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versity of Jo
ordan
Facu
ulty of Pharm
macy
De
epartment off Pharmaceu
utics and Phharmaceutic
cal Technolo
ogy
Pra
actical Pharmace
eutical Te
echnolog
gy I Man
nual
Fall Semesster
2011 - 201
12
Pr
Prepared By:
B
Suha A Al Muha
aissen
UINIVERSITY OF JORDAN
FACULTY OF PHARMACY
DEPTARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY
Method:
Pre-lab preparation (all students required to read the instructions for the relevant
experiment prior to attending the lab - 30 minutes per lab).
Laboratory time: 30 hours total (10*3 hours)
Learning content:
Full details of the experimental procedures and background information are provided
in the laboratory schedules. Students are expected to read these schedules prior to
entering the laboratory. This will allow them to carry out the experiment quickly and
efficiently, and to understand the experiment and the data analysis methods
requested in the schedule. All practical sessions will be run by a member of
academic staff, assisted by postgraduate Teaching Assistants and members of
technical staff these will advise on experimental techniques and be available for
consultation on any other aspect of the practical course. Students are encouraged to
seek assistance at any time.
Students are required to complete all the experiments in the schedule and to write
laboratory reports to contribute to group reports for the individual experiment, as
appropriate. Practical's run as-full day (three-hour) sessions. A series of
supplementary questions form a part of the assessment of certain experiments to
which students are expected to give brief but informative answers. Students should
use the background information.
It is imperative that safe working procedures and practices are adhered to
throughout. Safety glasses and laboratory coats must be worn at all times when in
the laboratory.
Students are required to complete group reports for certain experiments before they
leave the practical session. Other group and individual reports should be handed in
one week after the practical session. Reports handed in late without prior agreement
or medical evidence will be subject to a penalty in accord with standard University
practice. The report will subsequently be marked and appropriate constructive
comments will be provided. The marked laboratory reports will be returned as soon
as possible and normally for the next laboratory session or within two weeks from
submission.
Assessment:
The module will be assessed by 8 written reports. For two practicals the practical
report will include full details of the experimental procedure, results, discussion and
answers to questions posed in the laboratory schedule. For the other practicals
students will contribute to group reports, which should conform to guidelines which
will be provided.
Learning Outcomes/Skills:
Deductive reasoning
Numerical Analysis
Written/oral communication
Information retrieval and analysis
Practical application of theory
Report writing
Course Outline
Required
Experiment Title Expected Dates
Time
Introduction 1 week 25/09/2011 - 29/09/2011
Marks:
Group Reports
Log-Book 30%
Evaluation
Mid-Term exam: 30%
Final Examination: 40 %
Univ
versity of Jo
ordan
Facuulty of Pharm
macy
Department of Pharmaaceutical Sciences and Technology
y
Pra
actical Pharmace
eutical Te
echnolog
gy I Man
nual
Cy
ycle ( 1 )
W
Week 1 W
Week 2 Week 3 Week 4
Group A Exp
periment 1 Exp
periment 2 Ex
xperiment 3 Experiment
E t4
Group B Exp
periment 2 Exp
periment 1 Ex
xperiment 4 Experiment
E t3
Group C Exp
periment 3 Exp
periment 4 Ex
xperiment 1 Experiment
E t2
Group D Exp
periment 4 Exp
periment 3 Ex
xperiment 2 Experiment
E t1
EXPERIMENT (1)
POWDER MIXING (P.M.)
INTRODUCTION
Aim of Mixing:
The main aim of powder mixing in pharmaceutical practice is to achieve dose
uniformity in solid dosage form (tablets, capsules, and powders), particularly so
important in case of very potent drugs like Digoxin, Ethinyl estradiol.
- Parameters affecting Mixing:
1. Particle Parameter: like particle size, particle shape, size distribution,
particle density, Cohesive forces, Hygroscopic properties, Hardness.
2. Type of mixer: speed, batch volume and movement.
3. Segregation tendency of individual components based on density
difference.
- Mechanisms of Mixing: Diffusion, Convection, and Shearing.
- Efficiency of Powder Mixing using different mixers is affected by:
1. Presence of Blades
2. Filling Volume
3. Agitation Speed
Revolvo-Cube Mixer:
- motor drive mixer
- The housing in the Cube Mixer is manufactured from stainless steel.
- Equipped with Baffles but not Blades
- Tumbling movement.
- Cube mixer is problematic due to the presence of corners, why?
EXPERIMENTAL:
a. Materials:
Lactose, Sodium Salicylate,
b. Apparatus:
Revolvo-Cube Mixer, UV/VIS Spectrophotometer.
c. Method:
2. Place the powders in the mixing chamber of the Revolvo-Cube Mixer (place
powder of the largest quantity (lactose) first then Na-Salicylate)
5. Determine the content of Na-Salicylate in each sample at each time (all samples
will be analyzed at each time interval. Follow the analytical technique described
below:
a. Put each sample in 100 mL Volumetric Flask.
b. Add 10 - 15 mL of distilled water and mix until all powders are completely
dissolved.
c. Complete the volume by D.Water up to the 100 mL mark then mix well.
d. Measure the samples absorbance using UV/VIS spectrophotometer:
• Blank should be 0.20% w/v Lactose in D.Water (200 mg Lactose in 100 mL
V.Flask, dissolve lactose in 10 - 20 mL of D.Water, then complete up to the
100 mL mark using D.Water.
