Mechanochemical synthesis of drug-drug eutectics of the anthelmintic drug, praziquantel, with NSAIDs

Abstract

Eutectic systems offer a crystalline, thermodynamically favourable route to enhance solubility, dissolution rate, and stability of poorly soluble pharmaceuticals. Here, we report the mechanochemical synthesis of four drug-drug eutectics of praziquantel (PZQ) along with nonsteroidal anti-inflammatory drugs (NSAIDs): paracetamol (HAD), aspirin (ASA), ibuprofen (IBP), and indomethacin (INM). Binary mixtures produced using neat grinding were characterised using hot-stage microscopy (HSM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and infrared (FT-IR) spectroscopy to determine the eutectic formation and compositions. DSC thermograms revealed single, endothermic melting events consistent with eutectic behaviour; PXRD patterns showed a simple superposition of the pure drug peaks, indicating that each component retained its crystalline identity without forming cocrystals. The eutectic compositions were further corroborated by binary phase diagrams and microscopic observations of melt behaviour. Solubility and dissolution studies demonstrated significant improvements for the eutectics vis-à-vis the pristine PZQ: thermodynamic solubility increased up to sevenfold (notably with PHAD and PASA), and 30-60 min kinetic dissolution improved by more than 50% for most of the systems. While tabletability remained robust, nondimensional entropy and enthalpy of mixing analyses suggested varying microstructures for the mixtures depending on the PZQ-coformer interactions. Overall, mechanochemically prepared PZQ-NSAID eutectics offer a scalable approach to enhance solubility and dissolution while maintaining crystallinity and potential therapeutic synergy.