Abstract
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.
Highlights
For many oral drugs, the rate-limiting step in intestinal absorption is dictated by the kinetics of dissolution of the active pharmaceutical ingredient from the solid form
For bases introduced as drug salts into an alkaline-pH solution, the charged drug in the supersaturated solution can disproportionate into oil or undergo precipitation into a new amorphous solid, with which charged water-soluble aggregates may coexist
Low-soluble compounds are often colloquially classified as ‘brick dust’ or ‘grease balls’ [11]. The solubility of the former type is mainly limited by a strong crystal lattice, making it difficult for the compound to dissociate from the solid form
Summary
The rate-limiting step in intestinal absorption is dictated by the kinetics of dissolution of the active pharmaceutical ingredient from the solid form. The supersaturation is typically achieved when the API is introduced in its amorphous form or in a charged form as a salt In such a supersaturated solution, drug molecules may self-associate as sub-micellar aggregates/clusters, if they are surface-active or polarizable. For bases introduced as drug salts into an alkaline-pH solution, the charged drug in the supersaturated solution can disproportionate into oil or undergo precipitation into a new amorphous solid, with which charged water-soluble aggregates may coexist. At the 2015 IAPC-4 meeting, the “Thermodynamic Solubility Measurement of Practically Insoluble Ionizable Drugs - Case Studies & Suggested Method Improvements” special session resulted in a ‘white paper’ publication drawing on expert consensus thoughts of researchers from six countries (Hungary, Russia, Serbia, Spain, Sweden, United States) [4].
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