• λmax for absorbance measurement is 254 nm
NB:
Absorbance linear range is (0.200 - 1.200), solutions of absorbance out of
this range should be diluted.
6. Calibration Curve:
a. Prepare 0.10gm% w/v of Na-Salicylate in D.Water ( place 100 mg Na-
Salicylate in 100 mL V.Flask, dissolve then complete volume up to the
100 mL mark with D.Water then mix well) → Standard Stock Solution
b. Withdraw 10, 20, 25 & 35 mL using volumetric pipettes from the
Standard Stock Solution and place each in a different 100 mL V.Flask
and complete the volume up to 100 mL mark with D.Water then mix well
→ Standard Solutions
c. Measure the standard solutions absorbances using D.Water as a blank,
and at λmax = 254 nm.
N.B.
Sampling is an integral part of mixing because at anytime, spot samples generate the data
necessary to evaluate the quality of the mixture. The data for statistics are generated by assaying
the active ingredient(s) in a number of random samples taken from the blend at a specified time.
The mean assay value of a group of random samples taken from the mixture is a measure of the
central tendency of the batch population (active ingredient content).
In addition of the mean, the spread or dispersion of individual samples about the mean can be
calculated by using the Standard Deviation or the Variance.
Ŷ
S= ∑
Variance:
Ŷ
V=∑ = S2
. . %
Results and Data Analysis
• Apply Beers Law to the calibration curve straight line equation as following:
A= a*b*C, where A is the Absorbance, a is absorptivity (slope of the
straight line equation), b is cell bath (= 1 cm), and C is the concentration
of the substance of interest.
y = Slope x ‐ (Y‐intercept)
R² = 0.9999
Concentration, g%
Mixing Samples Analysis
1000mg/gm
• Calculate the concentration of each sample in mg% w/w.
% / 200 mg is the sample weight
e.g. Sample no. 1 concentration mg% w/w = * 100%
• Calculate: mean, Standard Deviation (S), Variance (V) (V= S2), and Coefficient of
Variation (C.V.) (Relative Standard Deviation, RSD) of the five samples
concentrations in mg% w/w at each sampling time.
Always use Excel tables
and equations
. . %
Mixing Time, Sample Number Standard Coefficient
Concentration Mean Variance
minutes 1 2 3 4 5 Deviation of Variation
Absorbance A1 A2 A3 A4 A5
5 mg% w/v
mg% w/w
Use Excel sheets, tables, and equations to perform all required data
analysis
Examples on Mixing Profiles:
Mixing Profile of Non‐Segregated Mixtures of
Homogenous Particle Size
Coeffecient of Variation
Optimum Mixing Time: the least time required to
achieve the lowest coefficient of variation.
Plateau
Mixing Time, minutes
Mixing Profile of Segregated Mixtures of Non‐
Homogenous Particle Size
Coeffecient of Variation
120
100
80
Optimum Mixing Time
60
40
20
0
0 10 20 30 40 50
Mixing Time, minutes
INTRODUCTION:
2. Filling volume of mill: the balls should only occupy two thirds (2/3) of the
chamber.
3. Milling time.
EXPERIMENTAL:
a. Materials:
Coarse Sucrose
b. Apparatus:
- Rotary Ball Mills with ceramic spherical charges
- Sieves and Shaker (Jolting Sieving Apparatus )
- Stop Clock
c. Method:
NB: all equipment and tools should be cleaned prior to use.
NB:
• The cascading speed of 30 rpm measured by tachometer should be used.
• The sieves used are analytical tools, in order to maintain sieves of good
quality, they should be handled with care, and removal of powder from the
mesh should be done only by gentle brushing.
Results and Data Analysis
9 For each samples of the five (un-milled sucrose, 10, 20, 30 & 40 minutes) do the
following analysis:
Assume this to be a large pore size e.g. 2 mm, such that all un-milled
particles will pass through
Interval Mid-Point
Cumulative % Over Size is defined as the percentage of particles that have particle
sizes lager than the interval lower limit.
Ex.1: Cumulative % Over Size for 1st interval = * 100% = 100%
∑
Cumulative % Under Size is defined as the percentage of particles that have particle
size smaller than the interval upper limit.
Ex.1: Cumulative % Under Size for 1st interval = * 100%
∑
100%
9 Plot on the sample sheet:
Cumulative % Over Size vs. Intervals Lower Limits, and
Cumulative % Under Size vs. Intervals Upper Limits
Unmilled Sucrose Particle Size Analysis
100
Cumulative % Retained
Cumulative %
Over Size
50
Cumulative %
Under Size
Pore Size, mm
Milling Time, minutes
50
30‐minute
40
30
20
10
0
Pore Size Intervals Mid Point, mm
EXPERIMENT (3)
GRANULATION OF POWDERS (GR)
INTRODUCTION:
Granulation, the process for producing large aggregates from smaller particles, is
widely used in the pharmaceutical industry, especially in the manufacture of
compressed tablets. Granular materials have several advantages when compared
with fine powders:
1. Improved flow properties
2. Improved bonding properties
3. Increased densification, reduces the volume of bulk powders
4. Controlled size and shape
5. Segregation of incompatible components
6. Controlled porosity
7. Reduction of dust hazards
The production of granular materials can be achieved by dry or wet methods, the
later having more common usage in pharmaceutical systems.
