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Quality control of solid dosage form

A) Physical tests**
Physical tests Chemical tests

 Hardness 1. Content uniformity

 Tablet thickness
2. Assay of Active ingredient
and diameter
3. Dissolution
 Friability
 Weight variation
 Disintegration

Official Tests: Weight variation, disintegration, dissolution, content of drug

Non-Official Tests: Hardness, friability.

1. Hardness (crushing strength):

It is the load required to crush the tablet when placed on its edge.

Q. Why do we measure hardness?

• To determine the need for pressure adjustments on the tableting machine.

• Hardness can affect the disintegration. So if the tablet is too hard, it may not disintegrate in the required period
of time & ultimately bioavailability is affected. And if the tablet is too soft, it will not withstand the handling during
subsequent processing like coating, packaging & shipping/ transportation.

Normally tested by mechanical tester. Now a days with automatic operation.

Common hardness tester.

Strong-Cobb; Stokes-Monsanto33; Eureka; Pfizer units
Q. How a mechanical tester works?
Procedure:
 Mechanical tester measures resistance to crushing of a tablet
 Force is applied by a beam
 One end of beam is attached to pivot, controlled mechanically by motor
 Other end rests on tablet
 Motor moves the beam which apply force on tablet when tablet breaks a micro switch stops the motor
 Breaking strength is shown by digital indicator

 Hardness Variation:

It depends on:

o force of compression,

o concentration and type of binding agent

o method of tablet preparation

o If the tablet initially is too hard, it may not disintegrate in the requisite period of time.

o If it is too soft, it may not withstand the necessary multiple shocks occurring during handling, shipping, and
dispensing.

o If a tablet is too hard, first check the disintegration. If it is in limits then the batch or lot is passed

Acceptable hardness range Newton is 5-10 Kg/cm 2

I Kg = 9.8 Newton

I Newton =0.102 Kg

2. Tablet
Thickness and diameter
Checking of thickness and diameter is usually an in-process control during production

Dimensional specifications of tablets are important because of many reasons e.g.

i. Packaging requirements
ii. Patient compliance
iii. Thickness is often related to tablet hardness
iv. Directly affect the dissolution and assay results

Instruments used
i. Micrometer
ii. Vernier caliper
 iii. Now a days digital micrometers are available

VinSyst tablet thickness & diameter tester

3. Friability
Friction and shock during tableting can cause tablets to chip, cap or break.

It is normally applied to uncoated tablets

Loss of weight due to abrasion or friction is the measurement of friability of tablet.

B.P.2007
 Roche Friability tester

o Friability is determination of general compressed, uncoated tablets

o Conforms other physical tests, such as tablet breaking force.
o Use drum of transparent synthetic polymer with polished internal surfaces with minimum static build up
o Internal diameter of drum is between 283-291 mm and a depth between 36-40 mm
o Curved projection having an inside radius between 75.5-85.5 mm, tumbles the tablets
o It extends from the middle of the drum to the outer wall.
o One side of the drum is removable.
o The outer diameter of the central ring is between 24.5-25.5 mm.
o Drop height of the tablet is 156.0 mm ± 2.0 mm
o The horizontal axis of a device rotates at 25 ± 1 rpm.
o At each turn the tablets roll or slide and fall onto the drum wall or onto each other.
o It the unit mass is equal to or less than 650 mg, take a sample of whole tablets corresponding as near as possible to
6.5 g.
o Take a sample of 10 whole tablets with a unit mass of more than 650 mg.
o The tablets are carefully dedusted prior to testing.
o Accurately weigh the tablet sample, and place the tablets in the drum.
o Rotate the drum 100 times, and remove the tablets. Remove any loose dust from the tablets as before, and
accurately weigh.

Generally, the test is performed once.

o If visibly cracked, cleaved, or broken tablets are present in the tablet sample after tumbling, the sample
fails the test.
o If the results are difficult to interpret or if the weight loss is greater than the targeted value, the test is
repeated twice and the mean of the 3 tests determined.
 Test complies if a maximum loss of mass (obtained from a single test or from the mean of 3 tests) is not greater
than 1.0 per cent of the total weight.
If tablet size or shape causes irregular tumbling, adjust the drum base so that the base forms an angle of about 10°
with the horizontal and the tablets no longer bind together when lying next to each other, which prevents them from
falling freely.

