CONTENT UNIFORMITY

&
DISSOLUTION TEST
Presented by:
Dr Gul Rehman Elmi
 CONTENT UNIFORMITY
 Testing for content uniformity helps ensure that the
strength of a therapeutic product remains within specified
acceptance limits
 The potency of tablets or dosage form are expressed in
terms of;
o Milligram of drug
o Microgram of drug
o Gram of drug
 CONTENT UNIFORMITY

 The label strength shows potency of dosage form

 On bases of potency of drugs
1. High potency drugs (with low dose)
2. Less potent drugs (with high dose)
 CONTENT UNIFORMITY

 Factors affecting content uniformity are;

1. Non uniform distribution of drugs; may be due to
o Improper compaction of powder mixture
o Improper granulation

2. Segregation of mixture during manufacturing

3. Tablet weight variation
CONTENT UNIFORMITY

 Uniformity of tablets is analyzed by 2 methods;

1. Weight variation
• Performed for tablets with ≥ 25% drug substance in
total dosage form
2. Content uniformity
• Done for all types of tablets
 PROCEDURE OF CONTENT UNIFORMITY

 Randomly select 30 tablets from batch

 Grind all tablets individually and perform assay of 10
tablets individually
 Assay can be performed as specified in monograph by;
1. dissolution method, involving spectroscopic techniques
2. Titration method
 PROCEDURE OF CONTENT UNIFORMITY

 Test will pass

 If 9 out of 10 tablets have 85-115% drug and the 10th tablet
have 75-125% drug
 If test fails;
 Assay the remaining 20 tablets individually and all 20 tablets
should have 85-115%
DISSOLUTION TEST
 INTRODUCTION
Dissolution is a process in which a solid substance
solubilizes in a given solvent i.e. mass transfer from the
solid surface to the liquid phase.

Rate of dissolution- It is the amount of drug substance that

goes in solution per unit time under standardized
conditions of temperature, pH and solvent composition
and constant solid surface area.

The rate of dissolution quantifies the speed of the

dissolution process.
 Importance &
Importance & need
need for
forDissolution
DissolutionTesting
Testing

Tablet or
Capsules
Disintegration
Drug in
Granules or Dissolution Drug in Absorption blood, other
solution
aggregates (in vivo) fluids , and
(in vitro or tissues
Deaggregation in vivo)

Fine
particles
 Importance & need for Dissolution Testing
Dissolution testing is of utmost importance in following
aspects;

Reliable Predictor of drug in-vivo dissolution performance

Rate limiting factor in determining drug physiological
availability
As Quality control tool for monitoring the uniformity and
reproducibility of production batches.
As Research tool in optimizing parameters and ingredients
in new drug formulation.
It is widely accepted as animal experimentation has been
restricted under the Act of Prevention of cruelty of animals.
 Dosage forms requiring dissolution

• Tablets
• Capsules
• Suppositories
• Suspensions
• Topical dosage forms like creams ,gels,
ointments, etc
• Transdermal patches.
 USP/NF Parameters or Factors affecting Dissolution

USP/NF specifies the following specifications for dissolution

testing of any drug or dosage form
 Type of dissolution medium or emersion fluid
 Volume of dissolution medium (1, 2 or 4 Liter)
 Apparatus to be used
 Speed of apparatus (RPM)
 Time limit of test
 Assay procedure
 Dissolution media
Common dissolution media used (suggested by different
guidelines):
 Purified water
 Diluted acid (0.1N HCl)
 Buffered aqueous solutions
 Simulated gastric fluid (with or without enzymes)
 Simulated intestinal fluid (with or without enzymes)
 Official Dissolution Apparatus
USP Type- I Basket Type

USP Type- II Paddle Type

USP Type- III Reciprocating Cylinder

USP Type- IV Flow Through Cell

USP Type- V Paddle Over Disk

USP Type- VI Rotating Cylinder

USP Type- VII Reciprocating Holder

Official Dissolution Apparatus
 USP APPARATUS # 1 (Basket Apparatus)

