drug during routine screening and mixing, which may prevent uniform
distribution of the drug in the granulation.
The equipment and procedures used in direct compression are basically screening or
milling and mixing.
Direct compression has some advantage such as:
- Low labor input
- A dry process
- Fewest processing steps
Selection of anti-tubercular agents as model drugs:
The novel, fast disintegrating system was applied to model drug to verify its
practical use. The tablet characteristics containing high dose anti-tubercular agents
52
(Isoniazid, Rifampicin) as a model drug were evaluated. Rifampicin and Isoniazid are the
drugs of choice for treating tuberculosis. Fixed dose combination of two, three or four
drugs is a preferred dosage form for efficient reduction in viable bacterial population and
minimizing development of resistance to anti-tubercular drugs. The lower dose
combination formulations of Isoniazid and Rifampicin were formulated to identify the
possible cause for the significant impaired bioavailability of Rifampicin in Fixed Dose
Combination (FDC).
Method of Preparation of Isoniazid Dispersible Tablets:
Different Isoniazid dispersible tablet formulations were prepared by direct
compression technique according to the formula given in Table no. 1. The concentration
of disintegrants was selected based on factorial design. A total of 4 formulations were
prepared. All the ingredients were passed through 60 mesh sieve separately and collected.
The drug and Avicel pH 101 were mixed in a small portion of both and each time
53
blended to get a uniform mixture in a geometrical order. The tablets were then
compressed using 10 mm size punches to get a tablet of 100 mg Isoniazid using hydraulic
press with suitable standard punches and stored in a well-closed container till use. In the
first set 4 batches of Isoniazid fast dispersible tablets were prepared using different
concentration of sodium starch glycolate and other super disintegrants.
Method of Preparation of Rifampicin Dispersible Tablets:
In experimental batches the total weight of Rifampicin was kept constant i.e. 100
mg. The optimum concentration of disintegrant was selected based on its concentration
required to disintegrate tablet within 3 minutes under experimental formula and
conditions of preparation. A total of 4 formulations were prepared. All the ingredients
were passed through 60 mesh sieve separately and collected. The Rifampicin and Avicel
pH 102 were mixed in a small portion of both and each time blended to get a uniform
mixture in a geometrical order. The tablets were then compressed using 10 mm size
punches to get a tablet of 100 mg uniform weight using hydraulic press with suitable
standard punches and stored in a well-closed container till use. In the first set 4 batches
of Rifampicin fast dispersible tablets were prepared using different concentration of
sodium starch glycolate and other super disintegrants.
Method of Preparation of Isoniazid and Rifampicin Combination Dispersible
Formulations:
In experimental batches the total weight of Isoniazid & Rifampicin was kept
constant i.e. 50 mg respectively, to determine efficiency of the formulation at lower
concentration. The optimum concentration of disintegrant was selected based on the
disintegration of formulation within 3 min. A total of 4 formulations were prepared. All
the ingredients were passed through 60 mesh sieve separately and collected. The
Isoniazid, Rifampicin and Avicel pH 102 were mixed in a small portion of both and each
54
time blended to get a uniform mixture in a geometrical order. The tablets were then
compressed using 10 mm size punches to get a tablet of 100 mg uniform weight using
hydraulic press with suitable standard punches and stored in a well-closed container till
use.
In the first set 4 batches of Isoniazid and Rifampicin combination fast dispersible
tablets were prepared using different concentration of sodium starch glycolate and other
super-disintegrants.
3) Characterization and Evaluation of the Formulations:
(a) Precompression parameters:
115
(i) Drug Excipient Compatibilities Studies:
The compatibility of drug and polymers under experimental condition is
important prerequisite before formulation. It is therefore necessary to confirm that the
drug does not react with the polymer and excipients under experimental condition and
should not affect the shelf life of product. This is confirmed by Fourier Transform
Infrared Spectroscopy (FTIR). It is a powerful technique for functional group
identification of the drug molecules hence the chemical interaction of drug with the other
excipients.
In the present study, the potassium bromide disc (pellet) of drug and excipients
were prepared for recording the FTIR spectra. The spectra were taken in the
transmittance range of 4000-450 cm
-1
. The pure drugs such as Isoniazid, Rifampicin and
its formulation were subjected to IR studies.
(ii) Angle of repose ():
The frictional forces in a loose powder or granules can be measured by the angle
of repose. Angle of repose is indicative of the flow behavior of the powders, which is
55
very important parameter to have good content uniformity within the developed
formulations. Angle of repose is the maximum angle possible between the surface of a
pile of powder or granules and the horizontal plane. It is calculated from the following
equation:
tan = h/r
= tan
-1
(h/r)
Where, u = angle of repose, h = height and r = radius
The fixed weight of granules was allowed to flow through the funnel fixed to a
stand at definite height. The angle of repose was then calculated by measuring the height
and radius of the heap of granules formed.
(iii) Bulk density:
The accurately weighed amounts of granules were taken in 25 ml measuring
cylinder. Volume of granule packing was recorded before tapping thereafter measuring
cylinder containing granule was tapped 100 times on a plane hard wooden surface and
tapped volume of packing recorded. Both loose bulk density (LBD) and tapped bulk
density (TBD) were calculated by following formula:
Packing of Volume
Powder of Mass
Density) Bulk (Loose LBD =

Packing of Volume Tapped
Powder of Mass
Density) Bulk (Tapped TBD =
(iv) Compressibility index:
Percent compressibility of powder mix was determined by Carrs compressibility
index calculated by following formula.
100
TBD
LBD TBD
% index s Carr'
=
56
(b) Post compression parameters:
1. Appearance:
116
Uncoated tablets were examined under a lens for the shape of the tablet and
colour was observed by keeping the tablets in light.
2. Dimension:
116
Thickness and diameter were measured using a calibrated dial caliper. Three
tablets of each formulation were picked randomly and dimensions determined.
3. Hardness test:
116
Hardness indicates the ability of a tablet to withstand mechanical shocks while
handling. The hardness of the tablets was determined using Monsanto hardness tester. It
is expressed in kg/cm
2
. Three tablets were randomly picked and analyzed for hardness.
The mean and standard deviation values were also calculated.
4. Friability test:
117
The friability of tablets was determined using Roche Friabilator. It is expressed in
percentage (%). Ten tablets were initially weighed (W
initial
) and transferred into
friabilator. The friabilator was operated at 25 rpm for 4 minutes or run up to 100
revolutions. The tablets were weighed again when it was subjected to friabilator (W
final
).
% Friability of tablets should be less than 1% to be accepted as per Indian
Pharmacopoeia. Percent friability was then calculated by following equation:
100
=
l W
l W W
F
initia
fina initial
5. Weight variation test:
117
Ten tablets were selected randomly from each batch and weighed individually to
check for weight variation. A little variation is allowed in the weight of a tablet by U.S.
57
Pharmacopoeia. The following percentage deviation in weight variation is allowed. In all
formulations, the tablet weight is less than 324 mg, hence 7.5 percentage deviations are
allowed.
Average weight of a tablet Percentage deviation
130 mg or less 10
>130 mg and <324 mg 7.5
324 mg or more 5
6. Drug content uniformity:
118
Tablet containing 100 mg of drug (Rifampicin/Isoniazid) was dissolved in 100 ml
of Phosphate Buffer (pH 6.8). The drug was allowed to dissolve in the solvent. The
solution was filtered; 1 ml of filtrate was taken in 50 ml of volumetric flask and diluted
upto mark with phosphate buffer (pH 6.8) and analyzed spectrophotometrically at
max
261 nm and 333 nm. The concentration of drug (Rifampicin/Isoniazid) in mg/ml was
obtained by using standard calibration curve of the drug. Claimed drug content was 100
mg per tablet. Drug content studies were carried out in triplicate for each formulation
batch.
7. Wetting time:
119
The method was reported by Schmid P, et al. A conventional method was used to
measure wetting time and capillarity of the oral dispersible tablets. The tablet was placed
in a petridish of 6.5 cm diameter, containing 10 ml of water at room temperature, and the
time for complete wetting was recorded. To check for reproducibility, the measurements
were carried out six times and the mean value was calculated.
58
Petridish (i.d=6.5 cm)
Tablet
Tissue Paper
10.75 cm
1
2

c
m
Tissue Paper
Simple Method for the Measurement of Wetting Time of a Tablet
8. Water absorption ratio:
115
A piece of tissue paper folded twice was placed in a small petridish containing 6
ml of distilled water. A tablet was put on the paper and time required for complete
wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R,
was determined using equation:
10
) (
=
Wb
Wb Wa
R
Where, Wb = weight of the tablet before water absorption
Wa = weight of the tablet after water absorption
Water absorption was calculated in triplicate.
9. In vitro dispersion time:
119
Tablet was placed in 10 ml phosphate buffer solution, pH 6.8. Time required for
complete dispersion of a tablet was measured referred as dispersion time.
10. In vitro disintegration time:
117,122
The process of breakdown of a tablet into smaller particles is called as
disintegration. The in-vitro disintegration time of the dispersible formulation was
59
determined according to US Pharmacopoeia monograph for tablet disintegration testing,
using the Electrolab tablet disintegration apparatus. The disintegration time was defined
as the time necessary for the fast disintegration formulations to completely disintegrate
until no solid residue remains. Phosphate buffer pH 6.8 (simulated saliva fluid)
maintained at 37
C as the immersion liquid. The temperature of the medium was

