Preparation, Characterization, and Water-Assisted Phase Transformation of Sulfuric and Sulfonic Salts of Sulfamethoxazole─Hydrogen Sulfate, Mesylate, and Tosylate

Abstract

Sulfamethoxazole is a widely used antibacterial agent with poor aqueous solubility, categorized as Class II or IV in the Biopharmaceutical Classification System. The preparation and characterization of three pharmaceutically acceptable molecular salts of sulfamethoxazole with strong acids was performed. The integrity of the parent drug in the salts and the 1:1 stoichiometry of the tosylate and mesylate salts were assessed by solution nuclear magnetic resonance. The single crystal diffraction results of the new solid phases (hydrogen-sulfate, mesylate, and tosylate) confirmed their proposed structures and provided a good understanding of the interactions that stabilize their structure. These studies confirmed that salt formation took place through protonation of the primary amino group, being in agreement with the mid-infrared spectral analysis, where modifications were observed in the amino N–H stretching vibration, while the C = N stretching signal of the isoxazole ring remained essentially unperturbed. The solids were systematically characterized using vibrational spectroscopy (mid- and near-infrared) and thermal methods (thermomicroscopy, thermogravimetry, and differential scanning calorimetry). In addition, powder X-ray diffractometry was employed to confirm the uniqueness and purity of the new phases. The solubilities of the solid phases in pure water and 10^–2 M HCl, as well as their intrinsic dissolution rates, were also determined, realizing that salt formation resulted in a modest increase in solubility. Powder X-ray diffraction analysis of the dissolution residues revealed that the salts underwent a solvent-assisted phase transformation to sulfamethoxazole form I and/or to sulfamethoxazole hemihydrate, being this the possible cause for the observed of lack of the salt formation advantage.