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Date Published: 15/01/2024
Abstract Views: 309
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DOI: https://doi.org/10.51298/vmj.v534i1.8091
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Vol. 534 No. 1 (2024)
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Các bài báo
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Lữ , T. P. ., Trần , V. H. ., & Trương , N. T. . (2024). SYNTHESIS AND REFERENCE STANDARD ESTABLISHMENT OF ALLOPURINOL IMPURITY F (ETHYL-(E/Z)-3-(2-CARBETHOXY-2-CYANOETHENYL)AMINO-1H-PYRAZOL-4-CARBOXYLAT). Vietnam Medical Journal, 534(1). https://doi.org/10.51298/vmj.v534i1.8091

SYNTHESIS AND REFERENCE STANDARD ESTABLISHMENT OF ALLOPURINOL IMPURITY F (ETHYL-(E/Z)-3-(2-CARBETHOXY-2-CYANOETHENYL)AMINO-1H-PYRAZOL-4-CARBOXYLAT)

Thiện Phúc Lữ , Việt Hùng Trần , Ngọc Tuyền Trương

Main Article Content

Abstract

Background: Allopurinol is a priority drug prescribed in gout treatment and is currently listed as an essential drug by the Ministry of Health of Vietnam [1]. Impurity F allopurinol (Ethyl-(E/Z)-3-(2-carbethoxy-2-cyanoethenyl)amino-1H-pyrazol-4-carboxylate) is an impurity in processing the synthesis of allopurinol that has the potential to cause cancer mutated and regulated under mandatory testing in USP-NF-2023 [2],[6]. However, the F allopurinol impurity standard is currently very expensive (over 800 USD/25mg) and is not readily available, affecting testing and drug quality control [7]. Objectives: Synthesis of F allopurinol impurities at laboratory scale qualified to establish reference standards in Vietnam. Materials and methods: Impurity F allopurinol is synthesized from ethyl (ethoxymethylene) cyanoacetate and hydrazine hydrate 50% with molar ratio and temperature and reaction time were investigated for ease of purification and high purity. Developed a process to determine purity using HPLC-PDA and evaluated vial uniformity and purity values ​​at 03 GLP laboratories in the Institute of Drug Quality Control in Ho Chi Minh City. Results: Successfully synthesized F allopurinol from ethyl(ethoxymethylene)cyanoacetate and hydrazine hydrate 50% with molar ratio 4 :1; reaction temperature 60oC, for 30 minutes. The substant structure was determined by UV-Vis spectroscopy; IR compared with standard, MS high-resolution, 13C-NMR, and 1H-NMR spectra showed results consistent with the F allopurinol impurity structure. The purity determination procedure by HPLC-PDA was validated with stationary phase: Gemini – NX C18 column (15 cm; 4.6 mm; 5µm), column temperature: 25 °C, mobile phase: acetonitrile – formic acid, pH = 2.5 (35:65), flow rate: 1 ml/min, sample concentration 50 µg/ml in mobile phase, sample injection volume: 10 µl, wavelength 254 nm. Results of interlaboratory evaluation of purity with published value reached 99.5%. Conclusion: 2.5g of allopurinol F impurity has been synthesized on a laboratory with a purity of over 99%, and a process for determining the F impurity purity by HPLC-PDA has been developed to qualify for establishing a reference standard.

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References

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