Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability

Abstract

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.

Keywords: Amorphous; Computational prediction; Glass-forming ability; Physical stability; SVM.

Graphical abstract

Fig. 1

Stability results for Class II compounds; n = 18; stored above the T_g.

Fig. 2

Stability results for Class III compounds; n = 34; stored above the T_g.

Fig. 3

Stability results for Class III compounds that remained amorphous when stored above the T_g; n = 33.

Fig. 4

Relationship between the T_g and the solid-state type (amorphous/crystalline) after the stability study for Class II (blue star) and Class III (black circle) compounds.

Fig. 5

Relationship between the free energy change and the stability result (amorphous/crystalline) after storage above the T_g for Class II (blue star) and Class III (black circle) compounds.

Fig. 6

Prediction of glass stability using the support vector machine algorithm for all the study compounds that were amorphous after the stability study (green circle) and crystalline after the stability study (blue triangular). The crosses indicate the test set. Red line indicates the boundary generated by the SVM model.