title: Rheological and solid-state NMR assessments of copovidone/clotrimazole model solid dispersions.
abstract: This study aims to assess several model solid dispersions by using dynamic oscillatory rheology, solid-state NMR and other solid phase characterization techniques, and correlate their viscoelastic responses with processing methods and microstructures. A model active pharmaceutical ingredient (API), clotrimazole, was compounded with copovidone to form solid dispersions via various techniques with different mixing capabilities. Physicochemical characterizations of the resulting solid dispersions demonstrated that simple physical mixing led to a poorly mixed blend manifested by existence of large API crystalline content and heterogeneous distribution. Cryogenic milling significantly improved mixing of two components as a result of reduced particle size and increased contact surface area, but produced limited amorphous content. In contrast, hot melt extrusion (HME) processing resulted in a homogenous amorphous solid dispersion because of its inherent mixing efficiency. Storage modulus and viscosities versus frequency of different solid dispersions indicated that the incorporation of API into the polymer matrix resulted in a plasticizing effect which reduced the viscosity. The crystalline/aggregated forms of API also exhibited more elastic response than its amorphous/dispersed counterpart. Temperature ramps of the physical mixture with high API concentration captured a critical temperature, at which a bump was observed in damping factor. This bump was attributed to the dissolution of crystalline API into the polymer. In addition, heating-cooling cycles of various solid dispersions suggested that cryomilling and HME processing could form a homogeneous solid dispersion at low API content, whereas high drug concentration led to a relatively unstable dispersion due to supersaturation of API in the polymer.
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA. Electronic address: fengyuan.yang@merck.com.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Su
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA. Electronic address: chad-brown@merck.com.
authors.forename: Chad D
authors.initials: CD
authors.lastname: Brown
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Rosen
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rosenberg
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry; D003022:Clotrimazole / Q000737:chemistry*; D004339:Drug Compounding; D004548:Elasticity; D009682:Magnetic Resonance Spectroscopy; D011759:Pyrrolidines / Q000737:chemistry*; D012212:Rheology; D014753:Vinyl Compounds / Q000737:chemistry*; D014783:Viscosity
chemical_list: D000935:Antifungal Agents; D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate); D003022:Clotrimazole
keywords: Hot melt extrusion and amorphous solid dispersion; Rheology; Solid-state NMR