Transcript Comparative dissolution testing and applications

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
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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 vivo–in 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
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different salt forms of the API
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surfactants in the formulation
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solubilized liquid formulations in hard or soft gelatin
capsules
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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 1.2–6.8 (1.2–7.5 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
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.
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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
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Two or more products or batches containing the same API are
compared
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The strength of products / batches may or may not be the same
(depending on purpose of test)
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The dissolution conditions are similar, e.g.
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Apparatus, medium, volume, rotation speed & temp.
Minimize possible experimental differences in conditions
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Samples are taken at the same time points and the data
(dissolution profiles) compared
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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
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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
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Minimum of 3 time points (zero excluded)
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12 units (each in own dissolution vessel) for each product (for “official” purposes)
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Only one measurement should be considered after both products have reached
85 % dissolution
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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
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
900 ml or less
Temperature
37°C ± 0.5°C
Sampling points
10, 15, 20, 30, 45, (60, 120) min. (typical)
Units (individual)
12 for “official” studies
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Dissolution Testing
or
Typical time points
Immediate release tablets (capsules)
Rationale:
Point
Time
1.
Condition 1
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1
10
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15
2.
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≥ 85% dissolution of both products within 15
minutes
15 minute time point thus essential
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20
4
30
5
45
Dissolution Testing
Condition 2, for calculation of f2
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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
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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
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
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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.
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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
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SADC Guidelines (Draft)
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Dissolution Testing
Some conclusions
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Comparative dissolution
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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