Review article

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

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

Alex Avdeef orcid.org/0000-0002-3139-5442 ; in-ADME Research, 1732 First Avenue, #102, New York, NY 10128, USA
Elisabet Fuguet ; Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 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

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.

Keywords

shake-flask solubility; intrinsic solubility; water solubility; buffer solubility; thermodynamic solubility; Bjerrum curve; CheqSol; Potentiometric Cycling for Polymorph Creation; Henderson-Hasselbalch equation; aggregates; oligomers; micelles; hydrates; salts; polymorphs; cocrystals

Hrčak ID:

160663

URI

https://hrcak.srce.hr/160663

Publication date:

29.6.2016.

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