Understanding crystal nucleation through pressure-driven phase transformations

Student thesis: Doctoral Thesis

Abstract

This thesis investigates the nucleation and the discovery of new phases using solubility and high-pressure measurements of chiral and racemic solids of (RS)/(S)-2-(2-oxopyrrolidin-1-yl)butanamide. The cocrystallisation of this compound with a range of different coformers has been investigated using solubility measurements to alter the eutectic composition to aid the chiral resolution. Only one successful cocrystal was isolated and was observed to move the eutectic composition. However, this moved towards the chiral phase rather than the racemic composition hence reducing the phase space available for the chiral resolution. Whilst this result is less ideal, the ability to move the eutectic composition is demonstrated and the role of the cocrystal solubility in this process identified. To follow this study, the response of Levetiracetam and Etiracetam to high pressure was investigated with a view to identifying phase transitions that may be used in future measurements of nucleation using high pressure. In this work, both materials undergo phase transformations to new high-pressure phases. The changes to both were very subtle and difficult to analyse using Raman spectroscopy, which would have been the best method for phase identification during nucleation due to the speed of collection. The difference in the compression are analysed through void analysis as well as energy calculations to confirm the phase transition had taken place. Lastly, hydrochlorothiazide was identified as a potential compound to use in the nucleation measurements. The phase transition to a new phase occurs at ~0.5 GPa and the Raman spectrum indicated a distinct change over the phase transformation which was one of the key concepts for analysis. Unfortunately, the phase transformation is not reversible within a short time scale. The high-pressure form is stable as a solid for many months without transformation. This observation led the study on a different path to explore the formation and recovery of this high-pressure phase. The high-pressure parameters for the successful recovery of the phase were explored as well as the indexing of the new phase. A potential indexing of this new phase is identified, however, the solution of the new phase has eluded characterisation.
Date of Award7 Jun 2021
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde & EPSRC (Engineering and Physical Sciences Research Council)
SupervisorIain Oswald (Supervisor) & Joop Ter Horst (Supervisor)

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