TY - JOUR

T1 - Equilibrium solubility measurement of ionizable drugs - consensus recommendations for improving data quality

AU - Avdeef, Alex

AU - Fuguet, Elisabet

AU - Llinàs, Antonio

AU - Ràfols, Clara

AU - Bosch, Elisabeth

AU - Völgyi, Gergely

AU - Verbic, Tatjana

AU - Boldyreva, Elena

AU - Takács-Novák, Krisztina

PY - 2016/6/29

Y1 - 2016/6/29

N2 - 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.

AB - 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.

KW - Aggregates

KW - Bjerrum curve

KW - Buffer solubility

KW - Cheqsol

KW - Cocrystals

KW - Henderson-hasselbalch equation

KW - Hydrates

KW - Intrinsic solubility

KW - Micelles

KW - Oligomers

KW - Polymorphs

KW - Potentiometric cycling for polymorph creation

KW - Salts

KW - Shake-flask solubility

KW - Thermodynamic solubility

KW - Water solubility

UR - http://www.scopus.com/inward/record.url?scp=85019028134&partnerID=8YFLogxK

U2 - 10.5599/admet.4.2.292

DO - 10.5599/admet.4.2.292

M3 - Article

AN - SCOPUS:85019028134

VL - 4

SP - 117

EP - 178

JO - ADMET and DMPK

JF - ADMET and DMPK

SN - 1848-7718

IS - 2

ER -