Insight into Nucleation Kinetics of Flufenamic Acid Cocrystal Formulation in Solution: Investigating the Role of Polymeric Excipients through Combined Experimental and Computational Approaches

This thesis investigates the nucleation kinetics and molecular interactions in flufenamic acid (FFA) cocrystal systems, with a particular focus on the role of polymeric excipients. The impact of selected polymers, polyvinyl pyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyethylene glycol (PEG), and soluplus (SOL), on the nucleation and growth of cocrystals of FFA with theophylline (FFA-TP) and nicotinamide (FFA-NIC) was evaluated. Cocrystals, as multicomponent crystalline solids, offer enhanced solubility and dissolution for poorly water-soluble drugs. However, their dissolution processes often involve complex nucleation and crystallisation dynamics, which can revert the drug to its poorly soluble form. To address these challenges, this study employs a combination of experimental and computational techniques to understand nucleation mechanisms and the influence of polymers in stabilising supersaturated cocrystal solutions. The methodology integrates induction time measurements (Crystal16), solution-state Nuclear Magnetic Resonance (NMR), high-performance liquid chromatography (HPLC), molecular dynamics (MD) simulations, and solid-state characterisation techniques including X-ray powder diffraction (XRPD), attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), and differential scanning calorimetry (DSC), to assess structural and thermal properties. PEG significantly prolonged induction times with increases of 8.2-fold for FFA solutions, 13.8-fold for FFA-TP solutions and 13.3-fold for FFA-NIC solutions, indicating its role in stabilising supersaturated states. SOL exhibited moderate nucleation inhibition, while PVP and PVP-VA had minimal impact on nucleation inhibition. The combination of PVP-VA and SOL had a coformer-dependent effect, significantly delaying nucleation in FFA-TP solutions while accelerating nucleation in FFA-NIC solutions. These effects are attributed to non-site specific molecular interactions, including non-hydrogen bonding and hydrophobic interactions, which are elucidated through NMR and simulation data. Molecular dynamics simulations revealed that van der Waals (VDW) interactions dominated FFA aggregation, with RDF analysis showing polymer-induced disruption of FFA dimer formation. DOSY NMR experiments revealed polymer-dependent diffusion effects, PVP-VA and SOL significantly increased FFA mobility. PEG, in contrast, showed minimal enhancement of diffusion, instead acting as a stabiliser. Combinations of PVP-VA with PEG or SOL exhibited distinct trends, with PEG contributing steric stabilisation while SOL enhanced mobility. These findings further support the role of polymer selection in modulating nucleation dynamics and stabilising supersaturation. The study findings provide insight into the mechanistic role of polymeric excipients in cocrystal nucleation, offering a molecular-level understanding of how polymers influence nucleation, molecular interactions, and phase stability. The integration of experimental and computational approaches provides a comprehensive framework for addressing solubility challenges in poorly water-soluble drugs.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

De Montfort University

Year dc:date.issued

2025

Author dc:creator

• Alinda, Peace

Licence

• https://dora.dmu.ac.uk/bitstreams/062883f3-c706-41ea-8060-3395d365bca8/download