Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride

Abstract

As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited a much lower dissolution than that of its stable crystalline form arising from its gelation during the dissolution process. In the current study, a supramolecular coamorphous system of LH with l-cysteine hydrochloride (CYS) was prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. Surprisingly, in comparison to crystalline and amorphous LH, such a coamorphous system dramatically enhanced solubility (at least ∼50-fold in the physiological pH range) and dissolution (∼1200-fold) of LH, and exhibited superior physical stability under 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 the coamorphous system in the solid state and in aqueous solution were investigated. Fourier transform infrared spectroscopy, Raman spectroscopy, and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in the benzisothiazole ring of LH and the NH3 + group of CYS after coamorphization. A fluorescence quenching test with a Stern–Volmer plot and density functional theory 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 the 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.

Influence of the pKa Value of Cinnamic Acid and P-Hydroxycinnamic Acid on the Solubility of a Lurasidone Hydrochloride-Based Coamorphous System

“…Meanwhile, it was found that pHCA showed some shifts for −OH (836 → 840 cm –1 ), −COOH (862 → 859 cm –1 ), CC (1635 → 1628 cm –1 ), and aromatic ring (1605 → 1603 cm –1 ). In comparison to the reported amorphous LH, it can be found that the Raman spectra of coamorphous LH–CA/pHCA (1:1) had shifted remarkably. These obvious shifts indicate that the coamorphous LH and CA/pHCA (1:1) systems might be formed via intermolecular hydrogen bonds.…”

The Formation Mechanism of Epigallocatechin - 5-Hydroxymethylfurfural C Omplex Es By Molecular Simulation Combined with S Pectroscopy Techniques

“…Compared with the spectra of EGC and 5-HMF, the absorption peak positions of the complexes in these wavenumber changed greatly, and the intensity of the absorption peak becomes weaker. This may be the transformation from crystalline to amorphous form, with the disruption of lattice causing a change in molecular conformation [37]. In addition, no new chemical bonds and functional groups were observed in the FRIR spectra of the complexes.…”

Pemilihan Jenis Koformer dan Metode Preparasi dalam Sistem Penghantaran Sediaan Ko-Amorf

“…Teknologi Spektroskopi Raman hampir sama dengan Infra Red, perbedaannya yaitu pada Spektroskopi IR bergantung pada perubahan momen dipol, sensitif terhadap ikatan polar (seperti OH, N-H dan C=O), sedangkan Spektroskopi Raman, bergantung pada perubahan polarisasi molekul, sensitif terhadap ikatan non polar (seperti C-C, C-S, dan C=C). Oleh karena itu, dimungkinkan untuk memperoleh informasi struktur komplementer molekul dengan kombinasi spektroskopi IR dan Raman [69].…”