This apparatus has major parts

1. Vessel
 Glass made, transparent, with hemispherical bottom
 Number of vessels are mostly 6 but can also be 3-6
 Dissolution medium is placed in vessel
 Sometime, it is covered to prevent _______?
Vessel Capacity Height (mm) Internal diameter (mm)
1L 160-210 98-106
2L 280-300 98-106
4L 280-300 145-155
 USP APPARATUS # 1 (Basket Apparatus)
2. Assembly
i. Basket
 Cylindrical shape made up of stainless steel in form of
mesh
 Dosage form is placed in basket and basket is than
placed in vessel at a distance of 25±2mm between
bottom of basket and vessel
 Basket and shaft together are known as stirring element
ii. Shaft
 Made up of stainless steel # 316 (non-corosive),
attached to basket at lower end and motor at upper side
 Positioned vertically
 USP APPARATUS # 1 (Basket Apparatus)

2. Assembly
iii. Motor
 Speed regulating device attached to shaft
 Speed is set as 25-200 RPM as specified in monograph
3. Water bath (heating jacket)
 It is the heating device to control the temperature at
37±0.5oC or as specified
USP APPARATUS # 1 (Basket Apparatus)
 USP APPARATUS # 2 (Paddle Apparatus)
 Paddle apparatus assembly is same as that of basket
apparatus, only difference, basket is replaced with paddle
 Paddle and shaft are stirring element that are made up of
stainless steel
 Paddle thickness is 3.5mm and shaft has 10±0.5mm
diameter
 Distance between outside of paddle and bottom of vessel
is maintained at 25±2mm during test
 Sample is placed at bottom of vessel and allow sample to
sink down before the procedure
 USP APPARATUS # 2 (Paddle Apparatus)

Incase of floating sample,

1. Use sinker or sink material – why?
 Sinker is placed above the sample and prevents floating
 Sinker can be a non-reactive wire helix
2. Place floating tablet in dialysis membrane bag which
is attached to paddle
USP APPARATUS # 2 (Paddle Apparatus)
Product placement in Apparatus 1 & 2
 USP APPARATUS # 3 (Reciprocating
Cylinder)
 Why called reciprocating cylinder----??
 Used for extended release tablets and capsule (with
pellets)
Vessel
 Cylindrical, flat bottom, glass made with 325 mL
capacity
Reciprocating cylinder
 Consists of inert 100 mm glass cylinder with a mesh
screen at the bottom and top.
 Dosage form is placed in reciprocating cylinder
USP APPARATUS # 3 (Reciprocating
Cylinder)
 USP APPARATUS # 4 (Flow Through Cell)
3 major parts
1. Reservoir; For dissolution medium
2. Pump; pumps dissolution medium through cell holding a
sample at flow rate of 10-100 mL/min. Laminar flow is
maintained
3. Water bath/heating coil; Maintain temp at 37±0.5⁰C

 Dissolution medium is pumped from reservoir via

sample holder cell which dissolves the sample and
carries dissolved sample with it.
 Sample is filtered within the sample holding cell and
collected
USP APPARATUS # 4 (Flow Through Cell)
General Procedure Flowchart
1. Place dissolution
media
2. Assemble apparatus
and maintain temp
3. Place dosage form
4. Operate apparatus
5. Collect samples
6. Replace withdrawn
vol. with fresh medium
7. Filter sample
8. Perform Assay
 General procedure of Dissolution
 Place stated volume of dissolution medium in vessel of
specified apparatus. Mostly 1L (as 900 mL±1%) medium is used,
but we can use less or more than 1L medium
 Assemble apparatus and maintain temp of dissolution medium
at 37±0.5oC. It takes upto 10 mint. for medium to reach this temp
 Take 6 dosage form units and place 1 unit in each basket
 Now operate apparatus at specified rate and time
 Take samples from dissolution medium of each basket once (one
time sampling) or at specified time intervals in case of multiple
sampling (e.g., after 10, 30, 60, 90 min,…… so on).
 Incase of multiple sampling replace withdrawn medium with
equal volume of fresh medium
 General procedure of Dissolution cont.
 Sample should be collected from zone midway between
dissolution medium and top of basket and not less than 1cm
away from vessel wall
 Filter test sample by using syringe filters, if required
 Perform assay/analysis of sample as directed in individual
monograph by using as suitable assay method
Sampling Point
 Considerations at time of sampling
 We can take 2 types of sampling
1. One time sampling
 Take the specified volume (2-5 mL) of medium from each
basket once for assay and stop the procedure.
1. Multiple sampling
 Take samples from dissolution medium of each basket at
specified time intervals (e.g., after 10, 30, 60, 90 mint so on)
 Replace withdrawn medium with equal volume of fresh
medium
 The fresh medium must have same temperature and pH
 MONOGRAPHS
Parameter Monograph Specifications
Amoxicillin Capsule Methyl-Dopa Tablets
Dissolution medium Water 0.1N HCl
Vol. of medium 900 mL 900 mL
Apparatus USP apparatus 1 & 2 USP apparatus 2
Speed USP app 1 = 100 RPM 50 RPM
USP app 2 = 750 RPM
Time 60 minutes 20 minutes
Assay UV spectroscopy UV spectroscopy
Result Not less than 80% Not less than 80%
 Acceptance Criteria
Level/Stage No. of units tested Acceptance Criteria
S1 6 • Each unit is not less than Q* + 5%
• Average of 12 units (S1 +S2) is ≥
S2 6
Q, and no unit is less than Q – 15%
• Average of 24 units (S1+S2+S3) is
≥Q
S3 12 • Not more than 2 units are less than
Q – 15%
• No unit is less than Q – 25%

