Unlocking the reversibility of the mechanochemical synthesis of a pharmaceutical cocrystal

Abstract

Opposite transformations (synthesis or decomposition of the cocrystal) in the system “piroxicam (P) – succinic acid (S) – their 2:1 cocrystal (P2S)” are documented depending on the protocol of mechanical action (milling in a vibrational mill varying the impact to rolling ratio and the impact frequency; rolling in a rotational mill), and the presence of a fluid (ethanol, acetone, tetrahydrofuran) as an additive. A striking difference in the impact-to-rolling ratio appearing upon seemingly benign change to the milling jar shape was observed and studied with the help of acoustic analysis. The synthesis of P2S cocrystals occurred only in the presence of a solvent. The degree of transformation achieved after a fixed treatment time correlated with the solubility of P in the solvent. LAG of a mixture of P and S with an additive of acetonitrile gave a solvate cocrystal P4S x 2CH3CN instead of P2S. The decomposition of P2S cocrystals, on the contrary, was observed only when dry sample was ground. The frequency of impacts was shown to be directly related with the degree of the synthesis of P2S cocrystals in LAG experiments. Possible reasons for the observed effects are rationalized in terms of mechanochemical crystallization in the presence of liquids and solid-state decomposition resulting from shear stress.