Thesis

Solid-state control and analysis of active pharmaceutical ingredients

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Awarding institution
  • University of Strathclyde
Date of award
  • 2020
Thesis identifier
  • T15827
Person Identifier (Local)
  • 201561948
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • The research described herein entails solid-state screening investigations and characterisation of a number of active pharmaceutical ingredients to improve understanding of the range of structural diversity possible and specific factors that impact on specific systems. The pharmaceuticals investigated are the anticonvulsant oxcarbazepine (OXCBZ), the developmental cholesterylester transfer protein inhibitor evacetrapib (EVC) and a novel tetrazole analogue of EVC (TAEVC) that has been custom synthesised by Eli Lilly and Company. All three compounds were subjected to both solvent-based and solvent-free crystallisation protocols to target factors promoting the formation of novel crystal structures, characterise any novel crystal packing arrangements formed and explore how non-classical nucleation and growth mechanisms impact crystal morphology.;Experimental screening studies of OXCBZ enabled form III to be obtained via solution crystallisation and from physical vapour deposition onto various substrates. The R-3 crystal structure of this polymorph was determined for the first time using X-ray powder diffraction. OXCBZ form III was also found to crystallise with a striking twisted morphology. Detailed analysis using scanning electron and atomic force microscopy allowed tracking of the formation and evolution of the twisted crystals. Twisting from the vapour phase is proposed to result from surface energy-driven effects owing to aggregation of fibrous crystals. Theoretical models capable of describing twisting in solution-grown crystals are additionally presented.;Solid-state experiments conducted for EVC and TAEVC revealed the propensity of both compounds to crystallise in isostructural solvated forms. Over a dozen novel solvated salt cocrystals of EVC were isolated and characterised and an initial solid-form landscape was established for TAEVC which had never been subjected to solid-state screening and characterisation previously. The propensity of TAEVC to form a highly robust three-dimensional network of hydrogen bonds in the solid-state was noted, likely an indication of TAEVC molecules' preference to self-associate during nucleation and growth.
Advisor / supervisor
  • Florence, Alastair
Resource Type
DOI
Date Created
  • 2020
Former identifier
  • 9912970892502996

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