Vous êtes sur la page 1sur 36
Dissolution Testing Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators from National
Dissolution Testing Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators from National

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

2 |

Dissolution Testing

Dissolution testing: conventional tablets and capsules  It measures the portion (%) of the API that
Dissolution testing: conventional tablets and capsules  It measures the portion (%) of the API that

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

3 |

Dissolution Testing

Solid oral dosage forms Immediate release typically means that 75% of the API is dissolved within
Solid oral dosage forms Immediate release typically means that 75% of the API is dissolved within

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).

4 |

Dissolution Testing

Challenges in Dissolution Testing Dissolution testing in immediate-release (IR) solid dosage forms poses many challenges 
Challenges in Dissolution Testing Dissolution testing in immediate-release (IR) solid dosage forms poses many challenges 

Why in-vitro dissolution testing?

5 |

Dissolution Testing

Why in-vitro dissolution testing? 5 | Dissolution Testing
Why in-vitro dissolution testing? 5 | Dissolution Testing

Applications

  • 1. For selection of the formulation in the development phase

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

6 |

Dissolution Testing

Applications 1. For selection of the formulation in the development phase – By comparison of the
Applications 1. For selection of the formulation in the development phase – By comparison of the

Applications (cont.)

  • 2. It is a requirement for comparative dissolution data for the bio-batch and innovator batch

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

7 |

Dissolution Testing

Applications (cont.) 2. It is a requirement for comparative dissolution data for the bio-batch and innovator
Applications (cont.) 2. It is a requirement for comparative dissolution data for the bio-batch and innovator

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. an acceptable in vivo BE study of the highest strength against the comparator product

    • 2. demonstration of similarity of dissolution profiles,

    • 3. if the lower strength is proportionally similar in formula to the higher strength (bio-batch) and

    • 4. if all pharmacokinetic requirements are met

8 |

Dissolution Testing

Applications (cont.) 3. Demonstration of in vivo bioequivalence of one or more of the lower strength(s)
Applications (cont.) 3. Demonstration of in vivo bioequivalence of one or more of the lower strength(s)

Applications (cont.)

  • 4. Comparison of the release properties of pivotal batches

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

9 |

Dissolution Testing

Applications (cont.) 4. Comparison of the release properties of pivotal batches – To demonstrate in vitro
Applications (cont.) 4. Comparison of the release properties of pivotal batches – To demonstrate in vitro

Applications (cont.)

  • 5. Selection of the dissolution specifications for product release & stability purposes

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

10 |

Dissolution Testing

Applications (cont.) 5. Selection of the dissolution specifications for product release & stability purposes  Conditions
Applications (cont.) 5. Selection of the dissolution specifications for product release & stability purposes  Conditions

Applications (cont.)

  • 6. Post-approval amendment application

Assessment of formulation changes to demonstrate that the profiles of the amendment batch and the current batch are similar

11 |

Dissolution Testing

Applications (cont.) 6. Post-approval amendment application – Assessment of formulation changes to demonstrate that the profiles
Applications (cont.) 6. Post-approval amendment application – Assessment of formulation changes to demonstrate that the profiles

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

12 |

Dissolution Testing

Variables affecting dissolution  characteristics of the API e.g., particle size, crystal form, bulk density 
Variables affecting dissolution  characteristics of the API e.g., particle size, crystal form, bulk density 

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

13 |

Dissolution Testing

Mechanism of dissolution Dissolution test determines the cumulative amount of drug that goes into solution as
Mechanism of dissolution Dissolution test determines the cumulative amount of drug that goes into solution as

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

14 |

Dissolution Testing

Mechanism of dissolution First Step Cohesive properties of the formulated solid dosage form drug play a
Mechanism of dissolution First Step Cohesive properties of the formulated solid dosage form drug play a

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

15 |

Dissolution Testing

Mechanism of dissolution Second Step Solubilization of the drug particles depends on the physicochemical properties of
Mechanism of dissolution Second Step Solubilization of the drug particles depends on the physicochemical properties of

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)

Dosage form type and design affect dissolution testing (1) For intrinsic dissolution-limited absorption ( i.e., the

reduce the particle size of the API

Small particle size creates challenges as they can pass through filters and subsequently dissolve

