title: Nanoscale Infrared, Thermal, and Mechanical Characterization of Telaprevir-Polymer Miscibility in Amorphous Solid Dispersions Prepared by Solvent Evaporation.
abstract: Miscibility is of great interest for pharmaceutical systems, in particular, for amorphous solid dispersions, as phase separation can lead to a higher tendency to crystallize, resulting in a loss in solubility, decreased dissolution rate, and compromised bioavailability. The purpose of this study was to investigate the miscibility behavior of a model poorly water-soluble drug, telaprevir (TPV), with three different polymers using atomic force microscopy-based infrared, thermal, and mechanical analysis. Standard atomic force microscopy (AFM) imaging together with nanoscale infrared spectroscopy (AFM-IR), nanoscale thermal analysis (nanoTA), and Lorentz contact resonance (LCR) measurements were used to evaluate the miscibility behavior of TPV with three polymers, hydroxypropyl methylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), at different drug to polymer ratios. Phase separation was observed with HPMC and PVPVA at drug loadings above 10%. For HPMCAS, a smaller miscibility gap was observed, with phase separation being observed at drug loadings higher than ∼30-40%. The domain size of phase-separated regions varied from below 50 nm to a few hundred nanometers. Localized infrared spectra, nano-TA measurements, images from AFM-based IR, and LCR measurements showed clear contrast between the continuous and discrete domains for these phase-separated systems, whereby the discrete domains were drug-rich. Fluorescence microscopy provided additional evidence for phase separation. These methods appear to be promising to evaluate miscibility in drug-polymer systems with similar Tgs and submicron domain sizes. Furthermore, such findings are of obvious importance in the context of contributing to a mechanistic understanding of amorphous solid dispersion phase behavior.
authors: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors: Na
authors: N
authors: Li
authors: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors: Lynne S
authors: LS
authors: Taylor
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D003460:Crystallization; D004355:Drug Stability; D018625:Microscopy, Atomic Force / Q000379:methods; D036103:Nanotechnology / Q000379:methods*; D009842:Oligopeptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013055:Spectrophotometry, Infrared / Q000379:methods*; D013814:Thermal Conductivity
chemical_list: D009842:Oligopeptides; D011108:Polymers; D012997:Solvents; C486464:telaprevir
keywords: AFM; LCR; amorphous solid dispersion; nanoIR; nanoTA