Drug-silica systems: the impact of drug-loading process parameters on drug solid-state and release

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dc.check.date2027-05-31
dc.contributor.advisorCrean, Abina
dc.contributor.advisorO'Shea, Joseph
dc.contributor.authorAl-Dagamin, Tanweer Ziad Khalilen
dc.contributor.funderResearch Ireland
dc.date.accessioned2026-01-23T15:50:34Z
dc.date.available2026-01-23T15:50:34Z
dc.date.issued2025en
dc.date.submitted2025
dc.description.abstractIt is widely reported that newly developed drug candidates and many of the most widely marketed drugs exhibit poor water solubility. Consequently, there is a focus on tackling the issue of poor aqueous solubility to improve the oral bioavailability of poorly water-soluble drugs. Loading drugs onto mesoporous silica is one formulation strategy used to increase the solubility and dissolution rate of these drugs. This is achieved by distributing drug molecules onto mesoporous silica’s large surface area in a non-crystalline state. The main aim of this thesis was to investigate the influence of the drug loading process on drug’s solid state and release from drug-silica systems. The focus of this investigation was to understand how factors involved in a solvent-based drug loading process influence non-crystalline drug distribution on mesoporous silica and, hence, drug release performance. Two model compounds, felodipine and ritonavir, previously reported to have good glass-forming ability and stability, were chosen for this investigation. Syloid® 244 FP, an amorphous disordered silica, was used as a model silica. Chapter 1 provides a background and an overview of the literature related to this thesis topic. Chapters 2 to 4 of this thesis investigate drug loading factors and how they influence silica surface properties and loaded drug solid state. Chapters 5 and 6 explore how differences in non-crystalline drug solid state effects drug release from silica formulations. In chapter 2 the surface properties of Syloid 244 FP exposed to a wide range of solvents possessing different physicochemical properties and processed at different drying conditions were characterised. Syloid 244 FP dispersed in ethanol and dried at 60°C showed negligible impact on Syloid 244 FP surface chemistry, polarity and porosity, and hence was applied for drug loading when employing solvent evaporation as outlined in Chapters 3 and 4. Chapter 3 focused on the influence of the felodipine: silica ratio, with respect to the theoretical monolayer coverage (tMLC) of Syloid 244 FP, on drug solid state and drug distribution. It was demonstrated that loading the drug above the tMLC of silica leads to the formation of an amorphous drug phase, as indicated by the presence of a glass transition temperature, compared to loading below tMLC where no amorphous drug phase was detected. In Chapter 4, in addition to drug loading above and below tMLC, drug loading solution concentration was investigated using ritonavir as a model drug. Both ritonavir loading with respect to tMLC, and drug loading solution concentration were shown to influence both ritonavir solid-state and distribution on silica. Amorphous drug was detected at ratios above and below tMLC when employing low-concentration solutions. In contrast, employing high-concentration solutions has shown enhanced drug adsorption on the Syloid® 244 FP surface and into pores, as indicated by both dynamic vapour sorption (DVS) and nitrogen sorption analysis. The influence of ritonavir loading parameters on its release from ritonavir- Syloid® 244 FP systems was investigated under sink and non-sink conditions in Chapter 5. Both drug loading with respect to the tMLC, and drug loading solution concentration were shown to influence drug release kinetics under sink conditions, with faster release kinetics observed from ritonavir-Syloid® 244 FP systems loaded below the tMLC of Syloid® 244 FP, attributable to the drug being predominantly adsorbed onto the high surface area of Syloid® 244 FP. Furthermore, systems prepared using low ritonavir solution concentration resulted in slower release compared to systems prepared with high ritonavir solution concentration, which was most noticeable at ratios approaching and below the tMLC and attributed to the detected amorphous drug phase in these systems. Interestingly, the loading factors investigated had no significant effect on the supersaturation behaviour of the ritonavir-Syloid® 244 FP systems investigated. To further investigate the effect of silica on the supersaturation behaviour of drug-silica systems, Chapter 6 compared the behaviour of ritonavir and felodipine loaded Syloid® 244 FP systems. Findings reveal that loading both drug onto Syloid® 244 FP can result in drug release generating a supersaturated solution. However, the duration of supersaturation was aligned with the individual intrinsic drug properties and its tendency to recrystallise. The overall findings of this thesis demonstrated that the loading parameters investigated influence the ratio of amorphous and surface adsorbed non-crystalline drugs, which in turn impacts drug release under sink conditions. Additionally, loading the drugs investigated onto Syloid® 244 FP facilitated the generation of a supersaturated solution during release under non-sink conditions, while the duration of supersaturation was found to be drug-specific.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationAl-Dagamin, T. Z. K. 2025. Drug-silica systems: the impact of drug-loading process parameters on drug solid-state and release. PhD Thesis, University College Cork.
dc.identifier.endpage217
dc.identifier.urihttps://hdl.handle.net/10468/18452
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/Research Centres Programme/12/RC/2275/IE/Synthesis and Solid State Pharmaceutical Centre (SSPC)/
dc.rights© 2025, Tanweer Al-Dagamin.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMesoporous silicaen
dc.subjectRitonaviren
dc.subjectFelodipineen
dc.subjectCrystallineen
dc.subjectAmorphousen
dc.subjectDissolutionen
dc.subjectSolid-stateen
dc.titleDrug-silica systems: the impact of drug-loading process parameters on drug solid-state and release
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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