Dissolution Testing

Evaluation of quality and interchangeability of medicinal products

Training workshop for evaluators from National Medicines
Regulatory Authorities in East Africa Community
10-14 September 2007, Dar Es Salaam, Tanzania
Presented by
Rutendo Kuwana

Dissolution testing: conventional tablets and

capsules
It measures the portion (%) of the API that (1) has
been released from tablets/capsules and (2) has
dissolved in the dissolution medium during controlled
testing conditions within a defined period

The tablet thus first disintegrates

Then the API will be able to dissolve
Slow disintegration slow dissolution
The % API dissolved is determined with an appropriate
validated method: UV/VIS, HPLC, AA, GC, etc

Dissolution testing is also applicable to suspensions

and suppositories
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Dissolution Testing

Solid oral dosage forms

Immediate release typically means that 75% of the API

is dissolved within 45 minutes
Rapidly dissolving: 85% in 30 minutes
Very rapidly dissolving: 85% in 15 minutes

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Dissolution Testing

Challenges in Dissolution Testing

Dissolution testing in immediate-release (IR) solid dosage

forms poses many challenges
developing and validating the test method
ensuring that the method is discriminatory
addressing the potential for an in vivoin vitro
relationship (IVIVR) or correlation (IVIVC).

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Dissolution Testing

Why in-vitro dissolution testing?

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Dissolution Testing

Applications
1.

For selection of the formulation in the

development phase

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By comparison of the dissolution profiles of innovator

product with those of formulations
Hint: start with comparator product to see:
Immediate release?
Rapidly dissolving?
Very rapidly dissolving?
Disintegration testing can aid in the early phases
This should be a basic strategy in R&D to maximize the
chances of bioequivalence

Dissolution Testing

Applications (cont.)
2.

It is a requirement for comparative dissolution

data for the bio-batch and innovator batch

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Same batches as used in bioequivalence study

Submit report with data, profile comparison & discussion
(see report requirements)
This report forms part of pharmaceutical development report
Inclusion of the same report in the bioequivalence study report is
recommended

Dissolution Testing

Applications (cont.)
3.

Demonstration of in vivo bioequivalence of one or

more of the lower strength(s) of an FPP may be
waived based on
1.
2.
3.
4.

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an acceptable in vivo BE study of the highest strength

against the comparator product
demonstration of similarity of dissolution profiles,
if the lower strength is proportionally similar in formula to the
higher strength (bio-batch) and
if all pharmacokinetic requirements are met

Dissolution Testing

Applications (cont.)
4.

Comparison of the release properties of pivotal

batches

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To demonstrate in vitro similarity of such batches

This is considered essential for retention of efficacy and safety
Note that bioequivalence studies are done normally only once on a
bio-batch during development
It must be demonstrated that the product retains the dissolution
characteristics up to production scale
The studies should be submitted in dossier as part of the
FPP development report

Dissolution Testing

Applications (cont.)

5.

Selection of the dissolution specifications for

product release & stability purposes

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Conditions and acceptance criteria to be set

The dissolution profiles of the bio-batch should be used for
this purpose
A dissolution specification should be able to detect
inadequate release properties of the commercial batches
A generous dissolution limit has no quality selectivity

Dissolution Testing

Applications (cont.)
6.

Post-approval amendment application

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Assessment of formulation changes to demonstrate that the

profiles of the amendment batch and the current batch are
similar

Dissolution Testing

Variables affecting dissolution

characteristics of the API e.g., particle size, crystal form,

bulk density
product composition e.g., drug loading, and the identity,
type, and levels of excipients
manufacturing
equipment

process

e.g.,

compression

forces,

effects of stability storage conditions e.g., temperature,

humidity
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Dissolution Testing

Mechanism of dissolution

Dissolution test determines the cumulative amount of drug that

goes into solution as a function of time
Steps involved
liberation of the solute or drug from the formulation matrix
(disintegration)
dissolution of the drug (solubilization of the drug particles) in
the liquid medium
The overall rate of dissolution depends on the slower of these
two steps
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Dissolution Testing

