Student Name

______________________
Section
______________________
Time
AMMAN - JORDAN
______________________

Applied Science Private University

Faculty of Pharmacy
Department of Pharmaceutical Sciences and Pharmaceutics

Laboratory Manual for

Industrial Pharmacy
Course No. (907321)

Dr. Nizar Alzoubi

Dr. Eman Migdadi
Dr. Safwan Elian
Faten Odeh Msc

1
Content

Particle size analysis ...................................................................................................... 3

Particle size reduction .................................................................................................. 10

Powder mixing ............................................................................................................. 19

Granulation .................................................................................................................. 27

The flow properties of powders and granules .............................................................. 36

Tablets .......................................................................................................................... 49

Quality control of tablets ......................................................................................... …54

Tablet coating............................................................................................................... 76

Disintegration and dissolution of marketed diclofenac sodium enteric coated tablets 87

Dissolution of marketed diclofenac sodium extended-release tablets ......................... 91

Preparation and evaluation of extended release matrix tablets .................................... 94

2
EXPERIMENT I

Particle size analysis

Particle size and equivalent diameters

Powders generally are composed of particles that are, irregular in shape and very small in size
to allow measuring of dimensions. Furthermore, powders are normally composed of particles
that are different in size. This means that in order to give good representation, the size of
relatively large number of particles should be determined.
For these reasons it is impractical to measure more than one dimension. Therefore, solids are
considered to approximate to a sphere, which can then be characterized by determining its
diameter. This is an approximate representation of the particle size and is referred to as
equivalent diameter of the particle.

Equivalent diameters

Projected perimeter diameter (dp):

•The diameter of a circle that has the same perimeter as the projected image of the particle.

Projected area diameter (da)

•The diameter of a circle that has the same area as the projected image of the particle.

Volume diameter (dv)

•The diameter of a sphere that has the same volume of the particle.

3
Feret’s diameter (dF)
•The mean distance between two parallel tangents to the projected particle perimeter.

Martin’s diameter (dM)

•The mean length of the chord separating the projected particle into two equal areas.

Stokes diameter (dst)

•The diameter of a sphere that has the same sedimentation rate as the particle.

Sieve diameter (ds)

•The particle dimension that passes through a square aperture.

Mean particle size and particle size distribution

The mean particle size of an analyzed sample can be considered as a rough description for the
size of sample. However, it is unusual for particles to be completely monosized. Most
powders contain particles with a large number of different equivalent diameters.
The distribution of particles into different size ranges can be plotted in the form of histogram.
A histogram presentation allows different particle size distributions to be compared. The
value of the peak is the mode (highest frequency).

Presentation of size distribution

1) Frequency distribution curves (or histograms)
In these curves the number or weight of particles lying within a certain range of mean particle
size is plotted against the size range or mean particle size.

2) Cumulative frequency distribution (or histograms)

In these curves, either the cumulative percent over or under a particular size is plotted versus
particle size.

4
Number and weight distributions
If the data were collected by a counting technique such as microscopy, the data will be in
number distribution. Frequently, we are interested in obtaining data based on a weight, rather
than a number, distribution. Although this can be achieved by using a technique such as
sieving or sedimentation. It will be more convenient, if the number data are already at hand,
to convert the number distribution to a weight distribution, and vice versa.

Example:
Table 1.1: Number distribution and weight distribution

Fig 1.1: Frequency distribution curve for data in Table 1.1

5
Fig 1.2: Cumulative undersize frequency curve for data in table 1.1

Size distributions (Fig 1.3)

1) Normal distribution: The mode separates the frequency curve into two symmetrical halves.
2) Positively skewed: A frequency curve with an elongated tail towards the higher size range.
3) Negatively skewed: A frequency curve with an elongated tail towards the lower size range.
4) Bimodal: The frequency curve containing two peaks (two modes)

Fig. 1.3 Frequency distribution curves corresponding to: (a) normal distribution, (b)
positively skewed distribution (c) negatively skewed and (d) bimodal distribution.
Degree of skewness:

6
In order to quantify the degree of skewness of a particle population, the interquartile
coefficient of skewness (IQCS) can be determined as follows:

(c  a )  ( a  b )
IQCS 
(c  a )  ( a  b)

Where a is the median diameter and b and c are the lower and upper quartile points. The
IQCS can take any value between –1 and +1. If the IQCS is zero, then the size distribution is
practically symmetrical between the quartile points (Fig. 1.4)

Fig. 1.4. Determination of a, b and c for calculation of IQCS from cumulative undersize
curve.

7
Methods of particle size analysis
There are different methods used such as:
1- Optical microscopy
2- Electron microscopy
3- Sedimentation
4- Electrical stream sensing zone method
5- Laser light diffraction
6- Sieving

Some of these methods (like microscopy, coulter counter) give a size value for each particle
in the tested sample. Other methods (like sieving and sedimentation) do not give a size value
for each particle in the tested sample but classify the particles in the sample into size ranges
which can be presented as size distribution histograms from which average size can be
determined.

Sieving method
It consists of a sieve set "6-8 sieves" arranged in a way that coarser sieve will be on the top of
the finer. The sample will be placed on the top of the coarsest sieve, then the set will be
shaken so as the particles will be distributed on the sieves according to their sizes.
Two terms to express the sieve size are used: -
1) Based on particle diameter: - assuming particles are
spherical, the sieve pores will be made in a width
representing certain diameter "unit mm or µm”. For
example, sieve of 2mm means particles of diameter less
than 2mm will pass through whereas those of greater
than 2 mm or equal will be retained on the sieve.
2) Mesh no. = no of openings in linear inch.
As mesh no. increase particles that can pass through will have smaller size (Table 1.2).

8
Table 1.2: US mesh openings

Practical work:
You will be given a set of size data for particles. You should do the following:
1. Draw the frequency size distribution and the cumulative undersize and
oversize distribution curves.
2. Draw the number and weight distributions for the above data (both frequency
and cumulative distributions).
3. Find the values of median, mode and IQCS.

Comment on your results

9
EXPERIMENT II

PARTICLE Size reduction

Definition: -
It can be defined as the mechanical process of reducing the particle size for solids.

Pharmaceutical applications of size reduction: -

1. Specific surface area "surface area / unit wt" is increased by milling. This will
affect the therapeutic efficiency, since a given wt. of finely powdered
medicinal compound dissolves in a shorter time in body fluid leading to higher
bioavailability.
2. Particle size affects texture, taste & rheology of oral suspensions in addition to
absorption.
3. Extraction or leaching from animal glands and from plants is facilitated by
size reduction. The time required for extraction is shortened by the increased
area of contact between solvent & solid, also the distance that the solvent has
to penetrate in the material is reduced “rapid & complete Extraction”.
4. The drying of wet masses may be facilitated by size reduction.
5. Particle size control will influence flowability of powders which is important
in manufacturing of solid dosage forms like tablets and capsules.
6. The mixing of several solid ingredients is much easier and more uniform if the
ingredients are approximately same in size.
7. Lubricants used in compressed tablets and capsules functions by virtue of their
ability to coat the granules surface. A fine particle size is essential if the
lubricant is to function properly.
8. Making the color powders in the form of fine particles will lead to uniform
distribution of color when mixed with other powders and compressed in
tablets.

10
 Disadvantages of size reduction: -
Particle size reduction may lead to:
• Change of the polymorphic form
• Dehydration of hydrates
• Development of amorphous structure
• Damage of thermolabile drugs due to heat involved.
• Development of free static charge

Mechanisms of size reduction: -

1. Cutting: - by mean of sharp blades … like what happens in
cutter mill. This is suitable for fibrous material.

2. Compression: - by application of external force to crush

material … like what happens in roller mill (or in mortar &
pestle)

3. Impaction: - Material is hit by another object and both are

moving in different speeds.

4. Attrition: - Material is subjected to pressure and surfaces are

moving in relation to each other.

Ball mill: -
Ball mills consist of a hollow cylinder mounted such that it can be rotated on its horizontal
longitudinal axis. The cylinder contains balls that occupy 30-50% of the total volume. It
could be made of stainless steel or porcelain.
Ball mill works by both attrition and impaction. When it rotates at slow speed the
balls roles over one another providing attrition. As speed increases, the balls are carried up
the sides of the ball mill and fall on the material with impact action.

11
Factors that affect milling in ball mill include:
1. Speed of the machine: -
As speed increases too much centrifugation will occur. Critical speed is the speed at which
balls start to centrifuge. At & above critical speed no size reduction occurs. At too low speed,
no impaction but only attrition occurs. The ball mill should be operated on Cascading
optimum speed which is the speed at which balls will break from horizontal and fall and roll
over one another (Fig 2.1).

Fig 2.1: Ball mill in operation, showing correct cascade action.

2. Ball size and weight: -

Small balls are used to give slower, but finer grinding. This is because they provide smaller
voids than larger balls, and thus the voids through which material can flow in without being
struck by balls is less.
Also, no. of impacts provided by small balls is greater, since they have lighter weight and
hence can climb to higher distance. Small balls facilitate the production of fine material, but
are ineffective in grinding large particles.
By increasing the Weight of balls, production of finer product is increased. This can be
achieved by using stainless steel balls.

