Indexing software
Several programs are available to index XRPD patterns, such as DICVOL (8), ITO (9), TOPAS (Bruker Corporation) (10), TREOR
(11) and X-Cell (Accelrys) (12). SSCI has developed its own proprietary indexing algorithm, which was designed specifically
with pharmaceutical crystal forms in mind. Indexing packages use various methods to generate trial unit cells that are tested
for consistency with the experimental pattern. Most of the trial unit cells are found to be inconsistent with the peak positions
and are rejected. XRPD patterns for materials with unit cells of higher symmetry (cubic, hexagonal, tetragonal) are relatively
easier to index because fewer degrees of freedom are necessary to account for the peaks. Such high-symmetry unit cells are
common for inorganic materials. Unit cells of lower symmetry (orthorhombic, monoclinic, triclinic) are more challenging to
index. Triclinic unit cells are particularly difficult because there are no restrictions on any of the unit-cell lengths or
angles. The overwhelming majority of pharmaceutical solids, however, crystallise in orthorhombic, monoclinic, or triclinic
crystal classes. More than 96% of crystal structures of pharmaceutically relevant molecules solved at SSCI adopt one of these
three crystal classes. Therefore, indexing programs that focus on the lower symmetry crystal classes are recommended for pharmaceuticals.
Indexing routines should be used by individuals with experience in diffraction and crystallography. Most indexing software
packages will output a best solution for any input pattern, but it is up to the user to determine if the proposed solution
is consistent with the input pattern. Because unit cells are not unique, a common problem is reporting the correct unit cell
in a nonstandard way. Another common problem is that a trial unit cell, which is a fraction of the correct cell, is reported,
and a higher symmetry is not recognised. Alternatively, too high a symmetry can be reported. Powder patterns of mixtures are
not indexable in principle, but indexing programs generally produce a nonsensible trial solution for mixture patterns that
should be rejected by the user. Some indexing packages, however, are able to successfully index a crystalline material in
the presence of a crystalline impurity. Knowledge of the molecular volume, degree of hydration and/or solvation, chirality
of the compound and common space groups can aid an expert in evaluating trial indexing solutions. For instance, although there
are 230 space groups, the frequencies at which they occur are far from equal. Work at SSCI on pharmaceutically relevant molecules
has shown that over 90% of chiral molecules are found to adopt one of four space groups (P21, P212121, C2, or P1) and more than 90% of nonchiral molecules adopt one of four space groups as well (P21/c, P-1, C2/c, or Pbca). Although indexing solutions have been determined for APIs in other space groups, these are less common. Proposed indexing
solutions outside of the common space groups should be scrutinised.
Conclusion
XRPD indexing can be used to extract information from high-quality XRPD patterns and add value to their interpretation. It
can be used to identify patterns that represent single phases as well as to determine if patterns represent the same or different
forms. Indexing of XRPD patterns for crystalline forms should be a routine part of solid form screening and analysis.
Richard B. McClurg*, PhD, is a research fellow, richard.mcclurg@aptuit.com
, and Jared P. Smit, PhD, is a research investigator, jared.smit@aptuit.com
, both at SSCI, a division of Aptuit LLC, 3065 Kent Ave., West Lafayette, IN, USA 47906.
*To whom all correspondance should be addressed.
Submitted: 2 May 2012. Accepted: 18 Sept. 2012.
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