{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/387102"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/387102","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Predictive Disintegration Process Modelling of Immediate Release Tablets Using Terahertz Technology","abstract":"In the drug product development process, linking Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) to Critical Quality Attributes (CQAs) like disintegration performance is essential, particularly during scale-up. Predicting disintegration for immediate-release tablets remains challenging due to the process complexity. This research addresses this by establishing a predictive and mechanistic framework based on terahertz (THz) characterisation and physics-informed modelling. This model aims to reduce reliance on labour-intensive, large-scale DoE within PAT and QbD frameworks, thereby saving resources and minimising chemical waste. Terahertz Pulsed Imaging (TPI) is employed to investigate the advancing liquid front during tablet hydration, capturing liquid transport kinetics and matrix evolution insights. To capture disintegration realistically, including matrix erosion often ignored in constrained setups, a novel open immersion cell was developed for THz liquid transport profiling. This uniquely enabled, for the first time, the development of a model where erosion dynamics within the Representative Capillary (RC) structure are proposed as the limiting factor for both liquid front propagation and overall tablet disintegration. The RC, a simplified representation of the evolving pore network, can be constructed based on void space evolution. This research develops and integrates two complementary models into a unified predictive framework. The Dynamic Void Fraction Evolution Model (DVFEM) describes particle/void evolution to construct the RC from fundamental material properties, while the Representative Capillary Erosion Model (RCEM) constructs the RC by interpreting empirical THz hydration profiles. This synergistic framework provides unprecedented, real-time insight into hydration and disintegration dynamics, establishing physically meaningful linkages for the mechanistic prediction of disintegration performance (a CQA) directly from formulation and processing parameters (CMAs/CPPs). Additional exploratory studies were also conducted: a thermodynamic analysis using calorimetry revealed correlations between heat release and hydration progress, and an effective THz-based tablet porosity methodology suitable for in-line measurement was investigated.","abstract_html":"In the drug product development process, linking Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) to Critical Quality Attributes (CQAs) like disintegration performance is essential, particularly during scale-up. Predicting disintegration for immediate-release tablets remains challenging due to the process complexity. This research addresses this by establishing a predictive and mechanistic framework based on terahertz (THz) characterisation and physics-informed modelling. This model aims to reduce reliance on labour-intensive, large-scale DoE within PAT and QbD frameworks, thereby saving resources and minimising chemical waste. Terahertz Pulsed Imaging (TPI) is employed to investigate the advancing liquid front during tablet hydration, capturing liquid transport kinetics and matrix evolution insights. To capture disintegration realistically, including matrix erosion often ignored in constrained setups, a novel open immersion cell was developed for THz liquid transport profiling. This uniquely enabled, for the first time, the development of a model where erosion dynamics within the Representative Capillary (RC) structure are proposed as the limiting factor for both liquid front propagation and overall tablet disintegration. The RC, a simplified representation of the evolving pore network, can be constructed based on void space evolution. This research develops and integrates two complementary models into a unified predictive framework. The Dynamic Void Fraction Evolution Model (DVFEM) describes particle/void evolution to construct the RC from fundamental material properties, while the Representative Capillary Erosion Model (RCEM) constructs the RC by interpreting empirical THz hydration profiles. This synergistic framework provides unprecedented, real-time insight into hydration and disintegration dynamics, establishing physically meaningful linkages for the mechanistic prediction of disintegration performance (a CQA) directly from formulation and processing parameters (CMAs/CPPs). Additional exploratory studies were also conducted: a thermodynamic analysis using calorimetry revealed correlations between heat release and hydration progress, and an effective THz-based tablet porosity methodology suitable for in-line measurement was investigated.","abstract_has_math":false,"creators":["Lee, Jongmin"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Zeitler, J Axel"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-04-15","date_published":"2025-04-15","updated_at":"2026-07-22T22:24:04Z","subjects":["Terahertz","Pharmaceutical Tablet","Disintegration","Mechanistic Model","Liquid Transport Profile","Representative Capillary","Representative Capillary Evolution Model","Dynamic Void Fraction Evolution Model","Disintegration Reaction Calorimetry","Immediate Release Tablet"],"languages":[],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/fd9829bd-d24c-4d3e-8d1a-34bd7d1f3d33/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000234762922"],"render_values":[{"text":"0000-0002-3476-2922","href":"https://orcid.org/0000-0002-3476-2922","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.120030","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Zeitler, J Axel"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["This research was supported by the Digital Design Capability project at GlaxoSmithKline Research & Development Ltd (reference G109393)."]},{"key":"dc:creator","label":"Author","values":["Lee, Jongmin"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000234762922"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-04-15"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/387102"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Terahertz","Pharmaceutical Tablet","Disintegration","Mechanistic Model","Liquid Transport Profile","Representative Capillary","Representative Capillary Evolution Model","Dynamic Void Fraction Evolution Model","Disintegration Reaction Calorimetry","Immediate Release Tablet"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/fd9829bd-d24c-4d3e-8d1a-34bd7d1f3d33/download","http://purl.org/NET/rdflicense/allrightsreserved"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.120030"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/dfde85de-a596-4d41-99a2-85c8ecf20304/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["In the drug product development process, linking Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) to Critical Quality Attributes (CQAs) like disintegration performance is essential, particularly during scale-up. 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This uniquely enabled, for the first time, the development of a model where erosion dynamics within the Representative Capillary (RC) structure are proposed as the limiting factor for both liquid front propagation and overall tablet disintegration. The RC, a simplified representation of the evolving pore network, can be constructed based on void space evolution. This research develops and integrates two complementary models into a unified predictive framework. The Dynamic Void Fraction Evolution Model (DVFEM) describes particle/void evolution to construct the RC from fundamental material properties, while the Representative Capillary Erosion Model (RCEM) constructs the RC by interpreting empirical THz hydration profiles. This synergistic framework provides unprecedented, real-time insight into hydration and disintegration dynamics, establishing physically meaningful linkages for the mechanistic prediction of disintegration performance (a CQA) directly from formulation and processing parameters (CMAs/CPPs). 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This uniquely enabled, for the first time, the development of a model where erosion dynamics within the Representative Capillary (RC) structure are proposed as the limiting factor for both liquid front propagation and overall tablet disintegration. The RC, a simplified representation of the evolving pore network, can be constructed based on void space evolution. This research develops and integrates two complementary models into a unified predictive framework. The Dynamic Void Fraction Evolution Model (DVFEM) describes particle/void evolution to construct the RC from fundamental material properties, while the Representative Capillary Erosion Model (RCEM) constructs the RC by interpreting empirical THz hydration profiles. This synergistic framework provides unprecedented, real-time insight into hydration and disintegration dynamics, establishing physically meaningful linkages for the mechanistic prediction of disintegration performance (a CQA) directly from formulation and processing parameters (CMAs/CPPs). 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