3. Load of the machine: -

The amount of material to be filled is expressed in ratio of volume of material to the void in
the ball charge. So efficiency of milling is increased as the amount of material is increased
until the void space is filled. After that more addition of material causes reduction in
efficiency of milling.

12
Practical work:
1- Weigh 500 g of coarse sucrose and place it in a ball mill filled with 20 large spherical balls
and 60 medium ones, secure the gasket and lid and place on the rollers. Cascading speed
should be around 120 rpm. Start milling and timing simultaneously.

2- Take samples of 50 g at 10, 20- & 30-min time interval and analyze for particle size
distribution using sieve analysis method.

3- Weigh accurately 50 g of the coarse sucrose and determine their particle size distribution
by using sieve analysis method.

Sieve analysis:
1- Weigh the sieves and collector tray provided to you and assemble them so that the smallest
mesh is above the collector tray followed by meshes that become progressively coarser
towards the top of the series.

2- Place the sample on the coarsest sieve, fit the lid and clamp the whole set securely in the
sieve shaking apparatus.

3- Switch on the shaker and run for 10 min. After shaking, loose each sieve in turn starting
with the coarsest one

4- Weigh the sieves and collector try with the powder retained on them.

5- Calculated the weight of powder retained on each sieve (and tray) by subtracting the
weight of empty (obtained in step 1) from the weight of filled sieve (obtained in step 4).

13
Tabulate your results as follow:

Sieve size Average Weight Wt. % Average Cumulative %

(mm) particle retained retained Particle Under
(gm) size X size
size (mm)
WT. %
retained

0-0.125 0+0.125 0.22 0.44 0.0625X 0.44

2 0.44

0.125-0.18 0.125.+0.18 0.22 0.66

2

0.18-0.25 0.3 0.96

0.25-0.355
0.355-0.85
0.95-1.4
Above 1.4
Total 50 100

Then calculate the average diameter or dav. of the powder:

dav =  (average particle size × wt.% retained)

100

Data should be represented graphically by drawing histograms, Frequency size distribution

and size distribution cumulative curves.

14
 REPORT:
1) Objective of the experiment:

2) Results:

Table 2.1 At zero time (no milling)

Sieve size Average Weight Wt. % Average Cumulative %

(mm) particle retained (g) retained particle under
size (mm) size X size
Wt. %
retained

Total

15
Table 2.2 After 10 min. milling

Average
Average Weight Wt. % particle Cumulative %
Sieve size particle retained (g) retained size X undersize
(mm) size (mm) WT. %
retained

Total

Table 2.3 After 20 min milling

Average
Average Weight Wt. % particle Cumulative %
Sieve size particle retained (g) retained size X undersize
(mm) size (mm) WT. %
retained

Total

16
Table 2.4 After 30 min milling

Sieve size Average Weight Wt. % Average Cumulative %

(mm) particle retained (g) retained particle undersize
size (mm) size X
WT. %
retained

Total

Table 2.5

Time of milling (min) Average particle diameter

(mm)
0
10
20
30

17
3) Curves:
Draw curves for:

a) Cumulative % under size vs. average particle

size for each table on the same graph paper.

b) Histogram & frequency size distribution (on the

same graph paper) for each table separately.

c) Average particle size vs. milling time.

4) Discussion of the results: Discuss the obtained results and write down your comments.

18
EXPERIMENT III

POWDER MIXING

Powder mixing is the process which results in uniform distribution of dissimilar particles
within a system.
The most important function of powder mixing is to ensure the content uniformity
especially in the production of low drug content dosage forms.

Types of mixtures according to their behavior: -

1- Positive mixtures: - formed from gases or miscible liquids, irreversible and passive ….
Do not need energy and do not get problems in mixing.

2- Negative mixtures: - like suspensions and emulsions … require work for their
formulation & tend to segregate. They are more difficult to form.

3- Neutral mixtures: - components here have no tendency to mix passively nor to segregate
… examples: - pastes, ointment and solid powders mixing.

Mechanisms of powder mixing:

1. Convection: - Movement of a group of adjacent particles from one place
to another within the mixture.

2. Shear: - It is the change in configuration of ingredients through the

formation of slip planes in the mixture (Layer of powder flows over
another layer)

3. Diffusion: - It is redistribution of particles by random movement of

particles relative to each other.

19
Cube mixer: -
Cube mixer is a tumbling mixer, in which ingredients are tilted by the rising side of
the drum until they exceed their normal angle of repose, hence they will fall over their selves.
Tumbling mixers are rotating vessels of variable shapes. The container will not rotate
around central axis in order, to avoid symmetry, because symmetry gives poor mixing.
Shear is the predominant mechanism of mixing in cube mixer. Diffusion also occurs
due to dilation of powder bed.

Factors affecting mixing efficiency in cube mixer: -

1- Shape of particles: -
Regular particles are easier to be mixed, but easier also to segregate, than irregular
ones.

2- Particle size and size distribution: -

Small particles are difficult to be blended, because it exhibits poor flowability. More
important than mean particle size is the particle size range. All materials should be reduced to
the same size approximately prior to mixing, since larger and smaller particles tend to
segregate.
Under agitation fine particles tend to dust out whereas large particles will settle down.
During agitation, small particles may segregate also by falling through the voids between
large particles.

3- Density: -
Difference in true density for different particles causes segregation.

4- Surface effects:
Such as adsorbed liquids, electrostatic charges and van der Waals forces.
Forces acting on the surface cause groups of particles to hold together as aggregates
and resist uniform dispersion.

20
5- Speed of cube mixer: -
High speed “at & above critical” cause centrifugation & at low speed cause low
shearing … Hence optimum speed should be used.

6- Mixing time
Time must be optimum. Short time may be insufficient, while long time may lead to
segregation (demixing).

Fig 3.1. Different designs of tumbling

mixers

Procedure:
1- Prepare two binary mixtures (400 g each) of powdered active ingredient (12.5 % W/W) in
coarse sucrose or fine lactose monohydrate.

2- Start mixing suing cube mixer.

3- Take 8 samples (200 mg each for coarse sucrose and fine lactose monohydrate) at 5, 15
and 30 minutes.
* Powder samples should be taken randomly from the powder mixture.

4- Determine the content of active ingredient in each sample using 10% V/V ethyl alcohol in
water at a (max) in the UV region.

21
 Report:
A- Objective of such experiment.

B- results:
Table 3.1: Mixing of active ingredient with coarse sucrose at 5 min.
Sample Sample wt Absorbance Conc. Dilution Mass fraction of
No (mg) mg/ml factor drug
1
2
3
4
5
6
7
8
Mean

S.D.

C.V. (%)

22
 Table 3.2: Mixing of active ingredient with coarse sucrose at 15 min.
Sample Sample wt Absorbance Conc. Dilution Mass fraction of
No (mg) mg/ml factor drug
1
2
3
4
5
6
7
8
Mean

S.D.

C.V. (%)

Table 3.3: Mixing of active ingredient with coarse sucrose at 30 min.

Sample Sample wt Absorbance Conc. Dilution Mass fraction of
No (mg) mg/ml factor drug
1
2
3
4
5
6
7
8
Mean

S.D.

C.V. (%)

23
 Table 3.4: Mixing of active ingredient with fine lactose at 5 min.
Sample Sample wt Absorbance Conc. Dilution Mass fraction of
No (mg) mg/ml factor drug
1
2
3
4
5
6
7
8
Mean

S.D.

C.V. (%)

Table 3.5: Mixing of active ingredient with fine lactose at 15 min.

Sample Sample wt Absorbance Conc. Dilution Mass fraction of
No (mg) mg/ml factor drug
1
2
3
4
5
6
7
8
Mean

S.D.

C.V. (%)

24
 Table 3.6: Mixing of active ingredient with fine lactose at 30 min.
Sample Sample wt Absorbance Conc. Dilution Mass fraction of
No (mg) mg/ml factor drug
1
2
3
4
5
6
7
8
Mean

S.D.

C.V. (%)

C.V. (%)

25
N. B: -
1- Mean = ∑ Mass fraction of drug /n
Where n= number of observations
2- Standard deviation (S.D.)
SD =

xi = Mass fraction of drug

x = mean.

3- Coefficient of variation (C.V.) = SD/mean X 100

C- Curves: -
Draw curves representing coefficient of variation vs. time for each mixture.

D- Comment on your result.

26
EXPERIMENT IV

GRANULATION

Introduction: -

Granulation is the process of producing large aggregates from smaller particles or

powders.
It is widely used in the pharmaceutical industry especially in the manufacturing of
compressed tablets and filling of capsules.
Furthermore, granules themselves can be considered as a dosage form which can be
directly taken by the patient.

** Reasons for granulation:

1- Improve the flow properties
2- Preventing segregation of powder mix components
3- Improve the compaction properties of the powder
4- Increase the bulk density (decrease the bulk volume of powder)
5- Controlled size and shape.
6- Reduction of dust hazards.
7- Reducing caking of hygroscopic powders

* Methods of granulation: -
1 - Dry granulation.
2- Wet granulation.