The work, in this experiment, will be confined to an investigation of some of the
factors, which may influence the properties of granules when produced by a wet
process i.e. massing and screening. The granules will be stored for use in the
tableting experiment.
Dry Granulation
This process is used when the product needed to be granulated may be sensitive to
moisture and heat. Dry granulation can be conducted on a press using slugging
tooling or on a roller compactor commonly referred to as a chilsonator. Dry
granulation equipment offers a wide range of pressure and roll types to attain
densification. However, the process may require repeated compaction steps to attain
the proper granule end point.
Process times are often reduced and equipment requirements are streamlined;
therefore the cost is reduced. However, dry granulation often produces a higher
percentage of fine or non-compacted products, which could compromise the quality
or create yield problems for the tablet. It requires drugs or excipients with cohesive
properties.
Wet Granulation
Wet granulation is a process of using a liquid binder or adhesive to the powder
mixture. The amount of liquid can be properly managed, and over wetting will cause
the granules to be too hard, and under wetting will cause them to be too soft and
friable. Aqueous solutions have the advantage of being safer to deal with than
solvents.
The problem that might appear during oven drying is when water moves from the
interior of the powder bed towards the hotter surface to evaporate; this creates
convection currents that, by mass flow, carry soluble drug or soluble dyes to the
surface. This leads to the formation of a depleted lower layer and enriched upper
layer. If proper mixing is not performed after such drying, dose non-uniformity and/or
mottling may result.
EXPERIMENTAL:
a. Materials:
Lactose, Starch Mucilage 7.5 gm% w/v, Sucrose Solution 50 gm% w/v.
b. Apparatus:
- Erweka Kneader
- Erweka Oscillating Granulator
- Magnetic Hot Plate
c. Method:
2. Pass enough large quantity of lactose through a 1.4 mm sieve to remove any
lumps or aggregates
3. Weigh 400 gm of the sieved lactose and transfer Erweka Kneader.
4. Start paste preparation by adding the binder (start with D.Water) portion-wise,
i.e. using a 10-mL measuring cylinder add several additions each of 3 mL of
D.Water every 30 second each time to different place, after each addition of
the binder cover the chamber and operate the kneader with medium velocity
for 30 seconds to 1 minute.
5. After the third addition and massing for 1 minute, turn the kneader off and test the
mixture for the end point, How?
The required end point is paste formation, which can be measured by taking
a mass from the mixture using your hand and squeezing it between the balm
and fingers, then hitting it with other hand index finger, if it remained coherent
and only broken from the peripheries then the end point is achieved, so return
the mass to the kneader and perform massing for extra 1 minute to ensure
homogeneity and get rid of any large agglomerate that might be formed.
If the squeezed mass break down completely, continue the addition of the
binder and check for end point using the above method after each addition till
end point is reached.
6. After achieving the end point, transfer the wet mass to an empty cleaned tray,
use spatula to completely remove the mixture from the kneader chamber.
7. Allow the paste to pass through the 1.6 mm sieve fitted to the Erweka Granulator
(oscillating granulator), collect the wet granules from the granulator in a pre-
weighed clean tray and spread to form a thin bed of granules.
8. Weigh the tray containing the wet granules, and record it as wet weight.
9. Dry the granules in preheated oven at 70 °C for 45 minutes.
10. After 45 minutes, remove the tray containing the dried granules from the oven
and record its weight as dry weight.
11. Pass the dry granules through 1.6 mm sieve fitted to the Erweka Granulator →
Re-granulation.
12. Put the granules in a appropriately labeled plastic bag (Granules A) and reserve
them in dry place closed place to be tested in Cycle 2.
13. Repeat steps 2 - 12 twice, first using Sucrose Solution 50 gm% w/v, and secondly
just enough Starch Mucilage 7.5 gm% w/v, (Granules B and Granules C),
respectively.
Distilled Water A X T1 W1 D1 P1 = D1 - T1 %1
Sucrose Solution
B Y T2 W2 D2 P2 = D2 - T2 %2
50g%
Starch Mucilage
C Z T3 W3 D3 P3 = D3 - T3 %3
7.5g%
INTRODUCTION
The effectiveness of tablet or capsule dosage forms relies on the drug dissolving in
the fluid of GIT prior to Absorption into systemic circulation.
Tablet Dissolution is a standardized method for measuring the rate of drug release
from a dosage form. (Dissolution defined as the process by which a known amount of
drug substance goes into solution per unit of time under standardized conditions.)
The principle function of the dissolution test may be summarized as follows:
1. Optimization of therapeutic effectiveness during product development and
stability assessment.
2. Routine assessment of production quality to ensure uniformity between
production lots.
3. Assessment of "Bioequivalence", that is to say, production of the same
biological availability from discrete batches of products from one or different
manufacturers.
