title: Is a distinctive single Tg a reliable indicator for the homogeneity of amorphous solid dispersion?
abstract: For an amorphous drug-polymer solid dispersion, a distinctive single T(g) intermediate of the two T(g) values of the two components has been widely considered as an indication of the mixing uniformity, which is critical for the stability of the amorphous drug against crystallization. In this study, two batches of amorphous solid dispersions consisting of BMS-A, a poorly water-soluble drug, and PVP-VA, were made by a twin-screw hot-melt extruder using different processing conditions. Both batches displayed an identical distinctive single T(g) that is consistent with the prediction of Fox equation assuming homogeneous mixing of the two components. Neither DSC nor PXRD detected any drug crystallinity in either batch. However, the two batches exhibited different physical stability against crystallization over time. The application of a Raman mapping method showed that the drug distributed over a much wider concentration range in the less stable solid dispersion. It is therefore experimentally demonstrated that, in the characterization of amorphous solid dispersions, a distinctive single T(g) may not always be a reliable indicator of homogeneity and optimal stability, and more examinations and new techniques may be required other than conventional studies.
authors.affiliation: Biopharmaceutics R&D, Bristol-Myers Squibb Company, One Squibb Drive, 105-2-1A, New Brunswick, NJ 08903, USA. feng.qian1@bms.com
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Raja
authors.initials: R
authors.lastname: Haddadin
authors.forename: John
authors.initials: J
authors.lastname: Gawel
authors.forename: Robert
authors.initials: R
authors.lastname: Garmise
authors.forename: Munir
authors.initials: M
authors.lastname: Hussain
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D004339:Drug Compounding; D004355:Drug Stability; D018613:Microscopy, Confocal; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D033362:Powder Diffraction; D011759:Pyrrolidines / Q000737:chemistry*; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D044366:Transition Temperature; D014753:Vinyl Compounds / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate)