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   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

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

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).

Why in-vitro dissolution testing?

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

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

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

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

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

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

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

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

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

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

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

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

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.

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)

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

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.

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

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

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

Multi-point dissolution Example of dissolution profile

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

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

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%

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

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)

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

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)

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)

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

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)

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