title: Effect of polymer type and drug dose on the in vitro and in vivo behavior of amorphous solid dispersions.
abstract: This study investigated the non-sink in vitro dissolution behavior and in vivo performance in rats of celecoxib (CCX) amorphous solid dispersions with polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) at different drug doses. Both in vitro and in vivo, the amorphous solid dispersions with the hydrophilic polymers PVP and HPMC led to higher areas under both, the in vitro dissolution and the plasma concentration-time curves (AUC) compared to crystalline and amorphous CCX for all doses. In contrast, the amorphous solid dispersion with the hydrophobic polymer PVA showed a lower AUC both in vitro and in vivo than crystalline CCX. For crystalline CCX and CCX:PVA, the in vitro AUC was limited by the low solubility of the drug and the slow release of the drug from the hydrophobic polymer, respectively. For the supersaturating formulations, amorphous CCX, CCX:PVP and CCX:HPMC, the in vitro performance was mainly dependent on the dissolution rate and precipitation/crystallization inhibition of the polymer. As expected, the crystallization tendency increased with increasing dose, and therefore the in vitro AUCs did not increase proportionally with dose. Even though the in vivo AUC for all formulations increased with increasing dose, the relative bioavailability decreased significantly, indicating that the supersaturating formulations also crystallized in vivo and that the absorption of CCX was solubility-limited. These findings underline the importance of evaluating relevant in vitro doses, in order to rationally assess the performance of amorphous solid dispersions and avoid confusion in early in vivo studies.
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: Nabil
authors.initials: N
authors.lastname: Chourak
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: Fauzan
authors.initials: F
authors.lastname: Khan
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: Johan
authors.initials: J
authors.lastname: Wendelboe
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
authors.affiliation: Department of Pharmacy, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
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; Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2430 Beerse, Belgium. Electronic address: rholm@its.jnj.com.
authors.forename: René
authors.initials: R
authors.lastname: Holm
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D008297:Male; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011108:Polymers
keywords: Amorphous solid dispersion; Bioavailability; Celecoxib; Dose-dependence; HPMC; IVIVC; In vitro; In vivo; Non-sink dissolution; PVA; PVP; Polymers; Poorly soluble drugs; Solubility enhancement; Supersaturation