Colorful Prothionamide Salt Forms with Enhancement in Water Solubility and Dissolution Behavior

Prothionamide (PRT) is used as an alternative to some first-line drugs in the treatment of multi drug-resistant tuberculosis. Suffering from its extremely low water solubility and physiological constraints, the clinical use of PRT is restricted. The crystal engineering technique has been proven to be a good way to improve its solubility, especially for salt formation. In this work, six colorful PRT salts, i.e., maleate, besylate, tosylate, phthalate, edisylate, and naphthalene disulfonate, were obtained for the first time and identified with solid-state characterization methods. The Hirshfeld surface and independent gradient model based on Hirshfeld partition calculation were used to study the weak interactions in crystal constitutions. With different counterions added into the unit cell and bonded with PRT cations through N+–H···O– hydrogen interactions, tremendous enhancement in water solubility and dissolution behavior was observed in all salts when compared with PRT. Solvation free energy and lattice energy were calculated to rationalize the increase in solubility values. Different colors exhibited in PRT salts were studied in detail with the molecular orbital caculation and visualization technique. The exploration in the landscape of PRT salt forms with increased water solubility and dissolution performance was highly promising for application in the drug-resistant tuberculosis treatment.