Investigating the Dissolution and Permeation Properties of Flufenamic Acid Cocrystals
The purpose of this study is to improve the solubility, dissolution rate and permeability of poorly water-soluble drugs by investigating the dissolution and permeation properties of flufenamic acid cocrystals in the presence of polymers. This study was separated into four tasks: (1) Formation of pharmaceutical cocrystals: Two pharmaceutical cocrystals of poorly water soluble active pharmaceutical ingredient (API) flufenamic acid (FFA) were synthesized, including 1:1 flufenamic acid-nicotinamide cocrystal (FFA-NIC CO) and 1:1 flufenamic acid-theophylline cocrystal (FFA-TP CO). The results of infrared spectroscopy (IR), differential scanner calorimetry (DSC) and x-ray powder diffraction (XRPD) confirmed the formation of cocrystals. (2) Effect of polymers on cocrystals supersaturated solution: The influence of three polymers (polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2-pyrrolidone (60%) and vinyl acetate (40%) (PVP-VA)) on FFA crystallization from FFA and FFA cocrystals supersaturated solutions was studied by measuring the nucleation induction time and desupersaturation rates of the supersaturated solutions in the absence or presence of crystals seeds. It was found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer and coformer/polymer was the key factor for maintaining the supersaturated state in cocrystal solution. (3) Study the mechanism of cocrystals dissolution: The dissolution mechanism of cocrystals in absence or presence of polymers was investigated by carrying out different dissolution experiments of both single and powdered cocrystals at multiple length scales, including molecular level, macroscopic level and bulk experiment. According to the results, FFA-NIC CO and FFA-TP CO have different dissolution mechanisms. The addition of polymers can alter the dissolution property of cocrystals by interacting with crystal face. ABSTRACT VIII (4) Investigation of permeation property of cocrystals: The key processes (kinetics of FFA cocrystals supersaturation and subsequent drug permeation) during cocrystals dissolution in the absence or presence of different concentration of polymers (PVP and PVP-VA) were systematically evaluated by using dissolution/permeation system in a side-by-side cell. Furthermore, the insight mechanism of the supersaturated solution and permeation behavior was explored by 1H NMR. We found that the permeation property of cocrystals is highly depended on the polymer type, coformer type and polymer concentration.
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