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 (1) and
saccharin (2) 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 1 and 2 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 1 and 2 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.