New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity

Hydrochlorothiazide (HCT) is a diuretic drug with poor solubility and permeability. Physicochemical properties of HCT have been modified by cocrystallization with piperazine (PPZ), tetramethylpyrazine (TMPZ), picolinamide (PCM), isoniazid (INZ), malonamide (MAM), and isonicotinic acid (INIC) using mechanochemical grinding (liquid assisted and neat). The solids obtained were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry and subjected to solubility and membrane permeability studies. SCXRD showed that the N-H...O sulfonamide catemer synthons found in the stable polymorph of pure HCT have been replaced by drug-coformer heterosynthons in the cocrystals. HCT-PPZ and HCT-PCM cocrystals showed improvement in solubility and membrane permeability/diffusion compared to the parent active pharmaceutical ingredient. The improved solubility and diffusion rates are due to the drug-coformer interactions in the new solid forms. A structure-property relationship is examined to evaluate the solubility and diffusion rates of the new solid forms. The cocrystal with INIC, which could not be prepared previously by conventional methods, was obtained by prolonged grinding for 6 days.