From Crystal Design to Pharmaceutical Drug Potential: A New Theophylline-Nitrate Monohydrate Cocrystal Salt with Enhanced Solubility and Antibacterial Activity

A multicomponent system of theophylline (TH) with nitric acid (HNO3), designated as THNO3, was synthesized via slow evaporation from ethanolic solution and structurally characterized as a monohydrate cocrystal salt. Single crystal X-ray diffraction revealed a triclinic system (P1-space group) comprising one neutral TH molecule, one theophyllinium cation (TH+), one nitrate ion (NO3 -), and one water (H2O) molecule per asymmetric unit. Hirshfeld surface analysis indicated dominant H & centerdot;& centerdot;& centerdot;H (34.4%) and O & centerdot;& centerdot;& centerdot;H/H & centerdot;& centerdot;& centerdot;O (30.7%) interactions, with the latter playing a key role in lattice stabilization. Crystal void mapping showed a low void volume (7.14%), suggesting efficient packing and structural stability. Raman spectroscopy, supported by calculations based on density functional theory (DFT), enabled suitable vibrational mode assignments. Thermogravimetric analysis revealed five thermal decomposition stages (300-660 K), with dehydration occurring at 304-347 K and confirming the monohydrate stoichiometry. Solubility assays in phosphate buffer (pH 6.8, 310 K) showed a 13.2% increase in the solubility of THNO3 (17.37 +/- 0.37 mg/mL) compared to the recrystallized pure TH, indicating potential for enhanced absorption and bioavailability. Antibacterial tests revealed bacteriostatic activity against Streptococcus mutans, highlighting the multifunctional activity of the new THNO3 solid dispersion. These findings underscore the relevance of formation cocrystal salts with inorganic acids as a strategy to improve physicochemical and biological properties of active pharmaceutical ingredients.