Rudiuk V. Synthesis of new polymorphic forms of active pharmaceutical ingredients and their effect on physico-chemical and pharmacological properties

Українська версія

Thesis for the degree of Doctor of Philosophy (PhD)

State registration number

0823U102067

Thesis Registration Form

0823U102067.pdf

Applicant for

Specialization

  • 161 - Хімічні технології та інженерія

Specialized Academic Board

ДФ 26.002.93; ID 3957

National Technscal University of Ukraine "Kiev Polytechnic Institute".

Essay

The thesis for a Doctor of Philosophy degree in speciality 161 «Chemical technologies and engineering». – National Technical University of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute", Ministry of Education and Science of Ukraine, Kyiv, 2023. The dissertation work is devoted to the study of the phenomenon of polymorphism of active pharmaceutical ingredients using the examples of the substances 6-Methyluracil, Enisamium, and Desloratadine, the preparation of new polymorphic forms of these substances, and the study of their physicochemical and pharmacological properties. The work examines preparative approaches to the synthesis of the active pharmaceutical ingredient - 6-Methyluracil and intermediate compounds. An evaluation of known synthesis methods was made for the possibility of use in industrial conditions and scaling. The most promising conditions for obtaining target substances and the possibility of scaling chemical stages and processes have been verified. The conditions for the two-stage synthesis of 6-Methyluracil based on commercially available raw materials - acetoacetic ethyl ester and urea - have been worked out. At the first stage, water was azeotropically distilled with hexane as a solvent under the catalysis of p-toluenesulfonic acid, and the corresponding ethyl ureidocrotonate was obtained. 6-Methyluracil was obtained by heating ethyl ureidocrotonate with aqueous alkali followed by the addition of hydrochloric acid to the reaction mixture. An industrial technology for the synthesis of the active pharmaceutical ingredient 6-Methyluracil was developed and implemented. The thesis consists of 246 pages of typewritten text, consists of an introduction, four chapters, general conclusions, a list of used sources and one appendix. The volume of the main text of the dissertation is 139 pages of printed text. The work is illustrated with 36 tables and 63 figures. The list of used sources contains 475 names, of which 468 are in Latin.

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Research papers

Рудюк В.В., Філатов А.А., Бабаджанова Л.А., Ягупольський Ю.Л., Левандовський І.А. Розробка промислової технології синтезу активного фармацевтичного інгредієнта «6-метилурацил» Питання хімії та хімічної технології, 2023. В. 4(149). С. 77-82. doi:10.32434/0321-4095-2023-149-4-77-82

Shishkina S.V., Shaposhnik A.M., Dyakonenko V.V., Baumer V.M., Rudiuk V.V., Yanchuk I.B., Levandovskiy I.A. New Polymorphic Modifications of 6‑Methyluracil: An Experimental and Quantum Chemical Study. ACS Omega, 2023. Vol. 8. Р. 20661-20674. doi:10.1021/acsomega.3c01231

Rudiuk V.V., Shaposhnik A.M., Baumer V.M., Levandovskiy I.A., Shishkina S.V. 4-[(Benzylamino)carbonyl]-1-methylpyridinium bromide hemihydrate: X-ray diffraction study and Hirshfeld surface analysis. Acta Crystallographica Section E: Crystallographic Communications, 2022. Vol. 78. Р. 496–499. doi:10.1107/S2056989022003784

Shishkina S.V., Shaposhnik A.M., Baumer V.M., Rudiuk V.V., Levandovskiy I.A. 4-[(Benzylamino)carbonyl]-1-methylpyridinium halogenide salts: X-ray diffraction study and Hirshfeld surface analysis. Acta Crystallographica Section E: Crystallographic Communications, 2022. Vol. 78. Р. 114–119. doi:10.1107/S2056989021013505

Rudiuk V.V., Shaposhnik A.M., Baumer V.M., Levandovskiy I.A., Shishkina S.V. Salts of 4-[(benzylamino)carbonyl]-1-methylpyridinium and iodide anions with different cation:iodine stoichiometric ratios. Acta Crystallographica Section E: Crystallographic Communications, 2021. Vol. 77. Р. 1219–1223. doi:10.1107/S2056989021011300

Shishkina S.V., Shaposhnyk A.M, Rudiuk V.V., Levandovskiy I.A. New polymorphic modifications of 6-methyluracil: experimental and quantum chemical study for the practical use // 64 Konwersatorium Krystalograficzne Polish Crystallographic meeting, Wroclaw, Poland, 5-6 Jule, 2023. P. 56-57. https://konkryst.intibs.pl/images/64KK2023book.pdf

Shaposhnyk A.M, Rudiuk V.V., Levandovskiy I.A., Baumer V.M., Margitich V.M. Crystal structures of Enisamium halogenides // 62 Konwersatorium Krystalograficzne Polish Crystallographic meeting, Edycja on-line, 24-25 June, 2021. P. 170-171. https://konkryst.intibs.pl/images/62KK2021book.pdf

Shaposhnyk A.M, Rudiuk V.V., Levandovskiy I.A., Baumer V.M., Shishkina S.V. Polymorphism of 6-methyluracil // MDPI "The 2nd International Online Conference on Crystals", 10-20 November, 2020. ID: sciforum-035747. https://iocc_2020.sciforum.net/#session1552

Рудюк В. В., Шапошник А. М., Левандовський І. А., Шишкіна С. В. Дослідження поліморфних модифікацій 6-метилурацилу. VIII Міжнародна конференція студентів, аспірантів та молодих вчених з хімії та хімічної технології, Київ, Україна, 22-23 квітня, 2020. C. 40. https://tnr.kpi.ua/images/Conferences/Conf-2020_3.pdf

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