Amorphization of crystalline active pharmaceutical ingredients via formulation technologies

Abstract

Amorphous Solid Dispersions (ASDs) were formulated to stabilize amorphous Active Pharmaceutical Ingredients (APIs). We investigated the feasibility of using spray-drying (SD) to generate ASD of indomethacin (IDMC) with a water-soluble polymer excipient poly(vinylpyrrolidone) (PVP), and compared the physicochemical properties of SD IDMC-PVP ASD to IDMC-PVP generated from our previous works via co-milling (COM) and supercritical anti-solvent (SAS) processes [1-3]. Various percentage weight mixtures of IDMC and PVP were dissolved in a mixed solvent (acetone:dichloromethane=80:20vol/vol.%) and spray-dried to generate SD samples. The SD samples were then characterized via Scanning Electron Microscopy (SEM, morphology), Thermogravimetric Analysis (TGA, composition), Powder X-ray diffraction (PXRD, crystallinity), accelerated physical stability testing, dissolution testing, Fourier-Transform Infrared Spectroscopy (FTIR, drug-polymer interaction) and Raman spectroscopy (amorphous spatial distribution). X-ray amorphous SD IDMC-PVP solid dispersions with up to 80wt% of IDMC and 20wt% of PVP were successfully generated, while SAS and COM generated ASDs only up to 60wt% of IDMC. SD, COM and SAS ASD particles were agglomerated spheres, multi-faceted blocks and agglomerated rounded fines, respectively. SAS and SD samples up to 60wt% of IDMC remained stable as X-ray amorphous forms for >6months after storage at 40°C/75%RH. The presence of broadened shoulder peaks at 1724cm−1 in the infrared spectra of SD ASDs can be attributed to hydrogen bonding, contributing to its improved physical stability which was not observed in the physically blended samples. Our results demonstrate that it is feasible to generate ASDs with improved physical stability and dissolution rates through SD with characteristics comparable to SAS and superior to COM.