title: High energy ball milling and supercritical carbon dioxide impregnation as co-processing methods to improve dissolution of tadalafil.
abstract: Tadalafil (TD) is a crystalline drug of a high melting point (Tm=299°C) and limited solubility in water (<5μg/mL). These properties may result in reduced and variable bioavailability after oral administration. Since the melting of TD is followed by its decomposition, the drug processing at high temperatures is limited. The aim of the research is, therefore, to improve the dissolution of TD by its co-processing with the hydrophilic polymer Soluplus® (SL) at temperatures below 40°C. In this study, two methods, i.e. high energy ball-milling and supercritical carbon dioxide impregnation (scCO2) are compared, with the aim to predict their suitability for the vitrification of TD. The influence of the amount of SL and the kind of co-processing method on TD thermal properties is analyzed. The results show that only the high energy ball milling process makes it possible to obtain a completely amorphous form of TD, with the characteristic X-ray 'halo' pattern. The intensity of the Bragg peaks diminishes for all the formulations treated with scCO2, but these samples remain crystalline. The MDSC results show that high energy ball milling is capable of forcing the mixing of TD and SL at a molecular level, providing a homogeneous amorphous solid solution. The glass transition temperatures (Tg), determined for the co-milled formulations, range from 79°C to 139°C and they are higher than Tgof pure SL (ca. 70°C) and lower than Tgof pure TD (ca. 149°C). In contrast to the co-milled formulations which are in the form of powder, all the formulations after scCO2impregnation form a hard residue, sticking to the reaction vessel, which needs to be ground before analysis or further processing. Finally, the dissolution studies show that not only has SL a beneficial effect on the amount of TD dissolved, but also both co-processing methods make the dissolution enhancement of TD possible. After co-processing by scCO2, the amount of TD dissolved increases with the decreasing amount of SL, whereas in the case of the co-milled formulations, the higher the amount of SL in the glassy solution is, the higher the amount of TD dissolved.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University Medical College, Poland. Electronic address: a.krupa@uj.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Krupa
authors.affiliation: Unité Matériaux et Transformations CNRS UMR 8207, University of Lille1, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Descamps
authors.affiliation: Unité Matériaux et Transformations CNRS UMR 8207, University of Lille1, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Willart
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University Medical College, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Jachowicz
authors.affiliation: Unité Matériaux et Transformations CNRS UMR 8207, University of Lille1, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Danède
mesh_terms: D002245:Carbon Dioxide / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D025924:Chromatography, Supercritical Fluid / Q000379:methods*; D006358:Hot Temperature; D012995:Solubility / Q000187:drug effects; D000068581:Tadalafil / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D002245:Carbon Dioxide; D000068581:Tadalafil
keywords: Dissolution enhancement; Glassy molecular alloys; High energy ball milling; Solid dispersions; Soluplus®; Supercritical fluids; Tadalafil