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As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly due to its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited much lower dissolution than that of its stable crystalline form arising from its gelation during dissolution process. In the current study, a supramolecular coamorphous system of LH with L-cysteine hydrochloride (CYS) was prepared and characterized by PXRD and DSC. Surprisingly, in comparison to crystalline and amorphous LH, such coamorphous system dramatically enhanced solubility (at least ~50-fold in physiological pH range) and dissolution (~1200-fold) of LH, and exhibited superior physical stability under the long-term storage condition. More importantly, the coamorphous system was able to eliminate gelation of amorphous LH during dissolution. In order to further explore the mechanism of such improvement, the internal interactions of coamorphous system in solid state and in aqueous solution were investigated. FTIR, Raman spectroscopy and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in benzisothiazole ring of LH and NH3+ group of CYS after co-amorphization. Fluorescence quenching test with Stern-Volmer plot and density functional theory (DFT) modeling, phase-solubility study and NMR test in D2O indicated that ground-state complexation occurred between LH and CYS in aqueous solution, which contributed to solubility and dissolution enhancement of LH. The current study offers a promising strategy to overcome poor solubility/dissolution and be able to eliminate gelation of amorphous materials by coamorphization and complexation.
This article was published in the following journal.
Name: Molecular pharmaceutics
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