title: Glass-forming ability of compounds in marketed amorphous drug products.
abstract: This note is about the glass-forming ability (GFA) of drugs marketed as amorphous solid dispersions or as pure amorphous compounds. A thermoanalytical method was complemented with an in silico study, which made use of molecular properties that were identified earlier as being relevant for GFA. Thus, molar volume together with effective numbers of torsional bonds and hydrogen bonding were used to map drugs that are as amorphous products on the market either as solid dispersion of without co-processed carrier as amorphous drug in a solid dosage form. Differential scanning calorimetry experiments showed that most compounds were stable glass formers (GFs) (class III) followed by so-called unstable GFs (class II) and finally, only vemurafenib was found in class I with increased crystallization propensity. The in silico results, however showed that all drugs were either clearly in the chemical space expected for GFs or they were borderline to the region that holds for high crystallization tendency. Interestingly, the pure amorphous compounds scattered in a very confined region of the molecular predictors. These findings can guide amorphous product development of future drug candidates. Based on the compound location in the given chemical space, amorphous formulation opportunities can be balanced against the risks of physical instability upon storage.
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wyttenbach
authors.affiliation: Institute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, 4132 Muttenz, Switzerland. Electronic address: martin.kuentz@fhnw.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004304:Dosage Forms; D005898:Glass / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013818:Thermogravimetry
chemical_list: D004304:Dosage Forms; D004364:Pharmaceutical Preparations
keywords: Amorphous drug; Glass-forming ability; Molecular prediction; Physical stability; Solid dispersion