UNIT 1

Introduction IPQC and

Dose Variation of Tablets
 UNIT 1

UNIT 1
Introduction to
In-Process Quality Control Test

In-process quality control may be performed at regular intervals during a process step or at the end of a process step.
The tests allow the formulation scientist to identify and follow all changes that may occur during applied technological
procedures. It gives the formulation scientist security that the finished products fulfil all quality requirements, most of all that all
the products should be safe for the patients.

In tablet formulation development and during manufacturing of tablet dosage forms, a number of quality control
tests are performed.

PHARMACOPOEIAL OR OFFICIAL TESTS NON-PHARMACOPOEIAL OR NON-OFFICIAL TESTS

Content of Active Ingredient/ Absolute Drug Content Test Tablet hardness or Crushing Strength Test
Content Test Friability Test
Uniformity of Content Tablet thickness
Uniformity of Weight
Disintegration Time Test
Dissolution Test

UNIT 1
WEIGHT VARIATION

WHAT IS WEIGHT VARIATION?

Tablet weight is mainly affected by factors such as tooling of the compression machine, head pressure, machine
speed and flow properties of the powder. Inconsistent powder or granulate density and particle size distribution are common
sources of weight variation during compression.

Variation between tablet with respect to dose and weight must be reduced to a minimum. Uniformity of weight is an
in-process test parameter which ensures consistency of dosage units during compression.

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UNIT 1

WHAT EQUIPMENT DO WE USE?

Digital Balance

HOW IS WEIGHT VARIATION COMPUTED?

1. Weigh 20 tablets selected at random and record their weight.

2. Determine the average weight.

3. Not more than 2 of the individual weights should deviate from the average weight by more than the % deviation
given on the table below and none deviates by more than twice that %.

Deviation % = Average weight - weight of tablet/ average weight X 100

WHAT ARE THE ACCEPTANCE VALUES?

USP STANDARDS MAXIMUM % DIFFERENCE ALLOWED IP STANDARDS

130 mg or less +-10% 84 mg or less
130 mg – 324 mg 84 mg – 250 mg
+-7.5%
More than 325 mg +-5% More than 250 mg
* weight variation tolerance for uncoated tablets

WHAT ARE THE FACTORS AFFECTING

WEIGHT VARIATION?

1. Compression of the tablet and compressive force.

2. Amount of binder
3. Method of granulation in preparing the tablet.

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UNIT 1
CONTENT UNIFORMITY

WHAT IS CONTENT UNIFORMITY?

Content uniformity test was developed to ensure content evenness of active drug substances within a narrow
range around the label claim in dosage units.

This test is crucial for tablets having a drug content of less than 2 mg or when the active ingredient comprises less
than 2% of the total tablet weight.

WHAT EQUIPMENT DO WE USE?

HOW IS CONTENT UNIFORMITY

COMPUTED?

1. 30 tablets are randomly selected.

2. 10 of these tablets are assayed individually according to the method described in the individual monograph
3. the requirements for content uniformity are met if the amount of active ingredient in nine (9) of the ten (10) tablets
lies within the range of 85% to 115% of the label claim

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UNIT 1
WHAT ARE THE ACCEPTANCE VALUES?

By the USP method, 30 tablets are randomly selected, 10 of these tablets are assayed individually according to the
method described in the individual monograph. Unless otherwise stated in the monograph, the requirements for content
uniformity are met if the amount of active ingredient in nine (9) of the ten (10) tablets lies within the range of 85% to 115%
of the label claim. The tenth tablet may not contain less than 75% or more than 125% of the labelled drug content.

If one or more dosage units do not meet these criteria, the remaining 20 tablets are assayed individually and none
may fall outside of the 85% to 115% range for the batch to be accepted.

WHAT ARE THE FACTORS AFFECTING

CONTENT UNIFORMITY?

1.
2.
3.

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Unit 2 2

UNIT 2
DISINTEGRATION TEST

WHAT IS DISINTEGRATION TEST?

It is recognized generally that the in vitro tablet disintegration test does not necessarily bear a relationship to the
in vivo action of a solid dosage form. To be absorbed, a drug substance must be in solution, and the disintegration test
is a measure only of the time required under a given set of conditions for a group of tablets to disintegrate into particles.
Generally, this test is useful as a quality-assurance tool for conventional (non-sustained- release) dosage forms.