27
** Dry granulation.
This process is sometimes known as “compression granulation”. In the dry
granulation, powder components are compacted by means of a tablet press (slugging) or
specially designed machinery called “roller compactor” followed by milling and screening.

The chief advantage of dry granulation is that it eliminates heat and moisture and
hence can be applied to hydrolysable compounds which would decompose appreciably
during moist granulation.

** Wet granulation
The most widely and most commonly used granulation technique although it involves
so many separate steps which require time, laboratory work and cost.

Heat and / or moisture sensitive drugs are affected by this method, yet, for the poor
cohesive powder it is the method of choice.

Wet granulation by traditional method involves the following procedures: -

1- Weighing.
2- Mixing.
3- Wet massing.
4- Screening of the damp mass.
5- Drying.
6- Dry screening.

When powder is wetted, liquid film will be formed on the surface which combines to form
bridges involving forces of surface tension and negative capillary tension, which represent
the most important step in the wet massing.
These forces are not enough and of low mechanical strength this state is called pendular
state.

28
 Pendular state

Increasing liquid content, bridges coalesce and increase in strength, and that is called
funicular state.

Funicular state

More addition of liquid will bring particles closer to each other and void spaces are
eliminated. And strength will be optimum by interfacial forces and negative capillary
pressure, this state is called capillary state which is the ideal and wanted in wet granulation.

Capillary state

Further increase of the liquid content will result in the formation of droplets state
where only surface tension holds droplets together and no longer interfacial forces.

29
 Droplet state

Part 1 (Traditional shear granulation)

Traditional method for wet granulation (shear granulation)

Traditional method often uses a planetary mixer for wet massing of the powders. Mixing of
powders is either done in a separate mixer or in the same planetary mixer (Fig 4.1). The
liquid is added as the paddles of mixer agitate the powder. The moist mass is then transferred
to a granulator (such as oscillating granulator (Fig 4.1). The rotor bars of this granulator
oscillate and force the moist mass through the sieve screen.
The mass should be sufficiently moist to form discrete granules:
 If excess liquid  strings of material will be formed
 If too dry  the mass will be sieved to powders and not granules
The granules can then be collected on trays and transferred to a drying oven or dried using
fluidized-bed drier.

30
Planetary mixer Oscillating granulator

Fig. 4.1. Machines normally used in traditional granulation

Disadvantages of tray drying:

• The drying time is long
• Dissolved material may migrate to the upper surface of the bed on the tray
• Granules may aggregate due to bridge formation at the points of contact of granules

 To deaggregate the granules and remix them a sieving stage is necessary after drying.

Procedure

1- Weigh 400 gm of lactose and transfer to the kneader (planetary mixer, orbital shaker), then
add 60 ml of starch mucilage, and mass for 5 minutes.

2- Remove the wet mass and pass through 1.4 mm sieve fitted to the oscillating granulator.
Collect the granules on a stainless-steel pan and spread to form a thin bed of granules.
31
Note: - spread gently to avoid the breaking of the granules.

3- Dry the granules in the oven at 70o C for 45 min

4- Pass the granules through 1.4 mm sieve fitted to ERWEKA Granulator (Screening).

32
Report
1- Why should we screen the granules formed after drying?

2- What are the mechanisms by which bonding occurs between particles in the granules?

3- Referring to the BP, write the way to prepare the starch mucilage used as a granulating
agent?

4- Define Surface Tension.

33
Part 2 (High shear granulation)

This type of granulator (e.g. Diosna, Fielder) is used extensively in pharmaceutics. The
machines have a stainless-steel mixing bowl containing a three-bladed main impeller, which
revolves in the horizontal plane, and a three-bladed auxiliary chopper (breaker blade) which
revolves either in the vertical or the horizontal plane (Fig 4.2).
The unmixed dry powders are placed in the bowl and mixed by the rotating impeller for a few
minutes. Granulating liquid is then added via a port in the lid of the granulator while the
impeller is turning. The granulating fluid is mixed into the powders by the impeller. The
chopper is usually switched on when the moist mass is formed, as its function is to break up
the wet mass to produce a bed of granular material.
Once a satisfactory granule has been produced, the granular product is discharged, passing
through a wire mesh which breaks up any large aggregates, into the bowl of a fluidized-bed
drier.
The advantage of the process is that mixing, massing and granulation are all performed
within a few minutes in the same piece of equipment. The process needs to be controlled with
care as the granulation progresses so rapidly that a usable granule can be transformed very
quickly into an unusable, over massed system. Thus, it is often necessary to use a suitable
monitoring system to indicate the end of the granulation process, i.e. when a granule of the
desired properties has been attained. The process is also sensitive to variations in raw
materials, but this may be minimized by using a suitable end-point monitor.

34
Fig. 4.2. High shear granulator (High speed mixer/granulator)

Procedure:

1- Weigh 200 g of paracetamol and 100 g microcrystalline cellulose 12 g of PVP and transfer
to the high shear granulator.
2- Switch on the impeller for 5 min for mixing.
3- While the impeller is mixing, switch on the chopper and add manually about 120 ml of
distilled water gradually through the small orifice at the cover of the granulator and mass for
5 minutes.
4- Collect the formed granules on a stainless-steel pan and spread to form a thin bed of
granules.
Note: - spread gently to avoid the breaking of the granules.
5- Dry the granules in the oven at 70o C for 45 min
6- Pass the dried granules through 1.4 mm sieve for deaggregation.

35
EXPERIMENT V

The Flow Properties of Powders and Granules

Introduction
Powders are employed in many pharmaceutical processes. The flow properties of
powders are of critical importance in the production of pharmaceutical dosage forms.
Pharmaceutical powders should be of good, rapid and regular flowability, i.e. free
flowing, for the following reasons: -
1- Uniform feed from storage containers or machine hoppers into the tablet dies and
capsule dosators, allowing uniform particle filling which maintains weight uniformity.

2- Uneven Powder flow can result in excess entrapped air within powders, which may
cause capping or lamination of tablets.

3- Uneven powder flow can result from excess fines which increase Particle –
die wall friction and increase dust contamination risks during powder transfer and processing.

Factors affecting Powder Flowability:

1- Particle size.
2- Moisture content
3- Particle shape
4- Particle density
5- Roughness of the surface
6- Electrostatic charges.

36
Effect of glidants on the flow properties

Some additives could be added to poorly flowing granules or powders to improve

their flow properties. Example of these materials is glidants (flow promoters, flow enhancers)
which are added in the dry state just before compression. They are not subjected to any moist
treatment.
Glidants consist of very fine particles that may act through different mechanisms to improve
powder flowability:
a- making the surface of the particles smoother.
b- Reducing electrostatic charges; by adhesion and cohesion.
c- Reducing the moisture adsorbed on the particle surface.
In this lab experiment the focus will be on the effect of some glidants on:
1- Flow Rate.
2- Angle of repose.
3- Compressibility of granules.

Examples of Glidants (flow promoters): -

1) Colloidal silicon dioxide used in 1% W/W or less.
2) Talc: used as glidant and lubricant in 5% W/W concentration.
3) Maize starch used in conc. of 2-5% W/W.
4) Magnesium stearate: used in conc. of 0.2-2% W/W.

Flowability of powder could be improved by one or more of following approaches:

1) Alteration of particles size and size distribution. This attained by
removal of fines and granular particles.
2) Alteration of particle shape or texture. This may be attained by spray
drying which produces spherical free flowing granules.
3) Alteration of surface electrostatic forces, by:
A- Reduction of frictional forces between particles.
B- Electrostatic charges in powder containers should be
discharged by earth connection.

37
 4) Drying of powders and storage under low humidity to minimize
moisture, this is because high moisture content of particles leads to
reduction in the powder flowability.
5) Alteration of process condition.
A- Using force feeders, by fitting vibrating baffles at the base of the feeding hopper.
B- Using of mechanically vibrated hoppers.
6) Addition of flow activators (glidants) e.g. Talc, maize starch, magnesium stearate or
silicon dioxide.

Methods for characterization of powder flow:

Indirect methods:
1. Angle of repose
2. Bulk density measurement
3. Shear cell determination
4. Critical orifice diameter

Direct methods:
1. Hopper flow Rate.
2. Recording flowmeter

Measurement of angle of repose.

Angle of repose gives a measure of the frictional forces which oppose the flow
of a loose powder.
Angle of repose is the maximum angle possible between the Surface of the
pile (heap) of powder and the horizontal plane.

38
 H 2H
tan   
1 / 2D D

Where
θ is the angle of repose
H is the height of a heap of powder
D is the diameter of heap of powder

The rougher and more irregular surface granules, the higher will be the angle
of repose.

o
Generally, powders with angles of repose greater than 50 have bad flow
properties, whereas powder having angle of repose close to 25 o have excellent flowability.

N. B

1- The angle of repose increases with decreasing particle size

2- The addition of glidant, e.g., talc in low concentration decrease the repose angle but
in high concentration it causes an increase.
3- Addition of fines increases the angle of repose.

39
Measurement of the Flow Rate
Powders may be free flowing or cohesive (sticky). The resistance to flow of particles,
especially granules with little cohesiveness may be determined by their flow rate through a
circular orifice of a funnel.
A good flow property is essential for the transport of granules through the hopper into
the dies.