constantly monitored with thermometer. A digital stopwatch was used to measure the
disintegration time to the nearest second. Only one tablet was analyzed at a time in order
to ensure maximum accuracy. At the end of each test, the basket rack assembly and the
plastic disk were thoroughly washed and dried to remove any trace of tablet excipients
and water. A total of six tablets were tested from each batch, the values reported are
mean standard deviation. The in-vitro disintegration time of tablet was determined
using disintegration test apparatus as per I.P. specifications.
11. In vitro dissolution studies:
123,124,125
Dissolution has emerged as a simple, rapid, and sensitive tool to judge the quality
of formulations. Based on the sound scientific principals of BCS, observed in vivo
differences in the rate and extent of absorption of a drug from two pharmaceutically
equivalent solid oral products may be due to differences in drug dissolution. Rate of
dissolution from immediate release dosage forms are generally affected by raw material
characteristics, formulation variables, and by storage. It therefore become apparent that
sensitive and reproducible dissolution data derived from physico-chemically and
hydrodynamically defined conditions can be used as a surrogate for the in vivo
bioavailability.
In vitro release studies were carried out using tablet dissolution test apparatus
USP XXIII. Objectives of in vitro dissolution tests are to show (1) Release of the drug
from tablet is as close as possible to 100 % (2) Rate of drug release is uniform from batch
60
to batch. Drug release obtained from formulations of different batches are bioavailable
and clinically effective.
Dissolution test for Isoniazid dispersible formulations:
The following procedure was employed throughout the study to determine the in
vitro dissolution rate for all the formulations.
Dissolution medium : 900 ml of phosphate buffer (pH 6.8) for 60 min.
Temperature : 37C 1C
Stirring speed : 100 rpm
Tablet taken : One tablet (drug content known) in each basket
Volume withdrawn : 10 ml every 2 minutes
Volume made up to : 10 ml
max
: 261 nm
Beers range : 1-20 g/ml
Dilution factor : 10 ml
Dissolution test for Rifampicin dispersible formulations:
USP XXIII dissolution apparatus type 1. The following procedure was employed
throughout the study to determine the in vitro dissolution rate for all the formulations.
Dissolution medium : Phosphate Buffer Saline (900 ml) pH 6.8
containing 0.02%w/v ascorbic acid.
Temperature : 37C 1C
61
max
: 333 nm
Dissolution test for Isoniazid and Rifampicin combination formulation:
USP XXIII dissolution apparatus type 1. The following procedure was employed
throughout the study to determine the in vitro dissolution rate for all the formulations.
The drug content in the formulation was estimated by the simultaneous estimation
method.
Dissolution medium : 900 ml of phosphate buffer (pH 6.8) containing
0.02%w/v ascorbic acid.
Temperature : 37
C1
C
max
: 261 nm, 333 nm
The various parameters related to dissolution which were evaluated in the present
work are as follows:
1. Drug release
2. Cumulative percentage drug release
3. Cumulative percentage drug retained
62
12. Curve Fitting Analysis:
The mechanism of drugs released from the matrix system was studied by fitting
the dissolution data in five different models.
i) Zero Order Equation
ii) First Order Equation
iii) Korsmeyer-Peppas Equation
iv) Higuchi Square Root Equation
v) Hixson Crowell Equation
13. Comparative In Vitro Drug Release Studies Between Formulations Developed
and Marketed Formulations:
Evaluations of formulations developed were subjected for comparative evaluation
of physicochemical parameters. In vitro drug release of the promising formulation was
compared with marketed product of Isoniazid, Rifampicin and combination formulations
viz. conventional tablet preparations.
Details of Marketed Product:
1) Solonex (INH Tablets)
Manufacturer- Macloads Pharma Ltd.
Mfg Date- May 2007
Expiry date- April 2009
Batch No.- 44026V
2) Macox (Rifampicin Tablets)
Manufacturer- Macloads Pharma Ltd.
Mfg Date- May 2007
Expiry date- April 2009
Batch No.- 47029V
63
3) Bicox-KID 50 (INH & Rifampicin combination Tablets)
Manufacturer- Overseas HC Pharma Ltd.
Mfg Date- May 2007
Expiry- April 2009
Batch No- AD4583 KL43
14. Scanning Electron Microscopy:
126,127,128
SEM has been used to determine particle size distribution, surface topography,
texture and to examine the morphology of fractured or sectioned surfaces. The SEM is
most commonly used for generating three dimensional surface relief images derived from
secondary electrons. The examination of the surface of polymeric drug delivery systems
can provide important information about the porosity and microstructure of the device.
Instruments Used:
- JEOL JSM-T330A Scanning Microscope
- JEOL JFC-1100E Ion Sputter
- LINK ANALYTICAL Electron Microscope Column
- Mamiya Camera
- NOVA FP4 Roll film 120 Black and White Negative film
Procedure for SEM Analysis:
The SEM analysis was conducted using a JOEL JSM-T330A Scanning
Microscope for the optimized formulations in three states:
- Dry tablet surface
- Fractured tablet surface
Following steps were performed for the study:
1) Dehydration:
As with SEM high vacuum is required for image formation and samples must be
thoroughly desiccated before entering the vacuum chamber, therefore samples were
thoroughly dried before analysis.
64
2) Mounting:
The dried sample was attached to the brass sample holder or stub using an
adhesive substance.
3) Coating:
Thin coating of an electron dense metal (gold) was applied to the mounted sample
using the JOEL JFC-1100E Ion Sputter which is having a vacuum chamber. The chamber
was evacuated using a rotary pump and an inert carrier gas, argon was introduced to
produce partial vacuum of 10
-2
mmHg. The argon atmosphere ionize by electrodes
located near gold metal foil, thereby heavy metal atoms were ejected from the foil,
covering the mounted sample with finely dispersed coating.
4) Imaging:
These samples were removed from the Ion Sputter and mounted on a sample
holder and placed in a LINK ANALYTICAL Electron microscope column and scanned
in a controlled raster pattern by an electron beam using JEOL JSM-T330A Scanning
Microscope. These electrons were collected with a detector which produced three
dimensional images of the sample surface on a TV screen attached to the microscope.
The images were printed on a NOVA FP4 Roll film 120 photographic film using a
Mamiya Camera at various magnifications.
15. Powder X-ray Diffraction Measurement
129,130,131
The powder X-ray diffraction measurement were conducted over a 5-40 2
range on a Siemans model D5000 diffractometer, equipped with monochromatic CuK
(1= 1.54060 A, 2=1.54438A) X-ray. The step width was 0.020 2/min with a time
constant of 0-5 sec. the integration of the crystalline reflections was achieved using the
Diffrac
plus
diffraction softwere (Eva, version 2.0, Siemans Energy and automation, Inc.
Madison, WI). The degree of crystallinity of samples was expressed as the percentage
65
ratio of the integrated intensity of the sample to that of hydrocellulose, a crystalline
standard prepared from cellulose by treating with 2.5 N HCl at boiling temperature.
16. Microbiological Screening
132-136
Anti-tubercular Activity:
Lawenstain-Jensens medium (L.J. medium) was used for the screening described
by Watt et al against human strain (H37Rv).
Preparation of media: its composition
Beaten egg (20 to 22 Henss egg, Depanding on size): 1000 ml
Mineral salt solution: 600 ml
Malachite green solution: 20 ml
Preparation of mineral salt solution:
Potassium dihydrogen Phosphate (Anhydron): 2.40 g
Magnesium Sulphate: 0.24 g
Magnesium Citrate: 0.60 g
Aspargine: 3.60 g
Glycerol: 12.0 ml
Water: 600 ml
All the above ingredients were dissolved by warming, in order to sterilize, the
solution was autoclaved at 121C for 25 min.
Malchite green Solution: Malchite green was dissolved in 100 ml of water and
autoclaved at 121C for 15 min.
Procedure:
The required number of eggs was broken aseptically to obtain 100 ml egg
solution and filtered through a piece of muslin cloth into conical flask containing glass
beads. 600 ml of mineral salt solution was added to the 1000 ml of egg solution, 20 ml of
malchite green solution was added and mixed well to get a uniform medium.
66
Anti-tubercular test of compounds:
A 10 mg equivalent formulation sample was dissolved in 10 ml of DMSO to get a
concentration of 1000 g/ml. Further dilutions were made with DMSO to get different
concentration such as 100 g/ml, 10 g/ml, 1 g/ml. 0.8 ml of each concentration was
pipette out into different Mac Carney bottles. To this, 7.2 ml of Lawenstain- Jensens
medium (L.J. medium) was added. These bottles were incubated at 75-85C for 2 hrs for
two successive days for solidification and sterilization.
Procedure for inoculation:
A sweep from H37Rv strain culture was discharge with the help of 22 S.W.
nichrome wire loop with a 3 mm external diameter, into a sterile distilled bijou bottle
containing six 3 mm glass beads and 4 ml of sterile distilled water. Each loopful of
growth was supposed to deliver 4 mg moist weight of bacilli. The bottle was shaken with
the help of a mechanical shaker for 2 min. this constituents the suspension. Using S.W.G.
nichrome wire loop, 3 mm external diameter, a loopful of suspension was inoculated on
the surface of each of Lawenstain-Jensens medium (L.J. medium) containing test
formulations.
Lawenstain-Jensens medium (L.J. medium) containing standard drug as well as
control Lawenstain-Jensens medium (L.J. medium) was also inoculated with
mycobacterium tuberculosis of L.J. H37Rv strain. The medium inoculated for 37C for 6
weeks reading were taken and tabulated. The data of screening is given in Table no. 30.
17. In-vivo Pharmacokinetic Study
Isoniazid:
137-139
In vivo pharmacokinetic studies were conducted using albino rats (Wister Rats).
Plasma concentration time profile of Isoniazid in plsma was determined using UV
67
method. In this study, Isoniazid dispersible tablets administered orally to rats and blood
samples were collected at 5, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 720 minutes. The
method used for determination is as follows:
Extraction procedure
Albino Rats (Wister Rats) were divided in 7 groups. One group was kept as a
control. 6 groups of animal were given Isoniazid dispersible tablet prepared in PBS. Drug
solutions were administered by oral route with the help of canula. The blood samples
were collected from retro-orbital eye plexus. All blood samples were centrifuged at 3000
rpm for 15 min. The supernatant (plasma) was deproteinized by adding acetonitrile (1
ml/ml). The samples were again centrifuged and 2 ml of these supernatant was diluted to
10 ml with PBS pH 7.4. Then 1 ml of this diluted blood serum was then made up to the
mark (10 ml) with PBS, then analyzed using spectrophotometer at 266 nm for drug
content against a similarly treated blood sample of control rats after proper dilution. The
observations are recorded and drug content in the plasma was determined.
Rifampicin:
140-142
In vivo pharmacokinetic studies were conducted using albino rats (Wister Rats).
The plasma concentration time profile of Rifampicin was determined using UV
spectrophotometer. In this study, Rifampicin dispersible tablets administered orally to
rats and blood samples were collected at 5, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 720
minutes. Drug concentration in plasma was determined using UV method. The method
used for determination was as follows.
Albino Rats (Wister Rats) were divided in 7 groups. One group was kept as a
control. 6 groups of animal were given Rifampicin dispersible tablet prepared in PBS.
68
Drug solutions were administered through the oral route with the help of canula. The
blood samples were collected from retro-orbital eye plexus. A 0.5 ml aliquot of sample
(plasma sample) was added 2 ml of 0.5M sodium dihydrogen phosphate. The mixture
was shaken mechanically with 7 ml of chloroform for 10 min. Then centrifuged at 3000
rpm for 15 min, the upper aqueous phase was aspirated off using syringe and 5 ml of the
lower organic phase were taken to dryness at 40C under reduced pressure. The residue
was dissolved in 0.5 ml of the mobile phase and Rifampicin level was determined using
UV spectrophotometer at 340 nm.
Isoniazid and Rifampicin combination tablets:
In vivo pharmacokiteic studies were conducted using albino rats (Wister Rats).
The plasma concentration time profile of Rifampicin was determined using UV
spectrophotometer. In this study, Rifampicin dispersible tablets administered orally to
rats and after 5, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 720 minutes drug
concentration were determined in blood.
Both drugs are extracted separately and analyzed as per above described methods
separately.
Pharmacokinetic Parameters Determination for Selected Formulations:
The plasma drug concentration after different time interval was measured. Drug
plasma prolife was plotted and the pharmacokinetic parameters such as AUC (Area under
curve), Cmax, Tmax, MRT (Mean residence Time) and Kel (Elimination constant) of the
drugs in different formulations was determined using Kinetica 5.0 software.
69
18. In vitro- In vivo Correlation:
Correlations between in vitro and in vivo (IVIVC) are often used during
pharmaceutical development in order to reduce development time and optimize the
formulations. A good correlation is a tool for predicting in vivo results based on the in
vitro data. IVIVC allows dosage form optimization with the fewest possible trials in man,
fixes dissolution acceptance criteria, and can be used as a surrogate for further
bioequivalence studies.
The FDA Defines IVIVC as a prediction mathematical model describing the
relationship between an in vitro property of an extended release dosage form (usually the
rate or extent of drug dissolution or release) and a relevant response e.g. Plasma drug
concentration or amount of drug absorbed.
Bases on the type of data used to establish the relationship, three main levels are
defined by the FDA.
Level A:
A correlation of this type is generally linear and represents a point-to-point input
rate (e.g. the in vivo dissolution of the drug from the dosage form). In a linear correlation,
the in vitro dissolution and in vivo input curve may be directly superimposed or may be
made to be super imposable by the use of a scaling factor. Non linear correlations, while
uncommon, may also be appropriate. In this context, the model refers to the relationship
between in vitro dissolution of an ER dosage form and an in vivo response such as
plasma drug concentration or amount of drug absorbed.
Level B:
Level B IVIVC uses the principle of statistical moment analysis. The mean in
vitro dissolution time is compared either to the mean residence time or to the mean in
vivo dissolution. Level B correlation does not uniquely reflect the actual in vivo plasma
70
level curve, because a number of different in vivo curves will produce similar mean
residence time values.
Level C:
Level C IVIVC establishes a single point relationship between a dissolution
parameter, for example, t 50% percent dissolved in 4 hours and a pharmacokinetic
parameters (e.g. AUC, Cmax, Tmax). Level C does not reflect the complete shape of the
plasma concentration time curve, which is the critical factors that reflects the complete
shape of the plasma concentration time curve, witch is a critical factor that define the
performance of ER products.
19. Stability Studies and Shelf Life Determination:
143,144
Stability of a drug has been defined as the ability of a particular formulation, in a
specific container, to remain within its physical, chemical, therapeutic and toxicological
specifications.
The purpose of stability testing was to provide evidence on how the quality of a
drug substance or drug product varies with time under the influence of a variety of
environmental factors such as temperature, humidity and light, and enables recommended
storage conditions, re-test periods and shelf lives to be established.
ICH specifies the length of study and storage conditions:
Long term testing- 25C2C /60% RH5% for 12 months
Intermediate term testing- 25C2C /60% RH5% for 06 months
Accelerated testing- 40C2C / 75% RH5% for 06 months
In the present study, stability studies were carried out at intermediate term testing-
25C2C/60% RH5% for 06 months and accelerated testing 40C/75% RH for a
specific time period up to 6 months for selected formulations.
71
Shelf life determination:
It is desirable to determine the stability of the active ingredient in the drug
formulations. Shelf life is the length of time required for the product potency to be
reduced to some percentage of its original value. For most products, this is the t90% or
time at which the product retains 90% of its original potency. Although the drugs
stability at room temperature is of interest, a stability study at room temperature would
take long time. Therefore, studies are conducted at elevated temperatures in accordance
with the Arrhenious equation:
K app=
-Ea/RT
Where,
K app=apparent rate constant (L/min-mol)
= frequency constant (min
-1
)
Ea= Activation energy (cal / mol)
R= gas constant (1.987 cal. /K mol)
T= absolute temperature (K)
The Arrhenious equation can be rewritten as:
In K app= In Ea/R . 1/T
Again, an equation of the form y=mx+b is generated, indicating that a semi-log
plot of Kapp vs. the reciprocal of the absolute temperature (1/T) should be yield a straight
line with a negative slope equal to Ea/R. This line can be extrapolated to the value of
1/T that corresponds to room temperature and rate constant for the reaction at room
temperature can be the predicted.
Finally, the self life of the drug at room temperature can be determined. Shelf life
is the time duration of the product for which at least 90% of the drug remains active, this
may be written as t90:
A t90 = 0.9A0
Where,
T90= the length of time for which at least 90% of the original drug is present
72
At90= the amount of drug present at time t90 (i.e. 90% of the original amount of drug)
A0= the amount of drug initially present (mg)
In order to find the value of t90, This equation relates the amount of drug remaining to
the time lapsed:
In At90=In A0-Kappt90
This equation can be simplified and rearranged;
In(0.9Ao)= In(Ao)-K app t90
In(0.9Ao/Ao)= - Kapp t90
In(0.9) = -Kapp t90
0.1054/Kapp = t90
The value of K app is taken at room temperature (T = 298 K) or the temperature
at which shelf life need to be determined. Based on above mentioned equation shelf life
of formulations were determined at 25C.
Chapter- V Results and Discussion
73
RESULTS AND DISCUSSION
The direct compression method has been used for fast disintegration tablets
formulation development of Isoniazid, Rifampicin and their combination. Effect of
various superdisintegrants such as Ac-di-sol, Sodium starch glycolate, Polyplastadone
XL and Kollidon CL was studies on various formulations parameters. The composition
of all batches is shown in Table No 1. The formulated tablets are shown in Plate No.1.
The tablets were then characterized for various physico-chemical parameters, surface
topology, X-ray power diffraction, Anti-tubercular activity and in-vivo bioavailability.
1. STANDARD CALIBRATION CURVE:
Standard calibration curve of Isoniazid and Rifampicin was obtained by plotting
absorbance vs concentration using UV spectroscopy. The
max
of Isoniazid and
Rifampicin in phosphate buffer saline, pH 6.8 was determined to be 261 nm and 333 nm
respectively, as shown in Figure 1. The absorbance values are tabulated in Table 2. The
standard calibration curves show the slope of 0.0891, 0.0884, and correlation coefficient
of 0.9976, 0.9945 respectively. The curve is found to be linear in the Beers range
between 1-10 g/ml.
2. COMPATIBILITY STUDY:
Compatibility studies were performed using IR spectrophotometer. The IR
spectrum of pure drug and physical mixture of drug and polymer were studied. The
characteristic absorption peaks of Isoniazid and Rifampicin were obtained.
The FTIR spectra of pure Isoniazid indicated the characteristic absorption stretch
for Strong C=O Stretch band (Amide II) at 1560 cm
-1
and broad bands between 3300 and
3000 cm
-1
for bonded N-H and C-H, stretch are obtained. The finger point region FTIR
spectra showed a characteristic sharp peak at 1670 and 1610, 1500 cm
-1
for C=O, ring
74
C=C and C=N. In comparison with the pure Isoniazid, the absorption peak of the spectra
for Isoniazid in its formulations showed no shift and no disappearance of characteristic
peaks suggest that there is no interaction between Isoniazid and other additives. No
degradation of Isoniazid molecule was observed during its formulation development,
hence the drug-excipient combinations used in the formulation development were
compatible under given set of experiments.
Similarly, The FTIR spectra of pure Rifampicin indicated the characteristic
absorption stretch for C=O group at 1572 cm
-1
and broad bands for N-H stretch was
obtained between 2800 and 2300 cm
-1
. The finger print region of FTIR spectra showed a
characteristic sharp peak at 1281 and 1040 cm
-1
for C-O-C acetyl group. In comparison
with the pure Rifampicin, the absorption peak of the spectra for Rifampicin in its
formulations showed no shift and no disappearance of characteristic peaks suggest that
there was no interaction between Rifampicin and other additives or no degradation in
Rifampicin molecule during formulation development. The spectras for all formulations
are shown in FTIR spectra no: 1 to spectra No: 19.
DISPERSIBLE TABLET FORMULATIONS:
Superdisintegrants represent a suitable material for formulating fast disintegrating
tablets by means of a traditional technology. The percent composition of the
formulations, adjusted by varying the content of the excipients ready to be compacted, is
shown in Table 1. Attention was also paid for the patient with possible dental caries or
weight problem during selection of sweetener, such as sucrose for formulation.
Sweetener lacking in calories was selected; and the taste of the formulation was also
improved by the use of appropriate flavors, with a narrow particle size distribution,
exhibiting low hygroscopicity, excellent chemical stability, direct compressibility and
rapid dissolution; moreover its negative heat of solution imports a cooling effect added to
75
the fresh feel in the mouth during dis-aggregation. Prior compression the powder blend
was accurately and homogenously blended.
No special equipment was adopted to compact the physical mixtures of the
tablets. Operative parameters were modulated in order to give the final tablets a
satisfactory de-aggregation time, but at the same time it was also necessary to maintain
mechanical resistance during processing and handling both in case of formulation
packing and its extraction from the container, before administration. Since fast
disintegrating tablets are less hard then conventional ones, due to a lower compression
employed (hardness is usually 3KPa.), these tablets can therefore be fragile and need
individual packaging.
Mixing speed has been shown to influence the rate of mixing cohesive powders,
where the generation of stronger shears forces as a function of rotational speed produced
improved mixing due to the cohesive inter-particulate forces of agglomerates being
exceeded. An investigation of the behaviors of agglomerates using a descrete elemental
method found the pattern of de-agglomeration to be affected by the frequency of
shearing. When subjected to steady shearing conditions, agglomerate break-up took place
along one axis as opposed to oscillatory shearing, where fractured clusters reunited with
the agglomerates. As expected, an increase in the shear rate had a beneficial impact on
dispersion of agglomerates. Faster speeds and higher shear Turbula mixers were found to
give rise to an enhanced, overall de-agglomeration process.
3. EVALUATION OF TABLETS:
(a) Precompression parameters:
(i) Angle of repose:
Angle of repose is indicative of flow behavior of the powders. Angle of repose
was determined to find out the flowability of drug and excipient combination. Table No.
76
3 shows the results obtained for angle of repose of all the formulations. The values were
found to be in the range of 26
.16' to 30.48'. All formulations showed angle of repose

