Theoretical and experimental study of pharmaceutical salts: a case of trimethoprim

Abstract

Trimethoprim (TMP) is a bacterial dihydroreductase inhibitor with broad-spectrum antibacterial properties. However, its oral absorption is limited by its low water solubility. Salification is one of the effective methods to solve this problem. This work proposes an efficient method for screening TMP salts using the conductor-like screening model for real solvents (COSMO-RS) model. 200 common compounds were introduced as candidates for screening. As a result, 39 hit compounds were subjected to experimental liquid-assisted grinding (LAG) with TMP, then 25 new solid phases were confirmed by PXRD. The solvent evaporation method was further used to acquire eight single crystals of TMP salts, whose structures were elucidated by single-crystal X-ray diffraction. Power X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier-transform infrared spectroscopy were employed to characterize seven of the TMP salts. Then, atoms-in-molecules was used to analyze intermolecular hydrogen bonding interactions in salts. Finally, we tested the equilibrium solubility and dissolution rate of the salt, which exhibited an increase in solubility. In a word, it is an effective screening method to obtain TMP salts combined with the COSMO-RS model and LAG method, which can be widely applied to other systems for screening of the target salts.