Flow rate = Weight of the powder in grams____ = ………. g/sec.

Time in seconds

The higher this value the better the flowability of the powder.

N. B
1- Particles of high density and low internal porosity tend to possess free flowability.
2- If the surface is rough, poor flowability will result due to friction and cohesiveness.
3- If the granules contain reasonable fine particles this will improve the flowability since they
will be adsorbed on large particles. But these fine particles must not reach 40% of the
granules otherwise it will decrease the flow rate.

Bulk density measurement

The ratio of mass (weight) to the volume is known as the density of the material.
The initial Bulk density (poured bulk density) of a powder can be determined by the
following equation:
M
Do =_________
Vo

40
Where:

Do = Initial bulk density

Vo = Volume occupied by the entire powder mass under the particular packing achieved
during measurement.

The final bulk density (Tapped bulk density) can be determined by the following equation:

Df = M
Vf

Where
Vf = the volume of powder bed after packing.

Df = Tapped bulk density

So the term (light powder) indicates low bulk density, whereas (heavy powder) means a
powder of high bulk density.

From initial and tapped bulk densities, % compressibility (Carr’s index of compressibility)
can be calculated by the following equation:

Df - Do
% compressibility = _________________ x 100%
Df

41
Compressibility is a measure of the potential bridge strength and stability of the powder. If
this parameter is less than 25% the powder has low compressibility and if it is higher than
25% it is a cohesive powder.

42
Test Procedures: -
Angle of repose and flow rate

There are so many different methods for measurement of the angle of repose. The
simplest way is to allow the material to flow through a funnel orifice onto a horizontal
surface beneath as follow: -
1- Hold the funnel in a stand, the orifice of the funnel is far from a white paper on the
bench 10 – 15 cm.
2- With a spatula, tightly close the orifice of the funnel; pour into the funnel
50 g of granules or lactose powder.
3-Using a stopwatch determine the time taken by the powder to flow completely from
the funnel orifice.
4- Mark the diameter of the conical heap Formed using a pencil.
5- Determine the bed height (H) using two rulers.
6- Remove the Powder and measure the diameter (D) of the bed in two planes at right
angles passing through the center of the bed, then take the mean value.
7- Repeat the same steps for at least 3 times and record the mean values
% compressibility
1- Introduce an accurately weighed amount (For example 50 g) of granules and lactose
powder into 100 ml graduated cylinder of the mechanical tapping apparatus.
Record the volume (cm) of the powder and calculate (Do) which is the Initial bulk
density before tapping (poured or fluff bulk density).
2- Set the mechanical tapping apparatus to 200 taps per minute and start tapping till the
powder volume become constant. Calculate Df which means the bulk density after tapping
(equilibrium or tapped density)

Effect of glidants
1) Add 0.5 %, 1%, 3%, 6%, W/W Talc to 50 g ready-made granules and shake well, Test the
mixture for angle of repose, flow rate and % compressibility.
2) Add 2.0%, 4.0%, 8.0%, 12.0%, W/W dry starch to 50 gm ready-made granules and shake
well, Test the mixture for angle of repose, flow rate and % compressibility.
3) Add 0.25%m 0.5%, 1.0% W/W Mg- stearate to 50 gm ready-made granules and shake
well. Test the mixture for angle of repose, flow rate and % compressibility.

43
Moisture content determination
Moisture content is the measurement of water content in wet solids (in weight per
weight basis) or it is the percentage of the weight of the dry solids (in dry weight basis).

Moisture content percent = _ Wt of water in the sample __ x 100

Wt of the dry sample

Increased moisture content usually decreases flowability by increasing cohesive forces.

Procedure:
Weigh 1.0 gm of dried granules on the moisture content determination apparatus.

44
Report

1) Flow behavior of lactose powder and granules

a) Flow rate:
Conc. W/W Weight of granules Average time Flow rate
(g) (s)

Granules

Lactose powder

b) Angle of repose: -
conc. W/W Average Average Angle
diameter (cm) height (cm) repose

Granules
Lactose powder

c) Bulk tapped density: -

conc. Bulk tapped Bulk tapped %
w/w volume volume density density compress-
(ml) (ml) (g/cm) (g/cm) ibility

Granules

Lactose
powder

d) Calculate moisture content of granules

Comment on your results *

45
2) Effect of glidant on flow behavior of granules

Talc
a) Flow rate:
Conc. W/W Weight of granules Average time Flow rate
(g) (s)

0%
0.5%
1%
3%
6%

b) Angle of repose: -
conc. W/W Average Average Angle
diameter (cm) height (cm) repose

0%
0.5%
1%
3%
6%

c) Bulk tapped density: -

conc. Bulk tapped Bulk tapped %
w/w volume volume density density compress-
(ml) (ml) (g/cm) (g/cm) ibility

0%
0.5%
1%
3%
6%

Comment on your results *

46
Maize starch
a) Flow rate: -
conc. W/W Weight (gm) Average time flow rate
rate (s)

0%
2%
4%
8%
12%

b) Angle of repose: -
conc. W/W Average Average angle of
diameter (cm) height (cm) repose

0%
2%
4%
8%
12%

C) Bulk- tapped density: -

conc. Bulk tapped Bulk tapped %
W/W volume volume density density compress-
(ml) (ml) (g/cm) (g/cm) ibility

0%
2%
4%
8%
12%

Comment on your results.

47
Mg stearate

a) Flow rate:
conc. w/w weight of Average time Flow rate
granules (g) (s) (g/s)

0%
0.25%
0.5%
1%

b) Angle of repose: -
conc. W/W Average Average Angle of
diameter (cm3) height (cm3) repose

0%
0.25%
0.5%
1%

c) Bulk- tapped density

conc. Bulk Tapped Bulk Tapped %
W/W volume volume density density compress ibility
(cm3) (cm3) (g/cm3) (g/cm3)

0%
0.25%
0.5%
1%

Comment on your results

48
EXPERIMENT VI

Tablets

Tablets are solid dosage forms containing a single dose of one or more active ingredients and
usually prepared by compressing uniform volumes of particles (powders or granules) into a
definite shape.

Methods of preparation of tablets:

1- direct compression process
2- Granulation:
a- wet granulation process
b- Dry granulation (Compression granulation)

1- Direct compression process

a- Weigh the suitable amounts of excipients and the drug. A
suitable size range is selected by sieving.
b- Mix well the active ingredient or ingredients and excipients, a
lubricant or disintegrant may be added when necessary.
c- Compress the above formula.

2- Wet or moist granulation process

a- Preparation of the active ingredients and excipients by
weighing the ingredients in the formula then mixing the
excipient, e.g., anhydrous lactose.
b- Preparation of the binding or granulating liquid e.g., water,
alcohol, acacia or starch mucilage, or solution of gelatin.
Prepare two batches: (A) using water or dilute ethanol and (B)
using starch mucilage. If the formula contains sucrose, lactose
or an adhesive in powder form a suitable granules mass can be
obtained by using water, diluted ethanol or diluted isopropanol
as the granulating liquid.
49
 c- Moist granulation, a granulating fluid is added to the
ingredients until a coherent or damp mass is obtained. Use
granulator (15-20 ml water as a granulating fluid).
d- Sieve the mass into coarse granules, by forcing it through a
sieve (1.4 to 0.8 mm).
e- Drying of the granules; spread out the granules on trays and dry
them in an oven at a temperature not exceeding 60 o C .
f- Sieve the dried granules.
g- Add lubricant, disintegrant and flavor when required.
h- Compress the last ingredients into tablets using the suitable
tablet machine.

Formulation additives: -
a) Diluents: e.g., lactose… they are used for bulking small dosage drugs to five a suitable
tablet size.
b) Binding agents: e.g., water sugar, solutions, mucilages of acacia and starch. These are
necessary to form the structure. This will be maintained after compression.
c) Disintegrants: e.g., starch, cellulose derivatives. They assist the disruption of the tablet
when on contact with the gastrointestinal fluids.
d) Compression aids: production problems can be minimized by using certain materials
including: -
1- Glidants
2- Lubricants
3- Antiadherent
The machine we are going to work on it in the lab is single punch tableting machine which
consists of the following parts: -
1- Hopper for holding & feeding granules.
2- A die to control the shape & size of the tablet.
3- The upper punch for applying pressure on the granules in the die.
4- A shoe for uniform feeding of the granules to the die from the hopper.
5- Track for guiding the movement of the punch.

50
The compression cycle: -
1- Filling stage: - The granules are emptied from the hopper into the feed
shoe which spread the granules over a wide area to provide the die a
uniform filling.
The down track guides the lower punch to the lowest position allowing the die to be filled.
Then lower part of the punch will be guided again to move up to control the weight of the
tablet & to start compression.

2- Compression stage: - upper punch will move downward resulting in

compression.
3- Ejection stage: - The lower punch goes upward over the track & the
upper punch goes upward resulting in tablet ejection.

Problems that may happen during tablet compression: -

A- Capping & Lamination: -
Capping: - partial or complete separation of the top or bottom crowns of the tablet
from it is body.
Lamination: - Separation of the tablet into two or more distinct layers.