within 31 which indicates good flow of powder mixture. Angle of repose little higher
above 30
is indicative of fair flow behavior of powder, hence F2 formulation showed fair

flow.
(ii) Bulk Density:
Both loose bulk density (LBD) and tapped bulk density (TBD) results were
shown in Table No. 3. The loose bulk density and tapped bulk density for all the
formulations varied from 0.52 gm/cm
3
to 0.59 gm/cm
3
and 0.63 gm/cm
3
to 0.75 gm/cm
3
respectively. The values obtained lies within the acceptable range and not large
differences found between loose bulk density and tapped bulk density. This result helps
in calculating the % compressibility of the powder.
(iii) Compressibility index:
Percent compressibility of powder mix was determined by Carr's compressibility
index. The percent compressibility for all the twelve formulations lies within the range of
13.23 to 17.46. All formulations showed good compressibility hence can be directly
compressed.
(b) Post-compression Parameters:
1. Appearance:
Examination of tablets from each batch showed flat circular shape with no cracks
and having white and reddish white colour.
2. Thickness test:
The thickness of the tablets from each formulation was measured by using dial
caliper by picking the three tablets randomly. The mean values are shown in Table No. 4.
77
The values are almost uniform in specific method. In direct compression method was
found in the range from 2.22 mm to 2.29 mm.
3. Hardness Test:
Table No. 4 shows results of hardness. Hardness test was performed by Monsanto
tester. Hardness was maintained to be within 4.14 kg/cm
2
to 4.67 kg/cm
2
. Since fast
disintegrating tablets are less hard then conventional ones, due to a lower compression
employed (Hardness is usually 3KPa.), these tablets can therefore be fragile and need
individual packaging. The lower standard deviation values indicated that the hardness of
all the formulations were almost uniform in specific method and possess good
mechanical strength with sufficient hardness. To obviate the difference in the hardness,
we added superdisintegrants in the formulations. In fact, a fast disaggregating tablet must
disintegrate in the saliva; harder tablets need a de-aggregating agent of a superior ability.
In this case Kollidon CL, Ac-Di-sol, Explotab and sodium starch glycolate were
employed.
4. Friability Test:
All formulations possess good mechanical strength. The study results are
tabulated in Table No. 4, was found well within the approved range (<1%) in all the
formulation. Friability of the tablets, lower then 1% in most cases, indicates that the
developed formulations can processed and handled without excessive care.
5. Weight Variation Test:
The percentage weight variations for all the formulation are tabulated in Table
No. 4. The average weight of the formulation was 261 mg. All the tablets passed weight
variation test as the % weight variation was within the pharmacopoeial limits of 7.5%.
The weights of all the tablets were found to be uniform. The result indicates the
formulation contains the appropriate amount of drug.
78
6. Drug Content Uniformity:
The content uniformity was performed for all formulations and results are shown
in Table No. 4. Five trials from each formulation were analyzed using
spectrophotometry. The mean value and standard deviation of all the formulations were
calculated. The drug content of the tablets were found between 96.44 0.5 mg to 96.21
0.55 mg for Isoniazid and 96.18 0.63 mg to 97.39 0.44 mg for Rifampicin
respectively. The results indicated that, in all the formulations the drug content was
uniform. The cumulative percentage drug released by each tablet in the in vitro release
studies were based on the mean content of the drug present in the respective tablet.
7. Wetting Time:
Wetting is closely related to inner structure of tablets. The record of the wetting
time was shown in Table No. 5. Tablet disintegration was affected by the wicking and
swelling of the disintegrant, and the wicking property would be closely related to the
pososity. Both the porosity and average pore size of tablets in all formulation decreased
with increase of the tablet hardness. The wicking property may also correlate to the
wetting behavior of the tablet. Wetting time of the tablet containing Ac-di-sol, Sodium
starch glycolate, polypastadone XL, Kollidon CL were 230 seconds. Wetting of the tablet
containing sodium starch glycolate was fastest among all and observed wetting time was
217 seconds. In the range of tablet hardness 2-5 kg, wetting time was not affected by
tablet hardness. The disintegration time of the formulation in the oral cavity increases
with increase in the wetting time. To shorten the disintegration time in the oral cavity for
the tablet, the addition of the disintegrant having a property of quick water uptake in the
formulation is preferable. It was considered that the rapid disintegration would be due to
its wettability. All superdisintegrants have high water absorption capacity and wicking
property which lead to faster swelling of the disintegrants. The tablet containing Ac-di-
79
sol significantly swelled and loosed the shape. It has been known that Ac-di-sol absorbs a
large amount of water, and swell. It is reported that disintegration of Polyplastadone XL
was by wicking mechanism, because disintegration time of tablets containing
Polyplastadone XL was delayed resulting the filling up of the tablet porosity, which
possessed hydrophobic property. Observed results suggested that the disintegrants added
into tablet formulation might cause the penetration of water in the tablet, and the
penetration rate of water would be altered. This parameter also duplicates disintegration
time in oral cavity as tablet is kept motionless on tongue; hence correlation between
wetting time and disintegration time in oral cavity can also be made.
8. Water Absorption Ratio:
The water absorption ratio results are tabulated in Table No. 5. The water
absorption ratio values of formulations F1 to F4 found in the range of 19.45 to 24.89 and
for F5 to F12 were in the range of 23.84 to 33.56 respectively.
The tablets formulated with Ac-di-sol, Kollidon CL were significantly swelled
and collapse, on the other hand, Sodium starch glycolate maintains the shape after
wetting. The wetting time of the Sodium starch glycolate(SSG) formulation was 218
seconds and rapid among the disintegrants used. On the other hand, the water absorption
ratio was 24.89. The water absorption ratio of Ac-di-sol formulation was 19.45 and the
obtained value was more then twice compared to the others. The water absorption ratio of
Ac-di-sol formulations suggested that dominant disintegration mechanism was kept
wicking but swelling. These results suggested that rapid disintegration of tablets
containing SSG was due to excellent wetting nature of SSG itself. The excellent wetting
nature of SSG was hardly affected by the compression force, but the wetting time of
Kollidon CL prolongs with increase it. Furthermore, the water absorption ratio of SSG
formulations was not affected by compression force but that of Polypladtadone XL
80
formulations showed a reverse tendency against compression force. The main mechanism
related to the disintegration was known as wicking and swelling. In spite of the excellent
water uptake performance, disintegration type of SSG and Ac-di-sol was different, and
their major character was resulted in the wicking and swelling of them, respectively. It is
reported that tablet disintegration was affected by the particle size, the degree of
substitution and the extent of crosslinkage of disintegrants. The structure difference
between SSG and Ac-di-sol may cause different disintegration behavior that are wicking
and swelling, respectively.
9. In vitro Dispersion Time:
In vitro dispersion time is measured by the time taken to undergo uniform
dispersion. Rapid dispersion within seconds has been observed in all the formulations.
On the basis of the de-aggregation time of the tablets, according to the EP IV Ed., almost
all the formulations developed can be defined Fast dispersible: the limit for de-
aggregation is in fact suggested as within 3 min. The values obtained are mentioned in
Table No. 6.
81
Tablets with Kollidon CL superdisintegrant demonstrate to be more quickly
dispersible with respect to those of the SSG; the time values in fact are quite different
for the four superdisintegrants. Kollidon CL being more efficient.
10. In vitro Disintegration Time:
The internal structure of tablets such as pore size distribution, water penetration
into tablets and swelling of disintegration substance suggested mechanism of
disintegration.
The results are shown in Table No. 6. This was determined as per I.P. for all the
formulations. All formulations showed disintegration time less than 3 minutes. A
disintegration characteristic of tablet is shown in Plate No. 2.
Disintegration time, which is affected by the hardness of the tablet, is related to
the nature of the disintegrant agent that allows the tablet to break up into smaller
fragment upon contact with physiological fluid. Kollidon CL is completely insoluble in
all commonly used solvents: as it swells in contact with water in a very predictable
manner, it is mainly used as a superdisintegrants. In contrast to other compounds the
capacity of swelling is reversible. Explotab is the sodium salt of carboxymethyl ether of
starch: practically insoluble in organic solvents, it absorbs water rapidly, resulting in
swelling which leads to rapid disintegration of tablets and granules. The content of
superdisintegrant agent, employed in formulation of this type, usually ranges between 10
% to 30 % w/w. This parameter appears to be the main factor responsible for the
difference in the disintegrating time. It has in fact reported that the main factor
influencing the disintegration time of the tablet varies among the use of various
disinetrgants for example, in the presence of Kollidon CL, is the compression force rather
than the disintegrant concentration which decide the disintegration; while with Explotab,
82
whatever the compression force, the disintegrant concentration leads to an increase of the
disintegration time.
11. In vitro Dissolution Studies:
All the twelve formulations were subjected for in vitro dissolution studies using
tablet dissolution tester USP XXIII. The samples were withdrawn at different time
intervals and analyzed at 261nm and 333nm respectively. Cumulative drug release and
cumulative % drug retained were calculated on the basis of mean amount of Isoniazid
and Rifampicin present in respective formulations.
The results obtained in the in vitro drug release for the formulations F1 to F12 are
tabulated in Table No.9 to Table no. 26. The cumulative percentage of Isoniazid released
as a function of time (t) for formulations F1 to F4 are shown in Fig No. 4 and
formulations F5 to F8 and Fig No. 11. Similarly combination formulation F9 to F12
release had shown in Figure No. 16 and 21 for Isoniazid and Rifampicin respectively.
Isoniazid dispersible formulations F1, F2, F3 and F4 prepared by direct
compression method was found to releases 100.57 %, 98.09 %, 98.45 % and 97.18% of
Isoniazid respectively. Rifampicin release form Rifampicin formulations F5, F6, F7 and
F8 was 99.21%, 98.11 %, 97.19 % and 96.28 % respectively, at end of 12 minutes.
Similarly, the release of Isoniazid and Rifampicin from combination formulations was
also investigated. The release of Isoniazid from combination formulations F9, F10, F11
and F12 was found to be 97.99 %, 96.72 %, 95.02 % and 94.11%. However, Rifampicin
release from combination formulations was found to be 90.35%, 87.18%, 84.74% and
84.93% respectively. This rapid dissolution might be due to fast breakdown of particles
of superdisintegrants and porous structure of the tablet. In all formulations the drug
release was nearer to 100 % within 12 minutes.
83
Cumulative % drug retained as a function of time were calculated for
formulations F1 to F12 (Table No. 27). The graphical representation is shown in Figure
No.5, 12, 17 and Fig No.22. Log cumulative percent drug released V/s time was also
calculated and mentioned in Table No.28.
Oral dispersible tablets are design to disaggregate in the oral cavity and usually
release and allow the active agent to dissolve remarkably fast in the saliva. Association
between the drug and superdisintegrants as in present case, introduces a control of the
release differences between uncoated formulations, where the drug is associated only
with a hydrophobic Avicel pH 102, and free drug were observed in preliminary tests
while the formulation take more then 15 minutes to dissolve, the free drug reaches
complete dissolution in more time. The control of the release is even more important for
tablets, where Isoniazid, Rifampicin release is affected only by the association with
superdisintegrants.
The release of Isoniazid and Rifampicin from all the formulations containing the
Kollidon CL as superdisintegrants is <60-70% after 6 mins. The association with Avicel
pH102 promotes the release, with respect to pure Isoniazid and Rifampicin, despite the
favorable pH of the dissolution medium; and also could limit the contact of the drug with
mouth mucosa, besides preventing dumping as a possible side effect.
The presence of the superdisintegrants Kollidon CL in the formulations F4, F8
F12 produced tablets dissolving more slowly with respect to Explotab. These tablets can
be defined as fast dispersible. It emerged also that the release appears to be governed
by simultaneous diffusion/erosion, since n values are lower then 0.5, where the release
is non-linearly related to the squire root of time (n=0.5) and diffusion appears the
dominant mechanism of the release.
Finally it is interesting to note that despite the presence of Kollidon CL as
superdisintegrants in the formulations, the pure Kollidon CL displays slow dissolution. It
84
was in fact reported that a close association between a drug and superdisintegrants
enables the formation of a state suitable to improve the dissolution rate in the present
case. The preliminary blend of the drug with superdisintegrants does not prevent any
