Quantification of Polymorphs in Solid Mixtures by Powder X-Ray Diffraction Using Multivariate
Analysis
L. MacEachern, M. Mirmehrabi
Solid State Pharma Inc.
Purpose
The most commonly used technique to evaluate polymorphs in a solid mixture is powder X-ray diffraction (XRD). Each polymorph
of an active pharmaceutical ingredient (API) in a solid mixture will produce a unique XRD pattern or “fingerprint”. It is critical to
have the ability to reliably quantify polymorphs of an API in a solid mixture to understand crystallization processes and ensure batch
consistency.
Quantification of polymorphs using XRD is often done using a single point method, wherein a single diffraction peak unique to a
specific polymorph is chosen for quantification. The single point method fails when there are preferred orientation effects in the XRD
or when there is significant peak overlap between polymorphs and/or excipients. For this reason, single point quantification methods
using XRD spectra are often avoided and instead characterization techniques such as infrared or Raman spectroscopy are employed.
Methods
Chemometric or multivariate least squares quantification methods utilize whole patterns or spectra for calibration and analysis, using
upwards of 500 data points per spectrum as opposed to a single point.
Results
Differences in particle size and morphology of APIs may give rise to preferred orientation effects in XRD spectra as illustrated in
Figure 1. Careful consideration must be made when selecting quantification methods for compounds exhibiting preferred orientation
or peak overlap in XRD spectra as different methods can yield substantially different results. Some case studies will be presented
illustrating the differences between single point and multivariate analysis for quantification of polymorphs in solid mixtures by XRD.
Conclusion
Chemometric least squares methods can be employed instead of single point methods for quantification using XRD to produce reliable
results, even with the presence of preferred orientation or peak overlap.