Pharmaceutical Polymorphism of a 5´-O-oxalatoyl Prodrug of Zidovudine (Azidothymidine)

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 to 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% relative humidity (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/cm 2 , whereas AZT-Ac-A exhibited a nonlinear profile.Therefore, the crystalline form demonstrated the advantages over the amorphous one in terms of solid-state stability and IDR, but the approaches to enhance its stability should be considered for further formulation of this prodrug.