Dissolution Behavior of Flufenamic Acid in Heated Mixtures with Nanocellulose

Flufenamic acid (FFA) is a problem drug that has up to eight different polymorphs and shows poor solubility. Variability in bioavailability has been reported in the past resulting in limited use of FFA in the oral solid dosage form. The goal of this article was to investigate the polymorphism and amorphization behavior of FFA in non-heated and heated mixtures with high surface area nanocellulose, i.e., Cladophora cellulose (CLAD). As a benchmark, low surface area microcrystalline cellulose (MCC) was used. The solid-state properties of mixtures were characterized with X-ray diffraction, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The dissolution behavior of mixtures was studied in three biorelevant media, i.e., fasted state simulated gastric fluid, fasted state simulated intestinal fluid, and fed state simulated intestinal fluid. Additional thermal analysis and dissolution tests were carried out following 4 months of storage at 75% RH and room temperature. Heated mixtures of FFA with CLAD resulted in complete amorphization of the drug, whereas that with MCC produced a mixture of up to four different polymorphs. The amorphous FFA mixture with CLAD exhibited rapid and invariable fasted/fed state dissolution in simulated intestinal fluids, whereas that of MCC mixtures was highly dependent on the biorelevant medium. The storage of the heated FFA-CLAD mixture did not result in recrystallization or changes in dissolution profile, whereas heated FFA-MCC mixture showed polymorphic changes. The straightforward dry powder formulation strategy presented here bears great promise for reformulating a number of problem drugs to enhance their dissolution properties and reduce the fasted/fed state variability.