This study aimed to formulate and optimize metolazone (MLZ) co-crystals incorporating fast-dissolving films (OFDFs) as an agreeable oral formulation for improving the bioavailability of the drug. The co-crystal formation between MLZ and different co-formers was performed using the solvent evaporation method. The MLZ co-crystal formula (MLZ-nicotinamide) with the highest dissolution parameters was loaded into OFDFs by the solvent casting method after being characterized by FT-IR, DSC, and PXRD. The formulated OFDFs were evaluated for their physicochemical properties. Using Statgraphics Centurion software, a full factorial design was used to examine the impact of formulation variables on the swelling index, the disintegration time, and the cumulative MLZ percent release after 10 min. The optimized OFDF was subjected to palatability, stability, and in vivo studies. Various co-formers lowered the melting point of MLZ, suggesting the development of different crystalline packing arrangements and the formation of co-crystals. All developed co-crystal formulations had higher values for relative dissolving rate (RD) and dissolution efficiency (DE%) when compared to pure MLZ. The obtained FTIR data could reflect the co-crystallization process between MLZ and nicotinamide, which was confirmed by the change of the PXRD pattern and the shift of the endothermic peak obtained by DSC. The optimized OFDF loaded with MLZ had a 4.57 swelling index, a 23.7 s disintegration time, and 99.8% MLZ released after 10 min. The optimized formula was stable for six months under the specified storage conditions. When evaluated in rabbits, the relative bioavailability of the optimized MLZ-OFDF was calculated to be approximately two-fold higher than that of the commercially available Efectinix® tablets.
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