title: The formation and physical stability of two-phase solid dispersion systems of indomethacin in supercooled molten mixtures with different matrix formers.
abstract: Amorphous solid dispersions (SDs) are a promising approach to improve the dissolution rate of and oral bioavailability of poorly water-soluble drugs. In some cases multi-phase, instead of single-phase, SD systems with amorphous drug are obtained. While it is widely assumed that one-phase amorphous systems are desirable, two-phase systems may still potentially exhibit enhanced stability and dissolution advantages over undispersed systems. The objective of the present study was to understand the solid-state properties of two-phase SDs with amorphous drug and their relation to physical stability. Two different types of excipients for SD formation were used, one being a polymer and the other a small molecule excipient. The supercooled molten SDs of a poorly water-soluble indomethacin (IND) with a graft copolymer, Soluplus® (SOL) and sugar alcohol, xylitol (XYL) were prepared. Supercooled molten SDs of IND with SOL were two-phase glassy suspension in which the amorphous drug was dispersed in an amorphous polymer matrix. A short-term aging of the SDs led to the formation of glassy suspensions where the crystalline drug was dispersed in an amorphous polymer matrix. These were physically stable at room temperature for the time period studied (RT, 23±2°C), but aging at high-humidity conditions (75% RH) recrystallization to metastable α-IND occurred. Interestingly, the SDs with XYL were two-phase amorphous precipitation systems in which the drug was in an amorphous form in the crystalline sugar alcohol matrix. The SDs of IND and XYL exhibited fast drug recrystallization. In conclusion, the preparation method of two-phase systems via co-melting in association with the rapid quench cooling is a feasible method for the formulation of poorly water-soluble drugs. The physical stability of these two-phase systems, however, is dependent on the carrier material and storage conditions.
authors.affiliation: Institute of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia. Electronic address: kristian.semjonov@ut.ee.
authors.forename: Kristian
authors.initials: K
authors.lastname: Semjonov
authors.affiliation: Institute of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia. Electronic address: karin.kogerman@ut.ee.
authors.forename: Karin
authors.initials: K
authors.lastname: Kogermann
authors.affiliation: Institute of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia. Electronic address: ivo.laidmae@ut.ee.
authors.forename: Ivo
authors.initials: I
authors.lastname: Laidmäe
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5E, 00014, University of Helsinki, Finland. Electronic address: osmo.antikainen@helsinki.fi.
authors.forename: Osmo
authors.initials: O
authors.lastname: Antikainen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5E, 00014, University of Helsinki, Finland. Electronic address: clare.strachan@helsinki.fi.
authors.forename: Clare J
authors.initials: CJ
authors.lastname: Strachan
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5E, 00014, University of Helsinki, Finland. Electronic address: henrik.ehlers@helsinki.fi.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ehlers
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5E, 00014, University of Helsinki, Finland. Electronic address: jouko.yliruusi@helsinki.fi.
authors.forename: Jouko
authors.initials: J
authors.lastname: Yliruusi
authors.affiliation: Institute of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia. Electronic address: jyrki.heinamaki@ut.ee.
authors.forename: Jyrki
authors.initials: J
authors.lastname: Heinämäki
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003080:Cold Temperature; D004355:Drug Stability; D007213:Indomethacin / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin
keywords: Indomethacin; Solid dispersion; Solid-state stability; Soluplus®; Supercooled molten mixture; Two-phase systems; Xylitol