Chemical stability of 4'-azidocytidine and its prodrug balapiravir.

Abstract

BACKGROUND:

R1479, a 4'-azidocytidine nucleoside analog, was developed for the treatment of Hepatitis C virus infection. Balapiravir (R1626) is the tri-isobutyrate ester prodrug of R1479 under clinical development to improve exposure of R1479 upon oral administration.

OBJECTIVE:

The chemical stability and the rate of azide release of R1479 and balapiravir were studied.

METHODS:

R1479 and balapiravir solutions were prepared at different pH values and stored at various temperatures. An ion pair high-performance liquid chromatography (HPLC) method with gradient elution was employed to analyze the prodrug, parent, and degradation products. Azide was measured using a reversed phase HPLC method with UV detection after formation of the 3,5-dinitrobenzoyl azide derivative with 3,5-dinitrobenzoyl chloride. The data were analyzed using initial rate and conventional first-order kinetic methods.

RESULTS:

R1479 degrades to cytosine and azide in aqueous solutions, whereas balapiravir mainly degrades to R1479 and mono- and diesters of R1479. The rates of azide release from R1479 and balapiravir were generally comparable with the corresponding amount formed of cytosine.

CONCLUSION:

Azide release is pH dependent and is faster in acidic solutions than in neutral solutions. The amount of azide released is significantly less from balapiravir than that from R1479, suggesting a potential advantage of the prodrug over the parent drug.

• Authors: Fujun Li, Xiaoyang Wu, Xu Hadig, Sujuan Huang, Lei Hong, Tony Tran, Michael Brandl, Tom Alfredson
• Journal: Drug development and industrial pharmacy (Drug Dev Ind Pharm) Vol. 36 Issue 4 Pg. 413-20 (Apr 2010) ISSN: 1520-5762 [Electronic] England
• PMID: 19778160 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Azides
• Nucleosides
• Prodrugs
• Cytidine
• 4'-azidocytidine
• balapiravir

Topics

• Antiviral Agents (chemistry)
• Azides (chemistry)
• Chemical Phenomena
• Cytidine (analogs & derivatives, chemistry)
• Drug Stability
• Hydrogen-Ion Concentration
• Nucleosides (chemistry)
• Prodrugs (chemistry)