Solubility and Dissolution Behaviour
Aqueous solubility is arguably the single most consequential physicochemical property assessed during preformulation, since a drug must dissolve before it...
Aqueous solubility is arguably the single most consequential physicochemical property assessed during preformulation, since a drug must dissolve before it can be absorbed, and inadequate solubility is the leading cause of poor oral bioavailability among modern drug candidates. Solubility is conventionally measured using the shake-flask method, in which an excess of solid drug is equilibrated with buffered aqueous media representative of the physiological pH range encountered along the gastrointestinal tract — typically pH 1.2, 4.5, 6.8, and 7.4 — with the dissolved concentration subsequently quantified by ultraviolet spectroscopy or high-performance liquid chromatography.
Because many drugs are weak acids or weak bases, their observed solubility varies substantially with pH, and preformulation scientists therefore construct a full pH-solubility profile to identify the pH of maximum solubility and to anticipate potential precipitation risks as the drug transits regions of differing gastrointestinal pH. A related and more fundamental parameter is the intrinsic solubility, defined as the solubility of the fully un-ionised form of the molecule; this value, related to the ionisation constant through the Henderson–Hasselbalch equation, provides a pH-independent measure of the compound's inherent aqueous affinity and is essential for rational salt-form and formulation selection.
Dissolution rate, distinct from equilibrium solubility, describes the kinetics with which solid drug enters solution and is most rigorously assessed through measurement of the Intrinsic Dissolution Rate using a rotating-disc apparatus, expressed in micrograms per square centimetre per minute. Intrinsic dissolution rate measurement is particularly valuable because it discriminates effectively between polymorphic forms and salt forms that may share similar equilibrium solubility but differ substantially in the rate at which they dissolve — a distinction of direct relevance to in-vivo absorption for rapidly cleared drugs.
Where a candidate molecule exhibits inadequate aqueous solubility, preformulation scientists evaluate its solubility in a panel of pharmaceutically acceptable co-solvents such as polyethylene glycol 400, propylene glycol, and ethanol, informing the design of liquid and semi-solid formulations. Where solubility remains a barrier to development, a range of solubility-enhancement strategies is considered at this stage, including cyclodextrin complexation, hot-melt extrusion to produce amorphous solid dispersions, co-solvency approaches, and pH-adjustment or salt-formation strategies, each of which is examined in greater depth in the chapters addressing novel drug delivery systems.