20.500.12556/RUL-121562 Vpliv procesnih pogojev na kristalizacijo esomeprazola Influence of process conditions on esomeprazol crystallization Razvili smo ekonomičen in učinkovit proizvodni postopek enantioselektivne sinteze esomeprazola z encimsko katalizirano reakcijo oksidacije pirmetazola v esomeprazol ter kristalizacijo esomeprazol magnezijeve soli v obliki dihidrata z določeno vsebnostjo R izomere. V doktorski nalogi smo definirali najpomembnejše dejavnike in parametre, ki vplivajo na učinkovitost proizvodnega postopka sinteze esomeprazola z encimsko katalizirano reakcijo ter na kakovost končnega proizvoda. Uskladili smo razmerje reagentov ter fizikalno-kemijske pogoje, kot so dovajanje in koncentracija kisika, velikost delcev substrata in proizvoda, homogenost reakcijske mešanice, preprečevanje penjenja, vrednost pH in konfiguracijo reaktorjev, vključno z mešali. Proces, ki smo ga razvili, je kompleksen, saj obsega kombinacijo kemijskih in encimsko kataliziranih reakcij ter različne tehnološke prijeme za zagotavljanje učinkovite izmenjave snovi. Sodi med največje izzive na področju industrijske aplikacije biokatalize, saj vključuje sočasno usklajeno delovanje treh encimov, regeneracijo kofaktorja v reakcijski mešanici, ki je relativno gosta suspenzija, nasičena s kisikom, dušikom in hlapi topil. V razvitem procesu smo združili vse potrebne atribute in parametre, s katerimi smo po eni strani z intenzivnim mešanjem zagotovili fizikalno-kemijske pogoje za delovanje encimskega sistema, po drugi strani pa preprečili denaturacijo encimov kot posledico penjenja in uspešno zaključili prenos v proizvodnji postopek. Kritični parametri vodenja pa so bili zračni tlak, režim mešanja ter vrednost pH. Z optimizacijo spremenljivk smo dosegli vsaj 96 % pretvorbo v manj kot 24 urah, kar je v skladu z našimi cilji glede ekonomičnosti postopka. V končni stopnji kristalizacije esomeprazol magnezijeve soli dihidrata smo raziskali kritične parametre za zagotavljanje ustrezne kvalitete materiala. Med kvalitativnimi parametri smo se osredotočili na kristalizacijo (R)-izomere in zagotavljanje ustreznega polimorfa. Preverili smo vpliv prisotnih soli, koncentracije (R)-izomere in učinkovine, topilni sistem, mešanje ter sušenje na potek in hitrost kristalizacije (R)-izomere ter na kvaliteto končne učinkovine. Z matematičnim modelom populacijskih bilanc smo popisali postopek kristalizacije R izomere. An economical and efficient production process of enantioselective synthesis of esomeprazole with an enzyme-catalyzed pyrmetazole oxidation reaction to esomeprazoleand crystallization of esomeprazole magnesium dihydrate polimorf with assured assay of R isomer was developed. In the doctoral thesis, we identified the most important factors and parameters that influence the efficiency of the production process of esomeprazole synthesis with the enzyme-catalyzed reaction and the quality of the final product. The amount of reagents, as well as physico-chemical conditions such as oxygen supply and concentration, particle size of the substrate and product, homogeneity of the reaction mixture, foaming prevention, pH value, and configuration of reactors including stirrer, were optimized. The developed process is complex since it involves a combination of chemical and enzymatically catalyzed reactions and various technological approaches to ensure effective mass transfer. It is one of the biggest challenges in the field of industrial biocatalysis, as it involves simultaneous, coordinated action of the three enzymes, the regeneration of the cofactor in the reaction mixture, which is a relatively dense suspension saturated with oxygen, nitrogen and solvent vapor. In the developed process we combined all the necessary attributes and parameters, that enabled us on one hand to provide physical and chemical conditions for the functioning of the enzyme system with intensive mixing, and on the other hand to prevent denaturation of the enzymes as a result of foaming and to successfully complete the transfer into the production process. The critical control parameters were air pressure, mixing conditions, and pH. By optimization of the variables, we achieved at least 96% conversion in less than 24 hours, which is in line with our goals regarding the cost-effectiveness of the process. Critical process parameters were investigated to ensure adequate material quality in the final stage of esomeprazole magnesium dihydrate salt crystallization. Among the qualitative parameters, we focused on the crystallization of the R-isomer and the assuring of the appropriate polymorph. The influence of the other salts impurities, the concentration of the R-isomer and the esomeprasole, the solvent system, mixing and drying on the course and rate of crystallization of the R-isomer and on the quality of the final active ingredient were studied. Using a mathematical model of population balances the crystallization of the R isomer was described. substrat pirmetazol encimatska reakcija oksidacije učinkovina esomeprazol industrijski reaktor z goščo zaključni proces kristalizacije pyrmetazole substrate molecule enzymatic oxidation reaction esomeprazole active ingredient industrial slurry reactor crystallization downstream process true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2020-10-15 16:25:00 2020-10-15 16:25:01 2022-09-02 03:59:56 0000-00-00 00:00:00 2020 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 539 38344195 Herga_Marko_-_Vpliv_procesnih_pogojev_na_kristalizacijo_esomeprazola.pdf Herga_Marko_-_Vpliv_procesnih_pogojev_na_kristalizacijo_esomeprazola.pdf 1 1C4F9120694CED331EBB9D7396FE1826 74df3e16890d8dec873e9c141eed72568a01b7bc6a1c6c58600759f62c95d4ed eb8dc2ee-a1ba-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=136533 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0