In silico and in vitro investigation of bile salts as coformers for edaravone coamorphous dispersion- Part I

Abstract

In the present study, we aimed to design the spray-dried coamorphous dispersion (COAM) of a neuroprotective agent-edaravone (EDR) with bile salts to improve oral bioavailability. After the initial screening of different bile salts, EDR-sodium taurocholate (NaTC) COAM showed 4-fold solubility than a pure drug in 1–7 pH range. In silico studies to select coformer for COAM revealed a narrow energy gap, easy charge transfer and high chemical reactivity between EDR and NaTC. The optimized EDR-NaTC COAM in a 1:1 molar ratio was characterized for solid state characterizations and in vitro release study. Hydrogen bond formation between the pyrazolone ring of EDR and the -OH group of the phenanthrene ring of NaTC was observed in the ATR-FTIR spectra of COAM. The DSC and XRPD data indicated the formation of an amorphous halo, whereas SEM photographs demonstrated porous, spherical particles of COAM. The pH-independent in vitro drug release of COAM was observed in 0.1 N HCl, pH 4.5 and 6.8 buffers which was 3-fold higher than EDR. The COAM was stable for 6 months at accelerated condition without showing a change in drug content or devitrification (Initial: 98.002 ± 0.942 %; Accelerated condition: 97.016 ± 1.110 %). Although coamorphous form and hydrogen bonding between EDR-NaTC dispersion were primarily responsible for improved dissolution, NaTC, an exceptional surfactant, has also contributed to it. Moreover, its exclusive structural characteristics could prevent the recrystallization of the drug in supersaturated conditions of the GIT and also minimize the effect of food on oral absorption of EDR which will be studied in animals in the second part of this work.