Influence of counterion transfer on the physicochemical properties of fixed dose combinations containing bedaquiline and clofazimine.

چکیده اصلی

Fixed-dose combinations (FDCs) offer significant advantages in the treatment of multidrug-resistant tuberculosis (MDR-TB), including reduced pill burden, increased treatment adherence, minimization of resistance development, and decreased relapse rates. A critical prerequisite for developing FDCs in single-unit formulations is ensuring physicochemical compatibility between the combined drugs, particularly for ionizable compounds. Bedaquiline (BDQ) and clofazimine (CFZ) are weakly basic drugs and promising candidates for next-generation antituberculosis FDCs. BDQ fumarate (BDQF) is widely used in the commercial product due to its improved solubility and oral bioavailability. This study provides a comparative evaluation of binary systems containing BDQ or BDQF with CFZ at different molar ratios, including 1:1, 1:2, and 2:1. Through physicochemical characterization using Fourier transform - InfraRed (FTIR) spectroscopy, X-ray powder diffraction (XRPD), apparent solubility and dissolution studies, we demonstrate that BDQF undergoes counterion transfer with CFZ, leading to the formation of new salts of either CFZ or BDQ. These new salts significantly enhance the dissolution behavior of CFZ in the BDQF-CFZ binary systems, which cannot be seen in the BDQ-CFZ systems. On the other hand, the dissolution rate of BDQF was also decreased in specific drug ratios. More specifically, we found that the ratio of 2:1 can synergistically enhance the solubility of CFZ, maintain the equibilirum solubility and provide adequate dissolution of BDQF. The findings provide mechanistic insights of selecting suitable drug forms in optimizing FDC performance and designing optimal formulations for MDR-TB therapy.

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