>>Amorphous Materials and Dispersions Characterization

Advanced Analysis of Amorphous Materials and Dispersions:

The characterization of amorphous materials is a further application of the Total Diffraction Analysis services offered by the Computational Chemistry Practice at Triclinic.

Through the application of in-house analytical software based upon the Debye diffraction theory, the local amorphous structure can be elucidated from an X-ray amorphous powder pattern. Amorphous materials as defined have no longer range molecular order but due to the molecular ‘shape’ they will possess some local short range molecular order. It is this local order that can be extracted from measured X-ray amorphous powder patterns. 

Characterization of a variety of X-ray amorphous materials has shown that different types of local molecular order can exist for organic molecular systems. In a significant number of materials, the X-ray amorphous form has a local molecular order that matches structural motifs seen in one or more of the crystalline polymorphs. As might be expected, these types of X-ray amorphous forms appear to crystallize readily. In some instances the type of local order observed can be modified by adopting a different production path way. 
Changes in the local structure observed as a function of time, temperature, humidity, solvent vapor or physical stress can often been seen as precursors to structural instability and re-crystallization. Characterization of local structure changes can be critical to the design of an effective aging study. For amorphous materials, the characteristic changes in the analytical signal can be subtle and a more robust analysis will benefit from a combination of different analytical techniques (for example IR/Raman spectroscopy, thermal methods and X-ray powder diffraction).

Amorphous Stability

A common method to improve the physical stability of an amorphous API is to manufacture a ‘dispersion’ of the amorphous API in an amorphous matrix. The most common matrix materials employed to date are polymers with high glass transition temperatures although in principal many different types of matrix materials may be used.  The primary physical property that determines the performance ability of the amorphous dispersion to stabilize the amorphous state of the API is the degree of mixing between the API and the amorphous matrix. In the liquid or solution state the API and matrix components may be intimately mixed at the molecular level but on formation of the solid state system, the API may begin to phase separate. The degree to which the phase separation has occurred in the solid state will govern the resulting physical stability of the amorphous ‘dispersion’. 

Systems where the API can be considered to be phase separated will behave like the pure amorphous API but will often undergo physical changes more slowly. Systems where the API and matrix remain a solid solution with intimate molecular mixing may form a stable binary system with no driving force to crystallize.  The concepts of molecular solid solutions and phase separated systems are defined by the physical structure and spatial relationships of the molecules within the solid-state. These are exactly the properties measured by X-ray (and neutron) diffraction.  The same in-house software Triclinic has developed to characterize the local molecular order of single phase X-ray amorphous materials can be utilized to determine the degree of mixing between an amorphous API and an amorphous carrier matrix.

Multiple Analytical Techniques

DSC measurements of glass transition temperatures will also give some idea as to the degree of mixing between an amorphous API and an amorphous matrix. Typically, is the observed glass transition temperature of the amorphous ‘dispersion’ (assuming one can be measured) is between the glass transition temperatures of the pure amorphous API and pure amorphous matrix then some degree of molecular intermixing is taking place.

For robust characterization of amorphous materials, a combined analytical approach using spectroscopic, thermal and diffraction methods is the preferred approach.  With recent advances in characterization software, considerably more information can now be extracted from amorphous materials using diffraction techniques than was previously possible. Characterization of the local molecular short-range order using X-ray powder diffraction data provides unique insight into single phase and multi component amorphous systems that is often directly related to the physical and chemical stability of the amorphous system.

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