contact between the drug and superdisintegrants, when present in the formulation,
promotion dissolution mechanism.
13. Comparative evaluation of formulations and marketed formulation for
physicochemical parameters
The promising formulations based on the evaluation studies were compared with
marketed product Solonex (Isoniazid-100 mg) and Macox (Rifampicin-100 mg). The
evaluation parameters tested and compared with in-vitro dissolution profile. The values
obtained for in-vitro dissolution study are recorded in Table No.8 and Table No.14.
The mean value of drug content uniformity observed was 99.28%. In vitro
dissolution was performed to compare the release behavior of the in-house and marketed
formulations. The marketed product attained 96.69 % and 97.62 % of Isoniazid and
Rifampicin release respectively in 12 minutes of dissolution study. In-vitro dissolution
profiles of marketed product in comparison to the formulated batches were indicate that
the in-house formulations F1, F2 gave the drug release of 100.7 % and 99.21 % for
Isoniazid and Rifampicin respectively. Hence it may be concluded that the drug release
was better in formulated formulation when compared to marketed product, therefore it
will have better and faster drug absorption hence drug activity.
15. Curve fitting analysis:
The results of dissolution data fitted to various drug release kinetic equations to
determine the drug release order from the formulations. Release rates were subjected to
kinetic treatment. The datas were grouped according to two modes
1) Cumulative percent drug released Vs. Time
85
2) Log cumulative percent drug retained Vs. Time.
The correlation coefficient and slope values obtained are shown in Table No.27.
The results were found to be linear for zero order release. It is concluded that release of
drug from formulations F1 to F7 followed Zero order and Formulation F 8 to F12
fallowed the mixed order. The plots are represented in Figure No. 4 to 8 and 11 to 26.
Further, the model fitting of the release profiles were performed using PCP
DISSO-V2 software to observe the mechanism. The correlation coefficient values
obtained for all five models are tabulated in Table No.29. After comparing the data of all
Pharmacokinetic models such as Zero order, first order, Highuchi, Korsemeyer-Peppas
and Hixon crowell models, it is concluded that the release of drug from the formulations
was governed by their its solubility and the particle size and they following Hixon
crowell model as a release model. It is observed that formulations F1 to F7 dissolution
(release) of the drugs follows zero order, which may be due to rapid diffusion or the
porous nature.
The 'n' value could be used to characterize different release mechanisms as:
n
Mechanism
0.5 Fickian diffusion
0.5 < n < 1 Non-Fickian diffusion
1 Case II transport
The results are represented in Table 27 and in the present study n value were
determined within 0.326 to 0.4461 for all the twelve formulations. Drug release occurred
via Fickian diffusion mechanism as n value range was found within 0 to 0.5.
The major quality issue associated with FDCs is the bioavailability of Rifampicin.
Rifampicin, one of the key components of the anti-TB chemotherapy cocktails, is
86
reported to have bioavailability problem in FDC formulations that raises the question of
therapeutic success of the current treatment.
The reasons hypothesized in the literature include raw material characteristics,
changes in the crystalline habit of the Rifampicin, excipients, manufacturing and/or
process variables, degradation in the gastro-intestinal tract, inherent variability in
absorption and metabolism. Other anti-tubercular components of FDC like Isoniazid,
Pyrazinamide and Ethambutol do not show any bioavailability problems as all these
drugs belongs to class I (highly soluble and highly permeable) of the Biopharmaceutic
Classification System (BCS). Rifampicin is the only hydrophobic component of the FDC
which belongs to BCS class II (low solubility and highly permeability) and is reported to
be absorbed by common pharmaceutical excipients. Further, Rifampicin shows pH-
dependent solubility affecting its absorption from gastro-intestinal tract. Rifampicin
being the only water insoluble component in the FDC, manufacturing of Rifampicin
containing FDC with all other highly water-soluble components is the most critical
process, which is further complicated as the number of processing steps such as grinding,
mixing, granulation, drying and compression are increased. The crystalline nature or
particle size of Rifampicin may be affected, thereby altered its bioavailability. Further,
common pharmaceutical excipients used in the tablets as binder, glidant, e.g. bentonite,
talc and kaolin; which rapidly and strongly adsorb Rifampicin and hence reduce its
gastrointestinal absorption. Thus, idiosyncratic behavior of Rifampicin can be explained
by physiological, physicochemical, pharmaceutical and manufacturing factors that affect
the absorption of Rifampicin from various dosage forms (explained in figure).
87
3. SCANNING ELECTRON MICROSCOPY:
All formulations were subjected to Scanning Electron Microscopy (SEM) to
examine the surface topography, texture of the formulations, morphology of fractured or
sectioned surfaces, that can provide important information about the porosity of the
device in the matrix of the formulations by subjecting the formulations to SEM in dry
state at the different magnifications, X500, X1000 X3000 using a JEOL JSM-T330A.
SEM images are shown in Plates No. 5 to 16. After examination the photographic results
obtained from SEM, it was observed that formulation F2, F6 and F10 contained particles
of similar microscopic geometric which reflects the particles sizes of the parent Potato
starches of the range of 10-100 m. Additionally, examination at higher magnification
suggested that the surfaces of the particles contained small, micron size, features.
However in case of Kollidon CL formulations (F4, F8, F10) no cracks were
observed, suggesting that the formulations had good mechanical properties. The small
increase in drug release may not necessarily be attributed to surface rupturing or creak
formation.
88
The particles on the tablet surface were more compressed then those inside, there
existed many empty spaces between the particles throughout the tablet where water could
be absorbed by capillary forces. At higher magnification, a detailed distribution of pores
can be observed. Upon contact with water or saliva, the particles could easily dissociate,
and the whole tablet disintegrated to form a paste, which is easy to swallow. As the
compression pressure increased, the pores become smaller. The porous structure of the
tablet was especially hard to observe.
4. X-RAY POWDER DIFFRACTOMETRY
X-ray powder diffractometry (XRPD) is a powerful technique for the
identification of the crystalline solid phases. Every crystalline solid phase has a unique
XRPD pattern, which can form the basis for its identification. The X-ray powder
diffraction (XRD) spectra of Isoniazid showed characteristic diffraction peaks in the
8.84, 7.30, 5.25, 2 Characteristic peaks of Isoniazid were detectable in the
formulations (F-1 to F4 and F-9 to F-12) samples. Similarly, The X-ray powder
diffraction spectra (XRPD) of Rifampicin showed diffraction peaks in the 13.65 and
14.35 2 ranges. Characteristic peaks of Rifampicin were detectable in the formulations
(F-5 to F8 and F-9 to F-12) samples with halo pattern, suggesting that the particles
crystallized in the presence superdisintegrants, and superdisintegrants did not undergo
structural modifications. However, the differences in the relative intensities of their peaks
may be attributed to differences in the crystalline or particle size of the sample. It is very
difficult to identify the presence of Avicel pH 102 or superdisintegrants in the XRPD
spectra as they are polymers with amorphous structure and no sharp peaks are apparent at
particular 2, due to the very low crystallinity of these components. X-ray powder
differection spectras are shown in XRD spectra No. 1 to 19.
89
5. ANTI- TUBERCULAR ACTIVITY
The recent emergence of multidrug-resistant stains of M. Tuberculosis
underscores the need to rapidly determine the susceptibility of isolates of M.
Tuberculosis to anti-microbial agents. As per the literatures, it is well established that
The MIC (minimum inhibitory concentration) of Isoniazid susceptibility was found at
0.06 g/ml; partially resistant, 0.12 to 1 g/ml and resistant 2 g/ml. Similarly, for
Rifampicin susceptibility was found at 0.25 g/ml; partially resistant, 0.5 g/ml and
resistant 1 g/ml. The anti-tubercular activity of the formulations is investigated in the
Lawenstain-Jensens medium (L.J. medium). H37Rv strain is used for the anti-tubercular
activity. The formulations are evaluated in two concentrations i.e. 100 l and 300 l. The
result indicates that all formulation active against the H37Rv strain, and possess the anti-
tubercular activity. The result of screening is tabulated in table no. 30.
6. IV-VIVO PHARMACOKINETIC STUDIES:
Pharmacokinetic studies of the formulations F-1, F-5 and F-9 were performed on
Wistar rats. These formulations were selected based on their higher in vitro drug release
prolife among all the formulations. Pharmacokinetic parameters of selected formulations
was determined and compared with the free drug i.e. Isoniazid and Rifampicin solutions.
Pharmacokinetic parameters such as area under the curve (AUC), Tmax, Cmax, half life
and elimination constant of the formulations were determined after oral administration of
the formulations based on plasma concentration prolife of the drugs at various time
points. Drug plasma prolife and all the pharmacokinetic parameter of the formulations
and free drug in the plasma blood is presented in figure No. 27 to 29 and Table No. 31 to
34 respectively.
The Pharmacokinetic values for Isoniazid dispersible tablets (F-1) was calculated
and data presented as area under the curve (AUC) -160.78 g/ml*h, Tmax - 0.5 h, Cmax-
90
65.91 g/ml, half life-2.21 h and elimination constant- 0.31 h, whereas the
Pharmacokinetic values of pure Isoniazid was presented as area under the curve (AUC)-
113.94 g/ml*h, Tmax- 1 h, Cmax- 38.53 g/ml, half life- 2.37 h and elimination
constant- 0.29 h. Similarly, the pharmacokinetic values for Rifampicin dispersible tablets
(F-5) was calculated and data presented as area under the curve (AUC)- 139.26 g/ml*h,
Tmax -1 h, Cmax- 34.76 g/ml, half life- 3.42 h and elimination constant- 0.31 h,
whereas the Pharmacokinetic values of pure Rifampicin was presented as area under the
curve (AUC)- 74.32 g/ml*h, Tmax- 0.75 h, Cmax- 29.64 g/ml, half life- 3.34 h and
elimination constant- 0.21 h.
The combination formulation of Isoniazid and Rifampicin (F-9) was also
studied for Pharmacokinetic values. The Pharmacokinetic values of Isoniazid from
combination dispersible tablets was calculated and presented as area under the curve
(AUC)- 119.88g/ml*h, Tmax- 0.5 h, Cmax- 65.91 g/ml, half life- 2.34 h and
elimination constant- 0.31 h, whereas the Pharmacokinetic values of pure Isoniazid was
presented as area under the curve (AUC)- 113.94 g/ml*h, Tmax- 0.5 h, Cmax- 49.97
g/ml, half life - 2.37 h and elimination constant- 0.29 h. Similarly, The Pharmacokinetic
values of Rifampicin from combination dispersible tablets was calculated and presented
as area under the curve (AUC) 147.16g/ml*h, Tmax -1 h, Cmax -45.34 g/ml, half life-
3.036 h and elimination constant -0.228 h. whereas, the Pharmacokinetic values of pure
Rifampicin was presented as area under the curve (AUC) -74.32 g/ml*h, Tmax- 0.75 h,
Cmax -29.64g/ml, half life- 3.34 h and elimination constant -0.21 h.
These results reveal that dispersible formulations showed preferential drug
bioavailability in the blood. It was also revealed that as compared to pure drug, higher
concentration of drug was bio-available to the blood after administering the dose in form
of dispersible formulations.
91
In Vitro- In Vivo Correlations:
An IVIVC should be evaluated to demonstrate that predictability of in vivo
performance of a drug product from its in vitro dissolution characteristics. It is
maintained over a range of in vitro dissolution release rates and manufacturing changes.
Since the objective of developing an IVIVC is to establish a predictive mathematical
model describing the relationship between an in vitro property and relevant in vivo
response. Isoniazid does not show any bioavailability problems as this drugs belongs to
class I (highly soluble and highly permeable) of the Biopharmaceutic Classification
System (BCS). Rifampicin is the only hydrophobic component of the FDC which
belongs to BCS class II (low solubility and highly permeability) and is reported to be
absorbed by common pharmaceutical excipients. On the basis of in vitro dissolution
release profile and in vivo pharmacokinetic values, it is concluded that Level A In vitro-
In vivo correlation could be established for the prepared dispersible formulations (F-1, F-
5 and F-9). Depending on the intended application of an IVIVC and the therapeutic index
of the drug, evaluation of predictability error internally and/or externally may be
appropriate. Evaluation of internal predictability is based on initial data used to define the
IVIVC model. Evaluation of external predictability is based on additional test data sets.
Application of one or more of these procedures to the IVIVC modeling process
constitutes evaluation of predictability.
A correlation should predict in vivo performance accurately and consistently.
Once this relationship has been achieved, in vivo dissolution can be used confidently as a
surrogate for the in vivo bioequivalence of ER drug products.
6. STABILITY STUDIES:
The formulations F-1, F-5 and F-9 were selected for stability studies on the basis
of their high cumulative % drug release and in vitro disintegration time, wetting time, in
92
vivo disintegration time and in vitro dispersion studies. The stability studies were carried
out at 25
C/60% RH and 40
C/75% RH for all the selected formulations up to 6 months.