Mechanism of dissolution

First Step

Cohesive properties of the formulated solid dosage form drug play a key
role disintegration and erosion

semi- solid or liquid formulations, the dispersion of lipids or partitioning of

the drug from the lipid phase is the key factor

If the first step of dissolution is rate-limiting, then the rate of dissolution is

considered to be disintegration controlled

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Dissolution Testing

Mechanism of dissolution

Second Step

Solubilization of the drug particles depends on the

physicochemical properties of the drug such as its
chemical form (e.g., salt, free acid, free base) and physical
attributes

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Dissolution Testing

Dosage form type and design affect dissolution testing (1)

For intrinsic dissolution-limited absorption (i.e., the

disintegration of the dosage form is rapid, but dissolution is
slow)
reduce the particle size of the API

Small particle size creates challenges as they can pass

through filters and subsequently dissolve

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Dissolution Testing

Dosage form type and design affect dissolution testing (2)

For solubility-limited absorption (intrinsic- solubility

controlled) enhance the transient solubility of the
API

different salt forms of the API

surfactants in the formulation

solubilized liquid formulations in hard or soft gelatin

capsules

non-crystalline materials

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Dissolution Testing

Media selection

For batch-to-batch quality testing medium selection may

be based on the solubility data and the dose range of the
drug product to ensure that sink conditions are met

The term sink conditions is defined as the volume of

medium at least greater than three times that required to
form a saturated solution of a drug substance.

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Dissolution Testing

Media selection (2)

When the dissolution test is used to indicate the

biopharmaceutical properties
- closely simulate the
environment in the GIT than sink conditions

First evaluate using test media within the physiologic pH

range of 1.26.8 (1.27.5 for modified-release
formulations)

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Dissolution Testing

Apparatus selection

Described in the United States Pharmacopoeia (USP)

under the General Chapters of Dissolution and Drug
Release

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Dissolution Testing

Discriminatory power

The discriminatory power of the dissolution method is the

methods ability to detect changes in the drug product.

Once a discriminating method is developed, the same

method should be used to release product batches for
future clinical trials, if possible.

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Dissolution Testing

Alternative methods to dissolution testing

In ICH Q6A permits use of disintegration testing as a

surrogate for conventional Compendial dissolution tests,
provided

highly soluble drug substances

intrinsic rate of solubilization is rapid
overall drug release rate is dominated by cohesive
properties of the formulation
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Dissolution Testing

Alternative methods to dissolution testing (2)

APIs with good solubility at gastric pH levels may be

granted BCS Class I and III classification i.e. may be
characterized by disintegration testing alone

In liquid filled capsule drug dissolved in solubilization aids

offering a true mechanism for drug release is likely to be
the rupture of the capsule
use disintegration
as a surrogate for the QC dissolution test

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Dissolution Testing

Multi-point dissolution?

In multipoint dissolution
multiple ( 3) samples are withdrawn from the dissolution
medium during dissolution testing
at pre-determined time points and
each sample is analysed for the % API dissolved
A graph of % API dissolved against time:

The dissolution profile

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Dissolution Testing

Multi-point dissolution
Example of dissolution profile

120

Dissolution (%)

100

80

60

40

20

Clarithromycin 250 mg tablets

0
0

10

20

30

WITHDRAWAL TIME IN MINUTES

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Dissolution Testing

40

50

Comparative dissolution testing

The principle

Two or more products or batches containing the same API are

compared

The strength of products / batches may or may not be the same

(depending on purpose of test)

The dissolution conditions are similar, e.g.

Apparatus, medium, volume, rotation speed & temp.

Minimize possible experimental differences in conditions

Samples are taken at the same time points and the data
(dissolution profiles) compared

Calculations: correct for volume change of dissolution medium

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Dissolution Testing

Comparative dissolution testing

Profile similarity determination
Two conditions to determine if the dissolution profiles
of two products/batches in a particular dissolution
medium are similar:
1.

If both the test and reference product show more than 85%
dissolution within 15 minutes, the profiles are considered to
be similar

2.

If this is not the case, apply point 2

Calculate the f2 value (similarity factor):

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No calculations are required

If f2 50, the profiles are normally regarded similar

Dissolution Testing

Comparative dissolution testing

Similarity factor f2

n = number of time points

R(t) = mean % API dissolved of reference product at time point x

T(t) = mean % API dissolved of test product at time point x

Minimum of 3 time points (zero excluded)

12 units (each in own dissolution vessel) for each product (for official purposes)

Only one measurement should be considered after both products have reached 85
% dissolution

RSD at higher time points 10%

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Dissolution Testing

Comparative dissolution testing

Dissolution conditions (study design)
Apparatus

Paddle, 50 (75) rpm

(choice)

Basket, 100 rpm

Dissolution media

1.

