Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)

Abstract

The importance of polymorphism in pharmaceuticals makes its study relevant. The aim of this study was to investigate the solid-state forms in which 3´-azido-2´,3´-dideoxi-5´-O-oxalatoyl-thymidinic acid (AZT-Ac), a zidovudine (AZT) prodrug with improved pharmacokinetic properties, may exist. Samples were prepared using different crystallization conditions, and characterized using powder X-ray diffraction, solid state nuclear magnetic resonance, differential scanning calorimetry, thermogravimetry and hot stage microscopy. Pharmaceutical relevant properties such as solid-state stability and intrinsic dissolution rate (IDR) at 37 °C in simulated gastric fluid (SGF) were also evaluated. AZT-Ac was found able to exist as a crystalline polymorph (AZT-Ac-C) and an amorphous phase (AZT-Ac-A), which were thoroughly characterized. At 40 °C/75% RH, AZT-Ac-A in part devitrified to AZT-Ac-C, and partially hydrolyzed to AZT after 7 and 14 days of storage, respectively. AZT-Ac-C was physically stable at 40 °C/75% RH but partly hydrolyzed to AZT after 14 days of storage. In SGF, AZT-Ac-C exhibited a linear ID profile and provided an ID rate of 0.494 mg/min/cm2 while AZT-Ac-A exhibited a nonlinear profile. Therefore, the crystalline form demonstrated advantages over the amorphous one in terms of solid state stability and IDR, but approaches to enhance its stability should be considered for further formulation of this prodrug.Fil: Kassuha, Diego Enrique. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bruno, Flavia Paola. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Laboratorio Fresenius Kabi; ArgentinaFil: Monti, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; Argentina. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; ArgentinaFil: Sperandeo, Norma Rebeca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentin