Thesis
From crystal to tablet : structural insights into the compression behaviour of pharmaceutical solids
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2026
- Thesis identifier
- T18202
- Person Identifier (Local)
- 202084208
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- This doctoral thesis advances the understanding of how pharmaceutical solids respond to applied pressure, from the molecular to the macroscopic scale, with relevance to the tabletting process. The compression of racemic ofloxacin and chiral forms γ-levofloxacin and levofloxacin hemihydrate was followed using single-crystal and powder X-ray diffraction across hydrostatic and non-hydrostatic conditions, with Raman spectroscopy used to confirm a solid-form change in one case. All three were shown to be soft, highly compressible solids dominated by dispersive π-stacking, with the most compressible direction perpendicular to the molecular stacks. Each structure compressed smoothly through the tabletting pressure range (< 0.3 GPa) but underwent distinct phase transitions at higher pressures; the transitions depended on hydration, particle size and pressure-transmitting medium. Subtle pressure-driven molecular rearrangements can be overlooked by conventional high-pressure data analyses. A new method and accompanying Python tool, MolDis, were developed to calculate and visualise pressure-induced molecular displacement relative to a reference molecule directly from variable-pressure diffraction data. MolDis was validated against paracetamol Forms I and II and applied to a set of acetanilides (4-chloroacetanilide, the monoclinic form of 4- methylacetanilide, metacetamol Form I), revealing the flattening of corrugated chains and layers and displacement normal to potential slip planes, complementing interaction-energy, void and slip-plane analyses. Lastly, X-ray Diffraction Computed Tomography was applied to intact pharmaceutical tablets, using glycolide as a pressure-sensitive marker. This nondestructive approach spatially resolved a non-uniform Form I to Form II transformation and, on storage, captured an unexpected hydrolysis to a previously unreported phase whose structure was solved by electron diffraction. Together, these studies follow the structural response to pressure across length scales, contributing to the understanding needed to anticipate mechanical behaviour and solid form change during pharmaceutical manufacturing.
- Advisor / supervisor
- Oswald, Iain
- Resource Type
- DOI
Relations
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PDF of thesis T18202 | 2026-10-13 | Public | Download |