(596bb) Using Vibrational Spectroscopy to Evaluate Solid Disperision Stability

Formulation of amorphous (non-crystalline) drug products has been suggested in order to counter the ever-present need to make drug products sufficiently soluble.  However, a major concern with amorphous pharmaceuticals is physical instability, where the higher free-energy form will spontaneously revert to the more stable (and less soluble) crystalline form.  Stabilization of these products via solid dispersions have been proposed to prolong the kinetic stability of these drugs.  Selection of appropriate analytical methods is essential to both monitor the physical stability, as well as gain knowledge of the effect of polymer dispersions and material characteristics (i.e., polymer type, drug loading, and compaction force) on the inhibition of crystallization in an intact dosage form under various environmental conditions. Raman and near-infrared spectroscopic methods have been evaluated and compared to powder x-ray diffraction.  Net analyte signal theory was used to generate multivariate figures of merit and provide a platform to compare methods directly.  Spectroscopic methods were found to be more accurate and have significantly lower detection limits than the standard x-ray analysis while providing much faster analysis times.  Moreover, the estimated kinetics and spectral changes occuring during storage for different formulations could be related to mechanisms of instability. Indomethacin is used as a model drug.