Dissolution in Perspective

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Dissolution in Perspective

• SAPRAA1 September 2006
• Joy E van OudtshoornJ B Pharmaceutical
  Consultants

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Dissolution in perspective

• Processes involved in absorption
• Solubility and Factors affecting dissolution rate
• Use of dissolution
• Setting QC specifications
• Comparative dissolution incl report
• Biowaivers
• Proportionally similar products
• foreign reference products
• amendments
• BCS
• Examples
• Conclusion

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Processes involvedAbsorption of API from an
intact tablet
Disintegration
Deaggregation
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Multiple pathways for intestinal absorption of a
compound
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Noyes and Whitney 1897 Fundamental relationship
between

• dC/dt K DS/Vh(Cs -Ct)
• rate of dissolution
• maximum solubility of the solute
• concentration at time t (final concentration)
• the larger the volume, the faster the dissolution
• Sink conditions - volume large - Ct ltlt Cs lt10
  or 15

Stagnant layer
Volume V
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Solubility definitions

• Pharmacopoeial
• Soluble
• Sparingly soluble
• Slightly soluble
• Very slightly soluble 1 000 mg / 1 to 10 litres
• Practically insoluble 1 000 mg /10 litres
  lt 90 mg / 900 ml
• BCS
• highly soluble max dose in 250 ml

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Factors affecting dissolution rate

• Physicochemical properties of the API
• Aqueous solubility, particle size, crystalline
  state
• Dosage form formulation factors
• Diluents, disintegrants, binders and granulating
  agents, lubricants, coatings, hardness,
  disintegration, capsule, transdermal components
• Conditions
• solute, agitation, temperature, apparatus,
  aeration, sinker, pH range (4,5 to 8,0 USP ionic
  strength ltEP)

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Factors affecting dissolution rate continued

• Apparatus and testing conditions
• apparatus USP I basket or USP II
  paddle
• medium 0,1 N HCl pH 1,2 4,5 6,8
  H2O FDA, other
• volume ³ 3 x saturated solution 500 to
  1 000 ml
• agitation basket 100 rpm, paddle 50 to
  75 rpm
• temperature 37 C 0,5 C ( case for 38
  rectal 32 transdermal)
• duration 10, 15, 20, 30, 45, 60 min
• 1, 2, 3, 4, 6, 8 h / complete
  profile
• assay method precision, linearity, recovery, loq

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Use of dissolution inproduct development and
manufacturing

• Guide in formulation development
• characterise API
• predict in vivo performance
• characterise clinical study and ba be batches
• identify critical manufacturing variables
• set dissolution specifications
• serve as surrogate for BA and BE,similarity of
  test and reference, biowaiver
• QC tool - monitor/assure batch to batch
  consistency
• formulation quality
• manufacturing process
• amendments - source, formulation, process,
  equipment

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Setting QC Specifications

• Acceptable clinical, ba or be batches
• USP or BP (monographs, general method incl S1,
  2, 3)
• FDA Drugs_at_FDA
• Develop - consider
• API solubility profile
• Apparatus and media and time points
• USP apparatus I basket 100 rpm
• USP apparatus II paddle 50 to 75 rpm
• 0,1 NHCl, pH 1,2 buffers pH 4,5 6,8 surfactant
  poorly sol
• profile eg 10, 15, 20, 30, 40, 60 mins to
  determine 1, or 2, or multiple testing time
  points

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Comparative dissolution

• Dissolution media
• 0,1 N HCl
• pH 4,5 buffer
• pH 6,8 buffer
• 12 units
• exactly same conditions
• same time points eg 10, 15, 20, 30, 45, 60 mins

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Comparison of dissolution profiles

• Similarity factor, f2, similarity in the
  percentage dissolution between two profiles
• f2 50. log1 (1/n)?t1 n (Rt -
  Tt)2-0.5.100
• Difference factor, f1, differences in the
  percentage dissolution between two profiles
• f1 ?t1 (Rt - Tt)/ ?t1 Rt.100