Formulations were analyzed at 1 month time interval for drug content and in vitro
disintegration time. These formulations showed not much variation in any parameter. The
results obtained are tabulated in table No.35, 36 and figure No.30. From these results it
was concluded that, formulations F-1, F-5 and F-9 are stable and retained their original
properties.
Shelf life (also referred to as expiration dating period):
The time period during which a drug product is expected to remain within the
approved shelf life specification, provided that it is stored under the conditions defined
on the container label. The combination of physical, chemical, biological, and
microbiological tests and acceptance criteria that determine the suitability of a drug
substance throughout its retest period, or that a drug product should meet throughout its
shelf life. The shelf life of selected formulations F1, F-5 and F-9 were determined,
average shelf life of Isoniazid dispersible tablets (F-1) was found to be 34.66 months,
whereas the average shelf life of Rifampicin dispersible tablets (F-5) was found to be 26
months at storage condition of 25
C/60% RH. The combination formulation of Isoniazid

and Rifampicin (F-9) was also studied for shelf life. The average shelf life of
combination dispersible tablets was found to be 52 months at storage condition of
25
C/60% RH.
93
PLATE NO. 1: MOUTH DISSOLVING TABLETS OF ISONIAZID
PLATE NO.2: DISINTEGRATION OF TABLET IN 60 SEC.
94
ANTI-TUBERCULAR ACTIVITY

PLATE NO. 3: CONTROL, F3 AND F4 FORMULATIONS AT 1ST DAY.
PLATE NO.4: CONTROL AND FORMULATIONS AT 1ST DAY.
95
IN-VIVO BIOAVAILABILITY STUDY
PLATE NO. 5: DOSE ADMINISTRATION IN MOUSE
PLATE NO.6: SAMPLE COLLECTION
96
SEM of different INH dispersible formulations.
F-1 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
97
F-2 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
98
F-3 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
99
F-4 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
100
SEM of different Rifampicin dispersible formulations.
F-5 Formulation
PLATE NO.1
PLATE NO.2
PLATE No.3
101
F-6 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
102
F-7 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
103
F-8 Formulation
PLATE NO.1
PLATE NO.2
PLATE No.3
104
SEM of different Isoniazid and Rifampicin Combination
Formulations.
F-9 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
105
F-10 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
106
F-11 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
107
F-12 Formulation
PLATE NO.1
PLATE NO.2
PLATE NO.3
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Chapter- VI Summary
212
SUMMARY
In present study, fast disintegrating tablets of Isoniazid, Rifampicin and their
combination formulations were successfully fabricated using direct compression method
to improve bioavailability of drugs with quick onset of action by disintegrating in oral
cavity within few seconds to achieve better patient compliance.
Fabricated tablets were evaluated for:
Pre-compression Parameters:
Powder flow properties (angle of repose), loose bulk density, tapped density and
% Carrs compressibility were determined for all the formulations which showed good
flow property and good compressibility of formulations.
Post compression parameters:
The shape and appearance of all formulations were found to be circular, white and
reddish white in colour. The uniform thickness, hardness and friability values of all the
formulation tablets prepared by direct compression method were within the
pharmacopeial limits and formulation was having enough strength to resist mechanical
stress, simultaneously maintained its fast disintegration profile. The drug content
uniformity and % weight variation of all the twelve formulations was found to be within
the limits.
All the twelve tablet formulations, disintegrated within 65 seconds. The
disintegration time for all the formulations such as in vitro disintegration, in vivo
disintegration, in vitro dispersion and wetting time found less than 230 seconds which
indicates rapid disintegration. Water absorption ratio showed good water absorptivity in
all formulations. Presence of sodium saccharine and mannitol in all the formulations
made formulations with good palatable taste. Various excipients had been used for
Chapter- VI Summary
213
various applications in the formulation, Ac-di-sol showed best disintegration property,
Avicel pH102 acts as diluent, binder and disintegrant.
In vitro dissolution results showed that maximum cumulative % drug release in
formulation F1 when compared to formulation F2, F3 & F4 for Isoniazid. However in
case of Rifampicin release, formulations F5 showed more release when compared to F6,
F7 & F8. In the case of combination formulations F9 showed more fast release when
compared to F10, F11 & F12. The direct compression method showed good results in
all parameters.
The various parameters were evaluated related to dissolution as follows:
1. Drug release
2. Cumulative percent drug release
3. Log cumulative % drug retained
4. Model fitting of the release profiles using five different models viz, zero order,
first order, Higuchi Matrix, Peppas model and Hixson-Crowel equation
The model fitting of release profiles using five different models indicated that
formulations F1, F2, F3, F4, F5, F6 and F7 showed zero order release and F8, F9, F10,
F11, F12 showed mixed order release. Slope of release model indiacates n value which
is found to be less than 0.5 which indicates that release occurred via Fickian diffusion.
The release of drug from formulation is solubility and particle size dependent. So, the
formulations are following Hixson-Crowel model as release model.
The X-ray powder diffraction (XRD) spectra of Isoniazid showed characteristics
diffraction peaks in the range of 8.84, 7.30, 5.25, 2. These characteristic peaks of
Isoniazid were detected in the formulations (F-1 to F4 and F-9 to F-12). Similarly, the
XRD spectra of Rifampicin showed characteristics diffraction peaks in the range of
13.65 and 14.35, 2 range. These characteristic peaks of Rifampicin were also detected
in the formulations (F-5 to F8 and F-9 to F-12). Samples with halo pattern were also
Chapter- VI Summary
214
observed in the diffraction spectra, suggesting that the particles crystallized in the
presence superdisintegrants, and superdisintegrants did not undergo structural
modifications.
After examination of images obtained from SEM, it was observed that
formulations contained particles of similar macroscopic geometric which reflects the
particles sizes of the starches of the range of 10-100 m. Additionally, examination at
higher magnification suggested that the surfaces of the particles contained small, micron
size features.
The formulations were also evaluated for anti-tubercular activity in two different
concentrations i.e. 100 l and 300 l and the result indicate that all formulations active
against the H37Ry strain, and possess good anti-tubercular activity.
In-vivo Pharmacokinetic studies of pure drug and its combination formulation
were performed in albino wister rat. Its concluded that dispersible formulations showed
preferential faster drug bioavailability in the blood. It was also revealed that as compared
to pure drug, higher concentration of drug was bio-available to the blood after
administering the dose in form of dispersible formulations. Pharmacokinetic study
indicates the better and faster bioavailability of the drug in the blood.
Stability studies were conducted for formulations F1, F5 and F9 at 25
C/65% RH
and 40
C/75% RH for 6 months. Various parameters like hardness, friability, drug

content uniformity, in vitro disintegration, wetting time were analyzed at a time interval
of 1 month till a period of 6 months. The shelf life was found to be 52 months for
combination formulations. Not much variation or change was observed in any parameters
throughout the study period and product was found stable.
Hence it is concluded that tablet formulated with direct compression method
showed better disintegration and drug release rate. The prepared tablets disintegrate in
Chapter- VI Summary
215
seconds without need of water and enhance the absorption, this leads to increased
bioavailability of Isoniazid, Rifampicin and their combination formulations. In-vitro anti-
microbial studies also revealed the anti-tubercular activity of formulations. On the light
of above results and justification it may be concluded that anti-tubercular drugs loaded
fast-dispersible tablet can be further explored for the oral treatment of tuberculosis.
Chapter- VII Conclusion
216
CONCLUSION
Rapid disintegrant tablets are converted into easy to swallow suspension on
contact with the saliva, after ingested in mouth. These are particularly useful in pediatric
or geriatric patients, can be taken without liquids. These Isoniazid and Rifampicin loaded
rapid disintegrant tablets may also be used in tuberculosis, especially to facilitate oral
treatment of tuberculosis. The developed formulation have suitable characteristics that
distinguish them from common solid dosage forms such as rapid de-aggregation,
combining advantages of both liquid and conventional tablet formulations, easy to
swallowing and possible taste masking components for an acceptable taste in the mouth.
The presence of a superdisintegrants makes it possible to produce sufficiently hard tablets
that still disaggregate within seconds and all the developed tablets can be considered as
fast dispersible. Finally these tablets can be prepared by means of a conventional
tabletting technique such as direct compression and are designed to exert a control of the
side effect of the drugs at gastric level.
Formulations containing Kollidon CL as super disintegrant may represent
examples of fast dispersible/ slow releasing tablets that offer an alternative to traditional
tablets for orally dispersible Isoniazid and Rifampicin tablets. Formulation of fast
disintegrating tablets of Isoniazid, Rifampicin and their combinations (Anti-tubercular)
was successfully attempted by direct compression technique.
From the findings obtained, it may be concluded that:-
- An attempt to develop fast dispersible tablets of Isoniazid, Rifampicin and their
combinations formulations was achieved with objcetive to improve bioavailability.
- The IR spectra revealed that, superdisintegrants and excipients used were compatible
with drug. The formulated tablets showed compliance for various physiochemical
217
parameters viz. tablet dimensions, hardness friability, weight variation, content
uniformity and disintegration.
- In vitro disintegration, in vivo disintegration, in vitro dispersion and wetting studies
showed good results in both methods, it has shown fast disintegration of the
formulation in in vitro and in vivo condition. Hence, it may be concluded that these
parameters shall affect the drug absorption leading to faster drug absorption. Water
absorption ratio studies indicated good absorptivity in all formulations.
- In vitro release studies of Isoniazid formulations revealed that 90% of drug was
released from the formulations within 12 minutes. Formulation F-1 showed faster
drug release in comparison to the marketed formulation of Isoniazid.
- Overall, the direct compression method formed tablet complying with the US
Pharmacopeia specifications in terms of its shape, size, drug content, formulation
strength and finally faster drug disintegration. Formulations F1, F5 & F9 tablets
disintegrated rapidly. The direct compression technique may be utilized in preparing
fast dispersible tablets.
- The scanning electron microscopy indicates that all formulations retained their size
and even shape.
- The Powder X-ray diffraction patterns confirmed the presence of stable Isoniazid,
Rifampicin in the all the formulations.
- The anti-tubercular activity indicates that all formulations are active against M.
Tuberculosis and other strains of M. Tuberculosis.
- The Pharmacokinetic studies indicate faster bioavailability of the drug in the blood. It
was also found that, as compared to pure drug, higher concentration of drug was
bioavailable to the blood after administering the dose in form of dispersible
formulations.
218
- Stability studies of formulation F-1, F-5 and F-9 indicated that the most suitable
storage temperature was 25C/60%RH for a period of 6 months. The shelf life of the
formulations was found satisfactory (i.e. 52 months).
- This work needs to be proved effective by its bioavailability, pre-clinical and clinical
studies.
It is my dream that when my grandchild goes to Medical School, Professors of
that generation should be teaching ..for centuries there was one disease that
used to affect people of developing and underdeveloped countries which was known
as tuberculosisand that this dreadful disease is now confined to textbooks and
completely eradicated from the face of the earth.
Chapter- IX Bibliograpy
219
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234
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Chapter- X Annexure
235
Chapter- X Annexure
236
Chapter- X Annexure
237
Chapter- X Annexure
238
List of Publications from Ph.D Research work.
1. Vikesh shukla, Manvi FV. Effect of Kollidon CL on release behavior of
Isoniazid and Rifampicin combination dispersible tablets for oral treatment of
tuberculosis. International Journal of drug development and research. Oct-
Dec 2010; 4(2): 892-906.
2. Vikesh Shukla, Manvi FV. Effect of two different superdisintegrants on
combination dispersible tablets of Isoniazid and Rifampicin for oral treatment of
tuberculosis. International Journal of drug delivery 2010;2:322-332.
3. Vikesh Shukla, Manvi FV. Effect of different superdisintegrants on Isoniazid
dispersible tablets for oral treatment of tuberculosis. Der Pharma Chemica,
July 2010;2(4):65-78.
4. Vikesh Shukla, Nanjawade BK, Manvi FV. Effect of different
superdisintegrants on Release behavior of Isoniazid and rifampicin dispersible
tablets for oral treatment of tuberculosis. International Journal of
Pharmaceutical Sciences, Sep- Dec. 2010;2(3):871-883.
Poster Presentations:-
1. Vikesh Shukla et. al. 62th Indian Pharmaceutical Congress, 2009
2. Vikesh Shukla et. al. 61th Indian Pharmaceutical Congress, 2008
3. Vikesh Shukla et al. National Conference on Nanotechnology and drug
discovery. 14th Nov. 2009. AEC Agra-UP
4. Vikesh Shukla et. al. International Conference-cum- workshop on Nanoscience
and Nanotechnology 12th and 16th Oct. 2009, Gurgaon, Haryana
5. Vikesh Shukla et. al. 59th Indian Pharmaceutical Congress, Varanasi,UP. 20th
Dec. 2007, Varansi-UP

