Preformulation studies of novel 5′-O-carbonates of lamivudine with biological activity: solubility and stability assays

Abstract

As a part of preformulation studies, the aim of this work was to examine the solubility and stability of a series of 5′-O-carbonates of lamivudine with proven antihuman immunodeficiency virus activity. Solubility studies were carried out using pure solvents (water, ethanol and polyethylene glycol 400 [PEG 400]), as well as cosolvents in binary mixture systems (water–ethanol and water–PEG 400). These ionizable compounds showed that their aqueous solubility is decreasing as the carbon length of the substituent moiety increases, but being enhanced as the pH was reduced from 7.4 to 1.2. Thus, 3TC-Metha an active compound of the series, with an intrinsic solubility at 25 °C of 17 mg/mL, was about 70 times more soluble than 3TC-Octa (0.24 mg/mL), and at pHs of 1.2, 5.8 and 7.4 had intrinsic solubilities of 36.48, 19.20 and 15.40 mg/mL, respectively. In addition, the solubility was enhanced significantly by using ethanol and PEG 400 as cosolvents. A stability study was conducted in buffer solutions at pH 1.2, 5.8, 7.4 and 13.0 and in human plasma at 37 °C. Stability-indicating high-performance liquid chromatography procedure was found to be selective, sensitive and accurate for these compounds and good recovery, linearity and precision were also observed.

• Aqueous stability
• cosolvency
• human plasma stability
• pH-solubility profiles
• prodrugs
• solubility

Acknowledgements

The authors gratefully acknowledge the financial support of Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECYT-UNC), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Agencia Nacional de Promoción Científica y Tecnológica (FONCYT) and Ministerio de Ciencia y Tecnología (MINCYT) of Argentina. The authors express their sincere thanks to Dr. L. Alassia (FILAXIS Laboratories) for supplying 3TC, and Banco de Sangre (UNC) for providing serum plasma. M.S.G and S.R also acknowledge the fellowships granted by SECYT-UNC and CONICET, respectively. M.A.R. is a research fellow of CONICET. We thank Dr. Paul Hobson, native speaker, for revision of the manuscript.