Investigating Intermolecular Interactions in Multi-Component Pharmaceuticals

Adjimani, Joseph Tettey (2024) Investigating Intermolecular Interactions in Multi-Component Pharmaceuticals. Doctoral thesis, University of East Anglia.

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Abstract

For many years, the question of how to improve the physical properties of Active Pharmaceutical Ingredients (APIs) without changing their covalent structure has challenged the pharmaceutical industry. The development of multicomponent crystal forms has emerged as a significant strategy for improving key properties such as solubility, stability, and bioavailability, while also providing additional avenues for addressing patent-related challenges. To facilitate the discovery of novel multicomponent forms, a deeper understanding of intermolecular interactions is crucial.

We present a systematic study of the intermolecular interactions of two common pharmaceutical cocrystal coformers: isonicotinamide (INA) and nicotinamide (NA). Despite their structural similarity, these compounds exhibit markedly different intermolecular interactions and, consequently, distinct cocrystal formation behaviours. This thesis encompasses database analysis and extensive experimental screening. We characterize new cocrystals, hydrates and solvates of INA and NA using solid-state techniques including Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction (PXRD), and solid-state Nuclear Magnetic Resonance (NMR). Solution-state intermolecular interactions are investigated through NMR titrations, Insensitive Nuclei Enhanced by Polarization Transfer (INEPT), Correlation Spectroscopy (COSY), and Nuclear Overhauser Effect Spectroscopy (NOESY).

Additionally, herein is the effective combination of time resolved PXRD and CLASSIC NMR to observe in-situ solid-state transformation between different stoichiometric ratios of hydroxybenzoic acid: cyclic amide cocrystal forms. We report the discovery of three new cocrystal forms: 2-HBA1:INA3, 3-HBA1:NA3, and 2,3-DHBA2:NA1 and successfully show the stepwise mechanism of formation of all three cocrystals. The necessary experimental conditions have been optimised to observe in-situ conversion from the 3-HBA1:NA1 cocrystal to this novel 3-HBA1:NA3 form, and from the 1:3 form back to the 1:1 in a time-resolved experimental set up. These in-situ NMR conditions are tested and verified by the conversion of 2,3-DHBA1:NA1 to 2,3-DHBA2:NA1. This comprehensive study provides important insights into the intermolecular interactions governing multicomponent crystal forms.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Depositing User:	Chris White
Date Deposited:	24 Nov 2025 11:26
Last Modified:	24 Nov 2025 11:26
URI:	https://ueaeprints.uea.ac.uk/id/eprint/101086
DOI:

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