Equilibrium solubility measurement of ionizable drugs - consensus recommendations for improving data quality

Alex Avdeef, Elisabet Fuguet, Antonio Llinàs, Clara Ràfols, Elisabeth Bosch, Gergely Völgyi, Tatjana Verbic, Elena Boldyreva, Krisztina Takács-Novák

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the "gold standard" shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation), use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method), solubility type (water, buffer, intrinsic), temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pKa, equilibration time (stirring and sedimentation), separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids.

Original languageEnglish
Pages (from-to)117-178
Number of pages62
JournalADMET and DMPK
Volume4
Issue number2
DOIs
Publication statusPublished - Jun 29 2016

Keywords

  • Aggregates
  • Bjerrum curve
  • Buffer solubility
  • Cheqsol
  • Cocrystals
  • Henderson-hasselbalch equation
  • Hydrates
  • Intrinsic solubility
  • Micelles
  • Oligomers
  • Polymorphs
  • Potentiometric cycling for polymorph creation
  • Salts
  • Shake-flask solubility
  • Thermodynamic solubility
  • Water solubility

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)

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  • Cite this

    Avdeef, A., Fuguet, E., Llinàs, A., Ràfols, C., Bosch, E., Völgyi, G., Verbic, T., Boldyreva, E., & Takács-Novák, K. (2016). Equilibrium solubility measurement of ionizable drugs - consensus recommendations for improving data quality. ADMET and DMPK, 4(2), 117-178. https://doi.org/10.5599/admet.4.2.292