Applications of Powder X-Ray Diffraction in Small Molecule Pharmaceuticals: Achievements and Aspirations.

Since the discovery of X-ray diffraction and its potential to elucidate crystal symmetry, powder X-ray diffraction has found diverse applications in the field of pharmaceutical sciences. This review summarizes significant achievements of the technique during various stages of dosage form development. Improved understanding of the principle involved and development of automated hardware and reliable software have led to increased instrumental sensitivity and improved data analysis. These advances continue to expand the applications of powder X-ray diffraction to emerging research fields such as amorphous systems, mechanistic understanding of phase transformations, and "Quality by Design" in formulation development.

Isothermal microcalorimetry to investigate the phase separation for amorphous solid dispersions of AMG 517 with HPMC-AS.

Understanding the crystallization kinetics of an amorphous drug is critical for the development of an amorphous solid dispersion (ASD) formulation. This paper examines the phase separation and crystallization of the drug AMG 517 in ASDs of varying drug load at various conditions of temperature and relative humidity using isothermal microcalorimetry. ASDs of AMG 517 in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were manufactured using a Buchi 290 mini spray dryer system. ASDs were characterized using modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM) prior to isothermal microcalorimetry evaluation, and crystallinity was measured using (19)F solid state nuclear magnetic resonance spectroscopy (SSNMR), before and after crystallization. The crystallization of ASDs of AMG 517 in HPMC-AS was significantly slowed by the presence of HPMC-AS polymer, indicating enhanced physical stability for the ASD formulations. A two-phase crystallization was observed by isothermal microcalorimetry at temperatures near the glass transition temperature (Tg), indicating a drug-rich phase and a miscible ASD phase. (19)F SSNMR showed that only partial crystallization of the drug occurred for the ASDs, suggesting a third phase which did not crystallize, possibly representing a thermodynamically stable, soluble component. Isothermal microcalorimetry provides important kinetic data for monitoring crystallization of the drug in the ASDs and, together with (19)F SSNMR, suggests a three-phase ASD system for AMG 517 in HPMC-AS.