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

Cocrystal (CC) and coamorphous (CM)techniques have become greentechnologies to improve the solubility and bioavailability of water-solubledrugs. In this study, hot-melt extrusion (HME) was employed to produceCC 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 selectivelyprepared depending on the barrel temperatures of HME at a constantscrew speed of 20 rpm and a feed rate of 1.0 g/min. IMC-NICCC was obtained at 105-120 degrees C, IMC-NIC CM was producedat 125-150 degrees C, and the mixture of CC and CM was obtainedbetween 120 and 125 degrees C (like a door switch of CC and CM). SSNMR combined with RDF and E (bind) calculationsrevealed the formation mechanisms of CC and CM, where strong interactionsbetween heteromeric molecules formed at lower temperatures favoredperiodic molecular organization of CC, whereas discrete and weak interactionsformed at higher temperatures promoted disordered molecular arrangementof CM. Additionally, IMC-NIC CC and CM showed enhanced dissolutionand stability over crystalline/amorphous IMC. This study providesan easy-to-operate and environmentally friendly strategy for the flexibleregulation of CC and CM formulations with different properties throughmodulation of the barrel temperature of HME.