title: Influence of polymer molecular weight on in vitro dissolution behavior and in vivo performance of celecoxib:PVP amorphous solid dispersions.
abstract: In this study, the influence of the molecular weight of polyvinylpyrrolidone (PVP) on the non-sink in vitro dissolution and in vivo performance of celecoxib (CCX):PVP amorphous solid dispersions were investigated. The dissolution rate of CCX from the amorphous solid dispersions increased with decreasing PVP molecular weight and crystallization inhibition was increased with increasing molecular weight of PVP, but reached a maximum for PVP K30. This suggested that the crystallization inhibition was not proportional with molecular weight of the polymer, but rather there was an optimal molecular weight where the crystallization inhibition was strongest. Consistent with the findings from the non-sink in vitro dissolution tests, the amorphous solid dispersions with the highest molecular weight PVPs (K30 and K60) resulted in significantly higher in vivo bioavailability (AUC0-24h) compared with pure amorphous and crystalline CCX. A linear relationship between the in vitro and in vivo parameter AUC0-24h indicated that the simple non-sink in vitro dissolution method used in this study could be used to predict the in vivo performance of amorphous solid dispersion with good precision, which enabled a ranking between the different formulations. In conclusion, the findings of this study demonstrated that the in vitro and in vivo performance of CCX:PVP amorphous solid dispersions were significantly controlled by the molecular weight of the polymer.
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; Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Julia Hoang
authors.initials: JH
authors.lastname: Nguyen
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, D-55128 Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, D-55128 Mainz, Germany.
authors.forename: Nadine Monika
authors.initials: NM
authors.lastname: Francke
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Erling B
authors.initials: EB
authors.lastname: Jørgensen
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, DK-2500 Valby, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Holm
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: Huiling
authors.initials: H
authors.lastname: Mu
authors.affiliation: Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, D-55128 Mainz, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Langguth
mesh_terms: D000818:Animals; D001682:Biological Availability; D000068579:Celecoxib / Q000737:chemistry* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D008297:Male; D008970:Molecular Weight; D011108:Polymers / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D011108:Polymers; D011205:Povidone; D000068579:Celecoxib
keywords: Amorphous solid dispersion; Celecoxib; IVIVC; In vivo; Molecular weight; Non-sink dissolution; PVP; ​In vitro