Nucleation of Supersaturated Flufenamic Acid Cocrystal Solutions in the Presence of a Polymer

Abstract

The nucleation kinetics and thermodynamics of two flufenamic acid cocrystal solutions, i.e., flufenamic acid and theophylline (FFA-TP) and flufenamic acid and nicotinamide (FFA-NIC), in the absence and presence of the polymer polyvinylpyrrolidone (PVP) or the copolymer vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA) have been investigated and compared with the pure FFA solution. Induction times have been collected under five equal parent drug supersaturation levels at 27 °C with at least 80 repetitive experiments in 1 mL solutions for each supersaturation level. Nucleation rates, extracted from the induction time distributions by accounting for a nucleus growth time, have been used to determine the interfacial energy and the pre-exponential factor within the framework of classical nucleation theory (CNT). It is shown that the cocrystal coformer played a significant role in inducing the precipitation of the cocrystal or the parent drug. Due to a lower solubility of the FFA-TP cocrystal in comparison with the parent drug FFA, FFA-TP complexes can be formed in the FFA-TP cocrystal solution, resulting in a delay in the solution nucleation of FFA-TP cocrystals. There was no significant difference in the nucleations of the FFA-NIC cocrystal and the pure compound FFA solutions, in which only FFA III crystals were precipitated with comparable nucleation induction times. Although PVP or PVP-VA is an effective surface precipitation inhibitor of the FFA cocrystals, its effectiveness in maintaining FFA in a supersaturated solution is rather limited. The influence of PVP or PVP-VA on the nucleation time of a supersaturated FFA cocrystal solution depends on both its concentration and constituent components in the solution. From a CNT perspective, it was revealed that the kinetic movement of the FFA-TP nucleus was altered by the polymer, leading to the promotion or hindrance of the nucleation. In contrast, NIC in the FFA-NIC solution system interacted with the polymer PVP or PVP-VA so that a lesser amount of NIC was absorbed on the surfaces of the nuclei, resulting in increased interfacial energy to delay the nucleation. The study has indicated that a good surface precipitation inhibitor, such as PVP or PVP-VA, is not guaranteed to be an effective bulk solution precipitation inhibitor. Additionally, optimization of both the type of polymer and its concentration is needed for the development of an effective cocrystal formulation.