The disintegration test is used as a control for tablets intended to be administered by mouth, except for tablets
intended to be chewed before being swallowed or tablets designed to release the drug substance over a period of
time. Exact specifications are given for the test apparatus, in as much as a change in the apparatus can cause a change
in the results of the test.

WHAT EQUIPMENT DO WE USE?

Disintegration Test Apparatus

The apparatus consists of a basket-rack assembly containing six open-ended transparent tubes of USP-specified
dimensions, held vertically upon a 10-mesh stainless steel wire screen.

HOW DOES THE EQUIPMENT WORK?

The apparatus consists of a basket rack holding six plastic tubes, open at the top and bottom; the bottom of the
tubes is covered with 10-mesh screen. The basket rack is immersed in a bath of suitable liquid, held at 37°C, preferably
in a 1-L beaker. The rack moves up and down in the fluid at a specified rate. The volume of the fluid is such that on the
upward stroke the wire mesh remains at least 2.5 cm below the surface of the fluid and descends to not less than 2.5 cm
from the bottom on the downward stroke. Tablets are placed in each of the six cylinders along with a plastic disc over
the tablet unless otherwise directed in the monograph. The endpoint of the test is indicated when any residue remaining
is a soft mass with no palpably soft core. The plastic discs help to force any soft mass that forms through the screen.

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Unit 2 2
HOW IS TABLET DISTEGRATION TESTED?

1. A tablet is placed in each of the six tubes of the basket, and through the use of a mechanical device.
2. The basket is raised and lowered in a bath of fluid (e.g., water, or as prescribed in the individual drug
monograph) at 29 to 32 cycles per minute, the wire screen always below the level of the fluid. For most normal
release tablets, the time permitted is 15 minutes.
3. Tablets are said to have disintegrated if no fragments (other than fragments of coating) remains on the screen,
or if particles remain, they are soft without an unwetted core.

WHAT ARE THE SPECIFIC USP METHODS OF DISINTEGRATION?

For Uncoated Tablets:

1. Start the disintegration test on 6 tablets
2. If one or two tablets from the 6 tablets fail to disintegrate completely within 30 minutes, repeat the same test
on another 12 tablets. (the whole test will consume 18 tablets)
3. Not less than 16 tablets disintegrate completely within the time
4. If more than two tablets (from the 18) fail to disintegrate, the batch must be rejected.
For Coated Tablets:
1. To remove or dissolve the coat, immerse the tablet in distilled water for 5 minutes.
2. Put the tablet in the apparatus in water or HCl for 30 minutes at 37C. If not disintegrated, put in intestinal fluid.
3. If one or two tablets fail to disintegrate, repeat on 12 tablets. So, 16 tablets from the 18 must completely
disintegrate within the time, if two or more does not disintegrate, the batch is rejected.

For Enteric Coated Tablets:

1. Put in distilled water for 5 minutes to dissolve the coat
2. Put in simulated gastric fluid for 1 hour.
3. Put in simulated intestinal fluid for two hours.
4. If one or two tablets fail to disintegrate, repeat on 12 tablets. So, 16 tablets from the 18 must completely
disintegrate within the time, if two or more does not disintegrate, the batch is rejected.

WHAT ARE THE ACCEPTANCE VALUES?

USP/BP STANDARDS FOR DISINTEGRATION TIME TEST

TYPE OF TABLET MEDIUM TEMPERATURE LIMIT
Normal Release
15 minutes or as per individual
Tablets (Uncoated Water 37  2C
monograph
Tablets)
60 minutes or as per individual
Coated Tablets Water 37  2C
monograph
i. Simulated No evidence of disintegration after 1
Delayed-Release/ 37  2C
Gastric Fluid TS hour
Enteric-Coated
ii. Simulated
Tablets 37  2C 1 hour or as per individual monograph
Intestinal Fluid TS
Buccal Tablets Water 37  2C 4 hours or as per individual monograph
Sublingual Tablets Water 37  2C as per individual monograph

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Saint Louis University – Department of Pharmacy

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Unit 2 2

WHAT ARE THE FACTORS AFFECTING

DISINTEGRATION OF TABLETS?

1. Medium Used
2. Temperature of the test media
3. Operator’s experience
4. Nature of the drug
5. The diluent used in the formulation
6. The type and concentration of binder used
7. Type and amount of disintegrant used including the method of incorporation
8. The presence of excessive lubricants and overly mixed lubricants
9. Compressional force used.

