Preview

Fine Chemical Technologies

Advanced search

The use of microfluidic hardware in the synthesis of oligohexamethylene guanidine derivatives

https://doi.org/10.32362/2410-6593-2021-16-4-307-317

Full Text:

Abstract

Objectives. To develop a method for the microfluidic synthesis of oligohexamethylene guanidine salts in a flow-type reactor and to evaluate its effectiveness in relation to the synthesis in a traditional capacitive reactor and compare the purities of products obtained by these methods.
Methods. The synthesis of oligohexamethylene guanidine bihydrocarbonate (OHMG-BHC) was done using microfluidic hardware and the classical approach in volume. The purity and structure of the resulting product were confirmed by 13C NMR spectroscopy and high-performance liquid chromatography (HPLC).
Results. The 13C NMR spectrum of OHMG-BHC in classical bulk synthesis demonstrates that the product is unbranched and contains additionally unidentifiable impurities, in contrast to the sample obtained by the microfluidic method. Furthermore, the HPLC analysis showed that the OHMG-BHC sample synthesized using microfluidic technology has a 1.5-fold lower content than the initial monomers.
Conclusions. The advantage of synthesizing OHMG-BHC in a flow-type reactor compared to the traditional method of synthesis in volume is demonstrated since a product with a higher degree of purity is obtained.

About the Authors

D. A. Akhmedova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies); Institutе of Рhаrmасеutiсаl Тесhnоlоgiеs
Russian Federation

Diana A. Akhmedova, Master Student, Department of Biotechnology and Industrial Pharmacy, M.V. Lomonosov Institute of Fine Chemical Technologies; Researcher

86, Vernadskogo pr., Moscow, 119571


Competing Interests:

The authors declare no conflicts of interest 



D. O. Shatalov
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Denis O. Shatalov, Cand. Sci. (Pharm.), Associate Professor, Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571


Competing Interests:

The authors declare no conflicts of interest.



I. S. Ivanov
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Ivan S. Ivanov, Postgraduate Student, Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571


Competing Interests:

The authors declare no conflicts of interest.



A. V. Aydakova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies); Institutе of Рhаrmасеutiсаl Тесhnоlоgiеs
Russian Federation

Anna V. Aydakova, Postgraduate Student, Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571


Competing Interests:

The authors declare no conflicts of interest.



A. Herbst
Wingflow AG
Switzerland

Alexander Herbst, Dr. Sci. (Eng.), General Director

Gänsacker 5, Frico AG, 5070


Competing Interests:

The authors declare no conflicts of interest.



L. Greiner
Manheim University of Applied Sciences
Germany

Lasse Greiner, Dr. Sci. (Eng.), Professor, Head of the Faculty of Biotechnology

10, Paul-Wittsack Street, Mannheim, 68163


Competing Interests:

The authors declare no conflicts of interest.



A. P. Kaplun
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Alexander P. Kaplun, Dr. Sci. (Chem.), Professor, Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571

Scopus Author ID 7006433250


Competing Interests:

The authors declare no conflicts of interest.



A. S. Zhurbenko
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Anton S. Zhurbenko, Student, Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571


Competing Interests:

The authors declare no conflicts of interest.



S. A. Kedik
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies); Institutе of Рhаrmасеutiсаl Тесhnоlоgiеs
Russian Federation

Stanislav A. Kedik, Dr. Sci. (Eng.), Professor, Head of the Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571

Scopus Author ID 7801632547


Competing Interests:

The authors declare no conflicts of interest.



References

1. Wanted: a reward for antibiotic development. Nat. Biotechnol. 2018;36(7):555. https://doi.org/10.1038/nbt.4193

2. Gil-Gil T., Laborda P., Sanz-García F., Hernando-Amado S., Blanco P., Martínez J.L. Antimicrobial resistance: A multifaceted problem with multipronged solutions. Microbiologyopen. 2019;8(11):e945. https://doi.org/10.1002/mbo3.945

3. Asyamova A.V., Gerunov V.I. Guanidine derivatives in medicine and agriculture. Vestnik of Omsk SAU. 2017:4(29):130–135 (in Russ.).

4. Pasero C., D’Agostino I., De Luca F., Zamperini C., Deodato D., Truglio G.I., Sannio F., Del Prete R., Ferraro T., Visaggio D., Mancini A., Guglielmi M.B, Visca P., Docquier J.-D., Botta M. Alkylguanidine Compounds as Potent Broad-Spectrum Antibacterial Agents: Chemical Library Extension and Biological Characterization. J. Med. Chem. 2018;61(20):9162–9176. https://doi.org/10.1021/acs.jmedchem.8b00619

5. Beliakov S.V., Shatalov D.O., Kedik S.A., Aydakova A.V., Zasypkina N.A. Preliminary in vitro and in vivo evaluation of specific activity of branched oligohexamethyleneguanidine hydrochloride. Drug Dev. Ind. Pharm. 2020;46(9):1517–1523. https://doi.org/10.1080/03639045.2020.1810267

6. Hua D., Hongtao Yu. New Antibiotics: Where Are They? Biomed. J. Sci. & Tech. Res. 2018;10(1):7629–7631. http://dx.doi.org/10.26717/BJSTR.2018.10.001909

7. Kovalenko A.V., Shatalov D.O., Kedik S.A., Gromakova A.I., Kaplun A.P., Ivanov I.S., Sterin I.V. The direction of development of drug therapy for infectious conjunctivitis (literature review). Problems of biological, medical and pharmaceutical chemistry. 2019;22(12):5−11 (in Russ.). https://doi.org/10.29296/25877313-2019-12-01

8. Vointseva, I.I., Gembitskiĭ P.A. Poliguanidiny–dezinfektsionnye sredstva i polifunktsional’nye dobavki (Polyguanidines are disinfectants and multifunctional additives). Мoscow: LKM-press; 2009. 304 p. (in Russ.). ISBN 978-5-9901286-2-0

9. Weia D., Maa Q., Guana Y., Hua F., Zhenga A., Zhangb X., Tengb Z., Jiangb H. Structural characterization and antibacterial activity of oligoguanidine (polyhexamethylene guanidine hydrochloride). Materials Science and Engineering. 2009;29(6):1776–1780.

