Solubility and Dissolution Rate Enhancement of Triamterene by a Cocrystallization Method

A potassium-sparing diuretic, triamterene, shows a low oral bioavailability with wide intersubject variation due to its poor aqueous solubility (45 μg/mL). To improve its solubility, a group of pharmaceutically acceptable coformers were screened with triamterene by slurry and liquid-assisted grinding methods, and dl-mandelic acid (<b>1</b>) and saccharin (<b>2</b>) successfully cocrystallized with triamterene to form one anhydrous and one monohydrate molecular salt, respectively. Both new forms were characterized by spectroscopic methods, thermal analysis, and X-ray diffraction. Their single crystal structures reveal that proton transfer from coformers to the nitrogen atom of the pyrimidine group in triamterene and the coformer anions thus connect to the protonated triamterene by multiple hydrogen bonded heterosynthons. The apparent solubility values and intrinsic dissolution rates of <b>1</b> and <b>2</b> in simulated gastric fluid (pH 1.20) are higher than those of parent drug, indicating the solubility of triamterene can be effectively improved by cocrystallization. The exposure of <b>1</b> and <b>2</b> to 0–95% RH levels and accelerated ICH condition of 40 °C/75% RH confirm their stability and the potential of these new forms to envisage new, more efficient formulations of triamterene