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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 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

[email protected]


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


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


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  • multiple (≥ 3) samples are withdrawn from the dissolution medium during dissolution testing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


Multi-point dissolutionExample of dissolution profile


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


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


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%


Comparative dissolution testingDissolution conditions (study design)


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)


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


Example 1Determination of similarity of profiles


Example 1 Determination of similarity of profiles (cont.)


Example 2Ciprofloxacin: two batches of same product

Apparatuspaddle 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


Example 2Ciprofloxacin: two batches (cont.)

Conclusion: The profiles in all three media can be regardedsimilar / not similar, since …………


Example 2Ciprofloxacin: two batches (cont.)

SGF without pepsin, pH 1.16Acetate buffer pH6.8


Example 2Ciprofloxacin: two batches (cont.)

Phosphate buffer pH 6.8


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)


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


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


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


    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


    Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (5)

    Combivir ® dissolution profileGen-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 ?


    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?


    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


    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 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


    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


    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

      • Example: Combivir ®(from limited data in Example 3)

        • 80% (Q) within 20 (15?) minutes for both APIs under conditions described in Example 3


    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


    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


    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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