Causes of capping & lamination: -

Mainly due to entrapped air during compression stage leading to sudden escape of it after
compression.
1- Speed of compression.
2- Presence of excessive fines.
3- Use of excessive pressure.
4- Influence of binder.
5- Over drying of granules.

B- Picking and Sticking

Picking: The removal of the surface material of tablet by sticking to punches.
Picking is of particular concern in case of engraved punches, especially with letters of small
enclosed areas like “B” and “A”, which are difficult to manufacture cleanly

51
Sticking: The adhesion of tablet material to the die walls.
Solving of picking and sticking:
 Engraved letters should be designed as large as possible
 Addition of lubricants and ant-adherents.
 Additional binder or change of binder may the granules more cohesive and therefore
less adhesive to the punches and die.
 Low melting materials (such as stearic acid and PEG) which may soften from the heat
of compression causing sticking may be replaced by higher melting point additives.
 High moisture content may cause sticking and this is solved by further drying

Procedure: -
Take granules prepared in the granulation experiment and mix them with sufficient
quanity of Mg stearate and talc in a tumbling mixer. Then, compress the granules using single
punch machine.

Fig. 6.1. The compression cycle of rotary tablet press

52
Fig. 6.2. The compression cycle of a single-punch tablet press

53
EXPERIMENT VII

Quality Control of Tablets

Aim of this lab

To test whether manufactured Paracetamol 500 mg tablets meet the required
standard of quality for uncoated immediate release tablets.

Theoretical part

What is Quality control?

Quality control (QC) is a set of tests intended to ensure that a manufactured
product adheres to a defined set of quality criteria or meets the requirements
(i.e. limits or specifications).

The procedures used to perform the quality control tests are often described in
Pharmacopeia. Such QC tests are therefore called pharmacopeial, official or
compendial tests. The Pharmacopeia specify certain QC tests according to the
type of dosage form. For example, for immediate release uncoated tablets the
following official (pharmacopoeial) tests should be performed:
1- Uniformity of weight.
2- Uniformity of drug content
3- Disintegration test.
4- Dissolution rate.
5- Friability
6- Crushing strength
The Pharmacopeia often defines also the specific limit for acceptance of the
results of each test.
54
QC tests not described in the Pharmacopeia are called non – official (non –
pharmacopoeial or non-compedial) tests and include:
1- Uniformity of diameter...

How to carry out official QC tests?

The various quality control tests should be performed on the dosage form, using
the equipment and following the procedures described in the Pharmacopeia.
Then, the quantitative (i.e. numerical) results obtained in each test should be
compared to the defined test limits for that specific dosage form (e.g. immediate
release uncoated tablets):
 If the experimental results fall within the specified limits the quality
control test is considered passed and the batch accepted.
 In contrary, if the results fail to comply with the limits, the test is failed
and the batch should be rejected, because it does not meet the required
quality criteria for that given test.

Therefore, the final outcome of quality control tests is purely qualitative: in fact,
quality control tests are either passed or failed.

In the present laboratory procedure and specifications indicated in the British

Pharmacopeia will be followed.

QC Test 1 - Uniformity of weight (mass)

Method
Weigh 20 tablets selected at random, record their weight and determine the
average weight. Not more than 2 (out of 20) of the tablets weights deviate from
the average weight by more than the percentage deviation shown in Table 7.1,
and no tablet deviate by more than twice that percentage.
55
Table 7.1: Allowed weight percentage deviations according to BP 2009
Average weight of Allowed
tablets Percentage deviation %
80 mg or less  10
More than 80mg  7.5
and less than 250
mg
250 mg or more 5

A schematic representation on the procedure for the evaluation of the

uniformity of weight (according to BP):

56
An illustrative example:
1- Measurement of the weight of 20 tablets.
2- Average weight of 20 tablets = Σ 20/20 = 200 mg
3- Determination of percentage deviation according to the average
weight (Table 8.1). →  7.5%
4- Calculation of upper limit of acceptance
200:100% = X:(100%+7.5%)
200:100% = X:(107.5%)
X= 215 mg
5- Calculation of lower limit of acceptance
200:100% = X:(100% - 7.5%)
200:100% = X:(92.5%)
X= 185 mg
6- Comparison of the individual weight of each tablet of the batch (20
tablets) between the upper and lower limits. Number of tablets
whose weight is between 185 mg and 215 mg.
- If no tablet deviates, the batch passes the pharmacopoeial test.
- If more than 2 tablets deviate; the batch must be rejected.
- If 1 or 2 tablets only deviate than upper and lower limits, carry out or
calculate the upper and lower limits for the double or twice that deviation
percentage. In our example the % deviation is 7.5 %, so the double deviation
becomes 15%.
7- Calculation of the upper limit for double the % deviation
200:100% = X:(100%+15%)
200:100% = X:(115%)
X= 230 mg
8- Calculation of the lower limit for double the % deviation
200:100% = X:(100%-15%)

57
200:100% = X:(85%)
X= 170 mg
9- Check if the weights of the one or two tablets, that lied outside
from the single percentage deviation, are between the upper and
lower limit of twice the allowed % deviation. In our case upper
limit = 230 mg and lower limit = 170 mg.
-If none of the one or two tablets deviates by more than double that
percentage the batch passes the pharmacopoeial test.
- If one or both tablets deviates by more than double that percentage the
batch should be rejected.

QC test 2- Uniformity of drug Content (BP 2009)

To evaluate a tablet potential for efficacy, the amount of drug per tablet needs to
be monitored from tablet to tablet.

“The test for uniformity of content is based on the assay of the individual
contents of active ingredient of a number of single-dose units to determine
whether the individual contents are within limits set with reference to the
average content of the sample”.

Method
“Using a suitable analytical method, determine the individual contents of active
ingredient of ten dosage units (e.g. tablets) taken at random.

The preparation complies with the test if each individual content is between
85% and 115% of the average content. The preparation fails to comply with the
test if more than one individual content is outside these limits or if one
individual content is outside the limits of 75% to 125% of the average content.
If one individual content is outside the limits of 85% to 115% but within the
58
limits of 75% to 125%, determine the individual contents of another twenty
dosage units taken at random. The preparation complies with the test if not more
than one of the individual contents of the thirty units is outside 85% to 115% of
the average content and none is outside the limits of 75% to 125% of the
average content.”

A schematic representation on the procedure for the evaluation of the

uniformity of content (according to BP):

59
Note: in most cases the uniformity of drug content test can be avoided: when the
tablets contain high dose of active ingredient (therefore most of the tablets
weight is drug), the uniformity of weight test is a suitable method to determine
content uniformity (and therefore the uniformity of drug content test can be
avoided).

According to the BP only when the drug present in the tablet is < 2 mg or < 2%
of the total weight of the tablet, the weight variation test is not sufficient to
assure uniform potency. Only in such case the uniformity of drug content must
be calculated.

QC test 3- Disintegration test (BP 2009)

Disintegration testing determines the time for a tablet to disintegrate (i.e. break
into particles) when immersed in some test fluid.

It is obvious that for immediate release tablets (where a prompt therapeutic

effect is needed) fast tablets disintegration is required. Several parameters
influence disintegration time:
 Test related parameters: disintegration medium and temperature (however
temperature should be fixed at 37 °C in any disintegration test)
 Formulation related parameters: compression force used to make the
tablets; type and amount of disintegrant present in the formulation; type
and amount of binder present in the formulation; type and amount of
lubricant present in formulation (lubricants such as Mg stearates and
other lipophilic lubricant can slow down tablet disintegration and
dissolution).

60
Apparatus
The disintegration apparatus consists of 6 glass tubes, open at the top, and held
against a 10-mesh screen at the bottom end of the basket rack assembly (Fig
7.1). A suitable device maintains the temperature of the liquid at 36° to 38°.

Fig. 7.1 Apparatus for the Disintegration of Tablets and Capsules

Method
To test for disintegration time, one tablet is placed in each tube (i.e. 6) and the
basket rack is positioned in specified medium at 37 ± 2°C. A standard motor
driven device is used to move the basket assembly containing the tablets up and
down. Perforated plastic discs may also be used for tablets that float (see Fig 7-
1-not used in our experiment). Operate the apparatus for the specified time (15
minutes for uncoated tablets). The tablet complies with the test, if all of the
tablets have disintegrated completely: this means that all particles pass through
the 10-mesh screen in the time specified and if any residue remains, it must
61
have a soft mass with no palpably firm core. For the test to be passed all the 6
tested tablets should disintegrate within the specified time. The BP limits for
disintegration times for immediate release tablets are given in Table 7.2.

Table 7.2: summary of BP limits for disintegration time of immediate release

tablets.

If one or two tablets from the 6 tablets fail disintegrate completely within the
specified time repeat the same test on another 12 tablets. (i.e. the whole test will
consume 18 tablets). Not less than 16 tablets disintegrate completely within the
time: this means that, if more than two tablets (from the 18) fail to disintegrate,
the batch must be rejected.

