Besides enhancing aqueous solubilities, cocrystals have the ability to fine-tune solubility advantage over drug, supersaturation index, and bioavailability. This review presents important facts about cocrystals that sets them apart from other solid-state forms of drugs, and a quantitative set of rules for the selection of additives and solution/formulation conditions that predict cocrystal solubility, supersaturation index, and transition points. Cocrystal eutectic constants are shown to be the most important cocrystal property that can be measured once a cocrystal is discovered, and simple relationships are presented that allow for prediction of cocrystal behavior as a function of pH and drug solubilizing agents. Cocrystal eutectic constant is a stability or supersatuation index that: (a) reflects how close or far from equilibrium a cocrystal is, (b) establishes transition points, and (c) provides a quantitative scale of cocrystal true solubility changes over drug. The benefit of this strategy is that a single measurement, that requires little material and time, provides a principled basis to tailor cocrystal supersaturation index by the rational selection of cocrystal formulation, dissolution, and processing conditions.

Cocrystals of a weakly basic drug (nevirapine) with acidic coformers are shown to alter the solubility dependence on pH, and to exhibit a pHmax above which a less soluble cocrystal becomes more soluble than the drug. The cocrystal solubility advantage can be dialed up or down by solution pH.

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The current treatment for cutaneous tuberculosis consists of oral coadministration of isoniazid (INH) and rifampicin, which is often related to hepatotoxic events. Alternatively, INH could be administered on the skin aiming to avoid or minimize these side effects. The high cutaneous permeation of this drug motivated the obtainment of a cocrystal of INH and resveratrol (RES), a lipophilic compound, to provide a local effect. In this study, isoniazid–resveratrol cocrystal (INH-RES) was synthesized by reaction crystallization method, and its structure was determined from single-crystal X-ray diffraction data. Cocrystal, drug, and coformer aqueous solubility was determined in the initial pH range from 1.2 to 7.4. Mathematical models based on cocrystal constituent ionization constants (pK a), solution pH, and cocrystal solubility product (K sp) were used to generate solubility diagrams as a function of pH. At all pH values studied, INH-RES was less soluble than INH. Permeation studies were performed with drug and cocrystal applied to porcine skin in Franz diffusion chambers. Cocrystal reduced the amount of permeated drug by 86%. The association with a coformer that has higher log P decreased INH permeation, highlighting the importance of considering the drug permeation route during the coformer selection.

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