Elmizoghi, Hassian
(2025)
Strategies for Raman analysis of pharmaceutical microarrays.
PhD thesis, University of Nottingham.
Abstract
Pharmaceutical systems include a variety of solid-state forms, each with unique characteristics. Polymorphs share an identical chemical composition but differ in their crystalline structures. Solid forms may consist just of the active pharmaceutical ingredient (API) or incorporate additional chemical entities. Examples of multicomponent solids include salts, solvates, cocrystals, and combinations. Solvates, often termed pseudo-polymorphs, incorporate solvent molecules within their structure, while hydrates, a type of solvates, specifically include water in their lattice. Salts contain the API in a charged state paired with counterions, whereas cocrystals consist of the API and coformers.
Piezoelectric, or 2D inkjet printing, was utilised as the primary technique for fabricating nanoarrays of APIs onto predefined designs on tunable solid substrates due to its precise control over the delivered quantities of printed materials, eliminating the risk of cross-contamination by avoiding direct contact with the substrate. A light optical microscope was employed to examine the behaviour of the printed droplets after solvent evaporation, transitioning to dried spots, and to verify the crystalline state of selected spots using polarised light within the same microscope. Raman spectroscopy was also applied as the main method to analyse the solid- state characteristics of the printed spots. The aim of this thesis was to develop a highly efficient method for pharmaceutical cocrystal screening using high throughput raman analysis.
Chapter three investigated the recrystallisation behaviours and morphological properties of pharmaceutical multicomponent solid systems comprising carbamazepine (CBZ) with nicotinamide (NCT) and picolinamide (PCN) on functionalised and gold-coated substrates. Glass slides were functionalised using tetraethyl orthosilicate (TEOS), increasing the water contact angle from 15.8° to 68.3°, indicating successful hydrophobic surface modification. A 2D inkjet printing technique was employed to deposit picoliter volumes of CBZ, NCT, and PCN solutions, facilitating the formation of microarrays for detailed crystal morphology and shape analysis. The printed microarrays were characterised using polarised light microscopy (PLM) to evaluate birefringence and morphological changes across a range of CBZ concentrations.
In the CBZ:NCT system, lower CBZ concentrations (0–16%) exhibited minimal crystallisation with irregular microcrystals. Intermediate concentrations (38–60%) showed enhanced nucleation and the formation of anisotropic crystals, while higher concentrations (70–100%) yielded homogeneous, highly birefringent needle-like crystals, indicating a transition to CBZ- dominated crystallinity. In contrast, the CBZ: PCN system demonstrated weaker birefringence and delayed crystallisation at low CBZ levels, with PCN dominating the morphology. As CBZ concentration increased (48–100%), well-ordered needle-like crystals characteristic of CBZ emerged, overshadowing PCN's influence. This chapter highlighted the impact of substrate functionalisation and composition on the crystallisation behaviour and optical properties of multicomponent solid systems. TEOS-functionalised surfaces promoted uniform crystal formation, providing an efficient platform for high-throughput screening of pharmaceutical formulations. The findings emphasised the critical role of CBZ concentration and coformer interactions in determining crystal morphology, offering insights into the design and optimisation of cocrystal systems.
Chapter four presented a high-throughput methodology for screening and characterising pharmaceutical multicomponent cocrystal systems using piezoelectric inkjet printing and Raman spectroscopy. The focus was on the polymorphic behaviour and intermolecular interactions in (CBZ) formulated with (NCT) and (PCN) across varying compositions (2% CBZ increments). CBZ, NCT, and PCN solutions were printed on gold-coated substrates as nanoarrays, and the crystallisation was examined using (PLM) and Raman spectroscopy.
Raman spectral analysis revealed distinct molecular and lattice vibrational modes indicative of crystalline state formation. The CBZ:NCT system exhibited significant spectral shifts and intensity changes, which were consistent with hydrogen bonding interactions that led to a cocrystal formation. In contrast, the CBZ:PCN system displayed minimal spectral changes, indicating weak interactions and the absence of new crystalline form. These findings underscored the role of coformer selection in cocrystal screening and demonstrated the utility of Raman spectroscopy for rapid, non-destructive analysis of solid-state pharmaceutical systems. This approach offered a scalable solution for early-stage drug development, optimising formulation design through advanced spectroscopic and computational techniques.
Chapter Five established and validated Differential Infrared Thermometry (DIRTY) as a novel, cost-effective method for determining the melting points of multicomponent pharmaceutical solid systems. Multicomponent systems of (CBZ) and (NCT) were prepared using liquid-assisted grinding (LAG) in various mole ratios and analysed using thermal imaging and Fourier Transform Infrared (FTIR) spectroscopy. DIRTY involved recording spatial thermal data during controlled heating with an infrared camera, enabling the characterisation of phase transitions through entropy-based metrics. The melting points of CBZ:NCT mixtures varied with molar ratios, ranging from 132.2°C to 163.8°C, demonstrating shifts influenced by CBZ content. Systems with higher CBZ content exhibited higher melting points and dominance of CBZ's thermal properties, while intermediate ratios (e.g., 1:1) showed distinct thermal behaviour indicative of potential cocrystal formation. FTIR analysis confirmed molecular interactions, with significant shifts in the amide carbonyl stretching and N–H stretching regions. These changes suggested hydrogen-bonding effects, most pronounced at intermediate NCT ratios. The findings demonstrated that DIRTY provided rapid thermal analysis comparable to traditional methods, with FTIR offering complementary molecular insights.
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