10. Bally F., Serra C. A., Brochon C., Hadziioannou G. Synthesis of Branched Polymers under ContinuousFlow Microprocess: An Improvement of the Control of Macromolecular Architectures. Macromol. Rapid Commun. 2011;32:1820−1825.

11. Manz A., Graber N., Widmer H.M. Miniaturized total chemical analysis systems: A novel concept for chemical sensing. Sensors and Actuators B. 1990;2(4):244–248.

12. Srinivasan R., Firebaugh S.L., Hsing I.-M., Ryley J., Harold M.P., Jensen K.F., Schmidt M.A. Chemical performance and high temperature characterization of micromachined chemical reactors. In: Proceedings of International Solid State Sensors and Actuators Conference (Transducers 1997). 1997;1:163–166. https://doi.org/10.1109/SENSOR.1997.613608

13. Schwalbe T., Autze V., Wille G. Chemical synthesis in microreactors. Chimia. 2002;56(11):636–646.

14. Marre S., Roig Y., Aymonier C. Supercritical microfluidics: Opportunities in flow-through chemistry and materials science. J. Supercrit. Fluids. 2012;66:251–264.

15. Kockmann N., Gottsponer M., Zimmermann B., Roberge D.M. Enabling continuous-flow chemistry in microstructured devices for pharmaceutical and fine-chemical production. Chem. Eur. J. 2008;14:7470–7477. https://doi.org/10.1002/chem.200800707

16. Bally F., Serra C. A., Brochon C., Hadziioannou G. Synthesis of Branched Polymers under ContinuousFlow Microprocess: An Improvement of the Control of Macromolecular Architectures. Macromol. Rapid Commun. 2011;32:1820−1825.

17. Ivanov I.S., Kedik S.A., Shatalov D.O., Legon᾽kova O.A., Aydakova A. V., Norin A.M., Khar᾽kovskaya M.D. Prospects for use of microfluidics for synthesis of alkylen guanidinetype compounds. Polymer Science. Series D. 2020;12:30–37 (in Russ.). https://doi.org/10.1134/S1995421221020088

18. Shatalov D.O., Kedik S.A., Beliakov S.V., Ivanov I.S., Aydakova A.V., Sedishev I.P. Method of producing branched oligohexamethylene guanidine salts having degree of purity sufficient for use thereof as pharmaceutical substance: RU Pat. 2729421. Publ. 06.08.2020. (in Russ.).

19. Kedik S.A., Sedishev I.P., Panov A.V., Zhavoronok E.S., Ha A.C. Branched oligomers based on a guanidine derivative and a disinfectant containing them: RU Pat. 2443684. Publ. 27.02.2012. (in Russ.).


Supplementary files

1. Hardware diagram of microfluidic synthesis: 1 – an aqueous solution of GHC and HMDA; 2 – a syringe pump; 3 – a microreactor; 4 – a control computer; 5 – a rotary evaporator.
Subject
Type Исследовательские инструменты
View (567KB)    
Indexing metadata
2. This is to certify that the paper titled The use of microfluidic hardware in the synthesis of oligohexamethylene guanidine derivatives commissioned to us by Diana A. Akhmedova, Denis O. Shatalov, Ivan S. Ivanov, Anna V. Aydakova, Alexander Herbst,Lasse Greiner, Alexander P. Kaplun, Anton S. Zhurbenko, Stanislav A. Kedik has been edited for English language and spelling byEnago, an editing brand of Crimson Interactive Inc.
Subject CERTIFICATE OF EDITING
Type Other
View (221KB)    
Indexing metadata
  • A method for the microfluidic synthesis of oligohexamethylene guanidine (OHMG) salts in a flow-type reactor was developed.
  • The efficiency of microfluidic synthesis in a flow-type reactor with a classical capacitive reactor was compared.
  • Spectral 13C NMR analysis of the OHMG dihydrocarbonate sample obtained during classical synthesis in volume showed that the product is unbranched and contains additionally unidentifiable impurities, unlike the sample obtained by the microfluidic method.
  • The high-performance liquid chromatography analysis showed that the sample of OHMG dihydrocarbonate synthesized using microfluidic technology had a 1.5 times lower content of the initial monomers.

For citation:


Akhmedova D.A., Shatalov D.O., Ivanov I.S., Aydakova A.V., Herbst A., Greiner L., Kaplun A.P., Zhurbenko A.S., Kedik S.A. The use of microfluidic hardware in the synthesis of oligohexamethylene guanidine derivatives. Fine Chemical Technologies. 2021;16(4):307-317. https://doi.org/10.32362/2410-6593-2021-16-4-307-317

Views: 197


ISSN 2410-6593 (Print)
ISSN 2686-7575 (Online)