QC test 4 - Dissolution Test BP 2009

Dissolution is performed to check the cumulative percentage release from the
dosage forms over time. Disintegration test does not give assurance that
particles will release drug in solution at an appropriate rate, that’s why
dissolution tests must be performed. For instance, in the case of immediate
release tablets, ideally the drug should be release from the tablet into the
medium within a short time, so to enable a fast therapeutic effect.

Apparatus I (Basket apparatus)

The BP or USP dissolution apparatus I (Basket apparatus) consists of a
cylindrical vessel with a hemispherical bottom, which may be covered, made of
glass or other inert, transparent material; a motor; a metallic drive shaft; and a
62
cylindrical basket (Fig. 7.3). The vessel is partially immersed in a suitable water
bath. The water bath or heating device permits holding the temperature inside
the vessel at 37 ± 0.5 °.

Fig. 7.3 Basket apparatus

Apparatus II (Paddle apparatus)

Same as Apparatus I described above, except that in the stirring element the
basket is replaced by a paddle (Fig. 7.4).

63
Fig. 7.4 Paddle apparatus

Method (from BP 2009)

Number of tablets tested: 6
Dissolution apparatus: paddle
Paddle rotation speed: 50 rpm
Dissolution medium: phosphate buffer pH 5.8
Volume: 900 ml
Temperature: 37 °C ± 0.5 °C
Determination of drug concentration: UV/VIS Spectrophotometer at 243 nm

Procedure
Before the dissolution
1- Preparation of the buffer solution used as dissolution medium.
64
2- Using the UV/VIS Spectrophotometer at 243 nm, construct a standard
calibration curve for paracetamol (absorbance vs paracetamol concentration).
This calibration curve will be used to determine the concentration of
paracetamol dissolved in the dissolution medium from the values of absorbance.

Dissolution test
1- Introduce the stated volume of the dissolution medium (900 ml) into each
vessel (i.e. 6) of the apparatus.
2- Warm the dissolution medium until maintained at 36.5 to 37.5 o C .
3- Place one tablet in the dissolution medium of each vessel (i.e. total of 6
tablets); allow the tablets to sink to the bottom of the vessel prior to the rotation
of the paddle.
4- Operate the apparatus immediately at the speed of rotation specified in the
individual monograph (in this experiment it is 50 rpm) and start timing
5- Take 10 ml samples with a pipette after the prescribed time (45 minutes).
Withdraw the samples from a point half – way between the surface of the
dissolution medium and the top of the rotating paddle or basket (see Fig. 7-4).
6- Using filter paper filter the sample.
7- Dilute the samples: take 1 ml from each filtrate and dilute it to 50 ml in
phosphate buffer pH 5.8 in a 50 ml volumetric flask.
8- Using a UV/VIS Spectrophotometer measure the absorbance of the 6 diluted
samples at a λ= 243 nm. The absorbance should be between 0.1 and 1.

65
9- Tabulate the results as follows:

Tablet Absorbance Conc. of drug DF Volume of Amount of % of drug

released medium drug (mg) released after
mg/ml 45 minutes

1
2
3
4
5
6

For example: If you test Paracetamol 500 mg tablets dissolved in 900 ml

dissolution medium.

For each tablet:

a- Absorbance values (from point 8-) are recorded
b- Concentration (mg/ml) = Absorbance / slope from calibration curve (ml/mg)
c- DF = Dilution Factor
d- Volume of medium = initial volume presents in the vessel at the time of
sampling.
e- Amount of drug dissolved (mg) = concentration (mg/ml) x DF x volume of
medium
f- % drug released after 45 minutes = Amount of drug dissolved x100
Labeled amount (500 mg)

Dissolution specifications for conventional-release dosage forms

The test is passed if for each of the 6 tablets tested not less than 80% of the
active substance is released within 45 minutes.

66
QC test 5 - Friability of uncoated tablets (BP 2009)
It is a mechanical strength test. Friability tests have been designed to assess the
resistance of the surface of the tablet to attrition. The friability test measures the
weight loss on subjecting tablets to a standard level of agitation for a specified
time.

Practical importance of friability test: coating, packaging and transportation are

generally not severe enough to break the tablet, but may abrade small particle
from tablet surface. To examine this, tablets are subjected to a uniform tumbling
motion for specified time and weight loss is measured.

Another application of friability tests is to detect sudden capping or lamination,

as tablets with no visible defect, might cap or laminate when subjected to
attrition.

Apparatus
A drum is used (see Fig. 7.5). One side of the drum is removable. The tablets
are tumbled at each turn of the drum by a curved projection. The drum is
attached to the horizontal axis of a device that rotates at 25 rpm. Thus, at each
turn the tablets roll or slide and fall onto the drum wall or onto each other.

67
Fig. 7.5 Tablet friability apparatus

Method
For tablets weighing up to 0.65 g each, take a sample of twenty tablets; for
tablets weighing more than 0.65 g each, take ten tablets. Place the tablets on a
sieve no. 1000 and remove any loose dust with the aid of air pressure or a soft
brush. Accurately weigh the tablet sample and place the tablets in the drum.
Rotate the drum 100 times (4 minutes at 25 rpm). When the time elapse
removes the tablets. Remove any loose dust from the tablets as before. If no
tablets are cracked, split or broken, weigh the tablets to the nearest milligram.

Expression of the results

The friability is expressed as the loss of mass and it is calculated as a percentage
of the initial mass.

Indicate the number of tablets used.

% (weight) loss = weight before – weight after x 100
weight before

68
Generally, the test is run once. A maximum loss of 1% of the mass of the tablets
tested is considered to be acceptable. If the mass loss is greater than 1%, repeat
the test twice and determine the mean of the three tests. The mean of the mass
loss for the three tests should be no more than 1% for the batch to be accepted.

QC test 6 - Crushing Strength test

It is a mechanical strength test. Crushing strength (also called hardness) test is
the amount of force needed to fracture/crush a tablet. So as compression force
increases crushing strength increases too (i.e. the higher the compression force
required to crush the tablet, the stronger the tablet). In crushing strength test the
force is generally applied diametrically to a tablet.

Crushing strength is an important feature of quality, since serious losses can

occur if tablets are not strong enough (too soft) to withstand vibration and stress
during coating, packaging and abuse handling by consumers. If the tablet is too
soft, it will not withstand the handling during subsequent processing such as
coating or packaging. On the other hand, hardness can affect the disintegration.
So, if the tablet is too hard, it may take too long to disintegrate. Therefore,
generally in immediate release tablets, hardness should be high enough to
withstand handling, yet not excessive to compromise fast disintegration.

Apparatus
In the hardness tester (Fig. 7.6), the tablet is placed between two jaws. One jaw
moves to apply sufficient force to the tablet to cause fracture. A calibrated load
cell measures the force applied. Results are expressed in Newton (N) or
Kilopond (kp).

69
Fig. 7.6 Crushing strength apparatus (hardness tester)

Procedure
Take 10 tablets from the batch and determine the hardness of each tablet using
the specified hardness tester. Calculate the mean of hardness of 10 tablets (in
Newtons); the suitable hardness value of tablets is not specified in the BP. This
is because hardness depends on tablet size (small tablets easier to crush) and
shape (oblong or oval tablets are easier to break than circular tablets).
Therefore, different tablet types will have different QC specifications.

70
Report:

1- Disintegration test: -
Done for the six tablets

tablet No. Disintegration

time (min)
1
2
3
4
5
6

Comments (is the test passed or failed?): -

2- Dissolution test: -

Tablet Absorbance Conc. of drug DF Volume of Amount of % of drug

released medium drug (mg) released after
mg/ml 45 minutes

1
2
3
4
5
6

Calculations:

71
Comments (is the test passed or failed?):

What is the aim of a dissolution test for tablets?

3-Uniformity of weight test:

Tablet No Weight (mg) Result

1
2
3
4
5
6
7 Average weight=
8
9 The allowed %
10 deviation =
11
12
13
14
15
16
17
18
19
20

72
Calculations: -

Comments (is the test passed or failed?): -

Is the uniformity of drug content test required for 500 mg paracetamol tablets? Explain also
why.

4- Hardness test: -
Done for 10 tablets
Tablet batch
No. (1)

1
2
3
4
5
6
7
8
9
10
Mean

73
Comments (is the test passed or failed?):

5- Friability test: -
batch no. Weight of tablets Weight of tablets after % loss Result
before test (gm) test (gm)

Calculations of % loss: -

State if any of the tablets was subjected to capping or lamination: -

Comments (is the test passed or failed?): -

74
Exercise 1
suppose that you have 1 mg bromazepam tablets, perform the uniformity of drug
content test, given the weight and drug content of 10 tablets taken at random
(provided to you by the Teaching Assistant)

Tablet No Drug Result

content
(mg)

1
2
3
4
5 Average
6 content=
7
8 The
9 allowed %
10 deviation=

Calculations: -

Comments (is the test passed or failed?): -

What is the aim the uniformity of content test?

What is the difference between the uniformity of weight and uniformity of drug content tests?
.