4. Prediction of "in-vivo" availability i.e. bioavailability (where applicable).
The rate at which a solid dissolves in a solvent was proposed by "Noyes and
Whitney" in 1897 and elaborated subsequently by other workers. The equation can
be written as:
K is called the intrinsic dissolution rate constant. Hydrophilic drugs have high intrinsic
dissolution rate as they have high S, while hydrophobic drug has low intrinsic
dissolution rate.
* When K > 1, absorption process is not dissolution limited.
* When K < 1, absorption process is dissolution limited.
EXPERIMENTAL:
a. Materials:
Revanin® 500 mg tablets, Acetaminophen (Paracetamol) powder, Monobasic
Potassium Phosphate, Sodium Hydroxide
b. Apparatus:
- Dissolution Apparatus
- UV/VIS Spectrophotometer
- pH meter
c. Method:
NB: all equipment and tools should be cleaned prior to use.
I. Dissolution Parameters:
Calibration Curve:
a. Prepare 0.050gm% w/v of Acetaminophen in Phosphate Buffer pH 5.8
(place 50 mg Acetaminophen in 100 mL V.Flask, dissolve using few 10
mL of the solvent then complete volume up to the 100 mL mark with
Phosphate Buffer pH 5.8) → Standard Stock Solution
b. Withdraw 1, 2, 3 & 4 mL from the Standard Stock Solution and place
each in 50 mL V.Flask and complete the volume up to 50 mL mark with
Phosphate Buffer pH 5.8 → Standard Solutions
c. Measure the standard solutions absorbances using Phosphate Buffer pH
5.8 as a blank at λ = 243 nm.
Results and Data Analysis
• Apply Beers Law to the calibration curve straight line equation as following:
A= a*b*C, where A is the Absorbance, a is absorptivity (slope of the
straight line equation), b is cell bath (= 1 cm), and C is the concentration
of the substance of interest.
y = Slope x ‐ (Y‐intercept)
R² = 0.9999
Concentration, mg%
Dissolution Samples Analysis
=
Vessel
= % mg% * DF Concentration
• Calculate the % Dissolved for each tablet using the following ratio: Claimed amount is the
labeled amount which is
% % equal to 500 mg
Q = 80%
Univ
versity of Jo
ordan
Facuulty of Pharm
macy
Department of Pharmaaceutical Sciences and Technology
y
Pha
armaceutical Tec
chnology
y Laboratory Man
nual
C
Cycle (2)
EXPERIMENT (1)
CHARACTERIZATION OF GRANULES (C.G)
INTRODUCTION:
The preparation of essentially all dosage forms involves the handling of solid
materials. Among all finished products, solid dosage forms are the most predominant
in terms of volume and value. The importance of solid-handling properties, especially
flow properties, cannot be overemphasized. The flow properties of solids have great
impact on the tableting and encapsulation processes since these dosage forms
manufacturing processes require flow of powder materials from a storage container
to filling station, such as tablets dies or capsule fillers. Weight uniformity of course is
dependent on the uniform and rapid flow of powders. The flow properties of solids
also have great influence on the mixing and de-mixing of powders that take place
before tableting or encapsulation.
There are some simple criteria that are useful to predict flow properties from
measurements made on static heap or bed of the powder and there are, listed below,
other tests may be included to characterize the granules.
1. Flow Rate
2. Angle of Repose
3. Bulk Density and Tapped Density
4. Moisture Content
5. Particle Size Analysis
Tan θ =
Pouring to the cylinder must not be directly into the cylinder. It has to be poured
through a funnel, which would allow for free flowing of individual particles, rather than
packed powder due to previous handling. After pouring, you may not have even
surface, which will make reading the volume difficult. For this, it is allowed or you to
make two taps by hand to make the surface even. Tapping should not produce
particle, or changes in particle size distribution of the tested material.
* 100
Values less than 1.25 indicate good flow (= 20 % Carr), whereas greater than 1.25
indicates poor flow (= 33 % Carr). Between 1.25 and 1.50, added Glidant normally
improves flow.
A simple relationship between angle of repose, Carr's index and the expected
powder flow is shown in the following Figure.
30
25 Very Poor Flow
Poor (flooding)
20
Carr's Index (%)
15 Fair
Good
10
5 Excellent
Flow
0
0 10 20 30 40 50
Angle of Repose (θ)
Figure: Relationship between Angle of Repose, Carr's Index of a powder and its flow
characteristics
% LOD = * 100%
A weighed sample is placed on the balance and allowed to dry until it is at constant
weight. The water lost by evaporation is read directly from the percent LOD scale.
2) Moisture Content:
% MC = * 100%
Example: If exactly 5 gm of moist solid is brought to a constant dry weight of 3 gm:
MC = * 100% = 66.7%
Whereas:
a. Materials:
Granules A, b, & C from Experimental Granulation (Experiment 3) (Cycle 1).
b. Apparatus:
Flow Rate Apparatus, Funnel, Bulk Density Apparatus, Jolting Sieving Apparatus,
Moisture Content Determination Apparatus.
c. Method:
Large Opening
1. Flow Rate:
Diameter = 15 cm
Funnel Orifice
Diameter = 3 cm
Free Standing Cone and
Fixed Funnel Apparatus
Height from the base
=14 - 15 cm
- Assemble the apparatus as shown in the diagram above (measure the funnel
height using a ruler).
