Solution Phase Aggregation of Pharmaceutical Multi-components

Abstract

Co-crystallisation has become a more contemporary approach for optimising pharmaceutical physicochemical properties of active pharmaceutical ingredients (APIs). Although both experimental and virtual methods can be employed for co-crystal screening, most experimental screening methods are trial-and-error processes and virtual methods mostly focus on solid-phase interactions but often overlook interactions in solution. Solution-based co-crystallisation is the most commonly used method in both laboratory and industrial scale. Therefore, it is of great importance to build up a new fast and systematic method to predict the formation of co-crystal with the consideration of solution state. Considerable effort is dedicated to understanding the solution structure, with varying degrees of success and a high dependency on the system, aiming to provide insights into the solid structure. The current work focuses on the solution aggregation between two solutes, the API and the co-former and aims to connect the pre-nucleation aggregates with co-crystal formation, hydrotropism mechanism, co-crystal properties and nucleation pathways. Nuclear magnetic resonance (NMR) spectroscopy with titration experiments is mainly used to explore the interaction between two solute species in solution, assessing the strength of the interaction. Ultraviolet-visible light spectroscopy complements the study of stronger interactions at lower concentration, while neutron total scattering combined with Monte Carlo simulation offers a comprehensive understanding of the whole solution structure. The properties of some co-crystals are also investigated including solubility, dissolution rate, taste and morphology. In chapter 3, the caffeine-benzoic acid co-crystal system is studied, due to its reported difficulty to crystallise from the solution phase. The strong pre-nucleation aggregation in three solvents corresponds to the co-crystal formation while the co-crystal is not obtained from the solvent where there are no detectable clusters, with the results verified against ternary phase diagrams. The result shows the link between pre-nucleation interaction in a specific solvent and the co-crystal formation from that solvent. NMR spectroscopy can thus be used as a fast and promising tool to predict co-crystallisation from specific solvents and to screen for suitable solvents. In chapter 4, we explore the interaction in solution between an API and a hydrotrope, which massively enhances the solubility of drugs without changing their crystal structure, aiming to elucidate the mechanism of hydrotropism. The solubility of caffeine at room temperature can be enhanced more than 20 folds by the addition of sodium benzoate acting as a hydrotrope. The result from NMR spectroscopy shows strong interaction between the two compounds in water. Neutron total scattering combined with simulation reveals pi stacking between caffeine and the benzoate anion, Coulombic interactions with the sodium cation and the strong hydrogen bond interaction between benzoate and water help increase the solubility of caffeine in water. Both methods serve as complementary techniques to provide a comprehensive understanding of this hydrotrope solutions. The taste masking effect of the bitter-tasting drug nevirapine by co-crystallisation with five co-formers is investigated in chapter 5. The co-formers benzoic acid, salicylic acid and maleic acid show strong interaction with nevirapine in solution, while glutaric acid and saccharin have weak and no interaction, respectively. From the taste results conducted by the electrical taste sensing system, the bitterness of nevirapine remains uncovered by saccharin or salicylic acid due to absence of interaction and as they themselves have a bitter taste. However, the bitterness is masked by the other three co-formers. The results show both solution aggregation and the taste of the pure co-former play an important role in taste masking. The investigation of molecular

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Cinzia Casiraghi (Supervisor) & Andrew Leach (Supervisor)