75
EXPERIMENT VIII

TABLET COATING

Types of tablet coating

There are three main types of coating:
1. Sugar coating
2. Film coating
3. Press coating (not covered in this lab)

Coating process in the first two types is based on:

I - the application of a coating liquid (solution or suspension) to tablets
II - movement of the tablet bed
III - use of heated air to facilitate evaporation of the solvent from the coating.
***Note: these three events happen simultaneously

Types of coating equipments:

1. Conventional pan system: the standard coating pan consists of a circular
metal pan mounted angularly on a stand. Heated air is directed into the pan and
onto the tablet bed surface and is exhausted by means of ducts positioned
through the front of the pan. The coating formula is added either by pouring or
by spraying.

2. Perforated Pan Systems: partially perforated drum that is rotated onto its
horizontal axis. In these coaters, the drying air is directed into the drum is
passed through the tablet bed and exhausted through perforations in the drum.
The coating liquid is applied to the surface of the rotating beds of tablets
generally through spraying nozzles.

76
3. Fluidized Bed Systems: Highly efficient drying system in which,
fluidization of the tablet mass is achieved in a columnar chamber by the upward
flow of the drying air. Tablets will rise in the center of the chamber and then
fall towards the chamber wall and move downward to re-enter the air stream at
the bottom. Due to the possibility of impaction in the process friable tablets are
difficult to coat. Coating solution is continuously applied from a spray nozzle
located at the bottom or are sprayed onto the top of the tablet bed.

TABLET FILM COATING

Film coating is the most modern and generally used method nowadays. It is
either immediate or modified release depending on the materials used.

Advantages of film coating

1) Reduction in coating time
2) Usually single stage
3) Small increase in tablet weight
4) No significant increase in disintegration time
5) Less chipping and cracking

Ingredients of film coating liquid formula

Film coating formula includes:
 Film former (Polymer).
 Plasticizer: material used to improve the quality (flexibility,
adhesion) of film (e.g. Polyethylene glycols, Propylene glycol,
Glycerin, Diethyl phthalate, Castor oil, mineral oil).
 Colorant.
 Solvent.
77
Ideal characteristics of film-coated tablets
1. Film coated tablets should display an even coverage of film and color.
2. Logos and break lines should be distinct and not filled.
3. The tablet must be compliant with finished product specifications and any
relevant compendial requirements (i.e. tablets should pass QC tests).

Coating faults and film defects

1- Picking and sticking (twining)
Overwetting will cause tablets to stick to each other
or to the coating pan.

2- Cracking and peeling

Tablet twinning
Film cracking and Film peeling may occur due to
inappropriate choice or concentration of plasticizer.

3- Blistering
It is the local detachment of the film from the core. Film peeling

This results from too rapid evaporation of the solvent from the core (called
overdrying). Milder drying conditions are indicated in this case.

4- Bridging
During drying, the film may shrink and pull away from the sharp corners of an
intagliation or bisect. Increasing the plasticizer content or changing the
plasticizer can decrease the incidence of bridging.

5- Bridging of logos
Partial or complete detachment of the coating in the region of the logo. Solved
by adding/changing plasticizer.

78
6- Orange peel effects
Inadequate spreading of the coating solution before drying causes a bumpy or
“orange peel” effect on the coating.
Causes:
– Two rapid drying (i.e. overdrying)
– High solution viscosity

*Note: efficient coating can be achieved only if the spraying rate and drying
rate are balanced. When spraying rate exceed drying rate overwetting will
result. When drying rate exceed spraying rate overdrying will result. Hence to
minimize overwetting: 1) the drying rate could be increased and/or 2) the
spraying rate could be decreased. The opposite approach should be used in
case of overdrying.

7- Color variation

79
Practical work:
Coat three different batches of tablets with the three coating formulas.
Film coating formulas (HPMC aqueous formula):
1-standard formula
2-plasticizer-free formula
3-viscous formula

1-standard formula
Ingredients Quantity
HPMC 2910 USP 4%
Propylene glycol USP 1.2%
Colorant Qs
Purified water qs to 100%

2-plasticizer-free formula
Ingredients Quantity
HPMC 2910 USP 4%
Colorant Qs
Purified water qs to 100%

3-viscous formula
Ingredients Quantity
HPMC 2910 USP 8%
Propylene glycol USP 1.2%
Colorant Qs
Purified water qs to 100%

80
Coating procedure

1. Remove dust from the tablet.

2. Weigh the batch of tablets to be coated.
3. Put tablets in coating pan.
4. Set temperature to about 30°C.
5. Roll tablet in the coating pan for about 10 min (10 rpm).
6. Apply coating solution on the tablet bed.
7. Allow adequate time for drying between applications.
8. Weight the dried coated tablet.

81
Report:

Calculate the percent increase in tablet weight for each of the three coating
formulas.

Mention the coating defects that occurred in your work for each of the three
coating formulas.

Which coating formula gives the best coating result? Try to explain why.

82
EXPERIMENT IX

TABLET SUGAR COATING

Sugar coating is the traditional method of coating tablets. It is less common

nowadays than film coating. In general, the equipments used in film coating
can, with suitable modification, be used for sugar-coating techniques. Methods
of applying the coating solution include manually using a ladle or by spraying.

The process consists of six steps, which are: sealing, sub-coating, smoothing,
coloring, polishing and printing (optional). Tablets are preferably concave (not
flat) with thin rounding edging. As the process is relatively long, the cores
should be relatively resistant to breakage, chipping, and abrasion. The process
of sugar coating lasts 8 hours or longer.

1. Seal Coating
It is a thin coating layer. The purpose of this coat is the prevention of moisture
into the tablet during coating. Overwetting causes: softening and affect physical
and chemical stability. Sealants materials:
1. Shellac
2. Zein
3. Cellulose acetate phthalate
4. Polyvinyl acetate phthalate.
83
2. Sub-coating
Objective: round the edging and build up the tablet size. Sub-coating increase
the size by 30- 100%. Sub-coating consists of alternately applying (by pouring)
a sucrose-based sticky solution to the tablets followed by a dusting of sub-
coating powders (e.g. CaCO3) and then drying. For spray processes, a sub-
coating suspension containing both the binder and the insoluble powder is
sprayed intermittently on the tablet bed.

3. Smoothing
Purpose: to cover and fill in the imperfections in the tablet surface caused by
sub-coating step. It is an essential step before the color application. Smoothing
generally consists of two phases:
 Applications of a first coating liquid (called grossing syrup) usually
containing some suspended powders (e.g. CaCO3) in syrup. The
aim of this coating is to fill imperfections.
 Applications of a second coating liquid of regular syrup to further
enhance the smoothness of the coating surface.

4. Coloring
No colour is added until the tablets are quite smooth. Colorants can be dissolved
or dispersed in diluted sucrose solutions and such liquid applied on tablet
surface.

5. Polishing
Polishing step is generally performed by applying a warm solutions of waxes
(beeswax or carnauba wax) in naphtha. Naphta is an extremely volatile solvent,
so its evaporation from the coating can happen at room temperature.

84
6. Printing
It is a common practice to identify all oral solid dosage forms with a
manufacturers logo, product name, dosage strength or other appropriate code.
For sugar coating such identification can be done only by printing using special
edible inks.

Sugar coating problems

1- Chipping of coating
Sugar coatings are inherently brittle. Addition of small quantity of polymer
often helps to improve structure integrity.
2- Cracking of the coating
Tablet cores that expand cause cracking. Expansion may result from:
– Moisture sorption (caused by inadequate drying during the coating
application)
– Stress relaxation of the core
3- Twinning
Results from drying after sticking of tablets.
4- Uneven color
Some possible causes:
1. Poor distribution of coating liquids.
2. Unevenness of the surface of the subcoat.
6- Blooming and sweating
This result from residual moisture. The moisture can diffuse out and affect the
product quality. Moderate levels of moisture egress cause the polish to take on a
fogged appearance (Blooming). With higher levels of moisture egress, the
moisture may appear like beads of perspiration (Sweating), which may cause
tablets stored in closed containers to stick.

85
Practical work:
Put in a tray one sugar coated tablet and one film coated tablet and cut them into
two halves and describe differences: -

86
EXPERIMENT X

Disintegration and Dissolution of Marketed Diclofenac

Sodium Enteric Coated Tablets

An enteric (or gastro-resistant) coat is designed to resist gastric fluids but to

disrupt when the coated tablet enters the duodenum or alkaline pH in the GIT.
Enteric coating is used to protect tablet core from disintegration in the acid
environment of the stomach for one or more of the following reasons:
1. Prevention of destruction of active constituents unstable at low pH.
2. To protect the stomach from the irritant effect of certain drugs.
3. To facilitate absorption of drugs those are preferentially absorbed
distal to the stomach.
The polymers used for enteric coating should be insoluble in aqueous media at
low pH. Therefore, these polymers possess free carboxylic acid groups on the
polymer backbone, which is ionized at high pH causing increase in polymer
solubility.

Examples of polymers used for enteric coating: Cellulose acetate phthalate,

Polyvinyl acetate phthalate, Hydroxypropyl methylcellulose phthalate, Acrylate
polymers (Eudragit® L, Eudragit® S).

87
Practical work:
Disintegration test for enteric coated tablets (BP 2009)
Introduce one tablet into each tube of the basket rack; suspend the rack in the
beaker containing 0.1 N HCl and operate for 120 min. Remove the rack from
the liquid. No tablet should show signs of cracks that would allow the escape of
the contents on disintegration.