Buffer pH 6.8 or simulated intestinal fluid

without enzymes

2.

Buffer pH 4.5

3.

0.1 M HCl or buffer pH 1.2 or simulated

gastric fluid without enzymes

All three media for full

comparison

or

Volume of media

900 ml or less

Temperature

37C 0.5C

Sampling points

10, 15, 20, 30, 45, (60, 120) min. (typical)

Units (individual)

12 for official studies

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Dissolution Testing

Typical time points

Immediate release tablets (capsules)

Point

Time

Rationale:
1.

10

15

20
2.

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Condition 1

30

45

Dissolution Testing

85% dissolution of both products within 15

minutes
15 minute time point thus essential

Condition 2, for calculation of f2

a minimum of 3 points are required

Only one measurement should be considered
after 85 % dissolution (both tablets)
20 minute time point thus first possible one (if 15
minute fails 1st condition)

Comparative dissolution testing

Comparison of products

Dissolution properties of two products (batches) regarded

as similar when
The profiles are similar
in all three media
Statements of instability or insolubility are not acceptable, but should be
demonstrated / justified

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Dissolution Testing

Example
Determination of similarity of profiles
Example 1-B

Example 1-A

% API dissolved

% API dissolved
Time
(min)

Tablet A
(Ref)

Tablet B
(Test)

Time
(min)

Tablet D
(Ref)

Tablet E
(Test)

10

87

94

10

55

57

15

96

99

15

72

78

20

99

99

20

85

91

30

100

99

30

97

100

45

101

99

45

102

100

60

101

99

60

103

101

f2 required?
f2 (n = N/A ?)
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Dissolution Testing

No, 85% in 15 min

profiles similar

f2 required?
f2 (n = 3 ?)

Yes
64 (similar)

Example
Determination of similarity of profiles (cont.)
Example 1-D

Example 1-C

% API dissolved

% API dissolved
Time
(min)

Tablet X
(Ref)

Tablet Y
(Test)

Time
(min)

Tablet A
(Ref)

Tablet Y
(Test)

10

29

34

10

87

55

15

38

41

15

96

72

20

47

50

20

99

85

30

63

64

30

100

97

45

80

79

45

101

102

60

95

91

60

101

103

f2 required?
f2 (n = 6 ?)
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Dissolution Testing

Yes
74 (similar)

f2 required?
f2 (n = 3 ?)

Yes
31 (not similar)

Reporting
Comparative dissolution data

Full report, including

Purpose of study
Products / batches information

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Batch number, manufacturing/expiry date, packaging, etc.

CoA & size for own batches (and BMR for bio-studies report)

Dissolution conditions and method

Analytical method or reference to part of dossier
Results (% API dissolved)
Tabulated
Graphically
Similarity determination / calculation
Conclusion

Dissolution Testing

Guidelines
WHO Prequalification
Supplement 1 [for use from July 2005 (CPH25)] to:

1.

Guideline on Submission of Documentation for Prequalification of Multi-source (Generic)

Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and
Tuberculosis
Dissolution testing
Others

Guidance for Industry. Waiver of In-Vivo Bioavailability and Bioequivalence Studies for
Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification
System. U.S. Department of Health and Human Services, Food and Drug Administration,
Center for Drug Evaluation and Research (CDER), August 2000.

CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. The
European Agency for the Evaluation of Medicinal Products CPMP/EWP/QWP/1401/98, July
2001

SADC Guidelines (Draft)

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Dissolution Testing

Some conclusions

Comparative dissolution

It is thus important

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should form an essential part of R&D of solid oral dosage forms

(including suspensions),
supports bio-studies,
is required for comparison of pharmaceutical release properties of
pivotal batches,
is used to set dissolution specifications, and
assists in post-approval changes

to conduct the studies under controlled conditions in the 3 media,

all as required by the guidelines,
to take samples for analysis at meaningful intervals and
to be able to determine similarity of profiles

Dissolution Testing