Exploring the novel green eutectic solvent for the synthesis of 4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide with benzoic acid cocrystal using a co-grinding technique

In the present study, the suitability of a green eutectic solvent, a mixture of menthol and camphor for cocrystal synthesis has been investigated to improve the biopharmaceutical properties of poorly water-soluble drugs. To explore this, piroxicam (PRX) (4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide), a non-steroidal anti-inflammatory drug was taken as a model drug and benzoic acid (BA) used as a co-former. An equimolar proportion of PRX and BA was ground in a mortar pestle with dropwise addition of the green eutectic solvent, and the ground solids were then dried and characterized to confirm the formation of the PRX-BA cocrystal. Powder X-ray diffraction and differential scanning calorimetry showed the potential formation of the cocrystal from the appearance of new peaks in the diffraction pattern and a change in thermal behavior, respectively. Fourier transform infrared spectroscopy revealed the formation of C-H center dot center dot center dot O and C-H center dot center dot center dot N hydrogen bonds between the OH or NH group of PRX with the carbonyl group of BA at the ratio of 1 : 1. PRX-BA cocrystals showed a 3-fold increase in the solubility, and an intrinsic dissolution rate with 15-fold improvement in the oral bioavailability in rats compared to the pure PRX. Thus, the green eutectic solvent-based grinding technology is a selective single step method for the continuous manufacturing of the cocrystal that can serve as an alternative to traditional methods of cocrystal synthesis.