The esterification stage of low-molecular-mass heparin (enoxaparin) production by hydrolytic depolymerization of unfractionated heparin was studied and consisted of treating previously synthesized benzethonium heparinate with benzyl chloride. The content of benzyl moieties in the synthesized heparin benzylates and their degree of benzylation were determined using HPLC, PMR, and 13C NMR methods. A carboxylic-acid content of 0.13 ± 0.01 mol/g in the starting heparin was calculated from these results. A new method for estimating the degree of heparin benzylation from PMR and HPLC data was proposed. The benzyl content in the heparin benzylates increased with increasing molar excess of benzyl chloride.
Similar content being viewed by others
References
N. B. Wilkinson (ed.), Heparin: Structure, Drug Delivery Applications and Clinical Outcomes (Pharmacology Research, Safety Testing and Regulations), Nova Biomedical, New York, 2014.
R. Bradshaw (ed.), Heparin: Structure, Function, and Clinical Implications (Advances in Experimental Medicine and Biology), Springer, Boston, MA, US, 1975.
R. Lever, B. Mulloy, and C. P. Page (eds.), Heparin – A Century of Progress (Handbook of Experimental Pharmacology), Springer, New York, 2012.
L. E. Frumin, G. A. Kostakova, et al., “Method of obtaining low-molecular heparin,” RU Pat. No. 2,512,768, Apr. 10, 2014; Byull. Izobret., No. 10, 2014.
E. M. Shulutko, Trudnyi Patsient, 9(4), 42 – 49 (2011).
M. N. Kudykin, Statsionarozam. Tekhnol.: Ambulat. Khir., No. 3 – 4 (59 – 60), 35 – 41 (2015).
A. A. Gadel’shina, Int. J. Appl. Fundam. Res., No. 9, 354 – 356 (2016).
O. L. Romanova and N. V. Sturov, Trudnyi Patsient, 9, No. 10, 32 – 36 (2011).
S. A. Golubev, Nov. Khir., 15(3), 83 – 90 (2007).
L. E. Frumin, E. S. Zhavoronok, A. V. Panov, et al., Biofarm. Zh., 10(2), 10 – 22 (2018).
Enoxaparin Sodium, Eur. Pharmacopoeia, 8.1, 3749 – 3751 (2014).
L. E. Frumin, K. P. Yur’eva, A. D. Askretkov, et al., Khim.-farm. Zh., 52(8), 46 – 50 (2018); Pharm. Chem. J., 52, 735 – 739 (2018).
S. A. Kedik, A. V. Panov, L. E. Frumin, et al., “Method for producing low molecular weight heparin,” RU Pat. 2,670,767, Oct. 25, 2018; Byull. Izobret., No. 33 (2018).
S. A. Kedik, A. V. Panov, L. E. Frumin, et al., “Laboratory apparatus for rinsing side products from powder chemical reaction products,” RU Pat. Appl. 186,728, Oct. 19, 2018; Byull. Izobret., No. 4, 2019.
Acknowledgments
The work was financially supported by the Ministry of Education and Science of the Russian Federation in the framework of the project part of a state task for 2017 – 2019 (Project 15.2463.2017/4.6).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 53, No. 10, pp. 40 – 45, October, 2019.
Rights and permissions
About this article
Cite this article
Frumin, L.E., Yur’eva, K.P., Matveev, A.V. et al. Determination of the Degree of Esterification in Heparin Benzylates During Synthesis of Enoxaparin, a Domestic Analog of Low-Molecular-Mass Heparin. Pharm Chem J 53, 852–857 (2019). https://doi.org/10.1007/s11094-019-02089-7
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11094-019-02089-7