Use of high-intensity X-radiation in solid-state characterization of pharmaceuticals

The overall goal of this project was to develop new approaches to characterize pharmaceutical phase transitions and to quantify solid phases. The investigations were classified into three categories: (i) Amorphous → crystalline transition, (ii) phase transitions during dehydration, and (iii) anhydrate → hydrate transition. The use of synchrotron X-rays allowed diffraction patterns to be acquired with a time resolution of 40 milliseconds. The 2-dimensional detector and transmission geometry allowed X-ray patterns to be obtained as 'snapshots' over a wide angular (2theta) range and minimized preferred orientation effects. For crystallinity quantification, a novel algorithm was developed for objective separation of crystalline and amorphous intensities from an X-ray pattern. An in situ crystallization approach was used to overcome the problem of inhomogeneity in mixing, which is a particularly serious issue at extreme mixture compositions. The estimated limit of detection, of crystalline sucrose in an amorphous matrix, was 0.2% w/w. The dehydration kinetics of theophylline monohydrate (M) was investigated using 2-dimensional XRD. Modeling of the dehydration profiles revealed that M dehydrated via a two-step pathway. The dehydration initiated with the M → metastable anhydrate (A*) transition, followed by the M → stable anhydrate (A) transition. The activation energies of the two processes were 110 and 146 kJ·mol -1, respectively. Polyvinylpyrrolidone (crystallization inhibitor) retarded the formation of A, which led to the build-up of A* in the dehydrated product. The activation energy for the M → A transition was higher in the presence of PVP. A decrease in the dehydration temperature and an increase in the PVP concentration, facilitated the build-up of A*. A pressure differential scanning calorimetric technique was developed for quantification of betaine hydrate when present as a mixture with anhydrous betaine. The limits of detection and quantification of this technique were 0.15% and 1.5% w/w, respectively. The effect of annealing on betaine anhydrate → monohydrate transformation was studied. The water uptake rate constant (k), based on the three-dimensional nucleation and growth model, for unannealed anhydrous betaine (0.075 +/- 0.002 min-1) was significantly higher than that for the annealed material (0.052 +/- 0.004 min-1).