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Unit 2 2

UNIT 2
DISSOLUTION TEST

WHAT IS DISSOLUTION TEST?

For certain tablets the monographs direct compliance with limits on dissolution rather than disintegration. Since
drug absorption and physiological availability depend on having the drug substance in the dissolved state, suitable
dissolution characteristics are an important property of a satisfactory tablet. Like the disintegration test, the dissolution
test for measuring the amount of time required for a given percentage of the drug substance in a tablet to go into
solution under a specified set of conditions is an in vitro test. It is intended to provide a step toward the evaluation of the
physiological availability of the drug substance, but as described currently, it is not designed to measure the safety or
efficacy of the tablet being tested. Both the safety and effectiveness of a specific dosage form must be demonstrated
initially by means of appropriate in vivo studies and clinical evaluation. Like the disintegration test, the dissolution test
does provide a means of control in ensuring that a given tablet formulation is the same as regards dissolution as the
batch of tablets shown initially to be clinically effective. It also provides an in vitro control procedure to eliminate
variations among production batches.

*Schematic of the drug release process from a tablet

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Unit 2 2

WHAT EQUIPMENT DO WE USE?

Dissolution Tester

HOW DOES THE EQUIPMENT WORK?

The apparatus consists of a basket rack holding six plastic tubes, open at the top and bottom; the bottom of the
tubes is covered with 10-mesh screen. The basket rack is immersed in a bath of suitable liquid, held at 37°C, preferably
in a 1-L beaker. The rack moves up and down in the fluid at a specified rate. The volume of the fluid is such that on the
upward stroke the wire mesh remains at least 2.5 cm below the surface of the fluid and descends to not less than 2.5 cm
from the bottom on the downward stroke. Tablets are placed in each of the six cylinders along with a plastic disc over
the tablet unless otherwise directed in the monograph. The endpoint of the test is indicated when any residue remaining
is a soft mass with no palpably soft core. The plastic discs help to force any soft mass that forms through the screen.

HOW IS DISSOLUTION TESTED?

USP Dissolution Apparatus I (Basket Method)

1. A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft connected to a
variable speed motor.
2. The basket is immersed in a dissolution medium (as specified in monograph) contained in a 1000 mL flask. The
flask is cylindrical with a hemispherical bottom.
3. The flask is maintained at 37  0.5C by a constant temperature bath.
4. The motor is adjusted to turn at a specified speed and sample of the fluid are withdrawn at intervals to
determine the amount of drug in solutions.

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Unit 2 2
USP Dissolution Apparatus II (Paddle Method)
1. It is the same as apparatus I, except the basket is replaced by a paddle.
2. The dosage form is allowed to sink to the bottom of the flask before stirring.

Schematic representations of Basket (left) and Paddle (right) Apparatus

USP DESCRIPTION OF THE DOSAGE FORM TO BE

IMAGE ROTATION SPEED
APPARATUS APPARATUS TESTED

Immediate-release
50 – 120 rpm tablets
I Basket (revolutions per
Delayed-release tablets
minute)
Extended-release tablets

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Unit 2 2

Immediate-release
tablets
II Paddle 25 – 50 rpm
Delayed-release tablets

Extended-release tablets

Immediate-release
Reciprocating 635 dpm (dips per tablets
III
Cylinder minute)
Extended-release tablets

Extended-release tablets
IV Flow-Through Cells N/A
Poorly soluble drugs

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Unit 2 2

V Paddle Over Disk 25 – 50 rpm Transdermal

VI Cylinder N/A Transdermal

VII Reciprocating Disk 30 rpm Extended-release tablets

*Type I and II USP apparatus are the most commonly used

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Saint Louis University – Department of Pharmacy

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Unit 2 2
HOW IS DISSOLUTION TEST CONDUCTED ON
SPECIFIC DOSAGE FORMS?

