? The amorphous phase of an insoluble small molecule drug is often desired in oral formulations.  These amorphous materials are thermodynamically unstable compared to crystalline phases.  The primary technique for identifying and analyzing crystalline phases is powder X-ray diffraction, PXRD.  However, no easily accessible primary technique exists to definitively identify and quantify the amorphous phase.  This leads to attempts to rationalize methods through comparison of PXRD, thermal, spectroscopy, and other techniques.  Traditional and ultra-fast differential scanning calorimetry, which are frequently used to evaluate thermodynamic properties, provide results that can be represent the physical properties related to amorphous and crystalline materials.  Additionally, IR, NIR, Raman, and their low frequency modes (ex. Terahertz, LFR) can provide information related to molecular arrangements, with the low frequency modes able to detect lattice modes.  The plethora of available techniques, along with the concept that a real amorphous standard may not exist, makes method development for amorphous identification and quantitation very challenging. A rational approach for selecting and developing validatable methods to quantify the amorphous phase in API and products will be presented.  This approach describes the physical properties that is best evaluated during method development, takes into account the relative chemical and physical properties of the amorphous and possible crystalline phases, as well as the presence and type of materials in a mixture, and finally the goal of the method which is aligned with the ICH Q6A guidance and the related validation guidances.

Rational physical analysis of amorphous APIs as pure and mixed phases

248th National Meeting (2014)

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