A SCIENTIFIC EXPLORATION OF CO-AMORPHOUS FORMULATION DRIVEN BY KNOWLEDGE BASED VIRTUAL SCREENING FOR SOLUBILITY AND BIOAVAILABILITY ENHANCEMENT OF DARUNAVIR
DOI:
https://doi.org/10.56782/pps.376Keywords:
Co-amorphous, Solubility enhancement, Oral bioavailability enhancement, Darunavir, Hansen Solubility ParameterAbstract
Co-amorphous systems (CAMS) have been studied as a solubility enhancement tool for the drugs facing solubility and bioavailability challenges. They have also been used to improve the stability with respect to amorphous state which is responsible for higher dissolution of the drug. This study aimed to obtain the mechanistic insights into co-amorphous formulation and improvement of the solubility of Darunavir, thereby establishing bioavailability advantage over the pure drug. To select the co-former, various virtual screening methods was employed such as the Hansen Solubility Parameter and Flory-Huggins Interaction Parameter, leading to the selection of Para-Amino Benzoic acid as a co-former. Various methods for preparation such as solvent evaporation, quench cooling and spray drying techniques were employed for co-amorphization. Based on dissolution performance the SE method was selected as it showed a 36.9-fold improvement in solubility, while dissolution studies demonstrated a 3.39-fold improvement. Dissolution studies of CAMS prepared by solvent evaporation method in 1:1 molar ratio established 1.19- and 1.25-fold better performance than 1:2 and 2:1 molar ratio, respectively. The prepared CAMS was characterized by FTIR, DSC, PXRD. Study of CAMS prepared by ex-vivo results demonstrated a 1.84-fold superior permeation, while in-vivo results confirmed a 1.72-fold improvement in oral bioavailability. Further, one-way analysis of variance (ANOVA) was applied to results of in vitro drug release, ex vivo permeation and in vivo pharmacokinetic study followed by Dunnett’s test, which revealed that the increase in drug release, permeation and oral bioavailability of CAMS, were statistically significant at a probability level of p < 0.05 when compared with the pure crystalline drug darunavir.
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