*Q is the amount of dissolved active ingredient specified in individual

monograph, expressed as a percentage of the labeled content.
 Case Study for Understanding
CASE
 Sample to be tested; Amoxicillin 500 mg capsule
 According to USP monograph each capsule must contain
>80% amoxicillin, thus, Q = 80%
 80% of 500 mg is 400 mg

 You have performed dissolution test and UV

spectroscopic assay as specified in monograph.
 Now how to interpret the results?
 Case Study for Understanding
Result Interpretation
1. Stage 1
i. Result 6 individual capsules must be greater than
Q+5%
 80% + 5% = 85%
 Means > than 85% or in mg it is > 425 mg
2. Stage 2
i. Average of 12 caps. must be ≥ Q (which is 80%), and,
ii. No unit is less than Q-15%
 80% - 15% = 65%
 Means > than 65% or in mg it is >325 mg
 Case Study for Understanding

3. Stage 3
i. Average of 24 capsule must be ≥ Q (which is 80%), and,
ii. Not more than 2 units are less than Q-15%
 80% - 15% = 65%
 Means > than 65% or in mg it is > 325 mg, and,
iii. No unit is less than Q-25%
 80% - 25% = 55%
 Means > than 55% or in mg it is > 275 mg
QC OF CAPSULES & POWDERS
(Other Than Discussed Earlier)
 CAPSULES
 Capsules are oral solid dosage forms with hard or soft shells
 They are of various shapes and sizes and contain a single
dose of one or more active ingredients
 Capsule surfaces may bear symbols or other markings
 Capsule shells are made of gelatin or other substances,
consistency of which may be adjusted by addition of
substances such as glycerol or sorbitol
 CAPSULES

 Shell should disintegrate in the presence of digestive fluids

so that contents are released
 Contents of capsules May be solid, liquid or a paste like
consistency
 The excipients should not cause deterioration of the shell
 CAPSULES
TYPES OF CAPSULES
 The different categories of capsule include:
1. Hard capsules
2. Soft capsules
3. Modified-release capsules (including delayed-release
capsules, gastro-resistant/enteric capsules and sustained-
release capsules, extended-/prolonged-release capsules)
 QC OF CAPSULES
Visual Inspection
 Unpack and inspect at least 20 capsules. They should be
smooth and undamaged
 Evidence of physical instability is demonstrated by gross
changes in physical appearance, like hardening, softening,
cracking, swelling, mottling or discoloration of shell
 QC OF CAPSULES
Moisture Permeation Test

 This test is performed by packaging the dosage unit with the

color revealing desiccant pellet
 Unit is exposed to known humidity over a specified time
Observe the color pellet for color change
 QC OF CAPSULES
Content Uniformity

 Individually determine the amount of active ingredient in

each of 10 units using the analytical method specified in the
individual monograph
 POWDERS
Visual Inspection

 Inspect the powder, using at least 20 containers for single

dose preparations
 Evidence of physical and/or chemical instability is
demonstrated by noticeable changes in physical appearance,
including texture [e.g. clumping] or color.