Insight into the Precipitation Inhibition of Polymers within Cocrystal Formulations in Solution Using Experimental...

This study investigated the role of various polymers as precipitation inhibitors in solutions of flufenamic acid (FFA) and its cocrystals with theophylline (FFA-TP) and nicotinamide (FFA-NIC). Through a combination of NMR spectroscopy, molecular dynamics simulations, and nucleation studies using Crystal16, we evaluated the effects of polyethylene glycol (PEG), polyvinylpyrrolidone-vinyl acetate (PVP-VA), and soluplus (SOL), both individually and in combinations, on the nucleation, diffusion, and self-association of FFA molecules in solution. ¹H NMR and DOSY measurements revealed that while PEG was highly effective in reducing molecular mobility, thus significantly delaying nucleation, PVP-VA facilitated nucleation by enhancing FFA diffusion and aggregation. SOL provided a balance, enhancing molecular mobility but maintaining a delayed nucleation effect, likely due to micellar encapsulation, as evidenced by line broadening in ¹H NMR. Combination systems such as PVP-VA-PEG and PVP-VA-SOL showed synergistic effects, with PVP-VA-SOL proving particularly effective in inhibiting FFA nucleation across all systems. Molecular dynamics simulations supported these findings by highlighting changes in intermolecular interactions and aggregation tendencies in the presence of each polymer. This comprehensive analysis suggested that selecting appropriate polymeric excipients, or combinations thereof, can finely tune the nucleation behaviors of drug solutions, offering a strategic approach to optimizing the stability of supersaturated drug solutions.