The Dissolution Procedure: Development and …

1 The Dissolution Procedure: Development and ValidationBased on: <1092> as published in PharmacopoeialForum, Vol. 31 (5), 2005Dr. Elisabeth KrugLilly ForschungGmbHGermanyDr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company2 Dissolution OutlineGeneral considerations for Dissolution proceduresMediumIn vivo In vitro correlationApparatusAgitationSinkersStud y DesignObservations SamplingFiltersAssayValidationAnalysisAc ceptance CriteriaDr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company3 Dissolution General Considerations Dissolution is a performance test, applicable to manydosage forms It yields data to allow an accept/reject decision One test amongst a series of others The USP provides the following General Chapters:Disintegration <701>Drug Release <724> Dissolution <711>MediumApparatus/Agitation RateStudy DesignAssayAcceptance CriteriaDr.

2 Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company4 Dissolution General ConsiderationsWhat is needed?Apparatus, medium, and test conditionsHow should the acceptance criteria look like?Should be representativefor multiple batches with the same nominal composition and manufacturing processWhat are the requirements for a Dissolution procedure? Must provide a method rugged andreproducibleas well as transferable Must be appropriately discriminating, capable of distinguishing significant changes in a composition or manufacturing process that might be expected to affect in vivoperformanceDr.

3 Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company5 Dissolution General Considerationsthe discriminating in vitrofor batches without differences in vivo What to do? Carefully evaluate whether the procedure is too sensitive or appropriately discriminating Assess the results from multiple batches that represent typical variability in composition and manufacturing parameters Intentionally vary manufacturing parameters (lubrication, blend time, compression force, drying parameters)Dr.

4 Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company6 Dissolution General more requirements for the Dissolution procedure Reflection of relevant changesin the drug product over time caused by temperature, humidity, photosensitivity, and other stress No significant analytical solution stabilityproblems should be associated with the test Not highly variable: RSD > 20% at 10 min or lessRSD > 10% at later time point Identify sources of variability: Formulation(API, excipients, manufacturing process, poor CU, process inconsistency, film coat, capsule shell aging, hardening or softening of dosage forms) Test procedureartifacts (coning, tablet sticking, air bubbles etc.)

5 Dr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company7 Dissolution OutlineGeneral considerations for Dissolution proceduresMediumIn vivo In vitro correlationApparatusAgitationSinkersStud y DesignObservations SamplingFiltersAssayValidationAnalysisAc ceptance CriteriaDr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company8 Dissolution Medium Criteria for Selection Physical and chemical datafor: drug substance Solubility and solution state stability as a function of pH Evaluation of influence of buffer, pH value and surfactants dosage unit Release mechanism (immediate, delayed, modified) Disintegration rate as affected by hardness, friability, presence of solubility enhancers, other excipientsDr.

6 Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company9 Dissolution Medium Sink ConditionThe term sink conditionis based on the theory that the drug concentration on both sides of the epithelial layer of the intestinal wall approach equilibrium in a short time and that the gastrointestinal tract acts as a natural sink; , the drug is absorbed instantaneously the moment it K S (Csat Csol)Where: dc/dt= Dissolution rate, K = Dissolution constantS = surface area Csat= concentration of saturated solutionCsol= concentration at any given timeUnder sink conditions(Csat>>>Csol) the concentration gradient effect is eliminated, thus a better representation of the performance of the dosage form is given (rather than a solubility issue of the drug substance)

7 Test Method should yield biopharmaceutically relevant results FIP Quantity of medium used should be not less than 3 times that required to form a saturated solution USP Solubility requirements (Sink Conditions) Desirable but not mandatory FDA Dr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company10 Dissolution Medium Acceptable with Justification Medium that does not provide sink conditionsis acceptable, if it has a better discriminatory power Aqueous-organic solvent mixturesare discouraged.

8 But acceptable with appropriate justification Purified wateris not ideal Disadvantage Source of water can determine quality pH value not controlled and can vary from day to day pH value of water can vary within the run Advantage Inexpensive Readily available Easy disposal Suitable for products with release rates independent from pH valueDr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company11 Dissolution Medium Selection for Oral Dosage FormsEvaluate Dissolution characteristicsin the physiologicalpH range for immediate release formulations for modified-release formulations Measure pH value before and after the test Evaluate solubilizingeffects of molarityof buffer or acidTypical Media dilute HClbuffer buffers simulated gastric or intestinal fluids: FASSIF, FESSIF, FASGF etc.

9 Water surfactants (with or without acids of buffers): polysorbate80, SLS, bile saltsFor highly soluble, highly permeablecompounds for selection of medium and apparatus, follow the FDA Guidance (FDA Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BiopharmacuticsClassification System, August 2000; )Dr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company12 Dissolution Medium Selection for Oral Dosage FormsVery poorly soluble compounds may require the addition :Surfactant (surface active agent) is a molecule that, when added to a liquid at low concentration, changes the properties of that liquid at a surface or structure:a hydrophilic and a hydrophobic of application.

10 Improvement of wetting / spreading compatibilizingformulation components modification of notto be used to improve performance of a formulation in vitroSLS/ SDS (anionic) CetylTrimethylAmmonium Bromide CTAB (cationic)Polysorbate80, Brij(nonionic) Lauryldimethylamine-oxide(LDAO)Dr. Elisabeth Krug25. Jan. 2006 -SAQC ompany ConfidentialCopyright 2000 Eli Lilly and Company13 Dissolution Medium Selection for Oral Dosage FormsThe lowestconcentration providing sink conditions is the one of choice!Profilesneed to be provided at several different surfactant Amount Released (% Label Claim) Polysorbate Polysorbate Polysorbate Polysorbate 801% Polysorbate 802% Polysorbate 80Dr.