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Comparative dissolution testing and applications

Comparative dissolution testing and applications. World Health Organization Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence Kiev - Ukraine 3 to 7 October 2005. Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy

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Comparative dissolution testing and applications

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  1. Comparative dissolution testingand applications World Health Organization Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence Kiev - Ukraine 3 to 7 October 2005 Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa iiftgd@puk.ac.za

  2. What is dissolution testing?tablets and capsules (conventional) • It measuresthe 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. GlossarySolid 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 Not part of presentation Modified-release dosage forms (consult Int.Ph., BP, USP) • Formulation deliberately changes release (slows down) • Extended-release (prolonged-release) Slower release throughout the GI tract • Delayed-release(enteric coated tablets) Resists gastric fluid & disintegrates in intestinal fluid

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 In multipoint dissolution • multiple (≥ 3) samples are withdrawn from the dissolution medium during dissolution testing • at pre-determined time points and • each sample is analysed for the % API dissolved • A graph of %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

  5. Multi-point dissolutionExample of dissolution profile

  6. Comparative dissolution testingThe principle • Two or more products or batchescontaining 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

  7. Comparative dissolution testingProfile similarity determination Two conditionsto 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

  8. Comparative dissolution testingSimilarity 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%

  9. Comparative dissolution testingDissolution conditions (study design)

  10. Typical time pointsImmediate release tablets (capsules) 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)

  11. Comparative dissolution testingComparison of products When are dissolution properties of two products (batches) regarded similar? • The profiles should be similar • in all three media • Statements of instability or insolubility are not acceptable, but should be demonstrated / justified

  12. Example 1Determination of similarity of profiles

  13. Example 1 Determination of similarity of profiles (cont.)

  14. Example 2Ciprofloxacin: two batches of same product Apparatus paddle at 50 rpm Medium 1: simulated gastric fluid without pepsin (SGF) (900 ml) Medium 2: acetate buffer pH 4.5 (900 ml) Medium 3: phosphate buffer pH 6.8 (900 ml) Temp.: 37°C ± 0.5°C (start, middle, end) Units: Twelve tablets per medium, each batch Sampling:Manual, through in-line filter (0.45 μm PVDF unit)at 10, 15, 20, 30 and 45 minutes Analysis: HPLC analysis for ciprofloxacin

  15. Example 2Ciprofloxacin: two batches (cont.) Conclusion: The profiles in all three media can be regardedsimilar / not similar, since …………

  16. Example 2Ciprofloxacin: two batches (cont.) SGF without pepsin, pH 1.16 Acetate buffer pH6.8

  17. Example 2Ciprofloxacin: two batches (cont.) Phosphate buffer pH 6.8

  18. Ciprofloxacin (cont.) Solubility is pH dependent: • “Highly soluble” at pH < 6 • 100% dissolution obtained in pH 4.5 and pH 1.16 • At pH 6.8 and 40°C the solubility is about 0.2 mg/ml • Explains 40% dissolution for 500 mg dose !! 40°C▼ Questions: • What dissolution level should ciprofloxacin 250 mg tablets be able to reach in pH 6.8 medium? • Should a change in particle size affect the dissolution rate? X. Yu et al. Pharm. Research, 11, 522-527 (1994)

  19. Example 3Lamivudine 150 mg & zidovudine 300 mg tablets Source, WHO publication: • Ongoing Monitoring of Antiretroviral Products as Part ofWHO’s Prequalification Project. Journal of Generic Medicines (accepted for publication, January 2006 edition) • Samples from PQ project or bought/requested • Apparatus: paddle at 75 rpm • Medium: 900 ml 0.1 M hydrochloric acid, 37°C • Sample times: 5, 10, 15, 20, 30 and 45 minutes • Analysis: HPLC • Data presented for individual APIs in next tables

  20. Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (2)

  21. Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (3)

  22. Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (4) • Conclusion (considering only 0.1 M HCl as medium) • 3 products show profile similarity with Combivir®(≥ 85% in 15 minutes) • The profiles of Combivir® and Gen-1 are not similar • The products may still show bio-equivalency • The dissolution profiles of the APIs in a particular product are similar (true for all 5 products) • Examples: see profiles of Combivir® and Gen-1

  23. Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (5) Combivir ® dissolution profile Gen-1 dissolution profile 0.1 M hydrochloric acid 0.1 M hydrochloric acid Note the similarity of the API profiles of each product APIs highly soluble = dissolution controlled by disintegration time Is particle size of APIs expected to be critical ?

  24. Example 3Clarithromycin tablets – Proportional formulations • 2 strengths prepared from same granulate • f2 = 31 • Profiles not similar ! • Solubility of the API in buffer pH 6.8 “low” according to BCS • Do you expect that particle size or polymorphism may have effect on the profiles?

  25. Effect of Particle Size on Dissolution of Nevirapine Tablets (Source: Ranbaxy) 1 Viramune 2 Nevipan 90% < 31 3 Nevipan 90% < 81 f2 :1 vs 2 = 72✔ f2 :1 vs 3 = 31X f2 :2 vs 3 = 34X 1 2 3 http://www.who.int/medicines/organization/par/FDC/VKAroraWHOGenevaDec.ppt

  26. 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

  27. Applications (cont.) • It is a requirement of the prequalification programme to submit 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 form part of pharmaceutical development report • Inclusion of the same report in the bioequivalence study report is recommended

  28. 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 • Consult the bio-guideline, also for reverse situation

  29. 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

  30. 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 • Example: Combivir ®(from limited data in Example 3) • 80% (Q) within 20 (15?) minutes for both APIs under conditions described in Example 3

  31. Applications (cont.) • Post-approval amendment application • A requirement of a particular change may be to demonstrate that the profiles of the amendment batch and the current batch are similar • Consult guideline on variations

  32. 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

  33. 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

  34. 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

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