16 |

Dissolution Testing

Dosage form type and design affect dissolution testing (1) For intrinsic dissolution-limited absorption ( i.e., the
Dosage form type and design affect dissolution testing (1) For intrinsic dissolution-limited absorption ( i.e., the

Dosage form type and design affect dissolution testing (2)

For solubility-limited absorption (intrinsic- solubility

controlled)

API

enhance the transient solubility of the

different salt forms of the API

surfactants in the formulation

solubilized liquid formulations in hard or soft gelatin capsules

non-crystalline materials

17 |

Dissolution Testing

Dosage form type and design affect dissolution testing (2) For solubility-limited absorption (intrinsic- solubility controlled) API
Dosage form type and design affect dissolution testing (2) For solubility-limited absorption (intrinsic- solubility controlled) API

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.

18 |

Dissolution Testing

Media selection For batch-to-batch quality testing medium selection may be based on the solubility data and
Media selection For batch-to-batch quality testing medium selection may be based on the solubility data and

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 1.2–6.8 (1.2–7.5 for modified-release formulations)

19 |

Dissolution Testing

Media selection (2) When the dissolution test is used to indicate the biopharmaceutical properties - closely
Media selection (2) When the dissolution test is used to indicate the biopharmaceutical properties - closely

Apparatus selection

Described in the United States Pharmacopoeia (USP)

under the General Chapters of Dissolution Release

and Drug

20 |

Dissolution Testing

Apparatus selection Described in the United States Pharmacopoeia ( USP ) under the General Chapters of
Apparatus selection Described in the United States Pharmacopoeia ( USP ) under the General Chapters of

Discriminatory power

The discriminatory power of the dissolution method is the method’s 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.

21 |

Dissolution Testing

Discriminatory power The discriminatory power of the dissolution method is the method’s ability to detect changes
Discriminatory power The discriminatory power of the dissolution method is the method’s ability to detect changes

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

properties of the formulation

22 |

Dissolution Testing

dominated

by

cohesive

Alternative methods to dissolution testing In ICH Q6A permits use of disintegration testing as a surrogate
Alternative methods to dissolution testing In ICH Q6A permits use of disintegration testing as a surrogate

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 as a surrogate for the QC dissolution test

Alternative methods to dissolution testing (2) APIs with good solubility at gastric pH levels may be

use disintegration

23 |

Dissolution Testing

Alternative methods to dissolution testing (2) APIs with good solubility at gastric pH levels may be
Alternative methods to dissolution testing (2) APIs with good solubility at gastric pH levels may be

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

24 |

Dissolution Testing

Multi-point dissolution? In multipoint dissolution – multiple (≥ 3) samples are withdrawn from the dissolution medium
Multi-point dissolution? In multipoint dissolution – multiple (≥ 3) samples are withdrawn from the dissolution medium

Multi-point dissolution Example of dissolution profile

100 120 0 Clarithromycin 250 mg tablets 80 60 40 20 Dissolution (%) 40 20 30
100
120
0
Clarithromycin 250 mg tablets
80
60
40
20
Dissolution (%)
40
20
30
50
10
0

WITHDRAWAL TIME IN MINUTES

25 |

Dissolution Testing

Multi-point dissolution Example of dissolution profile 100 120 0 Clarithromycin 250 mg tablets 80 60 40
Multi-point dissolution Example of dissolution profile 100 120 0 Clarithromycin 250 mg tablets 80 60 40

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

26 |

Dissolution Testing

Comparative dissolution testing The principle  Two or more products or batches containing the same API
Comparative dissolution testing The principle  Two or more products or batches containing the same API

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

No calculations are required

If this is not the case, apply point 2

  • 2. Calculate the f2 value (similarity factor):

If f2 ≥ 50, the profiles are normally regarded similar

27 |

Dissolution Testing

Comparative dissolution testing Profile similarity determination Two conditions to determine if the dissolution profiles of two
Comparative dissolution testing Profile similarity determination Two conditions to determine if the dissolution profiles of two

Comparative dissolution testing

n = number of time points

Similarity factor f2

Comparative dissolution testing n = number of time points Similarity factor f2 R(t) = mean %

