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Development of multidimensional model for prediction i control of quality target tablet profile manufactured by wet granulation process

dc.contributor.advisorIbrić, Svetlana
dc.contributor.otherĐuriš, Jelena
dc.contributor.otherGrujić, Branka
dc.contributor.otherKovačević, Aleksandar
dc.creatorMillen, Nada
dc.date.accessioned2020-03-09T09:13:03Z
dc.date.available2020-03-09T09:13:03Z
dc.date.available2020-07-03T09:49:12Z
dc.date.issued2019-12-24
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/12187
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7337
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:21573/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=2048436834
dc.description.abstractVlažna granulacija je složen proizvodni proces izrade tableta. Ovaj proces je podložan uticaju mnogobrojnih varijabli, što predstavlja izazov prilikom transfera proizvodne tehnologije. Predmet istraživanja doktorske disertacije je olakšanje pocesa transfera tehnologije vlažne granulacije korišćenjem pristupa principa dizajna kvaliteta (engl. Quality by design – QbD) i različitih algoritama mašinskog učenja. Prvi deo ovog rada istražuje značaj i obim uticaja formulacionih i procesnih promenljivih na kritične atribute kvaliteta (engl. Critical quality attributes – CQA) tableta. Istraživan je uticaj nerastvornog punioca trikalcijum-fosfata (TKF) na vreme raspadanja i čvrstinu tableta u procesu vlažne granulacije. Ovaj ekscipijens nije prethodno izučavan u ovom kontekstu zbog toga što se u farmaceutskom razvoju najčešće zamenjuje dikalcijum-fosfatom. Uticaj koncentracije trikalcijum-fosfata i superdezintegratora natrijum-skrobglikolata (NSG) i uticaj procesnih parametara (količina vode u rastvoru za granulaciju, veličina otvora sita i sadržaj vlage) su procenjeni istovremeno u cilju razvoja matematičkih modela za predviđanje kritičnih atributa kvaliteta tableta (vreme raspadanja i čvrstina) i uspešnog vođenja procesa transfera tehnologije vlažne granulacije. Povećana koncentracija natrijum-skrobglikolata je skratila vreme raspadanja ali je imala negativan uticaj na čvrstinu tableta. Procesni parametar sa najviše uticaja na vreme raspadanja je bio sadržaj vlage dok je veličina otvora na situ (koje je korišćeno prilikom mlevenja suvog granulata) bio najznačajniji procesni parametar za čvrstinu tableta. Pri upotrebi sita sa manjom veličinom otvora u procesu mlevenja dobijeni su optimalni rezultati za analizirane atribute kvaliteta tableta kad je količina vode u rastvoru za granulaciju bila na višem nivou. Kada je za mlevenje granula korišćeno sito sa većom veličinom otvora, najbolji rezultati za atribute kvaliteta tableta su dobijeni kad je količina vode u rastvoru za granulaciju bila na nižem nivou. Razvijeni su matematički modeli koji opisuju uticaj ispitivanih faktora na vreme raspadanja i čvrstinu tableta. Pouzdanost matematičkih modela je procenjivana tokom procesa transfera sa laboratorijskog na komercijalni nivo proizvodnje...sr
dc.description.abstractWet granulation is a complex manufacturing process. It is influenced by the multiple variables which presents challenges to the scale-up process. The objective of this PhD dissertation research is to use a quality by design (QbD) approach i multiple machine learning algorithms in facilitating wet granulation process scale-up. The first part of this reseach investigates the significance i extent of influence of both formulation i process variables on the critical quality attributes (CQAs) of tablets. The influence of insoluble diluent - tribasic calcium phosphate on disintegration time i tablet hardness, in the wet granulation process, was examined. This excipient was not previously studied in this context as it is frequently replaced with dicalcium phosphate in the pharmaceutical development practice. The influence of tricalcium phosphate i the superdisintegrant sodium starch glycolate, as well as the influence of process parameters (water concentration in granulation solution, screen hole size i moisture content) were used together to develop mathematical models that could be used in prediction of tablet CQAs (disintegration time i hardness) i facilitate wet granulation scale up process. Higher concentrations of sodium starch glycolate shortened disintegration time but negatively influenced tablet hardness. The most significant factor influencing disintegration time was moisture content while a screen hole size (used for dry granulate milling) was the most significant factor influencing tablet hardness. The use of a smaller screen hole size in milling process produced the optimal results for tablet quality attributes when water amount in granulation solution was high. The best results for tablet quality attributes are achieved when a larger hole screen size, used in milling process, was applied in conjuction with the low water amount, used in granulation process. Developed mathematical models describe the influence of analysed parameters on disintegration time i tablet hardness. Those equations were evaluated during scale-up process from laboratory to commercial scale. Experimental i predicted mean values were found to be statistically similar, which proves the effectiveness of the models in scale-up projects. In the second part of this research the aim was to further investigate the extent of influence of critical variables through application of multipe machine learning algorithms...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Фармацеутски факултетsr
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectdizajn kvalitetasr
dc.subjectQbDen
dc.subjectvlažna granulacijasr
dc.subjecttransfer tehnologijesr
dc.subjectraspodela veličine česticasr
dc.subjectmašinsko učenjesr
dc.subjecteksperimentalni dizajnsr
dc.subjectrad kompakcijesr
dc.subjectrad dekompakcijesr
dc.subjectelastični oporavaksr
dc.subjecttrikalcijum-fosfatsr
dc.subjectwet granulationen
dc.subjectscale-upen
dc.subjectparticle size distributionen
dc.subjectmachine learning modelingen
dc.subjectdesign of experimentsen
dc.subjectcompaction worken
dc.subjectdecompaction worken
dc.subjectelastic recoveryen
dc.subjecttricalcium phosphateen
dc.titleRazvoj multidimenzionalnog modela za predviđanje i kontrolu ciljnog profila kvaliteta tableta izrađenih postupkom vlažne granulacijesr
dc.title.alternativeDevelopment of multidimensional model for prediction i control of quality target tablet profile manufactured by wet granulation processen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24752/IzvestajKomisije22299.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24751/Disertacija.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_12187


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