- Weigh 100 gm of the granules and determine the time to flow through funnel
using stop watch.
- Repeat three times and determine the average flow time.
- Calculate the Flow Rate:
Height
Cone of Powder D1
D2
- Allow the system to tap until a constant volume is reached (600 taps). Record
the volume of the tapped granules (Tapped Volume).
4. Moisture Content:
- Of one of the three batches weigh (using a foil paper) 1.0 gm of the dried
granules (Wet Weight) on the Moisture Content Determination Apparatus,
put on the heating system at the level 11, leave until a constant weight is
reached and read out the read (Dry Weight), then calculate the following:
Compressibility Index=
Here,
Here,
Bulk Density= = T gm/mL
CI %= *100%
Angle of Repose Analysis:
Angle of
granules Diameter, cm Height, cm
Radius Repose
Trial 1 Trial 2 Trial 3 Average cm Trial Trial Trial
Code Binder Average Tan θ θ
D1 D2 Average1 D1 D2 Average2 D1 D2 Average3 Diameter 1 2 3
A D.Water
B Sucrose
C Starch
Lactose
Radius =
Average Height =
Tan θ =
θ= θ
Moisture Content Analysis:
Granules
Wet Weight, gm Dry Weight, gm MC % LOD %
Code Binder
A Distilled Water ≈1
B Sucrose ≈1
C Starch ≈1
Lactose ≈1
MC% = * 100%
LOD% = * 100%
DISCUSSION:
Record your results and compare the findings between the three granules, justifying
the differences.
EXPERIMENT (2)
EFFECT OF ADDITIVES ON THE PHYSICSL PROPERTIES OF
GRANULES (A.G)
INTRODUCTION:
There are many formulation additives and process variables involved in the
granulation step; and all of these can affect the characteristics of the granulation
produced. Therefore methods to measure certain granulation characteristics have
been developed to monitor granulation suitability for tableting.
1. Effect of Glidant:
2. Effect of Lubricant:
For example, Mg-Stearate acts as lubricant only up to 1%, if added in more than 1%
→ hydrophobic layers will be formed at surfaces → retardation of disintegration and
dissolution.
3. Effect of Disintegrant:
Disintegrants assist the disruption of the tablet when in contact with gastro-intestinal
fluids.
Disintegrants expand and dissolve when wet, causing the tablet to break apart in the
digestive tract, releasing the active ingredients for absorption. Disintegrant types
include:
They ensure that when the tablet is in contact with water, it rapidly breaks down into
smaller fragments, facilitating dissolution.
NB.
Disintegrant will not affect flow until being added in high concentration, e.g. Starch is
used in ratios 5 - 10%
EXPERIMENTAL:
a. Materials:
Granules A, b, & C from Experimental Granulation (Experiment 3) (Cycle 1), Talc,
Mg-Stearate
b. Apparatus:
Flow Rate Apparatus, Funnel, Bulk Density Apparatus.
c. Method:
1. Effect of Glidant:
- Prepare the following mixtures of Talc in Granules B (total mixture weight is
100 grams).
Mixture (1): 0.50 % w/w Talc in Granules B:
In a plastic bag put 99.50 grams of Granules B and 0.50 gram Talc
then mix well and test the resulted mixture for:
a. Flow Rate
b. Angle of Repose
c. Bulk and Tapped Density
NB.
• Use the same procedure used in experiment 1 in this cycle.
• All powders should be reserved and collected carefully to be used in mixture
(2) preparation
2. Effect of Lubricant:
- Prepare the following mixtures of Mg-Stearate in Granules B (total mixture
weight is 100 grams).
Mixture (1): 0.25 % w/w Talc in Granules B:
In a plastic bag put 99.75 grams of granules B and 0.25 gram Mg-
Stearate then mix well and test the resulted mixture for:
a. Flow Rate
b. Angle of Repose
c. Bulk and Tapped Density
NB.
• Use the same procedure used in experiment 1 in this cycle.
• All powders should be reserved and collected carefully to be used in mixture
(2) preparation
Mixture (2): 0.50 % w/w Talc in Granules B:
In a plastic bag put mixture (1) and 0.25 gram Mg-Stearate then mix
well and test the resulted mixture for:
a. Flow Rate
b. Angle of Repose
c. Bulk and Tapped Density
NB.
• Use the same procedure used in experiment 1 in this cycle.
• All powders should be reserved and collected carefully to be used in mixture
(3) preparation
Use the same equations and method used in experiment 1of this Cycle to find
out the flow properties measured.
A. Effect of Glidant:
Angle of
Diameter, cm Height, cm
Radius Repose
Talc % w/w
Trial 1 Trial 2 Trial 3 Average cm Trial Trial Trial Tan
Average θ
D1 D2 Average1 D1 D2 Average2 D1 D2 Average3 Diameter 1 2 3 θ
0.50
1.00
3.00
6.00
B. Effect of Lubricant:
DISCUSSION:
1. Record your results and compare the findings between the different additive
concentrations.
2. Discuss your findings and propose a formula of good granules for tableting.
3. List other Glidants, Lubricants, and Disintegrants, and there useful
concentrations.