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%

28 |

Dissolution Testing

Comparative dissolution testing n = number of time points Similarity factor f2 R(t) = mean %
Comparative dissolution testing n = number of time points Similarity factor f2 R(t) = mean %
Comparative dissolution testing Dissolution conditions (study design) Apparatus • Paddle, 50 (75) rpm or (choice) •
Comparative dissolution testing
Dissolution conditions (study design)
Apparatus
Paddle, 50 (75) rpm
or
(choice)
Basket, 100 rpm
Dissolution media
1.
Buffer pH 6.8 or simulated intestinal fluid
without enzymes
2.
Buffer pH 4.5
All three media for full
comparison
3.
0.1 M HCl or buffer pH 1.2 or simulated
gastric fluid without enzymes
Volume of media
Temperature
Sampling points
Units (individual)
900 ml or less
37°C ± 0.5°C
10, 15, 20, 30, 45, (60, 120) min. (typical)
12 for “official” studies
Dissolution Testing
29 |

Typical time points Immediate release tablets (capsules)

Rationale: Point Time 1. Condition 1 1 10 – ≥ 85% dissolution of both products within
Rationale:
Point
Time
1.
Condition 1
1
10
≥ 85% dissolution of both products within 15
minutes
15 minute time point thus essential
2
15
3
20
2.
Condition 2, for calculation of f2
4
30
a minimum of 3 points are required
Only one measurement should be considered
after 85 % dissolution (both tablets)
5
45
20 minute time point thus first possible one (if 15
minute fails 1 st condition)
Dissolution Testing
30 |

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

31 |

Dissolution Testing

Comparative dissolution testing Comparison of products Dissolution properties of two products (batches) regarded as similar when
Comparative dissolution testing Comparison of products Dissolution properties of two products (batches) regarded as similar when

Example

Determination of similarity of profiles

 

Example 1-A

 

% API dissolved

Time

Tablet A

Tablet B

(min)

(Ref)

(Test)

  • 10 87

 

94

  • 15 96

 

99

  • 20 99

 

99

  • 30 100

 

99

  • 45 101

 

99

  • 60 101

 

99

f2 required?

No, ≥ 85% in 15 min

f 2 (n = N/A ?)

f2 (n = N/A ?)

profiles similar

32 |

Dissolution Testing

Example 1-B % API dissolved Time Tablet D Tablet E (min) (Ref) (Test) 10 55 57
Example 1-B
% API dissolved
Time
Tablet D
Tablet E
(min)
(Ref)
(Test)
10
55
57
15
72
78
20
85
91
30
97
100
45
102
100
60
103
101
f2 required?
f2 (n =
3
?)
Yes
64 (similar)

Example

Determination of similarity of profiles (cont.)

 

Example 1-C

 
 

% API dissolved

Time

 

Tablet X

Tablet Y

(min)

(Ref)

(Test)

10

29

34

15

38

41

20

47

50

30

63

64

45

80

79

60

95

91

f2 required?

 

Yes

f2 (n =

6
6

?)

74 (similar)

33 |

Dissolution Testing

Example 1-D % API dissolved Time Tablet A Tablet Y (min) (Ref) (Test) 10 87 55
Example 1-D
% API dissolved
Time
Tablet A
Tablet Y
(min)
(Ref)
(Test)
10
87
55
15
96
72
20
99
85
30
100
97
45
101
102
60
101
103
f2 required?
f2 (n =
3
?)
Yes
31 (not similar)

Reporting Comparative dissolution data

Full report, including

Purpose of study

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

Dissolution conditions and method

Products / batches information

 

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

Analytical method or reference to part of dossier

Results (% API dissolved)

Tabulated Graphically Similarity determination / calculation Conclusion

34 |

Dissolution Testing

Reporting Comparative dissolution data Full report, including  Purpose of study Batch number, manufacturing/expiry date, packaging,
Reporting Comparative dissolution data Full report, including  Purpose of study Batch number, manufacturing/expiry date, packaging,

Guidelines

WHO Prequalification

  • 1. Supplement 1 [for use from July 2005 (CPH25)] to:

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)

35 |

Dissolution Testing

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

Some conclusions

Comparative dissolution

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

It is thus important

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

36 |

Dissolution Testing

Some conclusions  Comparative dissolution – should form an essential part of R&D of solid oral
Some conclusions  Comparative dissolution – should form an essential part of R&D of solid oral