INDUKAKA IPCOWALA COLLEGE OF PHARMACY
TESTING OF DOSAGE
Guided by: Sunil L. Baldania
Dimal A. Shah
Prepared by: Shweta Singh
3rd Sem (P.A)
What is Physical
Physical stability means that :
• The formulation is totally unchanged through out its shelf-
life and has not suffered any changes by way of
appearance, organoleptic properties, hardness, brittleness,
particle size etc.
It affects :
• Pharmaceutical elegance
• Drug content uniformity
• Drug release rate. 2
• The physical parameters associated with tablets are :
associated properties including slurry pH.
• The general appearance of a tablet, its visual identity and
overall „elegance‟ is essential for consumer acceptance and
lot- to- lot uniformity and general tablet- to- tablet uniformity,
and for monitoring trouble free manufacturing.
• The control of general appearance involves the
measurement of a number of tablet‟s size, shape, colour,
presence or absence of an odour, taste, surface texture,
physical flaws and consistency, and legibility of any
• The “hardness” of a tablet are usually assessed by
subjecting the tablets to a diametral failure test.
• The tablet is placed (as shown in Figure) between two
anvils, one of which is stationary. The other anvil is
moved at constant speed against the tablet, and the
force (as a function of time) is recorded.
Tablets are made either by wet processing (wet
granulation) or by dry processing (direct compression or
A binder in solution is added to the powder mixture, it
forms soft bridges between particles, and when the
granulation is dried then these bridges become hard.
During compression bond form between particles & the
hardness of the tablet is tied in with the strength of the
In order to form a bond, the particles or binder bridges
must first be exposed to pressure that exceed the
elastic limit of the material.
• On failure, the material will either deform plastically or
experience the brittle fracture.
• A material that flows well and has a low elastic limit is,
therefore, easy to transform into a tablet, and several
such materials, known as direct compression
ingredients, are used in the manufacture of
• In these cases drug is simply mixed with the direct
compression excipient (and other excipients),
lubricated, and compressed.
• If the drug content is less than (approximately) 20%
then the tablet will (generally) have the properties of the
direct compression ingredient.
• At higher percentages, direct compression is usually
only feasible if the drug substance itself is fairly
compressible. (i.e., has a low elastic limit)
• The hardness of a tablet will be a function of the
strength of the bond and the number of bonds.
• Hence it is the average bond density and the standard
deviation of the bonds that are really of importance.
• Tablets require a certain amount of resistance to friability, to
withstand mechanical shock of handling in manufacture,
packaging, and shipping.
• The lab friability tester is known as ROCHE FRIABILATOR.
• Pre-weighed tablets is placed in friabilator, which is then
operated for 100 revolutions.
• The tablets are then dusted and reweighed.
• Tablets that lose less than 0.5%-1.0% of their weight are
generally considered acceptable.
• Softening can be associated with chemical interaction.
• Several furoic acids when tableted with microcrystalline
cellulose, will cause a specific interaction leading to the
formation of carbon monoxide (rather than
decarboxylation of the acid).
• This interaction is not slow at 550c, and it causes the
tablets to crumble. At room temperature the effect is
• Since a tablet, when produced, is not in equilibrium,
there will be a redistribution of moisture. 10
• This could make the bonds of a lower or a higher
moisture content, and there may for this reason be a
change in hardness during a fairly short period of time
• The moisture content of granules, when they are made
initially, is a function of their particle size.
• When granules are dried, each is associated with one
given drying time, t*.
• Since the drying is a diffusional process, conventional
diffusion theory predicts that the amount of moisture left
in a granule m, in relation to the initial amount m0, is
given to a first approximation where D is the diffusion
coefficient of water in the granule and a is its diameter.
• The larger granules will have a higher moisture content
at the beginning, but the moisture will equilibrate on
• It is of interest, in cases where moisture equilibrates and
causes change in hardness on storage, to be able to assess
the extent of moisture transfer within the tablet.
• However, Zoglio et al. (1975) have shown that in some
cases (spray dried sucrose granules) there will be no
redistribution of moisture between larger and smaller
• In such cases (Shepky, 1974), the thermogravimetric
method may be of advantage.
• With a tablet designed to contain a specific amount of drug in a
specific amount of tablet formula, the weight of the tablet being
made is routinely measured to help ensure that a tablet contain
the proper amount of drug.