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FIGURE NO. 4: PLOT OF CUMULATIVE % DRUG RELEASE Vs TIME OF
DIFFERENT FORMULATIONS OF ISONIAZID (ZERO ORDER PLOT)

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FIGURE NO. 6. PLOTS OF CUMULATIVE % DRUG RELEASED Vs. ROOT TIME
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STUDIES) [HIGUCHI MATRIX]
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FIGURE NO. 7. PLOTS OF LOG CUMULATIVE DRUG RELEASE Vs. LOG TIME
OF DIFFERENT FORMULATIONS OF ISONIAZID (IN-VITRO RELEASE
STUDIES) [PEPPAS]
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FIGURE NO. 8. PLOTS OF CUBE ROOT OF % DRUG RETAINED Vs. TIME OF
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STUDIES) [HIXSON CROWELL]
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FIGURE NO. 9. STANDARD CALIBRATION CURVE OF RIFAMPICIN AT max 333nm

FIGURE NO.10. PLOT OF CUMULATIVE %DRUG RELEASED Vs. TIME OF PURE
DRUG RIFAMPICIN
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FIGURE NO. 13. PLOT OF LOG CUMULATIVE %DRUG RETAINED Vs TIME OF
DIFFERENT FORMULATION OF RIFAMPICIN (IN-VITRO RELEASE
STUDIES) [FIRST ORDER PLOT]
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FIGURE NO. 14. PLOTS OF CUMULATIVE %DRUG RELEASED Vs. ROOT TIME
OF DIFFERENT FORMULATIONS OF RIFAMPICIN (IN-VITRO
DRUG RELEASE STUDIES) [HIGUCHI MATRIX]
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FIGURE NO. 15. PLOTS OF LOG CUMULATIVE DRUG RELEASE Vs. LOG TIME
OF DIFFERENT FORMULATIONS OF RIFAMPICIN (IN-VITRO RELEASE
STUDIES) [PEPPAS]
1.65
1.7
1.75
1.8
1.85
1.9
1.95
2
2.05
2.1
2.15
0 0.2 0.4 0.6 0.8 1 1.2
LOG TIME
L
O
G

C
U
M
U
L
A
T
I
V
E

%
D
R
U
G

R
E
L
E
A
S
E
D

F1
F2
F3
F4

FIGURE NO. 16. PLOTS OF CUBE ROOT OF % DRUG RETAINED Vs. TIME OF
DIFFERENT FORMULATION OF RIFAMPICIN FORMULATIONS (IN-VITRO
RELEASE STUDIES) [HIXSON CROWELL]
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 2 4 6 8 10 12 14
TIME (MINUTE)
C
U
B
E

R
O
O
T

%

D
R
U
G

R
E
T
A
I
N
E
D

F1
F2
F3
F4

0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
F1
F2
F3
F4
C
U
M
U
L
A
T
I
V
E

%

D
R
U
G

R
E
L
E
A
S
E
D
TIME (MINUTE)
FIGURE NO. 17. PLOT OFCUMULATIVE %DRUG RELEASED Vs TIME OF ISONIAZID
INDIFFERENTCOMBINATIONFORMULATTION[ZEROORDERPLOT]

0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0 2 4 6 8 10 12 14
L
O
G

C
U
M
.

%

D
R
U
G

R
E
T
A
I
N
E
D
F1
F2
F3
F4
L
O
G

C
U
M
U
L
A
T
I
V
E

%

D
R
U
G

R
E
T
A
I
N
E
D
TIME (MINUTE)
FIGURE NO. 18. PLOT OF LOG CUMULATIVE % DRUG RETAINED Vs TIME FOR
ISONIAZID IN DIFFERENT COMBINATION FORMULATTION IN-VITRORELEASE
STUDIES [FIRST ORDER PLOT]

FIGURE NO. 19. PLOTS OF CUMULATIVE %DRUG RELEASED Vs ROOT TIME
FOR ISONIAZID IN DIFFERENT COMBINATION FORMULATIONS (IN-VITRO DRUG
RELEASE STUDIES) [HIGUCHI MATRIX]
0
10
20
30
40
50
60
70
80
90
100
0 0.5 1 1.5 2 2.5 3 3.5 4
ROOT TIME
C
U
M
U
L
A
T
I
V
E

%

D
R
U
G

R
E
L
E
A
S
E
D

F1
F2
F3
F4

FIGURE NO. 20. PLOTS OF LOG CUMULATIVE DRUG RELEASE Vs LOG TIME
FOR ISONIAZID IN DIFFERENT COMBINATION FORMULATIONS (IN-VITRO
RELEASE STUDIES)[PEPPAS]
1.6
1.65
1.7
1.75
1.8
1.85
1.9
1.95
2
2.05
2.1
0 0.2 0.4 0.6 0.8 1 1.2
LOG TIME
L
O
G

C
U
M
U
L
A
T
I
V
E

%
D
R
U
G

R
E
L
E
A
S
E
D

F1
F2
F3
F4

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 2 4 6 8 10 12 14
F1
F2
F3
F4
C
U
B
E

R
O
O
O
T

%

D
R
U
G

R
E
T
A
I
N
E
D
TIME (MINUTE)
FIGURE NO. 21. PLOT OF CUBE ROOT OF % DRUG RETAINED Vs TIME FOR
ISONIAZID IN DIFFERENT COMBINATION FORMULATTION IN-VITRORELEASE
STUDIES [HIXSON CROWELL]

0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14
F1
F2
F3
F4
C
U
M
U
L
A
T
I
V
E

%

D
R
U
G

R
E
L
E
A
S
E
D
TIME (MINUTE)
RIFAMPICININDIFFERENTCOMBINATIONFORMULATTIONS [ZEROORDERPLOT]

FIGURE NO. 23. PLOT OF LOG CUMULATIVE % DRUG RETAINED Vs TIME FOR
RIFAMPICIN IN DIFFERENT CONBINATION FORMULATION (IN-VITRO
RELEASE STUDIES) [FIRST ORDER PLOT]
0
0.
0.
0.
0.
1
1.
1.
1.
1.
2
0 2 4 6 8 1 1 1
TIME (MINUTE)
L
O
G

C
U
M
U
L
A
T
I
V
E

%

D
R
U
G

R
E
T
A
I
N
E
D

F
F
F
F

FIGURE NO. 24. PLOTS OF LOG CUMULATIVE DRUG RELEASE Vs LOG TIME
FOR RIFAMPICIN IN DIFFERENT COMBINATION FORMULATIONS (IN-
VITRO RELEASE STUDIES) [PEPPAS]
1.6
1.65
1.7
1.75
1.8
1.85
1.9
1.95
2
2.05
2.1
0 0.2 0.4 0.6 0.8 1 1.2
LOG TIME
L
O
G

C
U
M
U
L
A
T
I
V
E

%
D
R
U
G

R
E
L
E
A
S
E
D

F1
F2
F3
F4

FIGURE NO. 25. PLOTS OF CUMULATIVE %DRUG RELEASED Vs. ROOT TIME
FOR RIFAMPICIN IN DIFFERENT COMBINATION FORMULATIONS (IN-VITRO
DRUG RELEASE STUDIES) [HIGUCHI MATRIX]
0
10
20
30
40
50
60
70
80
90
100
0 0.5 1 1.5 2 2.5 3 3.5 4
ROOT TIME
C
U
M
U
L
A
T
I
V
E

%

D
R
U
G

R
E
L
E
A
S
E
D

F1
F2
F3
F4

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 2 4 6 8 10 12 14
F1
F2
F3
F4
C
U
B
E

R
O
O
O
T

%

D
R
U
G

R
E
T
A
I
N
E
D
TIME (MINUTE)
FIGURE NO. 26. PLOT OF CUBE ROOT OF % DRUG RETAINED Vs TIME FOR
RIFAMPICIN IN DIFFERENT COMBINATION FORMULATTION IN-VITRORELEASE
STUDIES [HIXSON CROWELL]

1
10
100
0 2 4 6 8 10 12
L
O
G

P
L
A
S
M
A

C
O
N
C
E
N
T
R
A
T
I
O
N
(
g
/
m
l
)
TIME (HOURS)
Formulation (F-1) Isoniazid
Isoniazid Free Solution
FIGURE NO. 27. DRUG PLASMA PROFILE OF FORMULATION 1 (F-1) AND ISONIAZID
SOLUTION

1
10
100
0 2 4 6 8 10 12
L
O
G

P
L
A
S
M
A

C
O
N
C
E
N
T
R
A
T
I
O
N
(
g
/
m
l
)
TIME (HOURS)
Formulation (F5), Rifampicin
Rifampicin Free Solution

FIGURE NO. 28. DRUG PLASMA PROFILE OF FORMULATION 5 (F-5) AND
RIFAMPICIN SOLUTION

1
10
100
0 2 4 6 8 10 12
L
O
G

P
L
A
S
M
A

C
O
N
C
E
N
T
R
A
T
I
O
N
(
g
/
m
l
)
TIME (HOURS)
Formulation (F-9), Isoniazid
Formulation (F-9), Rifampicin
Isoniazid Free Solution
Rifampicin Free Solution

FIGURE NO. 29. DRUG PLASMA PROFILE OF COMNINATION FORMULATION 9 (F-9),
FREE ISONIAZID AND RIFAMPICIN SOLUTION

80
85
90
95
100
105
F1 (INH) F5 (RIFA) F9-INH F9-RIFA
%

R
e
s
i
d
u
a
l

D
r
u
g
Formulation Types
1 Month
2 Month
3 Month
4 Month
5 Month
6 Month
STABILITY STUDY AT 40C
86
88
90
92
94
96
98
100
102
104
F1 (INH) F5 (RIFA) F9-INH F9-RIFA
%

R
e
s
i
d
u
a
l

D
r
u
g
Formulation Types
1 Month
2 Month
3 Month
4 Month
5 Month
6 Month
STABILITY STUDY AT 25C

