Studying effect of glyceryl palmitostearate amount, manufacturing method and stability on polymorphic transformation...

Rifaximin (RFX) exhibit polymorphism and commercial formulation contains the α form. The polymorphic transformation of the RFX in the drug product have significant effect on the clinical outcome. The focus of present work was to understand effect of formulation component and manufacturing method, and exposure to stability condition on polymorphic stability and dissolution of RFX tablets. The RFX tablets containing 2.5, 5 and 10% glyceryl palmitostearate (GPS) were manufactured by direct-compression and wet-granulation followed by compression. Ethanol was used as a granulating solvent. The tablets were packed in pharmacy vials and exposed to 40 °C/75% RH for four weeks. The tablets were characterized for polymorphic form by X-ray powder diffraction (XRPD) and Fourier infrared spectroscopy (FTIR), assay and dissolution. Before exposure to stability condition, dissolution ranged from 78.0 ± 2.3 to 81.9 ± 3.5%, and 72.7 ± 2.0 and 75.9 ± 5.8% in directly compressed and ethanol-granulated formulations, respectively. GPS amount of 10% caused a decrease in dissolution albeit insignificant (p > 0.05). The polymorphic forms of RFX were α and γ in directly compressed and ethanol-granulated formulations, respectively. There was a decrease in dissolution rate and extent after exposure to 40 °C/75% RH in directly compressed formulations. On the other hand, only dissolution rate was affected in ethanol-granulated formulations. The dissolution ranged from 52.8 ± 2.0 to 70.0 ± 3.0% in directly compressed formulations after four weeks exposure to 40 °C/75% RH exposure. A decrease in dissolution was linked to polymorphic transformation of the drug and GPS in the formulations after exposure to stability condition. XRPD and FTIR data indicated α to β transformation in directly compressed formulations while no polymorphic change was observed in ethanol-granulated formulations. In conclusion, this study clearly showed effect of formulation and manufacturing variables, and stability exposure on the polymorphic stability and dissolution of RFX, which may have clinical ramification.