Preformulation studies of EFdA, a novel nucleoside reverse transcriptase inhibitor for HIV prevention. (August 2014)

• Record Type: Journal Article
• Authors: Zhang, Wei; Parniak, Michael A.; Mitsuya, Hiroaki; Sarafianos, Stefan G.; Graebing, Phillip W.; Rohan, Lisa C.
• Is Part Of: Drug development and industrial pharmacy. Volume 40:Number 8(2014:Aug.)
• Page Start: 1101
• Page End: 1111
• Publication Date: 2014-08
• Subjects: Pharmaceutical chemistry -- Periodicals; Pharmaceutical industry -- Periodicals; Drug Industry -- Periodicals; Technology, Pharmaceutical -- Periodicals; 615.05
• DOI: 10.3109/03639045.2013.809535
• Languages: English
• ISSNs: 0363-9045

Abstract

<abstract> <title>Abstract</title> <p>4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a novel nucleoside analog of great interest because of its superior activity against wild-type and multidrug-resistant HIV-1 strains, and favorable safety profiles <italic>in vitro</italic> and <italic>in vivo</italic>. The aim of this work was to provide preformulation information of EFdA important for delivery system development. A simple, accurate and specific reverse-phase high performance liquid chromatographic (RP-HPLC) method with UV detection was developed for quantification of EFdA. In addition, physicochemical characterizations including pH solubility profile, octanol/water partition coefficient (Log P<sub>o/w</sub>), DSC analysis, field emission scanning electron microscopy, and stability studies under various conditions were conducted. EFdA existed in planar or flake shape, with a melting point of ∼130 °C, and had a pH dependent solubility. The log P<sub>o/w</sub> value of EFdA was −1.19. The compound was stable upon exposure to pH levels from 3 to 9 and showed good stability at elevated temperature (65 °C). <italic>In vitro</italic> cytotoxicity assessments were performed in two different epithelial cell lines. In cell-based studies, the EFdA selectivity index (50% cytotoxic concentration [CC<sub>50</sub>] values/50% effective concentration [EC<sub>50</sub>]) was found to be greater than 1 × 10<sup>3</sup>. Permeability studies using cell- and tissue-based models showed that EFdA had an apparent permeability coefficient (P<sub>app</sub>) < 1×10<sup>−6 </sup>cm/s and that the paracelluar pathway was the dominant transport route for EFdA. Overall, EFdA possesses favorable characteristics for further formulation development.</p> </abstract>