FIGURE NO. 30. STABILITY STUDIES OF FORMULATION 1 (F-1), FORMULATION 5 (F-5) AND
FORMULATION 9 (F-9) AT 40C AND 25C
TABLE NO. 1. COMPOSITION OF ISONIAZID, RIFAMPICN AND COMBINATION FORMULATIONS
COMPOSITION OF DIFFERENT FORMULATIONS Ingredients (mgs)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Isoniazid 100 100 100 100 - - - - 50 50 50 50
Rifampicin -- -- -- -- 100 100 100 100 50 50 50 50
Avicel pH102 108 108 108 108 108 108 108 108 108 108 108 108
Ac-di-sol 17.5 -- -- -- 17.5 -- -- -- 17.5 -- -- --
Polyplasdone XL -- 17.5 -- -- -- 17.5 -- -- -- 17.5 -- --
Explotab -- -- 17.5 -- -- -- 17.5 -- -- -- 17.5 --
Kallidon CL -- -- -- 17.5 -- -- -- 17.5 -- -- -- 17.5
Mannitol 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5 17.5
Sodium Saccharine 7 7 7 7 7 7 7 7 7 7 7 7
Magnesium Stearate 7 7 7 7 7 7 7 7 7 7 7 7
Flavor 4 4 4 4 4 4 4 4 4 4 4 4
Blank space (dace) indicate that those components not present in the formulations
TABLE NO. 2. STANDARD CALIBRATION CURVE OF ISONIAZID AND RIFAMPICIN IN PHOSPHATE BUFFER (pH 6.8)
Absorbance Measurement
Concentration (g/ml)
Isoniazid* Rifampicin**
1 0.129 0.124
2 0.169 0.208
3 0.279 0.302
4 0.362 0.397
5 0.444 0.429
6 0.534 0.506
7 0.638 0.586
8 0.717 0.635
9 0.81 0.702
10 0.889 0.798
*Isoniazid absorbance measured at
max
261 nm, INH Correlation (r) = 0.9976
**Rifampicin absorbance measured at
max
333 nm, RIFA Correlation (r) = 0.9945
TABLE NO. 3. PRE-COMPRESSION PARAMETERS: CHARACTERIZATION OF FORMULATION POWDER
Formulations Angle of Repose
()
Loose Bulk Density
(gm/cm
3
)
Tapped Bulk Density
(gm/cm
3
)
% Compressibility Appearance
F1 28.16 0.56 0.65 13.84 White
F2 30.48 0.59 0.68 13.23 White
F3 28.45 0.53 0.64 17.18 White
F4 29.64 0.55 0.66 16.66 White
F5 26.16 0.52 0.63 17.46 Reddish
F6 26.48 0.55 0.65 15.38 Reddish
F7 26.45 0.59 0.69 14.49 Reddish
F8 27.64 0.54 0.75 16.92 Reddish
F9 29.32 0.57 0.68 16.17 Reddish white
F10 27.01 0.55 0.64 14.06 Reddish white
F11 26.73 0.59 0.69 14.49 Reddish white
F12 27.20 0.54 0.65 16.92 Reddish white
TABLE NO: 4: POST-COMPRESSION PARAMETERS: EVALUATION OF TABLETS
Formulation
Code
Uniformity of
Thickness* (mm)
Hardness*
(kg/cm
3
)
Weight**
(mg)
Drug Content
Uniformity* (mg)
Friability
(%)
Test of
dispersion
F1 2.2560.057 4.260.08 2612.34 97.390.44 0.67 Passed
F2 2.2430.065 4.560.07 2611.97 99.060.21 0.65 Passed
F3 2.2540.103 4.140.07 2612,65 96.740.23 0.64 Passed
F4 2.2510.050 4.650.13 2613.01 96.440.55 0.71 Passed
F5 2.2470.065 4.480.04 2612.17 97.390.44 0.67 Passed
F6 2.850.035 4.380.08 2612.45 96.180.63 0.65 Passed
F7 2.2650.036 4.560.07 2612.62 96.580.53 0.64 Passed
F8 2.2870.047 4.160.07 2612.74 96.180.39 0.71 Passed
F9 2.2780.0647 4.630.13 2612.36 97.270.47 0.67 Passed
F10 2.2380.098 4.480.04 2612.86 99.060.21 0.65 Passed
F11 2.2870.047 4.380.08 2612.49 96.740.23 0.64 Passed
F12 2.2290.038 4.670.13 2612.75 97.390.44 0.71 Passed
*Tests performed, n=3
**Tests performed, n=10
TABLE NO. 5. POST-COMPRESSION PARAMETERS: WETTING TIME, WATER ABSORPTION RATIO
Formulation Code Wetting Time (Seconds) Water Absorption Ratio
F1 225.50 0.73 19.45 2.14
F2 218.01 1.77 24.89 1.43
F3 216.76 1.27 23.09 1.37
F4 229.58 1.47 25.56 2.74
F5 227.60 1.58 20.19 0.69
F6 220.58 1.56 23.34 1.66
F7 217.50 1.67 24.35 2.34
F8 227.71 1.24 24.45 1.54
F9 224.76 1.48 25.14 1.76
F10 224.58 1.67 24/.98 1/54
F11 217.60 1.48 25.43 1.53
F12 222.78 1.71 27.08 1.24
Data expressed at meanSD, all experiments performed in triplicate
TABLE NO: 6 POST-COMPRESSION PARAMETERS: IN VITRO DISPERSION TIME, DISINTEGRATION TIME
Formulation Code Disintegration Time (Second) Dispersion Time (Second) Mouth Feel
F1 25.12 1.142 136.28 1.56 +
F2 28.36 1.675 170.65 1.78 +
F3 30.12 1.140 128.00 1.0 +
F4 31.43 1.14 120.16 0.86 +
F5 26.15 0.837 143.43 1.16 +
F6 30.24 0.83 176.98 0.75 +
F7 33.42 1.16 156.28 1.56 +
F8 36.14 1.435 140.65 1.78 +
F9 27.52 1.72 146.76 1.0 +
F10 28.43 1.14 172.16 0.86 +
F11 32.15 0.837 165.19 1.16 +
F12 33.24 0.74 158.74 0.75 +
+ good palatable mouth feel
-' poor palatable mouth feel
TABLE NO. 7. IN-VITRO RELEASE PROFILE FOR ISONIAZID (INH)
Time
(min.)
Absorbance Concentration Drug Release
(mg/900 ml)
CLA
(mg)
Cumulative Drug
Release (mg/900ml)
% Cumulative Drug
Release
2 0.576 6.4 57.6 _ 57.6 57.6
4 0.639 7.2 64.8 0.57 65.37 65.37
6 0.716 8.0 72.0 0.65 72.65 72.65
8 0.802 9.2 82.8 0.72 83.52 83.52
10 0.946 10.8 97.2 0.83 98.03 98.03
12 1.009 11.07 99.63 0.98 100.66 100.66
Amount of INH present in the formulation 100 mg
TABLE NO. 8. IN-VITRO RELEASE PROFILE OF MARKETED ISONIAZID FORMULATION
Time
(min.)
(mg/900 ml)
CLA
(mg)
Cumulative Drug
Release (mg/900ml)
% Cumulative Drug
Release
2 0.517 5.7 51.3 - 51.3 51.3
4 0.587 6.6 59.4 0.51 59.91 59.91
6 0.687 7.8 70.2 0.59 70.79 70.79
8 0.740 8.4 75.6 0.70 76.3 76.3
10 0.814 9.3 83.7 0.76 84.46 84.46
12 0.923 10.65 95.85 0.84 96.69 96.69
TABLE NO. 9. IN-VITRO RELEASE PROFILE OF ISONIAZID FROM AC-DI-SOL (FORMULATION-1)
Time (T)
(mins)
Root T Log T Cumulative Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
%Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 57.6 57.6 42.4 1.76 1.62 3.48
4 2 0.6020 68.97 68.97 31.03 1.83 1.49 3.14
6 2.44 0.7781 76.28 76.28 23.72 1.88 1.36 2.87
8 2.82 0.9030 84.46 84.46 15.04 1.92 1.17 2.46
10 3.16 1.000 94.44 94.44 5.56 1.97 0.74 1.77
12 3.46 1.079 100.57 100.57 00 2 00 00
TABLE NO. 10. IN-VITRO RELEASE PROFILE OF ISONIAZID FROM SODIUM STARCH GLYCOLATE (FORMULATION-2)
Time (T)
(min.)
Root T Log T Cumulative
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 54.9 54.9 45.1 1.73 1.65 3.55
4 2 0.6020 65.34 65.34 34.66 1.81 1.53 3.26
6 2.44 0.7781 72.65 72.65 27.35 1.86 1.43 3.01
8 2.82 0.9030 82.92 82.92 17.08 1.91 1.23 2.57
10 3.16 1.000 89.02 89.02 10.98 1.94 1.04 2.22
12 3.46 1.079 98.09 98.09 1.91 1.99 0.28 1.24

