X-ray Powder Diffraction Pattern Indexing for Pharmaceutical Applications - Pharmaceutical Technology

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X-ray Powder Diffraction Pattern Indexing for Pharmaceutical Applications
Indexing is the process of determining the size, shape and symmetry of the crystallographic unit cell for a crystalline component responsible for a set of peaks in an X-ray powder-diffraction (XRPD) pattern. The authors discuss the valuable information that can be obtained from indexing and its applications in routine screening and analysis of solid forms.

Pharmaceutical Technology
Volume 37, Issue 1, pp. 56-61

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.


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,
, and Jared P. Smit, PhD, is a research investigator,
, 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.


1. W. Massa, Crystal Structure Determination (Springer, Berlin, Germany, 2nd ed. 2004).

2. R. A. Young, "Introduction to the Rietveld method," in The Rietveld Method, R. A. Young, Ed., (Oxford University Press, New York, NY, 1993), pp. 1-38.

3. C. A. Beevers and H. N. Hansen, Acta Cryst., B27, 1323–1325 (1971).

4. A. Burger and R. Ramberger, Mikrochim. Acta, 72 (3–4) 273–316 (1979).

5. R. F. Bryan and P. G. Forcier, Mol. Cryst. Liq. Cryst., 60 (3) 157–165 (1980).

6. Y. Miwa et al., Acta Cryst., B55, 78–84 (1999).

7. Results from research at SSCI, a division of Aptuit, West Lafayette, IN, USA, not previously published.

8. A. Boultif and D. Lour, J. Appl. Cryst., 37 (5) 724–731 (2004).

9. J. W. Visser, J. Appl. Cryst., 2 (3) 89–95 (1969).

10. A. A. Coelho, J. Appl. Cryst., 36 (1) 86–95 (2003).

11. P. E. Werner, L. Erikson, and M. Westdahl, J. Appl. Cryst., 18 (5) 367–370 (1985).

12. M. A. Neumann, J. Appl. Cryst., 36 (2) 356–365 (2003).


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