Replace the liquid in the beaker with phosphate buffer (pH 6.8) and operate the
apparatus for a further 60 minutes. Remove the rack from the liquid. The tablets
pass the test if all six have disintegrated.

Dissolution test for diclofenac sodium delayed-release Tablets (USP 2007)

acid stage —
Medium: 0.1 N hydrochloric acid; 900 mL.
Apparatus 2 (paddles constructed of, or coated with, polytef being used): 50 rpm.
Procedure— At the end of 2 hours, remove each Tablet, or the major portion thereof if the
Tablet is not intact, from the individual vessels, and subject them to the test in the Buffer
stage. To the 0.1 N hydrochloric acid remaining in each vessel, add 20.0 mL of 5 N sodium
hydroxide, and stir for 5 minutes. Determine the amount of C14H10Cl2NNaO2 dissolved
from UV absorbance at the wavelength of maximum absorbance at about 276 nm on filtered
portions of the solution under test in comparison with a Standard solution prepared as
follows.
Transfer about 68 mg of USP Diclofenac Sodium RS, accurately weighed, to a 100-mL
volumetric flask, add 10.0 mL of 0.1 N sodium hydroxide, dilute with water to volume, and
mix. Transfer 2.0 mL of this solution to a second 100-mL volumetric flask, dilute with a
mixture of 0.1 N hydrochloric acid and 5 N sodium hydroxide (900:20) to volume, and mix.
This Standard solution contains about 13.6 µg of USP Diclofenac Sodium RS per mL.
buffer stage—
pH 6.8 Phosphate buffer— Dissolve 76 g of tribasic sodium phosphate in water to obtain
1000 mL of solution. Mix 250 mL of this solution with 750 mL of 0.1 N hydrochloric acid,

88
and, if necessary, adjust with 2 N hydrochloric acid or 2 N sodium hydroxide to a pH of 6.8 ±
0.05.
Medium: pH 6.8 Phosphate buffer; 900 mL.
Apparatus 2: 50 rpm.
Procedure— At the end of 45 minutes, determine the amount of C14H10Cl2NNaO2
dissolved from UV absorbance at the wavelength of maximum absorbance at about 276 nm
on filtered portions of the solutions under test, suitably diluted with Medium, in comparison
with a Standard solution prepared as follows. Transfer about 68 mg of USP Diclofenac
Sodium RS, accurately weighed, to a 100-mL volumetric flask, add 10.0 mL of 0.1 N sodium
hydroxide, dilute with water to volume, and mix. Transfer 2.0 mL of this solution to a second
100-mL volumetric flask, dilute with Medium, as obtained in the Buffer stage, to volume, and
mix. This Standard solution contains about 0.02 mg of USP Diclofenac Sodium RS per mL.
Tolerances— Not less than 75% (Q) of the labeled amount of
C14H10Cl2NNaO2 is dissolved. "

89
Report

Calculate the percentage release from

Acid after 2 hrs

Buffer after 45 mins

Comment on the disintegration results

90
EXPERIMENT XI

Dissolution of Marketed Diclofenac Sodium Extended-

Release Tablets
Extended-release (ER) systems are used for improved therapy with long-term oral
administration of drugs due to their following advantages:

• Improving patient compliance, resulting from the reduction in the number and
frequency of doses.
• Reduction in the drug blood level fluctuations
• Improved treatment of many chronic diseases
• Maintenance of the therapeutic action of a drug during overnight no-dose period.
• Reduction of local and systemic side effects
• Reduction of the total amount of drug administered over the period of treatment.

The drug release is extended for a longer period of time than for immediate –release dosage
forms and in order to achieve this extended-release formulation use a chemical or physical
barrier to provide slow release of maintenance dose. Many formulation techniques have been
designed to build the barrier into the peroral dosage form. These include:
 the use of coating in conventional membrane-controlled and osmotic pump.
 embedding the drug in a wax, insoluble polymer or hydrophilic colloid matrix
 chemical binding to ion-exchange resins

work Practical:
Apply the method for dissolution of Diclofenac Sodium Extended-Release Tablets (Test 3) in
USP 2007 using commercially available tablets.
"Medium: 0.05 M phosphate buffer, pH 7.5; 900 mL.
Apparatus 1: 100 rpm.
Procedure— Determine the amount of C14H10Cl2NNaO2 dissolved by employing UV
absorption at the wavelength of maximum absorbance at about 276 nm on filtered portions of
the solution under test, suitably diluted with Medium, if necessary, in comparison with a
91
Standard solution having a known concentration of USP Diclofenac Sodium RS in the same
Medium.
Tolerances— The percentages of the labeled amount of C14H10Cl2NNaO2 dissolved at the
times specified conform to Acceptance Table 2.

Time (hours) Amount dissolved

2 between 22% and 42%
4 between 34% and 61%
8 between 52% and 82%
16 not less than 73%

Determine the percent dissolved at 45 minutes and 2 hours and compare with the percent
dissolved values at the same time intervals for enteric coated tablets

92
Report

Calculate the percentage release from extended release diclofenac sodium tablets after:

45 min

2 hrs

Comment on the release results comparing them with the release results of enteric tablets

93
EXPERIMENT XII
Preparation and evaluation of extended release matrix tablets

Introduction:

• The Extended-release dosage forms are products that release drug slowly, so that the
plasma concentrations are maintained at therapeutic level for a prolonged period of
time (usually between 8 and 12 hours)

Advantages of Extended Release Drug Delivery Systems

- Reduction in the drug blood level fluctuations →Reduction in adverse side effects and
improvement in tolerability.
- Improving patient compliance, resulting from the reduction in the number and
frequency of doses.
- Reduction in healthcare cost.
- Maintenance of the therapeutic action of a drug during overnight no-dose period.

Matrix Tablets

These are the type of extended release drug delivery systems, from which the drug is released
slowly as a result of dispersing it uniformly in swellable hydrophilic substances, an insoluble
matrix of rigid non-swellable hydrophobic materials.

94
Matrix tablets can be divided into three main types based on
retardant material:
1. Hydrophobic Matrices (Plastic matrices).
2. Lipid (Wax) Matrices.
3. Hydrophilic (Swellable) Matrices.

Matrices can be prepared by direct compression or via granulation (dry, wet or melt)

In cases of lipid matrices and insoluble polymer matrices, drug particles are dispersed in an
insoluble matrix former, with drug becoming available as a solvent enters the matrix and
dissolve the particles. Sustained release is produced due to the fact that the dissolved drug has
to diffuse through a network of small channels that exist between compacted insoluble
particles. Insoluble polymers that have been used in hydrophobic matrices include
polyethylene, polyvinyl chloride, ethyl cellulose and acrylate polymers and their copolymers.
Lipid matrix formers include hydrogenated vegetable oils, microcrystalline wax and carnauba
wax.

In the case of hydrophilic (swellable) colloid matrices, drug particles are dispersed in a
swellable matrix. On contact with GIT fluids the hydrophilic colloid components swell to
form a hydrated matrix layer. The outer hydrated layer will erode as it becomes more dilute.
Drug release occurs by diffusion of dissolved molecules through the hydrated matrix layer
and/or through erosion of matrix followed by dissolution.

95
The polymers used in the preparation of hydrophilic matrices are divided in to three broad
groups

1.Cellulose derivatives: methylcellulose 400 and 4000 cPs; hydroxyethyl cellulose;

hydroxypropylmethylcellulose (HPMC) 25, 100, 4000 and 15000 cPs; and sodium
carboxymethylcellulose.

2.Noncellulose natural or semisynthetic polymers: agar-agar; carob gum; alginates; molasses;

polysaccharides of mannose and galactose; chitosan and modified starches.

3. Polymers of acrylic acid; Carbopol 974 and 971, the most commonly used.

96
Practical work:
1. Calculate the quantities of ingredients required to prepare six tablets (300 mg) of the
following formulas:

Hydrophilic matrix tablets

Formula1 Formula 2
Paracetamol Paracetamol
10% HPMC 40% HPMC
1% Magnesium Stearate 1% Magnesium Stearate

Insoluble polymer matrix tablets

Formula1 Formula 2
Paracetamol Paracetamol
10% Kollidon SR 40% Kollidon SR
1% Magnesium Stearate 1% Magnesium Stearate

2. Mix the drug and polymer for 15 min. Then add 1 % Magnesium Stearate and mix for
other 5 min.
3. Compress 6 tablets using the single punch tablet machine.
4. Study the drug release from the tablets in dissolution apparatus using the following
conditions.
- Medium: Distilled water; 900 mL.
- Apparatus 1: 100 rpm.
- Maximum absorbance at about 244 nm.
- Slope of calibration =
5. Determine the percent of paracetamol dissolved at 45 and 120 minutes.
6. Draw the dissolution curves and compare the effect of the concentration of polymer
on drug release process.

97
Report

Calculate the percentage release of paracetamol from 1matrix tablets and fill results in the
following table:

HPMC Kollidon SR

10% 40% 10% 40%

% drug release
at 45 minutes

at120 minutes

Comment on the release results and final shape of tablets

98