title: Mechanism of Dissolution-Induced Nanoparticle Formation from a Copovidone-Based Amorphous Solid Dispersion.
abstract: Amorphous solid dispersions (ASDs) have been increasingly used to maximize human exposures from poorly soluble drug candidates. One well-studied advantage of ASDs is the increased amorphous drug solubility compared to crystalline forms. This provides more rapid dissolution rates. An additional advantage of ASDs is that the dissolution process of the ASD particle may also rapidly transform much of the drug present in the ASD particle to small (<1 μm) amorphous drug nanoparticles which will have fast dissolution rates. This work examines the mechanism by which this nanoparticle formation occurs by studying an ASD consisting of 70-80% copovidone, 20% anacetrapib (a low solubility lipophilic drug), and 0-10% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant). Nanoparticle formation is found to derive from a rapid amorphous drug domain formation within the ASD particle, driven by copovidone dissolution from the particle. The role of surfactant in the ASD particle is to prevent an otherwise rapid, local drug domain aggregation event, which we term "hydrophobic capture". Surfactant thus allows the amorphous drug domains to escape hydrophobic capture and diffuse to bulk solution, where they are reported as nanoparticles. This view of surfactant and nanoparticle formation is compared to the prevailing view in the literature. The work here clarifies the different roles that surfactant might play in increasing nanoparticle yields and extending the useful drug loading ranges in copovidone-based ASDs.
authors.affiliation: Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Harmon
authors.affiliation: Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Kendra
authors.initials: K
authors.lastname: Galipeau
authors.affiliation: Formulation Sciences, Merck Research Laboratories, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Formulation Sciences, Merck Research Laboratories, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Chad
authors.initials: C
authors.lastname: Brown
authors.affiliation: Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Wuelfing
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D057927:Hydrophobic and Hydrophilic Interactions; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011759:Pyrrolidines / Q000737:chemistry*; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D014753:Vinyl Compounds / Q000737:chemistry*
chemical_list: D011759:Pyrrolidines; D012996:Solutions; D013501:Surface-Active Agents; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate)
keywords: dissolution; hydrophobic capture; nanoparticles; scaffold particle; solid dispersion; solubility; surfactant