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.
Deep eutectic solvents (DESs), as one type of modern green solvent, have gained increasing interest in regulating the crystallization process. Crystal habit is one of the crucial physical properties affecting product processing and the quality of pharmaceutical preparations. Here, a highly unusual diamondshaped crystal of honokiol (HON, a natural bioactive compound with multiple pharmacological activities) was discovered from volatile HON-based DES. In non-DES solvents, HON grows as hexagonal crystals with the same growth mode along the opposite directions of the nonpolar b-axis. In contrast, the (010) face along the b-axis disappeared in volatile DESs, breaking the original crystal symmetry. Surface tension analysis revealed that the volatilization of co-formers (i.e., menthol and camphor in this work) in the DES destroyed its hydrogen bond network, generating two crystallization environments for HON. Primary trapezoidal HON crystals formed in the hole environment after evaporation of coformers at an early stage. The (010) face of trapezoidal crystal continuously grows in the molecular cluster environment due to its highest roughness and preferential adsorption with DESs and finally disappears to form diamond-shaped crystals. Furthermore, the diamond-shaped crystals show improved dissolution behavior and powder flowability compared to the hexagonal crystals. This study clarifies the DES supramolecular structure changes caused by its component volatilization and its regulating mechanism on the HON crystallization process, which might provide a new route and guidance for the crystal morphology modification of organic small molecules.
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