3. Mg-Stearate Effect on Flow Rate:
Angle of
Diameter, cm Height, cm
Mg-Stearate Radius Repose
% w/w Trial 1 Trial 2 Trial 3 Average cm Trial Trial Trial Tan
Average θ
D1 D2 Average1 D1 D2 Average2 D1 D2 Average3 Diameter 1 2 3 θ
0.25
0.50
1.00
EXPERIMENT (3)
QUALITY CONTROL OF TABLETS (Q.C.)
INTRODUCTION:
The manufacturer must give his assurance that the final product is of suitable
quality. Several Quality Control Test are performed, each batch of tablets is
released, such tests may include: Weight Uniformity, Content Uniformity, Friability
Test, Disintegration, and Dissolution Test.
1. Friability Test:
It is another measure of tablet's strength and it is related to a tablet's ability to with
stand both shock and abrasion without crumbing during the handling of
manufacturing, packaging, shipment, and consumer use.
Instrument and Method:
Instrument: Roche Friabilator.
Method: this device subjects a number of tablets (minimum weight = 6.5 gm) to the
compined effects of abrasion & shockey utilizing a plastic chamber which revolves at
25 rpm dropping the tablets a distance of 6 inch with each revolution. Normally, a
prewighed tablets sample is placed in the friabilator, which is then operated for 100
revolutions. The tablets then are dusted & reweighed. Conventional compressed
tablets that lose less than .5 to 1 5% in weight are generally acceptable. Some
chewable tablets & most effervescent tablets would have higher friability weight
losses, which accounts for the special stack packaging that may be required. When
capping is observed during friability testing; the tablet shouldn't be considered
acceptable, regardless of what the % weight loss result in.
Tablets friability may also influence by the moisture content of the tablets granulation
in the finished tablets. A low but acceptable moisture level frequently serves to act as
a binder. Very dry granulation that contain only fractional percentages of moisture will
often produce more friable tablets than will granules containing 2 to 4 % moisture.
2. Disintegration Time:
For most tablets the first important steps in order to enter the solution is the
breakdown of the tablet in to smaller particles or granules, this process is known as
disintegration. The time that it takes a tablet to disintegrate is measured in a device
described in the Pharmacopeias.
Apparatus:
The USP has long had a device to test disintegration. The device uses six glass
tubes, three in long open at the top & held against a 10-mesh screen at the bottom
end of the basket rack assembly. To test for disintegration time, one tablet is placed
in each test tube, and the basket rack is positioned in one-liter beaker of water, or
simulated gastric or intestinal fluid at 37± 2°C such that the tablet remain 2.5 cm
below the surface of the liquid on their upward movement and descent not closer
than 2.5 cm from the bottom of the beaker.
Perforated plastic disks may also be used in the test. These are placed on the top of
the tablets and impart an abrasive action to the tablets. The disks may or may not be
meaningful or impart more sensitivity to the test, but they are useful for tablets that
float.
The End Point:
To be in compliance with USP standards, the tablets must disintegrate and all
particles pass through the 10-mesh screen in the time specified. if any residue
remains, it must have a soft mass with no palpably firm core.
Factors affect Disintegration Time:
It has been established that one should not expect a correlation between
Disintegration & Dissolution. However, since the dissolution of a drug from the
fragmented tablet appears to partially or completely control the appearance of the
drug in the blood, disintegration is still used as a guide to the formulator in the
preparation of an optimum tablet formula and as in-process control test to ensure lot-
to-lot uniformity.
The formulator should be aware that the medium used, the temperature of the
medium, and the operator recording the results can have a significant effect on
disintegration time. In addition many factors involved with a tablet's formula and
method of manufacture can affect the disintegration such factors are: the nature of
the drug, the diluents used, the binder and its amount, the type and amount of
disintegrating agent, the type and amount of disintegrating agent, the type of amount
of lubricant, as well as the method of incorporation for all of these additives. The
compaction pressure used to make the tablets also influences the disintegration, in
general disintegration time's increase with an increase in pressure.
3. Thickness Uniformity:
Tablets thickness should be controlled with 5% or less of a standard value. Any
variation in tablet thickness should not be apparent to the unaided eye to maintain
product acceptance by consumer as well as to facilitate packaging.
At constant compressive load, tablet thickness varies with changes in die fill and
tablet weight. Whereas, with a constant die fill, thickness varies in variation in
compressive load.
Three set of factors influence tablet thickness and tablet thickness control:
1. The physical properties of raw materials including crystal form and true bulk
density.
2. Control of upper and lower punch lengths, which should be standardized.
3. The granulation prosperities including bulk density, tapped density, particle size,
and particle size distribution.
4. Tablet Hardness:
Tablet hardness is defined as the force required to break a tablet in a diametrical
compression test. A tablet requires a certain amount of strength or hardness to
withstand mechanical shocks of handling in its manufacturing, packaging, and
shipping. More recently, the relationship and importance of hardness as it may
influence disintegration and perhaps more significantly, drug dissolution rate, become
apparent.
Apparatus
To perform this test, a tablet is placed between two anvils. Pressure is applied to the
anvils, and the crushing strength that just causes the tablet to break is recorded.
Hardness is thus sometimes termed "Tablets Crushing Strength".
Factors Affect Tablet Hardness:
The hardness of a tablet is a function of many things all working together. The three
factors that were noted in the tablet thickness may also produce variation in tablet
hardness.
