title: Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions.
abstract: The preparation of amorphous solid dispersion (ASD) formulations is a promising strategy to improve the bioavailability of an active pharmaceutical ingredient (API). By dissolving the API in a polymer it is stabilized in its amorphous form, which usually shows higher water solubility than its crystalline counterpart. To prevent recrystallization, the long-term physical stability of ASD formulations is of big interest. In this work, the solubility of the APIs acetaminophen and naproxen in the excipient polymers poly(vinylpyrrolidone) (PVP K25) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was calculated with three models: the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the Flory-Huggins model (FH), and an empirical model (Kyeremateng et al., J. Pharm. Sci, 2014, 103, 2847-2858). PC-SAFT and FH were further used to predict the influence of relative humidity (RH) on the API solubility in the polymers. The Gordon-Taylor equation was applied to model the glass-transition temperature of dry ASD and at humid conditions. The calculations were validated by 18 months-long stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. The results of the three modeling approaches for the API solubility in polymers agreed with the experimental solubility data, which are only accessible at high temperatures in dry polymers. However, at room temperature FH resulted in a lower solubility of the APIs in the dry polymers than PC-SAFT and the empirical model. The impact of RH on the solubility of acetaminophen was predicted to be small, but naproxen solubility in the polymers was predicted to decrease with increasing RH with both, PC-SAFT and FH. At 25 °C/60% RH and 40 °C/75% RH, PC-SAFT is in agreement with all results of the long-term stability studies, while FH underestimates the acetaminophen solubility in PVP K25 and PVPVA64.
authors.affiliation: AbbVie Deutschland GmbH & Co. KG , Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, Germany.|TU Dortmund , Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lehmkemper
authors.affiliation: AbbVie Deutschland GmbH & Co. KG , Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, Germany.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Kyeremateng
authors.affiliation: AbbVie Deutschland GmbH & Co. KG , Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Heinzerling
authors.affiliation: AbbVie Deutschland GmbH & Co. KG , Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Degenhardt
authors.affiliation: TU Dortmund , Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
authors.forename: Gabriele
authors.identifier: 0000-0002-5038-9152
authors.initials: G
authors.lastname: Sadowski
mesh_terms: D000082:Acetaminophen / Q000737:chemistry; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D009288:Naproxen / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry*; D011205:Povidone / Q000031:analogs & derivatives* / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics; D044366:Transition Temperature
chemical_list: D005079:Excipients; D011145:Polyvinyls; D011759:Pyrrolidines; C505150:poly(N-vinylpyrrolidine); C549547:vinylacetate-vinylpyrrolidone copolymer; D000082:Acetaminophen; D009288:Naproxen; D011205:Povidone
keywords: Flory−Huggins; PC-SAFT; acetaminophen; amorphous solid dispersion; long-term stability studies; naproxen; phase behavior; polymer; relative humidity; thermodynamic model