• The USP weight variation test is run by weighing 20 tablets
individually, calculating the average weight, and comparing the
individual tablet weight to the avarage.
• The tablet meet the test if NMT 2 tablets are outside the
percentage limit and if no tablet differs by more than 2 times the
Avg. wt. of tablet Maxx % diff. allowed
130 or less 10
More than 324 5
• Tablets (whether coated or not) are usually subjected to
a disintegration test.
• The disintegration was the first in-vitro test used by the
U.S.P. It is now not obligatory compendially (but is
recommended); it has been replaced by the dissolution
• Hence, it is the more important test, but it will be seen
that there often is a correlation between the two, and
since the disintegration test is much more easily carried
• Disintegration of a tablet is a function of a several
• If the tablet disintegrates by virtue of a disintegrant which
expands, once it is wetted, then the most important
attribute is the rate at which the disintegrating liquid
penetrates the tablet, and hence the contact angle
between the solid and the liquid is of importance.
• The dissolution apparatuses
usually used are USP type-1
(basket) or USP type-2 (paddle).
• Dissolution testing of
pharmaceutical products is
carried out for several different
• In the early stages, the intent of
dissolution testing is to get a feel
for comparative estimated 17
• In preformulation, intrinsic dissolution rate constants
are usually estimated.
• Although it is not possible, in a direct manner, to tie this
in with an estimated bioavailability, it gives a feel for
whether the drug substance will be exceedingly
problematic, or (in rare cases) not problematic.
• This feel is comparative with the intrinsic dissolution
properties (obtained in a similar fashion) for other drug
substances previously developed.
• When a solid is compressed, then one might imagine
that at „full‟ compression, the tablet would be similar
to a perfect crystal, in that there would be no void space
left in it.
• This may be visualized as isolated pockets of void
space or, as the porosity increases, strings of void,
eventually terminating at the surface.
• The porosity at which latter situation is achieved is
denoted the threshold value.
• Threshold value for a drug & its excipients in
combination are important because they govern such
properties as dissolution, hardness & disintegration.
• In this concept, a cluster is defined as a group of
nearest neighbour sites where all positions consist of
the same component.
• There is a concentration where there is maximum
probability that the cluster will start to percolate, & this is
the percolation threshold.
Raw Materials for Capsules :
• The raw materials used in the manufacture of both hard
and soft gelatin capsules are similar.
• Both contain gelatin, water, colorants and optional
materials such as process aids and preservatives.
• soft gels are made up of gelatin, plasticizer, and
materials that impart the desired appearance (colorants
and/or opacifiers), and sometimes flavors.
• Gelatin is the major component of the capsules and
has been the material from which they have
traditionally been made.
• Gelatin has been the raw material of choice because
of the ability of a solution to gel to form a solid at a
temperature just above ambient temperate conditions,
which enables a homogeneous film to be formed
rapidly on a mould pin.
• Gelatin is a translucent brittle solid substance,
colorless or slightly yellow, nearly tasteless and
odorless, which is created by prolonged boiling of22
• Type A gelatin is derived from an acid-treated precursor
and exhibits an isoelectric point in the region of pH 9,
whereas type B gelatin is from an alkali-treated
precursor and has its isoelectric zone in the region of
Physical properties of gelatin :
• Gelatin is a protein product produced by partial
hydrolysis of collagen extracted from skin, bones,
cartilage, ligaments, etc.
• Gelatin melts when heated and solidifies when cooled23
• The colorants that can be used in capsules are of two
types: water soluble dyes, or insoluble pigments or
• Colorants can be either synthetic or natural, and are
used to impart the desired shell color for product
• Three most commonly used dyes are erythrosine,
indigo carmine and quinolone yellow.
• The two types of pigments used are iron oxides- black, red
and yellow and titanium dioxide which are white and used to
make the capsule opaque.
• Interaction of dyes and gelatin in capsule shells, especially
under light, could change the rate of drug release from
3. Process aids
• Preservatives and surfactants are added to the gelatin
solution during capsule manufacture to aid in
• Gelatin solutions are an ideal medium for bacterial
growth at temperatures below 55 c.
