title: Toward in silico prediction of glass-forming ability from molecular structure alone: a screening tool in early drug development.
abstract: We present a novel computational tool which predicts the glass-forming ability of drug compounds solely from their molecular structure. Compounds which show solid-state limited aqueous solubility were selected, and their glass-forming ability was determined upon spray-drying, melt-quenching and mechanical activation. The solids produced were analyzed by differential scanning calorimetry (DSC) and powder X-ray diffraction. Compounds becoming at least partially amorphous on processing were classified as glass-formers, whereas those remaining crystalline regardless of the process method were classified as non-glass-forming compounds. A predictive model of the glass-forming ability, designed to separate between these two classes, was developed through the use of partial least-squares projection to latent structure discriminant analysis (PLS-DA) and calculated molecular descriptors. In total, ten of the 16 compounds were determined experimentally to be good glass-formers and the PLS-DA model correctly sorted 15 of the compounds using four molecular descriptors only. An external test set was predicted with an accuracy of 75%, and, hence, the PLS-DA model developed was shown to be applicable for the identification of compounds that have the potential to be designed as amorphous formulations. The model suggests that larger molecules with a low number of benzene rings, low level of molecular symmetry, branched carbon skeletons and electronegative atoms have the ability to form a glass. To conclude, we have developed a predictive, transparent and interpretable computational model for the identification of drug molecules capable of being glass-formers. The model allows an assessment of amorphization as a formulation strategy in the early drug development process, and can be applied before compound synthesis.
authors.affiliation: Department of Pharmacy, Uppsala University , Uppsala Biomedical Center, P.O. Box 580, SE-75123 Uppsala, Sweden. denny.mahlin@farmaci.uu.se
authors.forename: Denny
authors.initials: D
authors.lastname: Mahlin
authors.forename: Sopana
authors.initials: S
authors.lastname: Ponnambalam
authors.forename: Mina Heidarian
authors.initials: MH
authors.lastname: Höckerfelt
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
mesh_terms: D002152:Calorimetry, Differential Scanning; D003198:Computer Simulation; D017076:Computer-Aided Design; D016002:Discriminant Analysis; D015195:Drug Design; D005898:Glass / Q000737:chemistry*; D016018:Least-Squares Analysis; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations