Keyhanfar, Diba; (2025) Cocrystallisation as an Odour Masking Strategy for the Development of Palatable Medicines. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis explores the use of cocrystal formation to improve medication palatability by masking the unpleasant odours of active pharmaceutical ingredients (APIs). Palatability challenges in drug formulations, such as undesirable taste, texture, and smell, can hinder patient adherence, particularly among paediatric and elderly populations. While taste masking is the focus of existing strategies, odour remains overlooked despite its impact on compliance. This research investigates cocrystallisation as a means to modify API odour by altering physicochemical properties like vapour pressure. Two crystal engineering strategies were employed to mask the odour of vitamin B derivatives, leading to the identification of eight new crystal forms, six for pyridoxine (PY) and two for thiamine (THI). Among these, a cocrystal of THI with vanillic acid demonstrated a notable improvement in odour. Human sensory panel evaluations confirmed that this cocrystal was generally perceived as more pleasant-smelling than the parent API, suggesting that odour masking was achieved through reduced volatility and the incorporation of a fragnant coformer. Further studies focused on cephalexin monohydrate (CPX·H2O), a widely used antibiotic with a known unpleasant odour. Two promising cocrystals, with thymol and acetylpyrazine, were identified, both exhibiting distinct odour modifications. Sensory evaluations of the acetylpyrazine cocrystal revealed a strong, popcorn-like scent. While some participants found this aroma appealing, others considered it too intense, highlighting the role of individual olfactory preferences in formulation acceptability. Overall, these findings demonstrate that cocrystallisation can be an effective strategy for modifying the perceived odour of APIs by reducing volatility and incorporating aromatic coformers. However, the variability in human olfactory perception underscores the need for refined sensory assessment methodologies and further research into tailored odour-masking strategies for pharmaceutical applications.

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