Nove farmaceutski prihvatljive soli 1-amino-3,5-dimetiladamantana i njihove kristalne forme

doctoral thesis

• Title (english): Novel pharmaceutically acceptable salts of 1-amino-3,5-dimethyladamantane and their crystal forms
• Author: Mihaela Tuksar
• Mentor: Ernest Meštrović (mentor)
• Mentor: Mirta Rubčić (komentor)
• Committee member: Dubravka Matković-Čalogović (predsjednik povjerenstva)
• Committee member: Mirta Rubčić (član povjerenstva)
• Committee member: Krunoslav Užarević (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2019-09-27, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

U okviru ovog rada pripremljeno je sedam novih soli 1-amino-3,5-dimetiladamantana
(memantina) s farmaceutski prihvatljivim kiselinama: sumpornom, fosfornom,
metansulfonskom, maleinskom i fumarnom kiselinom. Različitim metodama kristalizacije iz
otopine kao što su isparavanje, izlaganje definiranim uvjetima vlage i parama otapala,
suspendiranje u otapalu te dehidratacija/desolvatacija grijanjem, priređeno je ukupno šesnaest
kristalnih formi soli navedenih soli memantina. Pripremljene kristalne forme okarakterizirane
su prikladnim metodama analize u čvrstom stanju koje su uključivale metode termičke i
spektroskopske analize te difrakcijske i mikroskopske metode. Za četrnaest kristalnih formi
pripremljenih soli memantina difrakcijom rentgenskog zračenja na jediničnom kristalu
određene su molekulske i kristalne strukture.
Usporedbom ciljanih svojstava pripremljenih soli memantina, 3,5-dimetiladamantan-1-
ilamonijev hidrogensulfat forma 1 odabrana je kao najbolja alternativna sol 3,5-
dimetiladamantan-1-ilamonijevom kloridu, soli prisutne u lijeku na tržištu. Postupak
dobivanja i kristalizacije 3,5-dimetiladamantan-1-ilamonijevog hidrogensulfata forme 1 je
razvijen i optimiran. Konačno, 3,5-dimetiladamantan-1-ilamonijev hidrogensulfat forma 1
pripremljena je u uvećanom mjerilu od 1000 L.

Abstract (english)

Within this work, seven novel salts of 1-amino-3,5-dimethyladamantane (memantine) with
pharmaceutically acceptable acids: sulphuric, phosphoric, methanesulfonic, maleic and
fumaric acid were prepared. Using various methods of crystallization in solution such as
evaporation, sauna and slurry experiments as well as dehydration/desolvation by heating,
sixteen crystals forms of the mentioned memantine salts were prepared. The obtained
crystalline forms were characterized by suitable solid-state methods, which included thermal
and spectroscopic analysis as well as diffraction and microscopic methods. Single crystals of
the fourteen crystal forms were prepared, and their crystal and molecular structures were
determined by X-ray diffraction.
By comparing the target properties of the prepared memantine salts, 3,5-dimethyladamantane-
1-ylammonium hydrogensulfate form 1 was selected as the best alternative salt of the 3,5-
dimethyladamantane-1-ylammonium chloride, the salt present in the drug on the market. The
process of preparation and crystallization of 3,5-dimethyladamantane-1-ylammonium
hydrogensulfate form 1 was developed and optimized. Eventually, 3,5-dimethyladamantaneylammonium
hydrogensulfate form 1 was prepared on a larger scale, in 1000 L batch.

• Keywords: 3; 5-dimetiladamantan-1-ilamin; farmaceutski prihvatljive soli; kristalizacija; odabir soli; polimorfija; uvećanje procesa
• Keywords (english): 3; 5-dimethyladamantane-1-ylamine; pharmaceutically acceptable salts; crystallization; salt selection; polymorphism; process scale up
• Language: croatian
• URN:NBN: urn:nbn:hr:217:698103
• 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: 206 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2021-09-30
• Created on: 2019-10-22 10:11:13