Structural and property analysis of three novel pharmaceutical salt solvates synthesized from paliperidone and aromatic carboxylic acids

Abstract

Paliperidone (PLPT) is a pharmaceutical compound widely used in the treatment of psychiatric disorders. However, its limited solubility poses challenges for its formulation and bioavailability.In this study, three previously unreported salt solvates of PLPT were successfully synthesized: PLPT·PCBA·H2O (PCBA, para-chlorobenzoic acid), PLPT·NA·2H2O·2MeOH (NA, niacin acid), and PLPT·GA·2EtOH (GA, gallic acid). Considering the requirement of drying in actual production, the test samples were dried in a 333.15 K overnight and then used for TGA-DSC (thermogravimetric analysis-differential scanning calorimetry) testing. The results indicate that the thermal stability of PLPT·NA·2H2O·2MeOH was enhanced by approximately 40 K. The salt-like nature of these compounds was confirmed through ΔpKa calculations and single-crystal structure analysis, which revealed the formation of charge-assisted hydrogen bonds (N+-H···O−). Significant hydrogen bonding and π-π interactions were observed, as evidenced by 3D dnorm Hirshfeld surfaces and 2D fingerprint plots. They were characterized by predominant H···H, O···H, and N···H interactions, contributing to their structural stability. PXRD (powder X-ray diffraction) and IR (infrared spectroscopy) characterization provided further confirmation of the solvate formation. Notably, solubility experiments demonstrated a remarkable increase in the solubility of PLPT·NA·2H2O·2MeOH in simulated human body environments, exhibiting solubility enhancements of approximately 883.78 times, 166.57 times, 5.18 times, and 6.37 times across the range from pure water to pH 1.2. The remaining two salt solvates exhibit a notable enhancement in solubility under different pH conditions. An anomaly is observed only at pH 4, which is associated with the degree of protonation of PLPT and the intrinsic solubility of GA and PCBA. Dissolution rates indicate a significant improvement in all three salt solvates under various simulated human physiological environments, particularly at pH 6.8.These findings highlight the potential of these solvates as promising candidates for enhanced PLPT formulations. Dissolution rate experiments also indicate that the formation of salts significantly enhances the drug's dissolution rate. This study represents the first report on salt solvates of PLPT and provides valuable insights for the improvement of PLPT and other poorly soluble drug formulations.