Fig. 14.

Solubility of the basic drug NVP and its cocrystals with acidic coformers: (1:1) cocrystal NVP-MLE, and (2:1) NVP-SAC and NVP-SLC as a function of pH. Symbols represent solubilities determined from solutions saturated with NVP and/or cocrystal at 25°C. pH values correspond to equilibrium pH. As pH in increased the cocrystal and drug solubility curves approach each other and intersect at pH_max. The pH value at the intersection of the drug and cocrystal (NVP-SAC and NVP-SLC) solubility curves corresponds to pH_max or transition point above which a less soluble cocrystal becomes more soluble than drug. Curves were calculated from cocrystal and drug solubility-pH dependence according to equations ${\mathrm{S}}_{\text{cocrystal}}^{1:1}=\sqrt{{\mathrm{K}}_{\text{sp}}(1+{10}^{{\text{pK}}_{\mathrm{a},\mathrm{D}}-\text{pH}})(1+{10}^{\text{pH}-{\text{pK}}_{\mathrm{a}1,\text{CF}}}+{10}^{2\text{pH}-{\text{pK}}_{\mathrm{a}1,\text{CF}}-{\text{pK}}_{\mathrm{a}2,\text{CF}}})}$ and ${\mathrm{S}}_{\text{cocrystal}}^{2:1}=2\sqrt[3]{\frac{{\mathrm{K}}_{\text{sp}}}{4}{(1+{10}^{{\text{pK}}_{\mathrm{a},\mathrm{D}}-\text{pH}})}^2(1+{10}^{\text{pH}-{\text{pK}}_{\mathrm{a}1,\text{CF}}})}$ and parameter values presented in the text and in Table 3. Symbols represent: NVP solubility (NVP hydrate-open circles, NVP anhydrous-filled circles) and cocrystal solubilities from eutectic points (squares). Reproduced from ref. [73] with permission from The Royal Society of Chemistry.