Rosuvastatin-metformin co-processing: enhanced dissolution, oral bioavailability, and therapeutic efficacy through a solvent-minimized approach.

OBJECTIVE: Rosuvastatin calcium (ROS) exhibits poor aqueous solubility and dissolution-limited oral absorption. This study aimed to develop an oral co-processed fixed-dose combination of ROS and metformin HCl (MET) to enhance ROS dissolution and oral bioavailability.

SIGNIFICANCE: This work highlights wet co-grinding as a simple, solvent-minimized approach for improving the biopharmaceutical performance of ROS while supporting fixed-dose combination development.

METHODS: Rosuvastatin/metformin (ROS/MET) co-processed systems were prepared using a solvent-minimized wet co-processing approach. The formulations were evaluated for drug content and characterized using Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), thermal analysis (DSC/TGA), and scanning electron microscopy (SEM). In vitro dissolution studies were performed to assess drug dissolution behavior. In vivo comparative pharmacokinetic evaluation in rats (n = 3 per group) assessed oral bioavailability, in vitro-in vivo correlation (IVIVC) analysis and liver biodistribution, while anti-hyperlipidemic efficacy was assessed in hyperlipidemic rats (n = 6 per group) through biochemical and histopathological analyses.

RESULTS: The co-processed mixtures significantly enhanced rosuvastatin dissolution, with the 20:500 ROS ratio (F2) showing the best performance. Across pH 1.2, 4.5, and 6.8, F2 achieved Q5 values of 73.6%, 82.5%, and 92.7%, respectively, compared with 12.4%, 19.9%, and 28.6% for unprocessed ROS. Correspondingly, dissolution efficiency increased from 21.3-42.6% for ROS to 76.2-90.4% for F2. Comparative pharmacokinetic evaluation revealed a 21.5% increase in relative bioavailability, a 1.34-fold increase in Cmax, and a more rapid onset of action compared to unprocessed rosuvastatin. Additionally, the co-processed F2 demonstrated improved liver drug distribution and superior anti-hyperlipidemic effects in poloxamer 407-induced hyperlipidemic rats.

CONCLUSION: The co-processing of rosuvastatin with metformin presents a solvent-minimized and effective strategy to enhance the dissolution, bioavailability, and therapeutic efficacy of rosuvastatin. This approach holds promise for the clinical management of complex conditions such as dyslipidemia and type 2 diabetes mellitus.