Extended Release of Highly Water Soluble Isoniazid Attained through Cocrystallization with Curcumin

The aim of this study was to design and evaluate a cocrystal capable of releasing a highly water soluble drug, isoniazid (INH), over a period of longer than several hours by forming a cocrystal with curcumin (CUR). The 2:1 INH-CUR cocrystal can not only lower the dissolution rate of INH but also exhibit potential therapeutic synergy. A phase-pure INH-CUR cocrystal was obtained by rapid solvent removal above a threshold evaporation rate. The formation of an INH-CUR cocrystal was confirmed by powder X-ray diffraction and the construction of a temperature-composition phase diagram with differential scanning calorimetry. The pharmaceutical properties of the INH-CUR cocrystal, including hygroscopicity, stability, and dissolution performance, were compared to those of INH and CUR. Extended release of INH from the cocrystal was observed in both pH 1.2 and 6.8 buffers, while their release patterns behaved differently. The dissolution kinetics of INH-CUR cocrystal followed Fickian diffusion and was controlled by the cocrystal solubility and the mode of CUR recrystallization. At pH 1.2, a significant amount of CUR form III precipitated and recrystallized onto the surface of undissolved cocrystals after 4 h and thus substantially inhibited the INH release from cocrystals thereafter. On the other hand, ∼90% of INH was released linearly at pH 6.8 in the first 18 h, and complete release of INH was attained at 24 h. This work demonstrated that cocrystallization is a promising formulation strategy for achieving up to 48 h of drug release without using polymers.