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

ADMET and DMPK

Elisabet Fuguet¹  Clara Ràfols²  Elisabeth Bosch²  Tatjana Verbić³  Elena Boldyreva⁴  Antonio Llinàs⁵  Gergely Völgyi⁶  Krisztina Takács-Novák⁶  Alex Avdeef⁷ 

[1] Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, SpainandSerra-Húnter Program, Generalitat de Catalunya, Barcelona, Spain;Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain;Faculty of Chemistry, University of Belgrade, Dept. of Analytical Chemistry, Studentski trg 12-16, Belgrade 11158, Serbia;Institute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze, 18, Novosibirsk, 630128 Russia;RIA iMED DMPK, AstraZeneca R&D, Gothenburg, Sweden;Semmelweis University, Dept. of Pharmaceutical Chemistry, H-1092 Budapest, Högyes E. u.9, Hungary;in-ADME Research;

关键词: 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;   

DOI  :  10.5599/admet.4.2.292

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown