title: Comparative Study of Different Methods for the Prediction of Drug-Polymer Solubility.
abstract: In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.
authors.affiliation: Department of Biologics and Pharmaceutical Science, H. Lundbeck A/S , 2500 Valby, Denmark.|School of Pharmacy, Johannes Gutenberg University Mainz , 55099 Mainz, Germany.
authors.forename: Matthias Manne
authors.initials: MM
authors.lastname: Knopp
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Tajber
authors.affiliation: Pharmaceutical Engineering Group, School of Pharmacy, Medical Biology Centre, Queen's University , Belfast BT9, Northern Ireland.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Biologics and Pharmaceutical Science, H. Lundbeck A/S , 2500 Valby, Denmark.|NSM, Research Unit for Functional Biomaterials, Roskilde University , 4000 Roskilde, Denmark.
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Olesen
authors.affiliation: Pharmaceutical Engineering Group, School of Pharmacy, Medical Biology Centre, Queen's University , Belfast BT9, Northern Ireland.
authors.forename: David S
authors.initials: DS
authors.lastname: Jones
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kozyra
authors.affiliation: Department of Pharmacy, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Paluch
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Claire Marie
authors.initials: CM
authors.lastname: Brennan
authors.affiliation: Department of Biologics and Pharmaceutical Science, H. Lundbeck A/S , 2500 Valby, Denmark.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Healy
authors.affiliation: Pharmaceutical Engineering Group, School of Pharmacy, Medical Biology Centre, Queen's University , Belfast BT9, Northern Ireland.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Andrews
authors.affiliation: Department of Pharmacy, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000082:Acetaminophen / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D000068579:Celecoxib / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002701:Chloramphenicol / Q000737:chemistry*; D003460:Crystallization / Q000379:methods; D004355:Drug Stability; D015736:Felodipine / Q000737:chemistry*; D007213:Indomethacin / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry; D011760:Pyrrolidinones / Q000737:chemistry; D012995:Solubility; D013816:Thermodynamics; D014753:Vinyl Compounds / Q000737:chemistry
chemical_list: D011108:Polymers; D011760:Pyrrolidinones; D014753:Vinyl Compounds; D000082:Acetaminophen; D002701:Chloramphenicol; C042670:N-vinyl-2-pyrrolidinone; D011205:Povidone; D000068579:Celecoxib; C011566:vinyl acetate; D015736:Felodipine; D007213:Indomethacin
keywords: Flory−Huggins; amorphous; calorimetry (DSC); melting point depression; polymers; recrystallization; solid dispersion; solubility; thermal analysis; thermodynamics