An investigation into the influence of particle shape and size on powder tabletability
File(s)
Author(s)
Phillips, Izabela
Type
Thesis
Abstract
The evolution of a molecule before the final product reaches the patient is often a complex journey, involving both drug substance and drug product development, which are lengthy and intricate processes. Undoubtedly, the properties of the final particle of the active pharmaceutical ingredient influence the formulation of the oral solid dosage form.
Early developmental activities shape and provide direction for the latter stages of the development; therefore, gaining an early understanding of the relationship between particle attributes and oral solid dose formulation is crucial, yet this often remains a challenge in pharmaceutical industry. This difficulty arises from the nature of early process development in commercially relevant settings.
Once initiated, oral solid dosage formulation is largely practiced empirically due to its inherent complexity. Although the relationship between particle characteristics such as habit and size has been extensively studied using model compounds with promising results, these findings often lack industrial and commercial relevance.
This thesis summarises the research conducted on a specifically selected GSK asset in early development, initially focussing on revisiting early developmental activities. Two main themes were explored in parallel. The first examines evidence that the compound is prone to crystallising into different crystal shapes depending on the crystallisation solvent used. Subsequently, crystal habit modification was achieved through careful selection of solvent and crystallisation mode, satisfying a number of key criteria for commercial process design. The newly obtained material was then comprehensively characterised and assessed for its tabletting behaviour. The second theme focusses on crystallisation process improvement and assessing how process modifications affected particle properties and behaviour during tablet compaction. Both themes focus on particle habit, size, and solid dose tabletability.
Finally, a mixing study was designed using most common pharmaceutical excipients to investigate effects of mixing mode and order of addition on blend tabletability.
Early developmental activities shape and provide direction for the latter stages of the development; therefore, gaining an early understanding of the relationship between particle attributes and oral solid dose formulation is crucial, yet this often remains a challenge in pharmaceutical industry. This difficulty arises from the nature of early process development in commercially relevant settings.
Once initiated, oral solid dosage formulation is largely practiced empirically due to its inherent complexity. Although the relationship between particle characteristics such as habit and size has been extensively studied using model compounds with promising results, these findings often lack industrial and commercial relevance.
This thesis summarises the research conducted on a specifically selected GSK asset in early development, initially focussing on revisiting early developmental activities. Two main themes were explored in parallel. The first examines evidence that the compound is prone to crystallising into different crystal shapes depending on the crystallisation solvent used. Subsequently, crystal habit modification was achieved through careful selection of solvent and crystallisation mode, satisfying a number of key criteria for commercial process design. The newly obtained material was then comprehensively characterised and assessed for its tabletting behaviour. The second theme focusses on crystallisation process improvement and assessing how process modifications affected particle properties and behaviour during tablet compaction. Both themes focus on particle habit, size, and solid dose tabletability.
Finally, a mixing study was designed using most common pharmaceutical excipients to investigate effects of mixing mode and order of addition on blend tabletability.
Version
Open Access
Date Issued
2025-07-09
Date Awarded
2026-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Heng, Jerry
Publisher Department
Department of Chemical Engineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)