Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability.
Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (Tg) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12h at temperatures 20°C above or below the Tg. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20°C below the Tg. Fourteen of the Class II compounds crystallized when stored above the Tg whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e.g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the Tg. The use of a large dataset revealed that molecular features related to aromaticity and π-π interactions reduce the inherent physical stability of amorphous drugs.
Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden. Electronic address: amjad.alhalaweh@farmaci.uu.se.
Amjad
A
Alhalaweh
Department of Information Technology, Uppsala University, Lägerhyddsv. 2, hus 1, Box 337, SE- 751 05 Uppsala, Sweden.
Ahmad
A
Alzghoul
Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Denny
D
Mahlin
Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Christel A S
CAS
Bergström
D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004355:Drug Stability; D005898:Glass / Q000737:chemistry*; D013329:Structure-Activity Relationship; D060388:Support Vector Machine; D013696:Temperature; D013816:Thermodynamics; D044366:Transition Temperature
Amorphous; Computational prediction; Glass-forming ability; Physical stability; SVM