Implementation of pharmaceutical development using multivariate analysis of multi-criteria optimization on the example of the stage of purification of oligohexamethyleneguanidine hydrosuccinate

Objectives. The study set out to use mathematical modeling, in particular the method of multifactorial analysis of multicriteria optimization (MAMO), in the development of a pharmaceutical product.

Methods. After carrying out experimental tests based on the proposed algorithmic sequence, the obtained data were interpreted using MAMO.

Results. The possibility of using MAMO to solve the applied problem of purifying oligohexamethyleneguanidine hydrosuccinate (OHMG-HS), considered as a pharmaceutical precursor for the creation of medicines, was demonstrated.

Conclusions. The expediency of using the proposed algorithm as a tool for pharmaceutical development is substantiated by identifying dependencies of the influence of purification conditions on the final content of admixtures in the target product.

1. Singh K.S., Anand S., Dholpuria S., Sharma J.K., Shouche Y. Antimicrobial Resistance Paradigm and OneHealth Approach. In: Panwar H., Sharma C., Lichtfouse E. (Eds.). Sustainable Agriculture Reviews 46. Mitigation of Antimicrobial Resistance. 2020. V. 46. P. 1–32. https://doi.org/10.1007/978-3-030-53024-2_1

2. La-Rosa R., Johansen H.K., Molin S. Persistent Bacterial Infections, Antibiotic Treatment Failure, and Microbial Adaptive Evolution. Antibiotics. 2022;11(3):419. https://doi.org/10.3390/antibiotics11030419

3. Davydov D.S. The National Strategy of the Russian Federation for Preventing the Spread of Antimicrobial Resistance: Challenges and Prospects of Controlling One of the Global Biological Threats of the 21st Century. BIOpreparaty. Profilaktika, diagnostika, lechenie = BIOpreparations. Prevention, Diagnostics, Treatment. 2018;18(1):50–56 (in Russ.). https://doi.org/10.30895/2221-996X-2018-18-1-50-56

4. Kedik S.A., Shatalov D.O., Norin A.M., Belyakov S.V., Ivanov I.S., Aidakova A.V. Method for the separation of branched oligohexamethylenguanidine salts for their use as pharmaceutical substances (variants): RF Pat. RU2750869. Publ. 07.05.2021 (in Russ.).

5. Shatalov D.O., Kedik S.A., Belyakov S.V., Ivanov I.S., Aidakova A.V., Sedishev I.P. Method of producing branched oligohexamethylene guanidine salts having degree of purity sufficient for use thereof as pharmaceutical substance: RF Pat. RU2729421. Publ. 06.08.2020 (in Russ.).

6. Shatalov D.O., Kedik S.A., Ivanov I.S., et al. Development of a Promising Method for Producing Oligomeric Mixture of Branched Alkylene Guanidines to Improve Substance Quality and Evaluate their Antiviral Activity Against SARS-CoV-2. Molecules. 2021;26(11):3472. https://doi.org/10.3390/molecules26113472

7. Belyakov S.V., Kedik S.A., Krupenchenkova N.V., Demenyuk P.Yu., Shatalov D.O. The effect of branched oligo(hexamethylene)guanidine hydrochloride against clinically significant pathogens. Biofarmatsevticheskii zhurnal = Russ. J. Biopharml. 2019;11(6):28–37 (in Russ.).

8. Kedik S.A., Shatalov D.O., Panov A.V., Aidakova A.V., Ivanov I.S., Belyakov S.V. Combined drug preparation in form of solution for preparing spray for treating diseases of oral cavity: RF Pat. RU2687745. Publ. 16.05.2019 (in Russ.).

9. Kedik S.A., Shatalov D.O., Kovalenko A.V., Aidakova A.V. Ophthalmic preparation in the form of eye drops for preventing and treating infectious conjunctivitis caused by bacteria and viruses: RF Pat. RU2699377. Publ. 09.05.2019 (in Russ.).

10. 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. Tonk. Khim. Tekhnol. = Fine Chem. Technol. 2021;16(4):307–317 (Russ., Eng.). https://doi.org/10.32362/2410-6593-2021-16-4-307-317

11. Braun D., Sherdron G., Kern V. Prakticheskoe rukovodstvo po sintezu i issledovaniyu svoistv polimerov (A Practical Guide to the Synthesis and Study of the Properties of Polymers): transl. from German. Moscow: Khimiya; 1976. 256 p. (in Russ.). [Brown D., Sherdron G., Kern V. Praktikum der Makromolekularen Organischen Chemie. Heidelberg: Alfred Huthig, 1971.]

12. Efimov K.M., Gembitskii P.A., Martynenko S.V. Method for purification polyguanidine disinfecting agent from parent monomers: RF Pat. RU2237682. Publ. 10.10.2004 (in Russ.).

13. Antony J. Design of Experiments for Engineers and Scientists. First edition. Elsevier Science & Technology Books; 2003. 156 p.

14. Grzhibovsky A.M. The choice of a statistical criterion for testing hypotheses. Ekologiya cheloveka = Human Ecology. 2008;(11):48–57 (in Russ.).