DESIGN AND CHARACTERIZATION OF THE PHARMACEUTICAL COCRYSTAL OF RIFAXIMIN WITH CO-FORMERS FOR BOOSTING PHYSICOCHEMICAL PROPERTIES

Abstract

Objective: The present study investigates the improvement of the solubility of insoluble rifaximin through co-crystallization. Rifaximin is an inhibitor of Ribonucleic acid (RNA) synthesis in susceptible bacteria by binding to the beta-subunit of bacterial Deoxyribonucleic acid (DNA)-dependent RNA polymerase enzyme. Rifaximin belongs to the Biopharmaceutical Classification System (BCS) Class IV, with reduced solubility being the primary concern associated with its use.

Methods: Co-crystallization is one method of crystal engineering used to change the physicochemical characteristics of medications that are not very soluble. A co-crystal is a multi-component crystal with non-covalent interactions among the Active Pharmaceutical Ingredients and their co-formers. Auto Dock software was used for the virtual screening of 20distinct co-formers for rifaximin utilizing the molecular docking method. The parameters detected were interaction type and energy (Ei). After analyzing the data of the virtual study, an oxalic acid co-former was selected, and rifaximin co-crystals were fabricated by a solvent evaporation method. Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), In-vitro dissolution, Stability Studies, and Solubility studies were used to characterize co-crystals. The co-crystalized drug was compressed into a tablet dosage form and compared with the in-house formulation of the rifaximin tablet.

Results:  Molecular docking analysis revealed that oxalic acid exhibited the most favorable interaction with rifaximin, forming four hydrogen bonds with a binding energy of −2.3 kcal/mol, suggesting potential for cocrystal formation. FTIR spectra of the cocrystal showed shifts in the O–H stretch from 3427 cm⁻¹ to 3396 cm⁻¹ and in the C=O stretch from 1720 cm⁻¹ to 1706 cm⁻¹, indicating hydrogen bonding between rifaximin and oxalic acid. DSC thermogram of the cocrystal displayed a single, sharp endothermic peak at 208.52 °C, distinct from pure rifaximin (190.11 °C) and oxalic acid (189.45 °C), confirming the formation of a new crystalline phase. PXRD patterns showed new peaks at 2θ = 12.96°, 16.55°, and 24.42° for the cocrystal, which were absent in the pure drug and co-former, indicating the generation of a novel crystal structure. SEM images revealed significant morphological changes: pure rifaximin appeared as irregular coarse particles, while the cocrystal formed smooth, plate-like crystals with uniform surfaces. Saturation solubility of the cocrystal in 0.375% SLS phosphate buffer (pH 6.8) increased to 2.782 ± 0.21 mg/mL, compared to 0.3892 ± 0.09 mg/mL for pure rifaximin (p < 0.01), representing a 7.1-fold enhancement. The cocrystal-based immediate-release tablet showed 90.25 ± 1.76% drug release at 45 minutes, significantly higher than the pure drug tablet (64.37 ± 2.01%) and the marketed Rexigut tablet (73.15 ± 2.32%). Tablet content uniformity was 98.42 ± 1.6%, disintegration time was 4.8 ± 0.5 minutes, and friability was below 0.5%, meeting pharmacopeial standards. Stability testing under accelerated conditions (40 °C/75% RH) for 3 months showed no significant changes in PXRD patterns or dissolution behavior (post-stability drug release: 89.76 ± 2.01%), indicating physical and chemical stability.

Conclusion: Compared to pure rifaximin, these rifaximin co-crystals have significantly improved solubility and in-vitro dissolution. It potentially leads to improved therapeutic outcomes.