IMMEDIATE RELEASE
TABLET SUSTAINED RELEASE
CAPSULE SUPPOSITORIES
(CONVENTIONAL TABLET
TABLET)
DISSOLUTION
Type I and II (USP) Type II (USP) Type II (USP) Type I (USP)
APPARATUS

TEMPERATURE 37  0.5C 37  0.5C 37  0.5C 37  0.5C

TIME 30 minutes 7 hours 5 hours 60 minutes

TIME OF INTERVAL 5, 10, 15, 20, 25, 30 1-hour intervals 1-hour intervals 10, 20, 30, 40, 50, 60

Depending on tablet:

pH 1.2 Acidic Buffer pH 1.2 Acidic buffer pH 1.2 Acidic buffer

pH 7.4 Phosphate
MEDIA
pH 4.5 Acetate buffer pH 6.8 Phosphate pH 6.8 Phosphate buffer
buffer buffer
pH 5.8 Phosphate
buffer

RPM 75 – 100 rpm 75 – 100 rpm 75 – 100 rpm 50 – 75 rpm

VOLUME 1000 mL 1000 mL 1000 mL 1000 mL

Procedure for Immediate Release Tablet:

1. The tablet is added into a cylindrical vessel containing 1000 mL dissolution media having 75 rpm and
temperature of 37  0.5C.
2. Dissolution of tablet is conducted in 30 minutes in 5-minute intervals.
3. Five mL sample is removed and appropriate quantity of the sample is taken and absorbance is tested using
U.V. spectroscopy technique to the determine the rate of dissolution of the tablet.

Procedure for Sustained Release Tablet:

1. The tablet is added into a cylindrical vessel containing 1000 mL pH 1.2 Acidic media having 75 rpm for next
two hours at 37  0.5C.
2. pH 6.8 Phosphate buffer is added for the next five hours in 1-hour intervals.
3. Five mL sample is tested for absorbance using U.V spectroscopy to determine the rate of dissolution.

Procedure for Capsules:

1. The capsules are added into a cylindrical vessel containing 1000 mL pH 1.2 Acidic media having 75 rpm at 37 
 0.5C. pH 6.8 Phosphate buffer is added for the next 3 hours at 1 hour interval.
2. Take 5 mL sample to be tested for absorbance using U.V spectroscopy to determine the rate of dissolution.
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Unit 2 2
Procedure for Suppositories:
1. The suppository is added in a cylindrical vessel containing 1000 mL pH 7.4 Phosphate buffer having 75 rpm at
37  0.5C.
2. Dissolution is conducted at 10-minute intervals for 60 minutes.
3. Five mL sample is tested for absorbance using U.V spectroscopy to determine the rate of dissolution.

WHAT ARE THE ACCEPTANCE VALUES?

QUANTITY NUMBER OF
ACCEPTANCE CRITERIA
STAGE/LEVEL TABLETS TESTED
S1 6 Each tablet is less than D+5%
Average of 12 tablets (S1 + S2) is equal to or greater than D, and no tablet is
S2 6
less than D–15%
Average of 24 tablets (S1 + S2 + S3) is equal to or greater than D, not more
S3 12
than 2 tablets are less than D–15%, and no tablet is less than D-25%
*D is the amount of dissolved active ingredient specified in the individual monograph expressed as a percentage of the labeled
content

WHAT ARE THE FACTORS AFFECTING

DRUG DISSOLUTION?

I. Physiochemical properties of the drug

a. Polymorphic form: A metastable form of a solid has higher solubility and dissolution compared to its
stable counterpart.
b. Particle size: The smaller the particle size of a solid, the larger the particle surface area and the higher
the dissolution.
c. Salt form: A salt form of a drug has a higher aqueous solubility compared to its conjugate acid or
base, as well as higher dissolution.
d. Hydrates versus anhydrates: The anhydrous form shows higher dissolution than hydrates due to their
solubility differences.

II. Factors related to tablet manufacturing

a. The amount and type of binder can affect the hardness, disintegration, and dissolution of tablets.
b. The method of granulation, granule size, and size distribution can affect tablet dissolution.
c. The concentration and type of disintegrants used, as well as the method of their addition, can affect
disintegration and dissolution.
d. Compression load can influence density, porosity, hardness, disintegration, and dissolution of tablets.

III. Factors related to method of dissolution study

a. Composition of the dissolution medium, pH, ionic strength, viscosity.
b. Type of dissolution equipment.
c. Temperature of the medium
d. Volume of dissolution medium
e. Intensity of agitation
f. Sink or non-sink conditions (under a sink condition, the concentration of the drug should not exceed 10
– 15 % of its maximum solubility in the dissolution medium in use).
g. Sensitivity of analytical method used to determine drug concentration in the release medium.

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Saint Louis University – Department of Pharmacy