title: Influence of PVP/VA copolymer composition on drug-polymer solubility.
abstract: In this study, the influence of copolymer composition on drug-polymer solubility was investigated. The solubility of the model drug celecoxib (CCX) in various polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer compositions (70/30, 60/40, 50/50 and 30/70 w/w) and the pure homopolymers polyvinylpyrrolidone (PVP) and polyvinyl acetate (PVA) was predicted at 25 °C using a thermal analysis method based on the recrystallization of a supersaturated amorphous dispersion (recrystallization method). These solubilities were compared with a prediction based on the solubility of CCX in the liquid monomeric precursors of PVP/VA, N-vinylpyrrolidone (NVP) and vinyl acetate (VA), using the Flory-Huggins lattice theory (liquid monomer solubility approach). The solubilities predicted from the liquid monomer solubility approach increased linearly with increasing VP/VA ratio from 0.03-0.60 w/w. Even though the solubilities predicted from the recrystallization method also increased with increasing VP/VA ratio from 0.02-0.40 w/w, the predicted solubility seemed to approach a plateau at high VP/VA ratios. Increasing positive deviations from the Gordon-Taylor equation with increasing VP/VA ratio indicated strong interactions between CCX and the VP repeat unit, which was in accordance with the relatively high solubilities predicted using both methods. As the solubility plateau may be a consequence of steric hindrance caused by the size differences between CCX and the VP repeat units, it is likely that a CCX molecule interacting with a VP repeat unit hinders another CCX molecule from binding to the neighboring repeat units in the polymer chain. Therefore, it is possible that replacing these neighboring hygroscopic VP repeat units with hydrophobic VA repeat units, could increase the physical stability of an amorphous solid dispersion without compromising the drug-polymer solubility. This knowledge could be used advantageously in future development of amorphous drug delivery systems as copolymers could be customized to provide optimal drug-polymer solubility and physical stability.
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark; Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Malte Bille
authors.initials: MB
authors.lastname: Rask
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark; Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, D-55128 Mainz, Germany.
authors.forename: Matthias Manne
authors.initials: MM
authors.lastname: Knopp
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Olesen
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark; Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark. Electronic address: rhol@lundbeck.com.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000068579:Celecoxib / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D004355:Drug Stability; D057927:Hydrophobic and Hydrophilic Interactions; D011108:Polymers / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics
chemical_list: D011108:Polymers; D011145:Polyvinyls; C013215:polyvinyl acetate; D011205:Povidone; D000068579:Celecoxib
keywords: Amorphous solid dispersion; Copolymers; Differential scanning calorimetry (DSC); Flory–Huggins; Gordon–Taylor; Solubility