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Assessment of the stability of drugs in the amorphous and co-amorphous form in extrudates, pellets and tablets designed to circumvent drugs’ poor water solubility

2023-04Tese de doutoramento Acesso aberto
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorPinto, João F
dc.contributor.advisorDaniels, Rolf
dc.contributor.advisorWahl, Martin
dc.contributor.authorCosta, Nuno Gonçalo Ferreira da
dc.date.accessioned2024-06-03T08:57:12Z
dc.date.available2024-06-03T08:57:12Z
dc.date.issued2023-04
dc.date.submitted2022-12
dc.description.abstractThe synthesis of innovative drug substances has been seriously compromising the development of oral drug products with satisfactory bioavailability properties. Amorphization and co-amorphization of drugs have been described as promising strategies to enhance the bioavailability of poorly water-soluble drugs. Olanzapine (OLZ), an atypical antipsychotic drug used for the treatment of schizophrenia or bipolar disorder, was used as model drug due to its poor aqueous solubility and insufficient bioavailability. The solubility of the drug was enhanced by amorphization and co-amorphization with sulfonic acids. Among the sulfonic acids used to stabilize OLZ in the amorphous form (>6 months, at 25°C/75% relative humidity), saccharin yielded the co-amorphous system with the highest solubility and dissolution rate (145-fold and 4-fold enhancement compared to its crystalline counterpart, respectively), thus supporting its utilization in the manufacture of oral drug products. Tableting of powdered mixtures containing co-amorphous OLZ resulted in compacts with no evidence ofrecrystallization of the drug, regardless of the compression pressure imposed. These compacts presented high tensile strength and disintegration times, and thus, a fine-tuning of the formulation was conducted to ensure the rapid release of the drug. Unfortunately, the high cohesiveness and poor flowability of co-amorphous OLZ requires additional processing steps to enhance the flowability and guarantee the production of drug products with the desired quality. Consequently, wet granulation was considered through the application of different fractions of solvent and drying temperatures to materials. Whilst amorphous OLZ recrystallized back to its crystalline counterpart (form I) during processing, co-amorphous OLZ was stable to the stress conditions imposed to materials and, therefore, enabled the manufacture of drug products containing the highly soluble amorphous form. Overall, the work highlighted the stability of co-amorphous OLZ during the manufacture of oral drug products suggesting a higher bioavailability.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2024-05-24T11:59:49Z No. of bitstreams: 1 scnd990026354741666_td_Nuno_Costa.pdf: 5145304 bytes, checksum: cf69bccad0d35105ead305a42a6d1aa9 (MD5)en
dc.description.provenanceMade available in DSpace on 2024-06-03T08:57:12Z (GMT). No. of bitstreams: 1 scnd990026354741666_td_Nuno_Costa.pdf: 5145304 bytes, checksum: cf69bccad0d35105ead305a42a6d1aa9 (MD5) Previous issue date: 2023-04en
dc.identifier.tid101642334pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/64950
dc.language.isoengpt_PT
dc.subjectamorfização in-situpt_PT
dc.subject(co-)amorfopt_PT
dc.subjectcomprimidopt_PT
dc.subjectestabilidade físicapt_PT
dc.subjectpelletpt_PT
dc.subjectrevestimentopt_PT
dc.subject(Co-)amorphouspt_PT
dc.subjectcoatpt_PT
dc.subjectdissolution ratept_PT
dc.subjectin-situ amorphizationpt_PT
dc.subjectphysical stabilitypt_PT
dc.subjectsolubilitypt_PT
dc.titleAssessment of the stability of drugs in the amorphous and co-amorphous form in extrudates, pellets and tablets designed to circumvent drugs’ poor water solubilitypt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/137080/2018
oaire.awardNumberPTDC/CTM-BIO/3946/2014
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F137080%2F2018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FCTM-BIO%2F3946%2F2014/PT
oaire.fundingStreamOE
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication136561d2-4f5c-40c0-b791-8629ad1254fd
relation.isProjectOfPublication2c6d7fa3-12cf-4473-b518-0158b32831ed
relation.isProjectOfPublication.latestForDiscovery136561d2-4f5c-40c0-b791-8629ad1254fd
thesis.degree.nameTese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2023pt_PT

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