• Preservatives are added to the gelatin and colorant
solutions to reduce the growth of micro-organisms until
the moisture content of the gelatin film is below 16%
w/v. at moisture content below that value, the bacterial
population will decline in numbers with time.
• The materials used as preservatives include :
Sulphur dioxide which is added as the sodium salts bisulfite or
metabisulfite, sorbic acid or the methyl propyl esters of para
hydroxy-benzoic acid, and the organic acids, benzoic and
4. 4. Plasticizers
These are used to make the softgel shell elastic and
pliable. They usually account for 20-30%.
The most common plasticizers used in softgels is
glycerol, although sorbitol and propylene glycol are
used frequently often in combination with glycerol.
The amount and choice of the plasticizer contribute to
the hardness of the final product and may even affect
its dissolution or disintegration characteristics, as well
as its physical and chemical stability.
The choice of plasticizer & concentration is important in
ensuring optimum compatibility of shell with liquid fill
5. 5. Water
Water is the essential component of the soft gel shell &
usually accounts for 30-40 % of the wet gel formulation
and its presence is important to ensure proper
processing during gel preparation and softgel
Following encapsulation, excess water is removed from
the softgels through controlled drying. In dry gels the
equilibrium water content is typically in the range 5-8%
w/w, which represents the proportion of water that is
bound to the gelatin in the soft gel shell.
This level of water is important for good physical
stability, because in harsh storage conditions softgels
will become either too soft and fuse together, or too
6. 6. Opacifiers
An opacifiers are typically used in the wet gel
An opacifier, usually titanium dioxide may be added to
produce an opaque shell when the fill formulation is a
suspension, or to prevent photo degradation of light-
sensitive fill ingredients.
Titanium dioxide can either be used alone to produce
a white opaque shell or in combination with pigments
to produce a colored opaque shell.
Properties of empty capsule
Empty capsules contain a significant amount of water
that acts as a plasticizer for the gelatin film and is
essential for their function.
The standard moisture content specification for hard
gelatin capsules is between 13 % w/w and 16 % w/w.
The moisture content can be maintained within the
correct specification by storing them in sealed
containers at an even temperature.
Capsules are readily soluble in water at 37 C. When
the temperature falls below this, their rate of solubility31
Types of materials for filling into hard gelatin
Dry solids – powders, pellets, granules or tablets
Semi-solids – suspensions or pastes
Liquids – non-aqueous liquids
Types of excipients used in powder-filled capsules :
A. Diluents – usually present in the greatest concentration to
make up necessary bulk when quantity of active ingredient
is insufficient to make up the required bulk eg. Lactose,
maize starch, ca. sulfate etc.
B. Lubricants and Glidants – reduce powder to metal
adhesion and promote flow properties eg. Magnesium
C. Wetting agents – improve water penetration for poorly32
Quality control of capsules
• The hard and soft gelatin capsules should be
subjected to following tests for stability.
Size and shape
Thickness of capsule shell
Leaking test for semi-solid and liquid ingredients
from soft capsules
Weight variation test
Percentage of medicament test
1. Disintegration test
The disintegration of capsules is different from those of
tablets because the determination of end point is
difficult owing to the adhesive nature of shell.
The shell pieces after disintegration may agglomerate
forming large mass of gelatin taking more time to
dissolve and may adhere to the mesh thus, blocking the
According to USP, place one dosage unit in each of the
tubes of the basket with water or any other specified
medium (depends on individual monograph) maintained35
Attach a removable wire cloth with a plain square weave of
1.8-2.2 mm of mesh aperture and a wire diameter of 0.60-
0.655 mm to the surface of upper rack of the basket
Observe the capsules for a time limit (specified in individual
monograph), at the end of prescribed time, all of the
capsules must have been disintegrated excluding the
fragments from the capsule shell.
If 1 or 2 capsules fail, the test should be repeated on
additional of 12 capsules.
Then, not fewer than 16 of the total 18 capsules tested
should disintegrate completely.
Place each of the capsules in the apparatus 1, excluding air
bubbles from the surface of the capsule. Operate immediately
at specified rate within specified dissolution medium at 37 +
0.5C. Aliquots should be withdrawn at specified time points
mentioned in individual monograph.
The requirements are met if the quantity of active ingredients
dissolved conforms the following:
At stage 1 (S1): When 6 capsules are tested, amount of each
of the dissolved content should not be less than +/- 5% of the
mentioned in monograph.
