Cocrystallising acids and amides: towards pharmaceutical cocrystals

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dc.availability.bitstreamembargoed
dc.check.chapterOfThesisOpen Access: Embargo for 10 years. (as per Submission for Examination Form. No redaction of part of the thesisen
dc.check.date2031-09-30
dc.contributor.advisorLawrence, Simon E.en
dc.contributor.advisorMaguire, Anitaen
dc.contributor.authorStokes, Stephen P.
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2021-09-17T14:20:23Z
dc.date.available2021-09-17T14:20:23Z
dc.date.issued2021-07-20
dc.date.submitted2021-07-20
dc.description.abstractThe work presented in this dissertation focuses on the molecular features of small molecules and their interactions with pharmaceutically relevant molecules. Emphasis is placed on cocrystallisation; a method that facilitates the formation of multicomponent forms of molecules with non-ionisable or weakly ionisable functional groups. This research has been divided into nine chapters. Chapter 1 describes the concept of crystallisation and introduces supramolecular chemistry. Through the explanation of hydrogen and halogen bonding, which is prominent throughout this work, the concept of supramolecular synthons is unveiled for multicomponent compounds. Finally, applications of cocrystals involving pharmaceutically industrially relevant compounds amongst others are discussed. Chapter 2 gives an overview of the general procedures carried out in this work. Furthermore, a list of the analytical equipment employed is described. Chapter 3 initially describes the crystal landscape of the secondary amide γ-lactam, 2-pyrrolidone, 1, with extension to other lactam systems. This compound is of relevance as it is used routinely as a high boiling solvent in the pharmaceutical industry. A cocrystal screen of 1 was carried out with a range of amide and carboxylic acid based coformers, and fenamic acid active pharmaceutical ingredients (APIs). The common structural motifs of the successfully resolved single crystals were grouped and discussed, and the robustness of the cocrystal forming abilities of 1 demonstrated. Chapter 4 discusses the benzene fused γ-lactam, 2-oxindole, 2, which is the benzene fused analogue of 1. An initial polymorphic screen was employed with a subsequent cocrystal screen of 2 with a range of coformers similar to 1. From this, an investigation into the solid-state similarities between cocrystals of 1 and 2 was conducted, revealing both similarities and variations in the observed motifs. Chapter 5 focuses on a molecule of pharmaceutical relevance, namely modafinil, 3, an anti-narcoleptic drug. In an attempt to utilise the halogen bonding potential of both 3 and 1,4-diiodotetraflourobenzene, the discovery of a dihydrate of 3 is described with characterisation of the resultant solid-state structure. Chapter 6 focuses on 6-propyl-2-thiouracil, 4, an API used in the treatment of Graves’ disease. A cocrystal screening involving acids, amides, fenamic acids and other API molecules was conducted. The motifs of successful single crystal structures are discussed and the structural properties rationalised. Chapter 7 describes the synthetic strategies to synthesise four fenamic acid based molecules, two of which are novel molecules containing methylene linkers. Chapter 8 Conclusion summarising the main findings of the entire work. Chapter 9 Appendixen
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationStokes, S. P. 2021. Cocrystallising acids and amides: towards pharmaceutical cocrystals. PhD Thesis, University College Cork.en
dc.identifier.endpage337en
dc.identifier.urihttps://hdl.handle.net/10468/11953
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2021, Stephen P. Stokes.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectCocrystallisationen
dc.subjectCocrystalsen
dc.titleCocrystallising acids and amides: towards pharmaceutical cocrystalsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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