Note: Effervescent tablets and chewable tablets may have different specifications as far as friability is concerned. In the
case of hygroscopic tablets, a humidity-controlled environment is required for testing.

4. Weight Variation test

The weight variation test would be a satisfactory method for determining drug content uniformity of drug distribution.
Actual weight of tablet is affected by the diameter of the punch & die and weight adjustment cam on tablet
compression machine. Weight control on a tablet is continuously checked and adjusted during compression of tablets
of the whole batch. Normally done on uncoated tablets/(core tablets).

USP Specification
Average weight of tablet Percentage Percentage
deviation deviation
Permissible Unacceptable
± 10.0 % ± 20 %
130 mg or less than 130 mg
(90-110) % (80-120) %
± 7.5 % ± 15 %
More than 130 mg and less than 324 mg
(92.5-107.5)% (85-115)%
± 5.0 % ± 10 %
More than 324 mg
(95-105)% (90-110)%
Not an individual unit should exceed twice of the permissible limit ***** *****
 BP Specification
Average weight of tablet Percentage Percentage
deviation deviation
Permissible Unacceptable
± 10.0 % ± 20 %
80 mg or less than 80 mg
(90-110) % (80-120) %
± 7.5 % ± 15 %
More than 80 mg but less than 250 mg
(92.5-107.5)% (85-115)%
± 5.0 % ± 10 %
250 mg or more than 250 mg
(95-105)% (90-110)%
Not an individual unit should exceed twice of the permissible limit ***** *****
Procedure
 take 20 tablets and calculate the weight if an individual tablet
 Total weight of 20 tablets directly and by summing up the individual weight already determined to avoid the
performance error.
 calculate average weight the tablet (Avg. weight=weight of 20 tablets/20)
 apply the factor of weight variation according to the actual weight of the individual tablet
 not more than two of the individual weights deviate from the average weight by more than percentage shown
in the table and none of deviates more than twice that percentage.
 If the active drug forms greater part of the tablet more than ≥25 mg and ≥25% of the total weight of an
individual unit weight variation can be applied.
 Conversely content of uniformity is necessarily applied.

5. Disintegration Test:
a. Types of tablets for oral use which are subjected disintegration/dissolution test according to
monograph of International Pharmacopoeia; European Pharmacopoeia (Ph. Eur) ; British
Pharmacopoeia (B.P). or United States Pharmacopoeia (U.S.P.)/National Formulary (NF)
b. uncoated tablets;
c. coated tablets;
d. effervescent tablets;
e. soluble tablets;
f. dispersible tablets;
g. orodispersible tablets;
h. gastro-resistant tablets;
 i. modified-release tablets;
j. Tablets for use in the mouth.

6. Disintegration is the time required for a dosage form to break up in to granules of specified size
(or smaller) under carefully specified conditions of the monograph of that unit dosage form. In
disintegrated state any residue of the unit tablet/capsule, except fragments of insoluble coating or
capsule shell, remaining on the screen of the test apparatus is a soft mass having no palpably firm core.

Apparatus; The apparatus consists of a basket-rack assembly,

 1 litre, low-form beaker, 149 ± 11 mm in height and having an inside diameter of 106 ± 9 mm for the immersion fluid,
 a thermostatic arrangement for heating the fluid between 35 °C and 39 °C,
 a device for raising and lowering the basket in the immersion fluid at a constant frequency rate between 29 and 32 cycles
per minute, through a distance of 55 ± 2 mm.
 The volume of the fluid in the vessel is such that at the highest point of the upward stroke the wire mesh remains at least
15 mm below the surface of the fluid,
 Which descends to not less than 25 mm from the bottom of the vessel on the downward stroke.
 At no time should the top of the basket-rack assembly become submerged.
 The time required for the upward stroke is equal to the time required for the downward stroke,
 the change in stroke direction is a smooth transition, rather than an abrupt reversal of motion.
 The basket-rack assembly moves vertically along its axis.
 There is no appreciable horizontal motion or movement of the axis from the vertical.

