title: Evaluation of drug-polymer solubility curves through formal statistical analysis: comparison of preparation techniques.
abstract: In this study, the influence of the preparation technique (ball milling, spray drying, and film casting) of a supersaturated amorphous dispersion on the quality of solubility determinations of indomethacin in polyvinylpyrrolidone was investigated by means of statistical analysis. After annealing of the amorphous dispersions above the crystallization temperature for 2 h, the solubility curve was derived from the glass transition temperature of the demixed material using the Gordon-Taylor relationship and fitting with the Flory-Huggins model. The study showed that the predicted solubility from the ball-milled mixtures was not consistent with those from spray drying and film casting, indicating fundamental differences between the preparation techniques. Through formal statistical analysis, the best combination of fit to the Flory-Huggins model and reproducibility of the measurements was analyzed. Ball milling provided the best reproducibility of the three preparation techniques; however, an analysis of residuals revealed a systematic error. In contrast, film casting demonstrated a good fit to the model but poor reproducibility of the measurements. Therefore, this study recommends that techniques such as spray drying or potentially film casting (if experimental reproducibility can be improved) should be used to prepare the amorphous dispersions when performing solubility measurements of this kind.
authors.affiliation: Biologics and Pharmaceutical Science, H. Lundbeck A/S, Valby, DK-2500, Denmark; Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg-University Mainz, Mainz, D-55099, Germany.
authors.forename: Matthias Manne
authors.initials: MM
authors.lastname: Knopp
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Olesen
authors.forename: Per
authors.initials: P
authors.lastname: Holm
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Peter
authors.initials: P
authors.lastname: Langguth
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004339:Drug Compounding / Q000379:methods*; D004655:Emulsions; D006358:Hot Temperature; D007213:Indomethacin / Q000737:chemistry*; D008958:Models, Molecular; D010592:Pharmaceutic Aids / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D033362:Powder Diffraction; D015203:Reproducibility of Results; D012995:Solubility
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004655:Emulsions; D010592:Pharmaceutic Aids; D011205:Povidone; D007213:Indomethacin
keywords: amorphous; calorimetry (DSC); milling; polymers; solid dispersion; solubility; solvent evaporation; spray drying; supersaturation