(640d) Effect of Preparative Methods on the Polymorph Found in Crystalline Solid-Dispersions of Flufenamic Acid

A solid dispersion is a strategy that embeds active pharmaceutical ingredients (APIs) in a polymeric carrier: (a) to improve the solubility of poorly water-soluble APIs and more recently (b) as an alternative solid dosage formulation approach for continuous manufacturing (e.g. hot melt extrusion). Three main solid dispersion preparation techniques were employed: (i) fusion, (ii) solvent-evaporation, and (iii) solvent fusion methods. Although these techniques are also widely recommended as a pretreatment step for phase diagram determination, very little examples exist in the literature concerning the effect of these methods on the resulting polymorphic form of the API once the solid dispersion is obtained. Polymorphism is a critical quality attribute that allows molecules to exhibit multiple crystalline phases, which may affect the physicochemical properties (e.g. solubility, bioavailability, melting point). In this study, the influence of these preparation methods was studied for flufenamic acid (FFA), a polymorphic API, and polyethylene glycol (PEG 10,000), as polymeric carrier. The physical mixtures and solid dispersions were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and hot stage microscopy (HSM). The results show that the fusion method, applying fast and slow cooling profiles, lead to concomitant formation of FFA forms I and III. On the other hand, the solvent evaporation and solvent fusion methods, applying slow and fast evaporation, both lead to FFA form III. Moreover, the results show that the preparation methods have a significant influence on the phase diagrams determined, which are often used to justify the thermodynamic design space of manufacturing processes. Consequently, when employing compounds prone to display polymorphism, choosing a solid dispersion preparation method that enables polymorphic control is crucial to ensure (i) the accurate determination of the phase diagram and (ii) the quality attributes of the formulation in crystalline solid dispersions.