Quantification of crystallinity in substantially amorphous materials by synchrotron X-ray powder diffractometry

Purpose. The aim of this study was to develop a highly sensitive powder X-ray diffraction (XRD) technique for quantification of crystallinity in substantially amorphous pharmaceuticals, utilizing synchrotron radiation and a 2-D area detector. Methods. Diffraction data were acquired at the European Synchrotron Radiation Facility (France) using a 2-D charge-coupled device detector. The crystallization of amorphous sucrose was monitored in situ, isothermally at several temperatures in the range of 90 to 160°C. An algorithm was developed for separation of the crystalline and amorphous intensities from the total diffraction pattern. Results. The synchrotron XRD technique allowed powder diffraction patterns to be recorded with a time resolution of 40 ms. The gradual crystallization of sucrose is analogous to a series of physical mixtures with increasing content of the crystalline component. The in situ crystallization approach circumvented the problem of inhomogeneity in mixing-a potentially serious issue at extreme mixture compositions. The estimated limit of detection of crystalline sucrose in an amorphous matrix was 0.2% w/w, a considerable improvement over the reported value of ∼1% w/w with a conventional XRD. Conclusion. High-intensity XRD can discern subtle changes in the lattice order of materials. The first evidence of crystallization can serve as an indicator of the potential physical instability of the product.