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 investigatethe 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 crystallizationconditions and characterized using powder X-ray diffraction, solid-state nuclear magnetic resonance, differentialscanning calorimetry, thermogravimetry, and hot-stage microscopy. Pharmaceutical relevant properties such assolid-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 toAZT-Ac-C and partially hydrolyzed to AZT after 7 and 14 days of storage, respectively. AZT-Ac-C was physicallystable at 40°C/75% RH but partly hydrolyzed to AZT after 14 days of storage. In SGF, AZT-Ac-C exhibited a linearID profile and provided an ID rate of 0.494 mg/min/cm2, 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, butthe approaches to enhance its stability should be considered for further formulation of this prodrug.