1. Presented by Rutendo Kuwana
Dissolution Testing
Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators from National Medicines Regulatory Authorities in East Africa Community   September 2007, Dar Es Salaam, Tanzania
Presented by
Rutendo Kuwana

2. 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

3. 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

4. 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).

5. Why in-vitro dissolution testing?

6. Applications 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

7. Applications (cont.)
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

8. Applications (cont.)
Demonstration of in vivo bioequivalence of one or more of the lower strength(s) of an FPP may be waived based on
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

9. Applications (cont.)
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

10. Applications (cont.)
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

11. Applications (cont.) Post-approval amendment application
Assessment of formulation changes to demonstrate that the profiles of the amendment batch and the current batch are similar

12. 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 process e.g., compression forces, equipment
effects of stability storage conditions e.g., temperature, humidity

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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.

19. 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)

20. Apparatus selection
Described in the United States Pharmacopoeia (USP) under the General Chapters of Dissolution and Drug Release

21. 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.

22. 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

23. 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

24. 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

25. Multi-point dissolution Example of dissolution profile

26. 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

27. 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:
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
Calculate the f2 value (similarity factor):
If f2 ≥ 50, the profiles are normally regarded similar

28. 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%

29. Comparative dissolution testing Dissolution conditions (study design)
Apparatus
(choice)
Paddle, 50 (75) rpm or
Basket, 100 rpm
Dissolution media
All three media for full comparison
Buffer pH 6.8 or simulated intestinal fluid without enzymes
Buffer pH 4.5
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

30. Typical time points Immediate release tablets (capsules)1 10 2 15 3 20 4 30 5 45
Rationale:
Condition 1
≥ 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)

31. 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

32. Example Determination of similarity of profiles
Example 1-A
% API dissolved
Time (min)
Tablet A (Ref)
Tablet B (Test) 10 87 94 15 96 99 20 30
100 45
101 60
f2 required?
No, ≥ 85% in 15 min
f2 (n = N/A ?)
profiles similar
Example 1-B
% API dissolved
Time (min)
Tablet D (Ref)
Tablet E (Test) 10 55 57 15 72 78 20 85 91 30 97
100 45
102 60
103
101
f2 required?
Yes
f2 (n = 3 ?)
64 (similar)

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

34. Reporting Comparative dissolution data
Full report, including
Purpose of study
Products / batches information
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

35. Guidelines WHO Prequalification
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)

36. Some conclusions Comparative dissolution It is thus important
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