Salt formation is frequently employed to improve the solubility and bioavailability of pharmaceutical compounds. Solid-Liquid-Equilibrium (SLE) phase diagram that serves as the foundation for designing crystallization-based separation is introduced to facilitate the recovery of the desired salt form. Poorly-water soluble drugs with two ionizable groups were selected as examples. Pemetrexed, with confirmed monosodium and disodium salt forms, was used to demonstrate the approach that has been developed for the phase-diagram guided formation of such salts. A conceptual phase diagram for the system under consideration was first hypothesized; experiments were then performed to validate its phase behavior. An orally administered dapsone was next used to demonstrate the application of the prop...[ Read more ]

Salt formation is frequently employed to improve the solubility and bioavailability of pharmaceutical compounds. Solid-Liquid-Equilibrium (SLE) phase diagram that serves as the foundation for designing crystallization-based separation is introduced to facilitate the recovery of the desired salt form. Poorly-water soluble drugs with two ionizable groups were selected as examples. Pemetrexed, with confirmed monosodium and disodium salt forms, was used to demonstrate the approach that has been developed for the phase-diagram guided formation of such salts. A conceptual phase diagram for the system under consideration was first hypothesized; experiments were then performed to validate its phase behavior. An orally administered dapsone was next used to demonstrate the application of the proposed strategy. Dihydrochloric salt of dapsone was successfully formed alongside the experimental phase diagram; and it was found to have a solubility 80 times higher than that of the parent drug. Caco-2 cell assays were performed which showed that the intestinal permeability of the salt was as good as that of the parent drug, thus confirming the usefulness of the salt form.