At stage 2 (S2): when 6 capsules are tested, the average of 12
(both from step 1and 2) should be equal to or greater than 15%
and no capsule should be greater than 15%. 37
At stage 3 (S3): when 12 capsules are tested, the average of
24 capsules (all 1,2 and 3 steps) should be equal to or greater
than the amount mentioned in the monograph, not more than
two units are less than 15% and no unit s less than 25%.
NOTE: 15%, 25% represent Q1 and Q2 unless and
otherwise mentioned in the monograph.
2. Weight variation test
• 20 capsules are taken at random and weighed. Their
average weight is calculated, then each capsule is
weighed individually and their weight noted.
• The capsule passes the test if the weight of individual
capsule falls with in 90-110% of the average weight.
• If this requirement is not met, then the weight of the
contents for each individual capsule is determined and
compared with the average weight of the contents.
• The contents from the shells can be removed just by
emptying or with the help of small brush.
• From soft gelatin capsules the contents are removed
by squeezing the shells which has been carefully cut.
The remainder contents are removed by washing with
a suitable solvent.
• After drying the shells, they are weighed and the
content weights of the individual capsules are
• The requirements are met if :
(1) not more than 2 of the differences are greater than 10
% of the average net content and
(2) in no case the difference is greater than 25 %. 40
3. Content uniformity test
Hard capsules containing 25 mg or more of the drug
contents should meet content uniformity
Assay 10 capsules individually and calculate the
The requirement is met if the acceptance value of 10
capsules is less than or equal to 15%. If acceptance
value is greater than 15% or is about 25 % then, test
the next 20 units and calculate the acceptance value.
The 30 capsules if less than or equal to 15% (i.e 185-
115) and no individual unit is outside 25%, (i.e 175-
125) capsule passes the test.
• Raw materials
• The gelatin of the capsule shells should be assayed for
various physical properties like bloom strength, viscosity and
its loss (by atomic force microscopy).4 Chemical tests like
purity, microbial properties, and limits for heavy metals like
arsenic, ash content should be determined.
• The colorants should also be checked for purity, limits for
heavy metals, color properties, dye content, subsidiary dye
content and color value.
• The gel strength of gelatin is a measure of the cohesive
strength of the cross-linking that occurs between gelatin
• Bloom is determined by measuring the weight in grams
required to move a plastic plunger that is 0.5 inches in
diameter 4mm into 6.66%gelatin gel that has been held at
100C for 17hrs.
• Bloom may vary with the requirements, ranges from 150 to
• The higher the Bloom strength of gelatin used, the more
physically stable is the resulting capsule shell.
Viscosity of gelatin 43
• Unprotected soft capsules (i.e., capsules that can
breathe) rapidly reach equilibrium with the atmospheric
conditions under which they are stored.
• The variety of materials capsulated, which may have
an effect on the gelatin shell, together with the many
gelatin formulations that can be used, makes it
imperative that physical standards are established for
• The physical stability of soft gelatin capsules is
associated primarily with the pick-up or loss of water by
the capsule shell. 44
• If these are prevented by proper packaging, the above
control capsule should have satisfactory physical
stability at temperature ranging from just above
freezing to as high as 60 C, for the unprotected control
capsule, low humidities (less than 20 % RH), low
temperature (less than 2 C) and high temperatures
(greater than 38 C) or combinations of these
conditions have only transient effects.
The effect of temperature and humidity on capsule shell has been
shown in Table below :
• The capsule manufacturers routinely conduct
accelerated physical stability tests on all new capsule
products as an integral part of the product
• The following tests have proved adequate for
determining the effect of the capsule shell content on
the gelatin shell.
• The tests are strictly relevant to the integrity of the
gelatin shell and should not be confused as stability
tests for the active ingredients in the capsule content.
• The results of such tests are used as a guide for the46
• The test conditions for such accelerated physical
stability tests are shown in Table below :
PARTICLE SIZE & SHAPE
Size affects the average weight of tablet, DT,
wt. variation ,friability, flowability & drying rate.
The size & shape depends upon processing requirements &
The methods for determining size & shape are
4.By light scattering
It is not commonly used for granules but generally used for
If required particle size is measured & from this surface area
Most method used is gas absorption & air permeability.