Basket-rack assembly 
 The basket-rack assembly consists of 6 open-ended transparent tubes, each 77.5 ± 2.5 mm long and having an inside
diameter of 21.85 ± 1.15 mm and a wall 1.9 ± 0.9 mm thick;
 the tubes are held in a vertical position by 2 plates, each 90 ± 2 mm in diameter and 6.75 ± 1.75 mm in thickness,
 Plates have 6 holes, each 24 ± 2 mm in diameter, equidistant from the centre of the plate and equally spaced from one
another.
 Attached to the under surface of the lower plate is a woven stainless-steel wire cloth, which has a plain square weave with
2.0 ± 0.2 mm mesh apertures and with a wire diameter of 0.615 ± 0.045 mm.
 The parts of the apparatus are assembled and rigidly held by means of 3 bolts passing through the 2 plates.
 A suitable means is provided to suspend the basket-rack assembly from the raising and lowering device using a point on its
axis.

The design of the basket-rack assembly may be varied somewhat provided the specifications for the glass tubes and the screen
mesh size are maintained.

The basket-rack assembly conforms to the dimensions shown in Figure 2.9.1.-1. British pharmacopoeia

Condition:
 Temperature 37 ± 2o C.
 Movement: Upward and downward
 On upward movement tablets should remain 2.5cm below the surface of liquid and on downward movement
tablets should remain 2.5 cm above the bottom of fluid containing vessel
 Distance 5-6cm
 Speed… 28-32 cycles per minute
Uncoated tablets
 Place one tablet in each tube, add a disc to each tube
 Water as immersion fluid unless specified
 At the end of time specified, lift the basket, observe the tablets
 All tablets should disintegrate
 If one or 2 fail to disintegrate, repeat with 12 more tablets. 16 out of 18 tablets should disintegrate completely.
 USP------ less than 30 minutes
 BP------ less than 15 minutes

Plain Coated Tablets

 Place one tablet in each tube,
 Add disc to each tube. Simulated gastric fluid as immersion fluid
 After 30 minutes, lift the basket, observe the tablets
 All tablets should disintegrate
 If one or 2 fail to disintegrate, repeat with 12 more tablets. 16 out of 18 tablets should disintegrate completely.
 Film coated tablets ----------------------- NMT 30 minutes
 Sugar coated tablet---------------------- NMT 60 minutes

Enteric Coated Tablets

 If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an
enteric coating can be used, which is resistant to stomach acid, and dissolves in the less acidic area of the
intestines.
 Place one tablet in each tube,
 If soluble coating first immerse the assembly in water for 5 minutes at room temp.
 Operate without the discs with Simulated gastric fluid (0.1N HCl buffer solution of pH 1.2) as immersion
fluid
 After (1 hour-USP; 2 hours-BP) , lift the basket, observe the tablets
 No tablets should disintegrate or show cracks in the coating after (1 hour-USP; 2 hours-BP)
 Replace the disintegration medium with simulated intestinal fluid (phosphate buffer of pH 6.8 to use as
SIF). and add disk accordingly.
 After (45 minutes-USP; 1 hour-BP), lift the basket, observe the tablets
 All tablets should disintegrate completely
 If one or 2 fail to disintegrate, repeat with 12 more tablets. 16 out of 18 tablets should disintegrate
completely after 3rd hour.

Buccal and Sublingual tablets

 Same procedure as for uncoated tablets
 Only the use of discs is omitted
 Time is specified in the monographs
 Buccal Tablets (4 hours)
 Sublingual Tablets (2- 3 minutes)
Chewable coated tablets are not required to comply with the test.
Effervescent tablets
 Place 1 tablet in a beaker containing 200 ml of water R at 15-25 °C;
 Numerous bubbles of gas are evolved.
 When the evolution of gas around the tablet or its fragments ceases the tablet has disintegrated,
 Being either dissolved or dispersed in the water so that no agglomerates of particles remain.
 Repeat the operation on 5 other tablets.

The tablets comply with the test if each of the 6 tablets used disintegrates in the manner prescribed within 5 min,
unless otherwise justified and authorized.

B) Chemical Tests:
1) Content uniformity test
• The content uniformity test is to ensure that every dosage form contains equal amount of drug substance i.e.
active pharmaceutical ingredient within a batch.

Procedure:
 Randomly select 30 tablets.

 Ten of these are crushed and assayed individually.

 All 10 tablets must contain not less than 85% and not more than 115% (±15 %) of the labeled drug content

 If one but not more than one falls out of ±15 % range but within ±25 %, then assay remaining 20 tablets.