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Similarity factor f2

• same, at least 3 time points excl 0
• to use mean data cv (s rel )
• lt20 earlier time points, 10 later time pts
• one measurement only after both test reference
  85
• similarity assumed, calculation not necessary if
  85 at 15 minutes
• f2 ³ 50 profiles sufficiently similar, further in
  vivo studies not necessary

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Comparative dissolution report

• Full report, include at least
• Purpose of the study
• Product information for each batch
• b/n, manufacturing/expiry date, packaging, CoA,
  batch size (test)
• Dissolution conditions and method
• Validated analytical method ref to part of
  dossier
• Results ( API dissolved)
• tabulated, - graphically, - f2 calculations
• Discussion / conclusion

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Biowaivers - Similarity

• Proportionally similar product strengths
• Amendments
• Reference products
• BCS

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Proportionally similar

• IR tablets and capsules
• MR same API release mechanism tabs, beaded caps
• Proportionally formulated strengths
• 2.9.1 exactly the same proportion
• 2.9.2 ratios IPIs/total mass Amendment gdln
• 2.9.3 same total mass, low API
• Confirmed by comparative dissolution
• Same manufacturer, same site
• Appropriate be study on ³ 1 strength

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Post-registration/approval amendments

• Types of dissolution testing
• Case A - release test specification or
  pharmacopoeia
• Case B - multipoint, one medium specification or
  pharmacopoeial, specific time points or
  asymptote
• Case C - multipoint in 3 media, to 85 or
  asymptote
• Types of amendments
• Type A - unlikely to affect product quality,
  performance
• Type B - could have significant impact case B or
  C
• Type C - likely to have significant impact case
  B or C, IVIVC

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Foreign reference products

• Moeity must be registered in SA
• Different chemical form - safety/efficacy
• Product strength used or applied for within
  approved dose range
• Authorised by HA of country with which MCC aligns
  itself
• Similarity foreign reference product and
  innovator product in SA (test and reference
  resp) 3 media irrespective of API solubility
• Assay difference

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Foreign reference products continued

• no innovator product in SA
• old medicine - market leader - evidence
• other must comply with PA as above
• Moeity must be registered in SA
• Different chemical form - safety/efficacy
• Product strength used or applied for within
  approved dose range
• Authorised by HA of country with which MCC aligns
  itself
• and if relevant
• Appropriate link to registered moeity

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Test product

• Dissolution media
• 0,1 N HCl
• pH 4,5 buffer
• pH 6,8 buffer
• 12 units
• exactly same conditions
• same time points eg 10, 15, 20, 30, 45, 60
  minutes
• comparison with ref, similarity factor, not
  required if in vivo be study is included

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Biopharmaceutical Classification

• API is
• Highly soluble - highest dose is soluble in 250
  ml aqueous media over pH range 1,2 to 6,8 at 37
  C
• Highly permeable - human absorption ³ 85
• in vivo intestinal perfusion in humans
• in vitro permeation excised human, or animal
  tissue
• in vivo or in situ intestinal perfusion animal
  models
• in vitro permeation monolayer cultured epithelial
  cells eg Caco-2 cells
• published data

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BCS contd

• Very rapidly dissolving
• ³ 85 at 15 minutes
• Rapidly dissolving
• ³ 85 at 30 minutes
• Paddle 75 rpm basket 100 rpm
• Volume 900 ml
• Media
• pH 1,2 HCl
• pH 4,5 acetate buffer
• pH 6,8 phosphate buffer

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BCS
Wu and Benet
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Requirements BCS Biowaiver
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in vivo BE study with foreign ref
Also do 3 media
f2 3 media
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Conclusion

• Dissolution
• one of a number of testing parameters to describe
  or confirm quality, safety and efficacy -
  cannot be used alone
• appropriate after the product quality, safety and
  efficacy have been established
• measures
• not assay, nor impurities, nor degradation, etc
• release of API from solid, semi-solid dosage form
  

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