title: Investigating the Influence of Polymers on Supersaturated Flufenamic Acid Cocrystal Solutions.
abstract: The development of enabling formulations is a key stage when demonstrating the effectiveness of pharmaceutical cocrystals to maximize the oral bioavailability for poorly water soluble drugs. Inhibition of drug crystallization from a supersaturated cocrystal solution through a fundamental understanding of the nucleation and crystal growth is important. In this study, the influence of the three polymers of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2-pyrrodidone (60%) and vinyl acetate (40%) (PVP-VA) on the flufenamic acid (FFA) crystallization from three different supersaturated solutions of the pure FFA and two cocrystals of FFA-NIC CO and FFA-TP CO has been investigated by measuring nucleation induction times and desupersaturation rates in the presence and absence of seed crystals. It was found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer, and coformer/polymer was a key factor responsible for maintaining supersaturation through nucleation inhibition and crystal growth modification in a cocrystal solution. The supersaturated cocrystal solutions with predissolved PEG demonstrated more effective stabilization in comparison to the pure FFA in the presence of the same polymer. In contrast, neither of the two cocrystal solutions, in the presence of PVP or PVP-VA, exhibited a better performance than the pure FFA with the same predissolved polymer. The study suggests that the selection of a polymeric excipient in a cocrystal formulation should not be solely dependent on the interplay of the parent drug and polymer without considering the coformer effects.
authors: School of Pharmacy, De Montfort University , Leicester LE1 9BH, U.K.
authors: Minshan
authors: M
authors: Guo
authors: School of Pharmacy, De Montfort University , Leicester LE1 9BH, U.K.
authors: Ke
authors: K
authors: Wang
authors: Almac Science, Seagoe Industrial Estate , Craigavon BT63 5QD, U.K.
authors: Noel
authors: N
authors: Hamill
authors: Almac Science, Seagoe Industrial Estate , Craigavon BT63 5QD, U.K.
authors: Keith
authors: K
authors: Lorimer
authors: School of Pharmacy, De Montfort University , Leicester LE1 9BH, U.K.
authors: Mingzhong
authors: M
authors: Li
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D005439:Flufenamic Acid / Q000737:chemistry*; D008859:Microscopy, Polarization; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry; D012996:Solutions / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D011108:Polymers; D012996:Solutions; D011092:Polyethylene Glycols; D005439:Flufenamic Acid; D011205:Povidone
keywords: cocrystal; crystal growth; flufenamic acid; nucleation; polymers; supersaturation