 The requirements are met if not more than 1 of the 30 tablets results is outside the limits of 85-115%

Dose and ratio of the API

≥ 25mg or ≥ 25 % of the total weight < 25mg or < 25 % total weight
Uncoated Weight Variation Content of Uniformity

Film Coated Weight Variation Content of Uniformity

Other Coating Content of Uniformity Content of Uniformity

Note: Always follow the official monograph of pharmacopoeia or the approved method of testing by Drug Registration
Board
2) Assay:
 Grind 20 tablets in pestle and mortar.

 Take an aliquot (sample) equivalent to fundamental molecule (Base Value), representing a certain amount of
drug normally in a single unit.

 Dissolve in the appropriate diluent.

 Prepare the required dilution according to official method.

 Analysis performed as prescribed in monograph using one of the following methods

 Results obtained are expressed in percentages of the active pharmaceutical ingredient as claimed in the label of
the product and compared with the limits specified in monograph

Common Assay procedure involves:

 Titrimetric methods
 Potentiometric Titration
 Spectroscopic method
 UV spectroscopy
 HPLC
 Gas Chromatography
 Gravimetric assay
 Biological assay
 Microbial assay

3) Dissolution Test
 Solubility is a property of a solute which decides how far the solute would dissolve in a solvent to form a
particular solution under specified conditions.

Dissolution is the process where a solute dissolve in a solvent to form a solution.

 The effectiveness relies on the drug dissolving in the fluids of the gastrointestinal tract prior to
absorption into the systemic circulation
 Tablet Dissolution is a standardized method for measuring the rate of drug release from a dosage form.
 Drug dissolution testing is routinely used to provide critical in vitro drug release information.
 for quality control purposes, i.e., to assess batch-to-batch consistency of solid oral dosage forms such
as tablets, capsules (solid/soft gelation), granules
 For drug development, i.e., to predict in vivo drug release profiles.
 For evaluation of bioavailability
Dissolution rate: It may be defined as the amount of drug substance that goes into solution per unit time under
standardized conditions depends upon

 depends upon
 liquid/solid interface,
 temperature of medium
 solvent composition
 force/agitation

As drug absorption and physiological availability are largely dependent upon having a drug in dissolved state, so
suitable dissolution characteristics are important property of a satisfactory drug product.

Apparatus-1 (Basket Type):

 1000 ml cylindrical vessel with a slightly concave bottom made of glass or other inert transparent material
(height 16 cm, inside diameter 10 cm).
 Fittable cover having 4 ports. Shaft motor in center port, one of outer port for thermometer, other two for
removal and replacement of sample from medium.
 A variable speed motor attached with speed regulating device (25 rpm- 200 rpm). Motor may be raised and
lowered to position the basket.
 Shaft (rod) 30 cm in length and 6 mm thick
 small stainless steel wire mesh (40 mesh) basket. 3.66 cm high and 2.5 cm diameter.
 Water bath (temperature 37o ±0.5o C).

 Dissolution media: As specified in the monograph.500 ml or 900 ml

 Dissolution media placed in vessel which is previously immersed in bath. Allow the dissolution media to come
to a temp. 37o ±0.5o C.
 Place 1 tablet in the basket and attach to shaft and immerse the basket in the media so that a distance of 2.0
±0.2 cm between bottom of vessel and basket.
 Rotate at speed as specified in monograph usually 50-100 rpm
 Sample is withdrawn at specified interval and immediately replace with same quantity of fresh media.
 Samples are then filtered and analyzed.
 %age of drug dissolved is determined and compared with requirements specified.
 Test performed on 6 tablets. If 1 or 2 tablets fail to meet requirements of Q value (extent of dissolution), repeat
with 6 more tablets. Not less than 10 out of 12 tablets should meet requirements specified in monograph.


What is the difference between dissolution and disintegration?
 Disintegration time is the time required for a dosage form to break up in to granules of specified size
(or smaller) under carefully specified conditions.
 Whereas dissolution is a process by which solid substance enters in the solvent to yield a solution.

Apparatus-2 (Paddle Type ):

 It is same as apparatus-1, except the basket is replaced with a paddle.
 The dosage form is allowed to sink to the bottom of the flask before stirring.
 Apparatus 1 is superior to apparatus 2 for non-disintegrating tablets and floating tablets (helix as a sinker may
be used for floating tablets in case of apparatus 2)
 Inferior in case of tablets contains gums------ may clog to the mesh