Solid-State Chemistry and Pharmaceutical Co-Crystallisation of Poorly Soluble Antihypertensive Agents Using Green Solvent-Assisted Mechanochemistry

Solubility limitations of class II antihypertensive drugs including losartan, candesartan, and nifedipine restrict their oral bioavailability and create formulation challenges particularly relevant to Nigeria where affordable generic antihypertensive products are essential for population-level blood pressure management. Pharmaceutical co-crystallisation using complementary co-formers represents a crystal engineering strategy to modify solid-state properties including solubility without altering molecular structure, thereby avoiding regulatory reclassification. This study applied green solvent-assisted mechanochemical co-crystallisation to produce novel pharmaceutical co-crystals of losartan potassium and nifedipine with generally recognised as safe co-formers including nicotinamide, saccharin, and succinic acid. Co-crystal formation was characterised by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, solid-state NMR, and Raman spectroscopy. Solubility, intrinsic dissolution rate, and hygroscopicity were compared between co-crystals and parent drug forms. Crystal structure determination was performed by single crystal X-ray diffraction for selected co-crystal forms. In vivo pharmacokinetic evaluation compared co-crystal and parent drug absorption in Wistar rats. Losartan-nicotinamide and nifedipine-saccharin co-crystals demonstrated 2.8-fold and 3.4-fold intrinsic dissolution rate improvements respectively over parent drugs, confirmed by enhanced apparent solubility in biorelevant dissolution media. Pharmacokinetic studies in rats showed significantly higher area under the curve and maximum plasma concentration for both co-crystal forms. Green mechanochemical co-crystallisation metrics confirmed reduced solvent consumption compared to conventional slurry methods. These findings provide original solid-state pharmaceutical chemistry data supporting co-crystallisation as a viable solubility enhancement strategy for Nigerian affordable drug manufacturing. Keywords: co-crystallisation, mechanochemistry, solid-state chemistry, antihypertensive, solubility enhancement.