Switch between Cocrystal and Coamorphous Forms Depending on Thermal Modulation of Hot-Melt Extrusion

Abstract

Cocrystal (CC) and coamorphous (CM) techniques have become green technologies to improve the solubility and bioavailability of water-soluble drugs. In this study, hot-melt extrusion (HME) was employed to produce CC and CM formulations of indomethacin (IMC) and nicotinamide (NIC) due to its advantages like solvent-free and large-scale manufacturing. Interestingly, for the first time, IMC−NIC CC and CM were selectively prepared depending on the barrel temperatures of HME at a constant screw speed of 20 rpm and a feed rate of 1.0 g/min. IMC−NIC CC was obtained at 105−120 °C, IMC−NIC CM was produced at 125−150 °C, and the mixture of CC and CM was obtained between 120 and 125 °C (like a door switch of CC and CM). SS NMR combined with RDF and E bind calculations revealed the formation mechanisms of CC and CM, where strong interactions between heteromeric molecules formed at lower temperatures favored periodic molecular organization of CC, whereas discrete and weak interactions formed at higher temperatures promoted disordered molecular arrangement of CM. Additionally, IMC−NIC CC and CM showed enhanced dissolution and stability over crystalline/amorphous IMC. This study provides an easyto-operate and environmentally friendly strategy for the flexible regulation of CC and CM formulations with different properties through modulation of the barrel temperature of HME.

New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity

“…It was also proven that, using the hot melt extrusion method, it was possible to adapt the synthesis conditions in such a way that the obtained product will be either a co-crystal or a co-amorphous solid. For instance, Zhang, Qian, Heng et al found that in case of indomethacin (IMC) and nicotinamide (NIC), the temperature 105–120 °C allowed a co-crystal to be obtained, whereas the temperature 125–150 °C provided a co-amorphous solid dispersion . The authors concluded that at low temperatures, the system had high viscosity and slow molecular diffusion, which resulted in a system with low diffusivity and high homogeneity that favored the formation of strong interactions.…”