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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 testing and applications

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
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
glossary solid oral dosage forms
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
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  • multiple (≥ 3) samples are withdrawn from the dissolution medium during dissolution testing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
comparative dissolution testing the principle
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 testing profile similarity determination
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 testing similarity factor f 2
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%
typical time points immediate release tablets capsules
Typical time pointsImmediate release tablets (capsules)


  • 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
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 2 ciprofloxacin two batches of same product
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

example 2 ciprofloxacin two batches cont
Example 2Ciprofloxacin: two batches (cont.)

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

example 2 ciprofloxacin two batches cont16
Example 2Ciprofloxacin: two batches (cont.)

SGF without pepsin, pH 1.16 Acetate buffer pH6.8


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 !!



  • 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 3 lamivudine 150 mg zidovudine 300 mg tablets
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 3 lamivudine 150 mg zidovudine 300 mg tablets 4
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 3 lamivudine 150 mg zidovudine 300 mg tablets 5
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 ?

example 3 clarithromycin tablets proportional formulations
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




  • 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
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 cont28
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 cont29
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 cont30
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 cont31
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
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

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


  • 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
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