Hardness is a function of the applied pressure and is therefore a function of those
factors which cause the force to vary. As additional pressure is applied to make a
tablet, the hardness values increase, this relationship olds up the maximum value
beyond which increases in pressure cause the tablet to laminate or cap, thus
destroying the integrity of the tablet.
Tablets generally are harder several hours after compression than they are
immediately after compression. Lubricant can affect the tablet hardness when used
in too high concentration or mixed for too long period. The lubricant will coat the
granules and interfere with tablet bonding.
Larger tablet require a greater force to cause fractures (harder) than small tablet.
An appropriate balance between a minimally acceptable tablet hardness to produce
an adequate friability value and a maximum acceptable tablet hardness to achieve
adequate tablet dissolution may be required.
5. Weight Variation:
In manufacturing of tablet our aim is to produce tablet product that can be validated
as to its safety, efficacy, and reliability; so each tablet is designed to have certain
weight and to heck the uniformity of weight we fined in different pharmacopeias a
method for weight variation as follows:
Method:
The test is run by weighing 20 tablets individually, calculating the average weight,
and comparing the individual tablet weights to the average (as a percent of the
average weight of the sample). The tablets meet the USP weight variation test if no
more than two tablets are outside the percentage limit and no tablet differs by more
than twice the percentage limit. The weight variation tolerance for uncoated tablets
differs depending on average tablet weight:
130 or less 10
130 to 324 7.5
More than 324 5
The weight variation test is a satisfactory method of determining content uniformity of
tablets if
(1) The tablet is all-drug or essentially (90-95%) all-active ingredient, or
(2) The uniformity of drug distribution of the granulation or powder from which the
tablets are made is perfect.
The weight variation test is not sufficient to assure uniform potency of moderate to
low-dose drugs, in which excipients make up the bulk of the tablet weight.
a. Materials:
tablets
b. Apparatus:
Disintegration Tester, Hardness Tester.
c. Method:
NB: all equipment and tools should be cleaned prior to use.
1. Friability Test:
a. Place 6.5 grams of tested tablets (record this weight as tablets intial
weight) in the drum of the Roche Friabilator and close it.
b. Operate the instrument for 4 minutes using 25 rpm as rotational
speed.
c. After the time elapsed remove the tablets and dust them using a
brush.
d. Examine the tablets for any sign of capping, breakage, or breakage.
e. Weigh the tablet and record the weight as tablets final weight.
f. Calculate the Percentage Weight Loss using the following equation
2. Hardness Test:
a. Using the Hardness Tester, measure the hardness for 10 tablets.
b. Calculate the mean, standard deviation, and relative standard
deviation of the tested values.
3. Disintegration Test:
a. In the six cylinders of the Disintegration Tester "Rigid Basket Rack
Assembly” place 6 of the tested tablets.
b. Use the disintegration medium specified by BP.
c. Start testing the tablets, commence disintegration with timing.
d. Record disintegration time in minutes and calculate the average
Disintegration Time.
e. Compare your results with the BP specification.
4. Weight Variation Test:
a. Measure the weight of 20 tablets of the tested tablets, weight should
be measured in milligrams.
b. Calculate the Average Tablets Weight in grams.
c. For each tablet of the 20 tested tablets calculate the Maximum
Percentage Difference Allowed.
Maximum Percentage Difference Allowed
= * 100%
1. Friability Test:
Tablet Hardness
Tablet Number
kP
1
2
3
4
5
6
7
8
9
10
Average Tablet
Hardness, kP
Standard
Deviation
RSD
Tablet Thickness
Tablet Number
mm
1
2
3
4
5
6
7
8
9
10
Average Tablet
Thickness, mm
5. Disintegration Test:
Disintegration Time
Tablet Number
Seconds
1
2
3
4
5
6
Average Disintegration
Time, Seconds
DISCUSSION:
Discuss your findings in accordance to Pharmacopoeial specifications.
Univ
versity of Jo
ordan
Facuulty of Pharm
macy
Department of Pharmaaceutical Sciences and Technology
y
Pha
armaceutical Tec
chnology
y Laboratory Man
nual
C
Cycle (3)
TS PREP
TABLET PARATIO
ON AND TESTING
T G
EX
XPERIME
ENT
TABLET
TS PREP
PARATIO
ON AND TESTING
T G
Introductio
on
Afte
er you havve been exposed
e to
o various pharmaceu
utical opera
ations (mix
xing,
gran
nulation, sizze reduction and particcle size analysis), and
d to quality control tests of
tablets (hardne
ess, weight variability etc.),
e In this
s cycle, you
u will apply the knowle
edge
you gained from
f the previous
p tw
wo cycles in suggessting direcct compres
ssion
mulation, a procedure to ma
form anufacture the formu
ulation and
d after ta
ablet
nufacturing you need
man d to test the tabletts specifica
ations (weight variab
bility,
hard
dness, disin
ntegration and
a multipoint dissolutio
on).
Ob
bjective
a. Prepa
aration of four
f ent direct compression
differe n formulae using diffe
erent
diluen
nts.
b. Using
g "Hydraulicc Press" to compress
c at
a least three
e tablets off each formu
ula.
c. Consstructing a "Multipoint Dissolution
D Profile"
P fourr the collectted data.
