Processing of a novel mefenamic acid−paracetamol−nicotinamide cocrystal using gas anti-solvent process

This research aimed to enhance the dissolution rate of mefenamic acid (MEF) by preparing a novel cocrystal containing MEF, paracetamol (PAR) and nicotinamide (NIC) via the Gas Anti-Solvent (GAS) process. Box−Behnken design of experiments was implemented to evaluate impacts of various process variables on the dissolution rate of MEF and find optimal conditions for the production ternary system cocrystal with the highest dissolution rate of MEF. The results showed that the fastest dissolution time (t63.2) of 4.19 min was obtained when using the precipitation temperature of 25 °C, NIC−PAR−MEF molar ratio of 4.78:4.78:1 and % MEF saturation of 89.74 %. The obtained cocrystals from GAS at the optimal conditions exhibited an improved dissolution rate 16.40 times higher than that of unprocessed MEF. In order to obtain a product containing a ratio of MEF to PAR that is in line with commercially available drugs (MEF to PAR mass ratios are in the range of 0.4–1.54) and exhibiting a high dissolution rate of MEF, further experiments were conducted using different ratios of PAR to NIC. It was found that the GAS products prepared at 25 °C with the use of % saturation of MEF at 89.74 % and NIC−PAR−MEF molar ratio of 12:2.39:1 (OPT1) had t63.2 value of 2.88 min and MEF to PAR mass ratio of 0.65. When using the NIC−PAR−MEF molar ratio of 9.56:1:1 (OPT2), the product had t63.2 value of 3.30 min and MEF to PAR mass ratio of 1.52. [Display omitted] •Novel MEF–PAR–NIC cocrystals were successfully produced by GAS process.•Box−Behnken design was used to evaluate and optimize the GAS process parameters.•An increase in molar ratio of coformers to drug resulted in higher dissolution rate.•MEF–PAR–NIC cocrystal could dissolve faster than MEF–PAR and MEF–NIC cocrystals.•MEF–PAR–NIC cocrystals by GAS could dissolve 20 times faster than unprocessed MEF.