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

Authors

  • Alex Avdeef in-ADME Research
  • Elisabet Fuguet Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain and Serra-Húnter Program, Generalitat de Catalunya, Barcelona, Spain
  • Antonio Llinàs RIA iMED DMPK, AstraZeneca R&D, Gothenburg, Sweden
  • Clara Ràfols Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain
  • Elisabeth Bosch Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain
  • Gergely Völgyi Semmelweis University, Dept. of Pharmaceutical Chemistry, H-1092 Budapest, Högyes E. u.9, Hungary
  • Tatjana Verbić Faculty of Chemistry, University of Belgrade, Dept. of Analytical Chemistry, Studentski trg 12-16, Belgrade 11158, Serbia
  • Elena Boldyreva Institute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze, 18, Novosibirsk, 630128 Russia
  • Krisztina Takács-Novák Semmelweis University, Dept. of Pharmaceutical Chemistry, H-1092 Budapest, Högyes E. u.9, Hungary

DOI:

https://doi.org/10.5599/admet.4.2.292

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.

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Published

29-06-2016

How to Cite

Avdeef, A., Fuguet, E., Llinàs, A., Ràfols, C., Bosch, E., Völgyi, G., Verbić, 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

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