Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
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Date
2020-03
Journal Title
Journal ISSN
Volume Title
Publisher
Open Science Publishers LLP
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.
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Keywords
Crystallization, differential scanning calorimetry, drugs, nuclear magnetic resonance, nucleoside inhibitors, X-ray diffraction.
Citation
Diego E. Kassuha, Flavia P. Bruno, Gustavo A. Monti, Norma R. Sperandeo. Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine). Journal of Applied Pharmaceutical Science. 2020 Mar; 2020 Mar: 067-074