Abstract
We aimed to identify a suitable solvent [dimethyl acetamide (DMA), ethyl acetate, (EA), N-methyl pyrrolidone (NMP), cremophor-EL (CEL), transcutol-HP (THP), polyethylene glycol 400 (PEG-400), limonene and ethanol] based on experimental solubility, thermodynamic/computational parameters for subcutaneous (sub-Q) delivery. The "vanit Hoff" model validated solubility values in several solvents at "T = 298.2 K-318.2 K" and "p = 0.1 MPa". In silico prediction study was carried out for sub-Q delivery using GastroPlus. The selected KETO-DMA construct was evaluated for cellular interaction, cellular uptake (L929 cells), cytotoxicity (L929 and J774A.1) and antifungal activities (C. albicans, C. glabrata, C. Tropicalis, and A. niger). The maximum mole fractional solubility of KETO were found in three solvents such as DMA (4.8 x 10-2) > EA (2.8 x 10-2) > NMP (11.7 x 10- 3) at "T = 318.2 K". Analysis confirmed "endothermic and entropy" driven solubilization process. GastroPlus predicted pharmacokinetics parameters were influenced with nonsaturable metabolic clearance in subcutaneous tissue of human. Interaction study of KETO-DMA solution with Candida cells showed maximized cellular internalization. KETO-DMA solution exhibited poor cellular uptake by L929 cell lines (murine fibroblast cells) compared to KETO aqueous solution which was further supported with cytotoxicity study in L929 and J774A.1 cell lines. Reduced MIC values of KETO-DMA solution as compared to KETO aqueous solution against four strains corroborated improved efficacy of KETO probably due to augmented solubility in DMA and lack of surfactant. Thus, KETO-DMA solution can be a suitable construct for sub-Q delivery to control fungal infections.