Optimizacija sinteze omeprazola potpomognuta termodinamičkim istraživanjima

doctoral thesis

• Title (english): Optimization of omeprazole synthesis assisted by thermodynamic studies
• Author: Nina Vojčić
• Mentor: Ernest Meštrović (mentor)
• Mentor: Vladislav Tomišić (komentor)
• Committee member: Nikola Bregović (predsjednik povjerenstva)
• Committee member: Ernest Meštrović (član povjerenstva)
• Committee member: Leo Frkanec (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2020-09-29, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Opisana je optimizacija proizvodnog postupka sinteze djelatne tvari omeprazola. Svojstva tog
spoja, kao i njegovih sintetskih prekursora, temeljito su proučena fizikalno-kemijskim
istraživanjima procesa protonacije i otapanja. Određene su konstante ravnoteže protonacijskih
reakcija i termodinamičke veličine vezane uz solvataciju, tj. topljivost polaznih spojeva i
međuprodukta te entalpije i entropije njihova otapanja. S obzirom da je opisana optimizacija
temeljena na modifikaciji reakcijskog medija, sva mjerenja su provedena u čistom metanolu i
u različitim smjesama metanol/voda, omogućivši time odabir optimalnog otapala za sintezu
omeprazola. Dodatno je utvrđena neučinkovitost, odnosno nepotrebnost energetski vrlo
zahtjevnog povratnog hlađenja koji se redovito koristi u prvom koraku uobičajene proizvodne
sinteze. Slično vrijedi i za vremenski zahtjevnu trituraciju u postupku izolacije završnog
proizvoda. Naime, pokazano je da se vrijeme trajanja trituracije može značajno smanjiti.
Svi dobiveni rezultati detaljno su raspravljeni te je na temelju njih predložena modificirana
procedura priprave omeprazola. Nova, poboljšana procedura temeljena je na načelima “zelene
kemije”, pri čemu zahtijeva uporabu manje organskih otapala te pokazuje poboljšanu
energetsku i vremensku učinkovitost. Potvrđeno je i da se može primijeniti u proizvodnji
većih količina omeprazola.
Pristup predložen u ovom radu mogao bi se primijeniti na druge slične sustave, čime bi se
potencijalno poboljšao postupak priprave lijekova, istovremeno rezultirajući smanjenjem
ekološkog rizika i smanjenjem troškova proizvodnje.

Abstract (english)

Optimization of the synthetic procedure for production of active pharmaceutical ingredient
Omeprazole is presented. The properties of Omeprazole and its precursors were thoroughly
explored by physicochemical investigations of the corresponding protonation and solution
processes. The protonation equilibrium constants (KH) and solvation thermodynamic
properties, such as solution enthalpies and entropies, as well as solubility of the starting
materials and the intermediate were determined. Since the presented synthetic strategy was
based on the modification of the reaction media, all measurements were performed in pure
methanol and different methanol/water mixtures, which led to the selection of the solvent
optimal for the Omeprazole preparation. In addition, it was proven that the conventionally
used energetically demanding refluxing procedure in the first step of the Omeprazol synthesis
could be avoided. It was also shown that the period of trituration employed in the step
involving precipitation of the final product can be significantly reduced.
All the obtained results were thoroughly discussed, and aided the conception of the new
procedure for Omeprazole preparation. The improved (greener) procedure was based on the
processes demanding less organic solvents, at the same time being energy- and time-more
efficient. It was also proven that it could be implemented in the large scale production.
This work presents a concept which could be extended to other similar systems, improving the
synthetic procedures of highly used pharmaceuticals, while lowering ecological risks and
production expenses.

• Keywords: omeprazol; optimizacija; protonacija; utjecaj otapala; plan sinteze
• Keywords (english): Omeprazole; optimization; protonation; solvent effects; synthesis design
• Language: croatian
• URN:NBN: urn:nbn:hr:217:603034
• Promotion: 2020
• Study programme: Title: Doctoral study in chemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
• Type of resource: Text
• Extent: 94 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2020-10-12 11:26:22