THE USE OF THERMAL-ANALYSIS IN THE ASSESSMENT OF CRYSTAL DISRUPTION

The highly ordered crystal lattice of small organic molecules, such as drugs, contains defects resulting from the crystallization process. Pharmaceutical processing and impurities introduce further defects which cause partial disruption of the crystalline order decreasing the crystallinity and increasing the crystal energy, enthalpy, entropy and free energy. As a result, the intrinsic dissolution rate increases and other solid state properties, including the compaction (tableting) behavior, are changed, thereby accounting for interbatch variations. Differential scanning calorimetry (DSC) or differential thermal analysis (DTA) are used to measure the enthalpy of fusion at the melting point and hence the entropy of fusion. The negative slope of the plot of the entropy of fusion against the ideal entropy of mixing of a guest impurity in solid solution in the host solid affords the disruption index (d.i.) resulting from the presence of the guest. The significance and magnitude of d.i. are discussed. The change in the entropy of fusion resulting from the processing of the solid is used to calculate the entropy of processing, DELTAS(p), which is related to changes in various pharmaceutical properties. The uses of d.i. and DELTAS(p) are illustrated using a variety of pharmaceutical examples.