ADMET & DMPK

Yazarlar: Christel A.S. Bergström, Alex Avdeef

Konular:-

DOI:10.5599/admet.686

Anahtar Kelimeler:Solubility-pH,Shake-flask solubility,Intrinsic solubility,Thermodynamic solubility,Henderson-Hasselbalch equation,Supersaturation,Pre-nucleation clusters,Drug aggregates,Drug salts,Pharmaceutical cocrystals

Özet: Several key topics in solubility measurement and interpretation are briefly summarized and illustrated with case studies drawing on published solubility determinations as a function of pH. Featured are examples of ionizable molecules that exhibit solubility-pH curve distortion from that predicted by the traditionally used Henderson-Hasselbalch equation and possible interpretations for these distortions are provided. The scope is not exhaustive; rather it is focused on detailed descriptions of a few cases. Topics discussed are limitations of kinetic solubility, ‘brick-dust and grease-balls,’ applications of simulated and human intestinal fluids, supersaturation and the relevance of pre-nucleation clusters and sub-micellar aggregates in the formation of solids, drug-buffer/excipient complexation, hydrotropic solubilization, acid-base ‘supersolubilization,’ cocrystal route to supersaturation, as well as data quality assessment and solubility prediction. The goal is to highlight principles of solution equilibria – graphically more than mathematically – that could invite 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. The value of solid state characterizations is stressed but not covered explicitly in this mini-review.

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