Disssolution Pro
ofile showing Percent Dissolved
D vs
s. Time:
MultiP
Points Disssolution
n Profile
120
100
% Dissolved
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 1
11 12 13
Tim
me, hours
NB. On the sam
me graph draw the disssolution currves for eacch formulatio
on.
Functions of Excipients:
Avicel: ……………………………………………………………………
Lactose: ………………………………………………………………….
Starch: ……………………………………………………………………
Mg-Stearate: ……………………………………………………………...
HPMC: ……………………………………………………………………
DCP (Di-Calcium Phosphate): ………………………………………….
Concepts
• Immediate-Release: drug is released rapidly from the dosage form (Solution
(instantaneous release), Suspension, Disintegrating Tablets, etc.)
• Delayed Release: delay in the onset of drug release; e.g. enteric-coated tablets
(will be studied in "Practical Pharmaceutical Technology II")
• Sustained /Extended-Release: prolonged (slowed down) release from dosage
form.
Controlled-Release: special type of S.R. where release is zero-order.
MultiPoints Dissolution Profile
100
90
80
70
% Dissolved
60
Immediate
50
Delayed
40
Sustained
30
20 Controlled
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time, hours
EXPERIMENTAL:
a. Materials:
Paracetamol
Avicel 101:
Mg-Stearate:
Starch:
Lactose:
HydroxyPropylMethylCellulose (HPMC):
DiCalciumPhosphate (DCP):
b. Apparatus:
• Hydraulic Press
Single Punch press machine, for research purposes mainly.
• Dissolution Apparatus.
• Rotary Multi-Station Tableting Machine
c. Method:
• Targets:
‐ Batch Size = 10 grams
‐ Tablet Weight = 600 mg
‐ Drug Potency= 200 mg (Active Ingredient per tablet)
‐ Tablet Diameter = 12 mm
‐ Compression Force = 10 KN
• Sampling Methodology:
‐ Sample Volume: 5 mL
‐ Time Points: 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.50 hour, 2 hours
‐ Method: with replacement of equal volume from fresh medium kept at the
same tempreture.
• Formula:
General Formula
Ingredients % w/w Amount per tablet Amount per Batch
(per 600 mg) (per 10 gm)
Paracetamol 200 mg per tablet 200 mg 3.333 gm
Starch 5% w/w 30 mg 0.500 gm
Avicel 101 10% w/w 60 mg 1.000 gm
Mg-Stearate 1% w/w 6 mg 0.100 gm
Diluent q.s 100% 304 mg 5.067 gm
You are about to prepare the following four formulas:
Formula A
Paracetamol 200 mg per tablet
Starch 5% w/w
Avicel 101 10% w/w
Mg-Stearate 1% w/w
Lactose q.s 100%
Formula B
Paracetamol 200 mg per tablet
Starch 5% w/w
Avicel 101 10% w/w
Mg-Stearate 1% w/w
DCP q.s 100%
Formula C
Paracetamol 200 mg per tablet
Starch 5% w/w
Avicel 101 10% w/w
Mg-Stearate 1% w/w
HPMC q.s 100%
Formula D
Paracetamol 200 mg per tablet
Starch 5% w/w
Avicel 101 10% w/w
Mg-Stearate 1% w/w
Lactose : HPMC q.s 100%
in 1:1 ratio
Procedure:
NB: all equipment and tools should be cleaned prior to use.
• Tablets Preparation:
1. Sieve all ingredients using 1.4 mm mesh.
2. Weigh the required amounts to prepare 10 grams mixture.
3. Mix all ingredients, except Mg-stearate, together in a plastic bag for three
minutes.
4. Add Mg-Stearate and mix for 30 seconds (maximum 1 minute), why?
5. Weigh 600 mg of the mixture prepared above (three weights each of 600 mg).
6. Compress the three tablets using hydraulic press (follow the instructions of
your instructor).
7. Reserve the prepared tablets for dissolution testing (next practical session).
• Use the following calibration curve to do find out the samples concentrations.
Calibration Curve of 4‐Acetaminophenol in
Phosphate Buffer pH=5.8 at λ = 243 nm
1
y = 565.00x + 0.0195
0.8 R² = 0.9999
Absorbance
0.6
0.4
0.2
0
0 0.0005 0.001 0.0015 0.002
Concentration, gm%
Paracetamol in Phosphate Buffer pH 5.8, 50 rpm, 37 °C
(USP method)
100
90 Lactose Tablet
80
70 HPMC Tablet
% Dissolved
60
50 DCP Tablet
40
30 Lactose:HPMC Tablet
20
10
0
0 0.5 1 1.5 2
Sampling Time, hours
Dissolution Samples Analysis
,
%Dissolved = * 100%
,
Here…..
,
%Dissolved = * 100%
Active ingredient in the tested tablet (mg) ,
= tablet weight * ratio of the active in the tablet
Example at 1.5 hour:
Here……
Active ingredient in the tested tablet %Dissolved1.5 = * 100%
,
= tablet weight * mg
DISCUSSION:
• Co-relate each profile to the components of different formulas.
• Compare the resulted dissolution profiles to each other.
• Comment on your results.