In gas absorption, gas is absorbed as monolayer on
particles this is in term of calculated & converted to surface
In air permeability method the rate of air permeates a bed of50
Density may influence compressability,tablet porosity &
Dense hard granules may require higher load to produce
cohesive compact to reduce free granules seen on the
surface of tablets.
↑ compressibility ↑ DT, Dissolution, if DT is slower
dissolution is indirectly hampered.
Dense granules have less friability but cause a problem in
releasing the drug. 51
Methods to determine density:-
-Any solvent of low surface tension e.g.
Liquids should not masks granules solubilies in it, & having
property to penetrate the pores.
Density is then determine from volume of intrusion fluid
displaced in pycnometer by giving mass of granulation
Density (D) = M/ Vp-Vi
Vp - Total volume of pycnometer
Vi - vol. of intrusion fluid containing mass(M)
req. to fill pycnometer.
2. Bulk Density:-
Bulk density is given by equation
ρb = M/ Vb
More compressible bed of particulate less flowable
If less dense compressible more flowable
Granule strength and friability
They are important because they affect:-
1.changes in particle size distributions of
2.compressibility into cohesive tablets.
Granule strength & friability are measured by:-
2.Using Friability measurements
It is an ability of the granule to flow from hopper to die cavity
for tablet uniformity.
Flow property of granule are not uniform we are not getting
tablet of uniform size.
Flow property of material results from many forces
2.Surface tension force
3.Mechanical force caused by interlocking of irregular shape
5.Cohesive/ vander Waals forces
Forces also affect granule property such as particle size,
particle size distribution, particle shape, surface texture,
roughness & surface area.
If particle size of powder is ≤ 150µm the magnitude of
frictional & vander waals force predominate.
When particle size↑ mechanical & physical properties
become more important with packing properties.
In fig.(1) height is constant & powder is added through the
hopper until powder reaches tip of funnel.
In fig.(2) height is varied & base cone is fixed, powder is
added until height reaches at max.
In fig.(3) rectangle box is filled with powder & tipped until
content begins to slide.
In fig.(4) revolving cylinder with transparent end is made to
revolve horizontally when half filled with powder.
The max. angle that the plane of powder makes with
horizontal surface on rotation is taken as the angle of
• (1),(2) & (3) gives static angle of repose. While (4) gives
kinetic or dynamic angle of repose.
Angle of repose
• The angle of repose is the angle formed by the horizontal
base of the bench surface and the edge of a cone-like pile of
granules. Funnel used was a stainless steel funnel and the
size of the orifice was 10 mm and the height from the
beginning of funnel to end of orifice was 111 mm. The funnel
was fixed in place, 4 cm above the bench surface. After the
cone from 5 g of sample was built, height of the granules
forming the cone (h) and the radius (r) of the base were
measured. The angle of repose (θ) was calculated as
Ɵ value Flow property
Less than 30 Excellent flow
31 – 35 Good
36 - 40 Fair
41 – 45 Passable which may hang up
46 - 55 Poor which must be agitated or
greater than 56 Very poor
The amount of moisture present in the granule is called
Generally the granules contain 2% moisture. It is required
for the binding of the powder or granules during
compression in die cavity.
Percentage of moisture is calculated by using “moisture
Balance” or “IR Balance”.
IR Balance consist of simple balance which is placed I to the
casing in which the IR bulb is attached which produce heat61
The small amount of sample taken from oven to measure
moisture content & place in the moisture balance.
Initial reading should be note down after that we are initiated
the IR Bulb as IR bulb is initiated the moisture is removed
from the granules via heating after that note down the
% of moisture is calculated by,
% moisture content = Initial wt.- Final wt.
% fines means amount of powder remain in the granule.
Generally the amount is 15% of fines.
It is necessary for the tablet compression because if we are
using 100% granules then it is difficult to maintain hardness
of tablet because they having free space in the die cavity
after compression the tablet is crack due to air.
% fine can be calculated by using sieve method.
%fine should not be more than 15%.
1) Drug Stability, Principles and Practices, 3rd
edition, volume-107, edited by Jens T.
Carstensen, C. T. Rhodes
4) The theory and practice of industrial pharmacy,
3rd edition, edited by Leon Lachman.