TABLE NO. 11. IN-VITRO RELEASE PROFILE OF ISONIAZID FROM POLYPLASTADONE XL (FORMULATION-3)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 53.55 53.55 46.45 1.72 1.66 3.59
4 2 0.6020 62.63 62.63 37.37 1.79 1.57 3.34
6 2.44 0.7781 69.02 69.02 30.98 1.83 1.49 3.14
8 2.82 0.9030 78.99 78.99 21.01 1.89 1.32 2.75
10 3.16 1.000 89.88 89.88 10.12 1.95 1.00 2.16
12 3.46 1.079 98.45 98.45 1.55 1.99 0.19 1.15
TABLE NO. 12. IN-VITRO RELEASE PROFILE OF ISONIAZID FROM KOLLIDONE CL (FORMULATION-4)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 52.2 52.2 47.8 1.71 1.67 3.62
4 2 0.6020 60.82 60.82 39.18 1.78 1.59 3.39
6 2.44 0.7781 67.2 67.2 32.8 1.82 1.51 3.20
8 2.82 0.9030 78.07 78.07 21.93 1.89 1.34 2.79
10 3.16 1.000 88.98 88.98 11.02 1.94 1.04 2.22
12 3.46 1.079 97.18 97.18 2.82 1.98 0.45 1.41
TABLE NO. 13. IN-VITRO RELEASE PROFILE FOR RIFAMPICIN
Time
(min.)
(mg/900 ml)
CLA
(mg)
Cumulative Drug
Release (mg/900ml)
% Cumulative Drug
Release
2 0.507 6.3 56.7 _ 56.70 56.70
4 0.567 7.1 63.9 0.56 64.46 64.46
6 0.629 7.9 71.1 0.64 71.74 71.74
8 0.671 8.4 75.6 0.71 76.31 76.31
10 0.756 9.6 86.4 0.76 87.16 87.16
12 0.837 10.75 96.75 0.87 97.62 97.62
Amount of Rifampicin present 100 mg
TABLE NO. 14. IN-VITRO RELEASE PROFILE OF MARKETED RIFAMPICIN FORMULATION
Time
(min.)
Absorbance Concentration
Drug Release
(mg/900 ml)
CLA
(mg)
Cumulative Drug
Release (mg/900ml)
% Cumulative Drug
Release
2 0.517 6.40 57.6 - 56.7 56.7
4 0.597 7.50 67.5 0,57 64.46 64.46
6 0.663 8.30 74.7 0.64 71.74 71.74
8 0.747 9.50 85.5 0.71 76.31 76.31
10 0.791 10.10 90.0 0.76 87.16 87.16
12 0.857 10.65 95.85 0.87 97.62 97.62
Amount of Rifampicin present in formulation 100 mg
TABLE NO. 15. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM AC-DI-SOL (FORMULATION-5)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 56.25 56.25 43.75 1.75 1.64 3.52
4 2 0.6020 66.26 66.26 33.74 1.82 1.52 3.23
6 2.44 0.7781 74.46 74.46 25.54 1.87 1.40 2.94
8 2.82 0.9030 82.64 82.64 17.36 1.93 1.23 2.58
10 3.16 1.000 93.52 93.52 6.48 1.97 0.811 1.86
12 3.46 1.079 99.21 99.21 0.79 1.99 -0.10 0.92
Amount of Rifampicin present in the formulation 100 mg
TABLE NO. 16. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM SODIUM STARCH GLYCOLATE (FORMULATION-6)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 55.8 55.8 44.2 1.74 1.64 3.53
4 2 0.6020 64.34 64.34 35.66 1.80 1.55 3.29
6 2.44 0.7781 73.09 73.09 26.91 1.86 1.42 2.99
8 2.82 0.9030 84.43 84.43 15.57 1..92 1.19 2.49
10 3.16 1.000 91.74 91.74 8.26 1.96 0.91 2.02
12 3.46 1.079 98.11 98.11 1.89 1.97 0.27 1.23
TABLE NO. 17. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM POLYPLASTADONE XL (FORMULATION-7)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 55.8 55.8 44.2 1.74 1.64 3.53
4 2 0.6020 67.15 67.15 32.85 1.82 1.51 3.20
6 2.44 0.7781 73.57 73.57 26.43 1.87 1.42 2.97
8 2.82 0.9030 81.28 81.28 18.72 1.90 1.27 2.65
10 3.16 1.000 89.01 89.01 10.99 1.94 1.04 2.22
12 3.46 1.079 97.19 97.19 2.81 1.98 0.44 1.41
TABLE NO. 18. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM KOLLIDON CL (FORMULATION-8)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 55.35 55.35 44.65 1.74 1.64 3.54
4 2 0.6020 65.35 65.35 34.65 1.81 1.53 3.26
6 2.44 0.7781 72.2 72.2 27.8 1.85 1.44 3.02
8 2.82 0.9030 78.12 78.12 21.88 1.89 1.34 2.79
10 3.16 1.000 88.08 88.08 11.92 1.94 1.07 2.28
12 3.46 1.079 96.28 96.28 3.72 1.98 0.57 1.54
TABLE NO. 19. IN-VITRO RELEASE PROFILE OF ISONIAZID FROM AC-DI-SOL (FORMULATION-9)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 53.1 53.1 46.9 1.72 1.67 3.60
4 2 0.6020 60.83 60.83 39.17 1.78 1.59 3.39
6 2.44 0.7781 68.1 68.1 31.9 1.83 1.50 3.17
8 2.82 0.9030 78.08 78.08 21.92 1.89 1.34 2.79
10 3.16 1.000 88.98 88.98 11.02 1-94 1.04 2.22
12 3.46 1.079 97.99 97.99 2.01 1.99 0.303 1.26
Amount of INH and Rifa (Both) present in the formulation 50+50 = 100 mg
TABLE NO. 20. IN-VITRO RELEASE PROFILE OF ISONIAZID FROM SODIUM STARCH GLYCOLATE (FORMULATION-10)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)1/3
2 1.41 0.3010 51.3 51.3 48.7 1.71 1.68 3.65
4 2 0.6020 60.38 60.38 39.62 1.78 1.59 3.40
6 2.44 0.7781 69.00 69.00 31.00 1.83 1.49 3.14
8 2.82 0.9030 80.79 80.79 19.21 1.90 1.28 2.67
10 3.16 1.000 87.2 87.2 12.8 1.94 1.10 2.33
12 3.46 1.079 96.72 96.72 3.28 1.98 0.51 1.48
TABLE NO. 21. IN-VITRO RELEASE PROFILE OF ISONIAZID FROM POLYPLASTADONE XL (FORMULATION-11)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 53.1 53.1 46.9 1.72 1.67 3.60
4 2 0.6020 60.83 60.83 39.17 1.78 1.59 3.39
6 2.44 0.7781 67.2 67.2 32.8 1.82 1.51 3.20
8 2.82 0.9030 78.07 78.07 21.93 1.89 1.34 2.79
10 3.16 1.000 88.8 88.8 11.92 1.94 1.07 2.28
12 3.46 1.079 95.02 95.02 4.98 1.97 0.69 1.70
TABLE NO. 22: IN-VITRO RELEASE PROFILE OF ISONIAZID FROM KOLLIDONE CL (FORMULATION-12)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 52.52 52.52 47.8 1.72 1.67 3.62
4 2 0.6020 59.47 59.47 40.53 1.77 1.60 3. 43
6 2.44 0.7781 66.6 66.6 32.81 1.82 1.51 3.20
8 2.82 0.9030 75.36 75.36 24.64 1.87 1.39 2.90
10 3.16 1.000 87.15 87.15 12.85 1.94 1.10 2.34
12 3.46 1.079 94.11 94.11 5.89 1.97 0.77 1.80
TABLE NO. 23. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM AC-DI-SOL (FORMULATION-9)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 48.6 48.6 51.4 1.68 1.71 3.71
4 2 0.6020 55.38 55.38 44.62 1.74 1.64 3.54
6 2.44 0.7781 65.35 65.35 34.65 1.81 1.53 3.26
8 2.82 0.9030 75.35 75.35 24.65 1.87 1.39 2.90
10 3.16 1.000 80.85 80.85 19.15 1.90 1.28 2.67
12 3.46 1.079 90.35 90.35 9.65 1.95 0.98 2.12
TABLE NO. 24. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM SODIUM STARCH GLYCOLATE (FORMULATION-10)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 46.8 46.8 53.2 1.67 1.72 3.76
4 2 0.6020 53.56 53.56 46.44 1.72 1.66 3.59
6 2.44 0.7781 58.13 58.13 41.87 1.76 1.62 3.47
8 2.82 0.9030 65.38 65.38 34.62 1.81 1.53 3.25
10 3.16 1.000 78.95 78.95 21.05 1.89 1.32 2.76
12 3.46 1.079 87.18 87.18 12.82 1.94 1.10 2.34
TABLE NO. 25. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM POLYPLASTADONE XL (FORMULATION-11)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 43.3 43.3 57.7 1.63 1.76 3.86
4 2 0.6020 49.03 49.03 50.97 1.69 1.70 3.70
6 2.44 0.7781 56.29 56.29 43.71 1.75 1.64 3.52
8 2.82 0.9030 67.16 67.16 32.84 1.82 1.51 3.20
10 3.16 1.000 77.17 77.17 22.83 1.88 1.35 2.83
12 3.46 1.079 84.74 84.74 15.26 1.92 1.18 2.48
TABLE NO. 26. IN-VITRO RELEASE PROFILE OF RIFAMPICIN FROM KOLLIDON CL (FORMULATION-12)
Time (T)
(min.)
Drug
Released
(mg/900ml)
Cumulative
% Drug
Released
Cumulative
% Drug
Retained
Log
Cumulative
% Drug
Released
Log
Cumulative
% Drug
Retained
(% Retained)
1/3
2 1.41 0.3010 44.1 44.1 55.9 1.64 1.74 3.82
4 2 0.6020 50.84 50.84 49.16 1.70 1.69 3.66
6 2.44 0.7781 57.2 57.2 42.8 1.75 1.63 3.49
8 2.82 0.9030 68.97 68.97 31.03 1.83 1.49 3.14
10 3.16 1.000 78.98 78.98 21.02 1.89 1.32 2.75
12 3.46 1.079 84.93 84.93 15.07 1.92 1.17 2.47
TABLE NO. 27. KINETIC VALUES OBTAINED FROM IN-VITRO RELEASE DATA OF DISPERSIBLE FORMULATIONS
Plot of Log Cum. % Drug Retained V/s. Time (T)
(First Order Plot)
Plot Of Cum. % Drug Released V/s. Time (T)
(Zero order Plot)
Formulation
Slope (n) First Order Rate
Constant
Regression
Coefficient (r)
Slope (n) Zero Order Rate
Constant
Regression
Coefficient (r)
F-1 0.0371 0.0854 0.0553 6.980 -6.98 0.7993
F-2 -0.0121 -0.0278 0.0067 6.7873 -6.7873 0.81
F-3 -0.0179 -0.0412 0.013 6.8638 -6.8638 0.8361
F-4 -0.0029 -0.0066 0.0004 6.8277 -6.8277 0.8453
F-5 -0.0294 -0.0677 0.0356 6.9384 -6.9384 0.8115
F-6 -0.0180 -0.179 0.0148 6.8982 -6.8982 0.8147
F-7 -0.0021 -0.0048 0.0002 6.645 -6.645 0.7908
F-8 -0.0680 -0.156 0.0024 6.5548 -6.5548 0.795
F-9-INH -0.0107 -0.0246 0.0049 6.8389 -6.8389 0.8423
F-10-INH 0.0017 0.0056 6E
-05
6.828 -6.828 0.8442
F-11-INH 0.0111 0.025 0.0063 6.6732 -6.6732 0.8303
F-12-INH 0.0171 0.039 0.0155 6.5621 -6.5621 0.8311
F-9-RIFA 0.0327 0.075 0.0572 6.3486 -6.3486 0.8408
F-10-RIFA 0.0423 0.097 0.0917 6.0296 -6.0296 0.8452
F-11-RIFA 0.0452 0.104 0.01021 6.072 -6.072 0.876
F-12-RIFA 0.0441 0.101 0.0992 6.119 -6.119 0.868
TABLE NO. 28. KINETIC VALUES OBTAINED FROM IN-VITRO RELEASE DATA OF DIFFERENT DISPERSIBLE
FORMULATIONS
Plot of Cum. % Drug Released V/s.
Root Time (T)
[Higuchi Matrix]
Plot Of Log Cum. % Drug Released
V/s. Log Time (Log T)
[Peppas]
Plot Of [% Retained]
1/3
Vs. Time
[Hixson Crowell]
Formulation
Slope (n) Regression
Coefficient (r)
Coefficient (r)
Coefficient (r)
F-1 27.95 0.9678 0.2292 0.9857 -0.0604 0.0351
F-2 27.05 0.9716 0.2431 0.9865 -0.0066 0.0005
F-3 26.98 0.9757 0.2558 0.9636 -0.0040 0.0
F-4 26.73 0.9780 0.2570 0.9678 -0.0148 0.0025
F-5 27.63 0.9717 0.2286 0.9903 -0.0216 0.0052
F-6 27.44 0.9730 0.2337 0.9860 -0.0023 6E-05
F-7 26.70 0.9639 0.2221 0.9862 0.0189 0.0045
F-8 26.26 0.9630 0.2182 0.9793 0.0291 0.0105
F-9-INH 26.80 0.9763 0.2616 0.9672 0.0075 0.0006
F-10-INH 26.80 0.9823 0.2620 0.9812 0.0191 0.0042
F-11-INH 26.30 0.9736 0.2463 0.9678 0.0332 0.013
F-12-INH 25.83 0.9723 0.2398 0.9612 0.0412 0.020
F-9-RIFA 24.95 0.9802 0.2616 0.9672 0.065 0.0491
F-10-RIFA 24.94 0.9801 0.262 0.9812 0.0836 0.0765
F-11-RIFA 23.41 0.9828 0.2463 0.9678 0.871 0.0806
F-12-RIFA 23.70 0.9827 0.2398 0.9612 0.848 0.0781
TABLE NO. 29. KINETIC VALUES OBTAINED FROM IN-VITRO RELEASE DATA OF DIFFERENT DISPERSIBLE
FORMULATIONS
Formulation Code n value K value
Order of release
F1 0.3320 43.79 Zero order
F2 0.3322 41.88 Zero order
F3 0.3559 39.40 Zero order
F4 0.3471 38.80 Zero order
F5 0.3575 40.25 Zero order
F6 0.3555 40.14 Zero order
F7 0.3464 39.91 Zero order
F8 0.3426 40.84 Mixed order
F9-INH 0.3426 39.16 Mixed order
F9-RIFA 0.3980 32.46 Mixed order
TABLE NO. 30. ANTI-TUBERCULAR ACTIVITY OF ISONIAZID, RIFAMPICIN AND COMBINATION DISPERSIBLE
FORMULATIONS
ZONE OF INHIBITION AT DIFFERENT DRUG CONCENTRATION TEST COMPOUND
100 g 300 g
F1 No growth No growth
Control No growth No growth
Standard No growth No growth
TABLE NO. 31. IN-VIVO PHARMACOKINTIC STUDIES OF ISONIAZID FROM DISPERSIBLE FORMULATION (F-1) AND
FREE DRUG IN BLOOD
Parameter Formulation F-1 (Isoniazid) Isoniazid solution
Cmax (g/ml) 65.91 38.53
Tmax (h) 0.5 1
AUC
0 to 12h
(g/ml * h) 160.78 113.94
Kel (1/h) 0.31 0.29
t
(h) 2.21 2.37

MRT (h) 2.99 3.15
TABLE NO. 32. IN-VIVO PHARMACOKINTIC STUDIES OF RIFAMPICIN FROM DISPERSIBLE FORMULATION (F-5) AND
FREE DRUG IN BLOOD
Parameter Formulation F-5 (Rifampicin) Rifampicin Solution
Cmax (g/ml) 34.76 29.64
Tmax (h) 1 0.75
AUC (0 to 12h) (g/ml * h) 139.26 74.32
Kel (1/h) 0.20 0.21
t
(h) 3.42 3.34

MRT (h) 5.02 3.86
TABLE NO. 33. IN-VIVO PHARMACOKINETIC STUDIES OF COMBINATION FORMULATION (F-9) AND FREE DRUG IN
BLOOD
Parameter Formulation F-9
(Isoniazid)
Formulation F-9
(Rifampicin)
Isoniazid solution Rifampicin
Solution
Cmax (g/ml) 49.97 45.34 38.53 29.64
Tmax (h) 0.5 1 1 0.75
AUC (0 to 12h)
(g/ml * h)
119.88 147.16 113.94 74.32
Kel (1/h) 0.29 0.228 0.29 0.21
t
(h) 2.34 3.036 2.37 3.34

MRT (h) 3.22 4.45 3.15 3.86
TABLE NO. 34. IN-VIVO PHARMACOKINETIC STUDIES OF ALL THE SELECTED FORMULATIONS (F-1, F-5 AND F-9)
Parameter Formulation
F-1
(Isoniazid)
Isoniazid
solution
Formulation F-5
(Rifampicin)
Rifampicin
Solution
Formulation F-9
(Isoniazid)
Formulation
F-9
(Rifampicin)
Cmax (g/ml) 65.91 38.53 34.76 29.64 49.97 45.34
Tmax (h) 0.5 1 1 0.75 0.5 1
AUC (0 to 12h)
(g/ml * h)
160.78 113.94 139.26 74.32 119.88 147.16
Kel (1/h) 0.31 0.29 0.20 0.21 0.29 0.228
t
(h) 2.21 2.37 3.42 3.34 2.34 3.036

MRT (h) 2.99 3.15 5.02 3.86 3.22 4.45
TABLE NO. 35. STABILITY STUDIES- SHELF LIFE DETERMINATION AT 40C
Time
(months)
F1 INH
degraded (mg)
F1 INH
remaining
(mg)
F5 RIF
degraded
(mg)
F5 RIF
remaining
(mg)
F9 INH
degraded
(mg)
F9 INH
remaining
(mg)
F9 RIF
degraded
(mg)
F9 RIF
remaining
(mg)
1 0.37 99.63 1.72 98.28 1.445 48.555 0.5 49.5
2 3.2 96.8 2.98 97.02 2.21 47.79 1.5 48.5
3 4 96 4.33 95.67 2.435 47.565 2.5 47.5
4 5 95 6.67 93.33 2.795 47.205 3.5 46.5
5 6 94 7.48 92.52 3.11 46.89 4 46
6 7 93 9.19 90.81 3.32 46.68 4.55 45.45
TABLE NO. 36. STABILITY STUDIES- SHELF LIFE DETERMINATION AT 25C
Time
(months)
F1 INH
degraded
(mg)
F1 INH
remaining
(mg)
F5 RIF
degraded
(mg)
F5 RIF
remaining
(mg)
F9 INH
degraded
(mg)
F9 INH
remaining
(mg)
F9 RIF
degraded
(mg)
F9 RIF
remaining
(mg)
1 0.2 99.8 1 99 0.2 49.8 0.2 49.8
2 1 99 2 98 0.35 49.65 0.7 49.3
3 1.6 98.4 2.4 97.6 0.55 49.45 1 49
4 2.8 97.2 4 96 0.95 49.05 2 48
5 3.2 96.8 4.2 95.8 1.5 48.5 2.5 47.5
6 4 96 6 94 1.6 48.4 3.5 46.5

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i

C as the immersion liquid. The temperature of the medium was

.16' to 30.48'. All formulations showed angle of repose

is indicative of fair flow behavior of powder, hence F2 formulation showed fair

C/75% RH for all the selected formulations up to 6 months.

C/60% RH. The combination formulation of Isoniazid

C/75% RH for 6 months. Various parameters like hardness, friability, drug

(h) 2.21 2.37

(h) 3.42 3.34

(h) 2.34 3.036 2.37 3.34

(h) 2.21 2.37 3.42 3.34 2.34 3.036

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