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

Applications of indexing

Mixtures.Mixtures that are mistakenly designated as single forms can be time consuming and expensive, particularly in the later stage of development. This problem can be avoided early in the development process by indexing the XRPD pattern of the form(s) of interest. All of the allowed peak positions are identified once an indexing solution is obtained. Therefore, an XRPD pattern is known to be representative of a single crystalline phase once it is indexed. Mixtures of forms have peaks at positions that are incompatible with an indexing solution for one form. Consequently, mixtures of forms cannot be indexed using a single unit cell. It is advisable to have the XRPD patterns of all crystalline forms indexed to avoid unpleasant surprises during development.

It is important to note that an XRPD pattern that is not successfully indexed does not necessarily mean that the pattern is representative of a mixture. Poor data quality, significant peak overlap, elongated or compressed unit cells, preferred orientation artifacts and/or several weak reflections are all potential reasons why an XRPD pattern of a single phase may not index successfully. A successful indexing attempt reveals that the XRPD pattern is representative of a single crystalline phase. Although an unsuccessful attempt may be indicative of a mixture, it is not conclusive. Additional techniques are necessary to determine if the material is a mixture of forms.

Density estimates. Form stability has been correlated with density (4). Because indexing yields accurate unit-cell dimensions, the density of each form can be calculated provided that the contents of the unit cell are known. This can be useful when multiple anhydrous forms are discovered to determine the most and least dense crystal forms.

Variable hydrates, solvates and/or cocrystals. Multiple components may be incorporated into a crystal framework, resulting in hydrates, solvates and/or cocrystals. Multicomponent crystal forms can be stoichiometric or nonstoichiometric. Stoichiometric forms have a fixed ratio of water, solvent and/or coformer molecules per API. These fixed ratios are the result of discrete positions for molecules within the crystal structure. Because the crystal structures of stoichiometric forms are fixed, the XRPD peak positions occur at consistent diffraction angles. In contrast, nonstoichiometric forms have a range of compositions owing to flexible crystal frameworks that expand or contract to accommodate different amounts of water, solvent and/or coformer. As the crystal structure changes, the unit-cell geometry changes, and the XRPD pattern changes.

Table I: Cocrystal stoichiometry determination.
Stoichiometric cocrystals of p-coumaric acid and nicotinamide are examples for illustration. Table I presents the unitcell information for p-coumaric acid (5), nicotinamide (6) and two cocrystals containing different stoichiometries of the same two components (7). Indexing solutions for the components were taken from the Cambridge Structural Database (CSD) (5,6). XRPD patterns for each of the cocrystals were successfully indexed. The volume per asymmetric unit for the 1:1 cocrystal (345 3) is in agreement with the sum of the volume per asymmetric unit for the components (339 3 ). The 1:1 stoichiometry was confirmed using single crystal-structure determination. The volume per asymmetric unit for the 2:1 cocrystal (538 3) is in agreement with the weighted sum of its components (533 3). The 2:1 stoichiometry was confirmed using solution 1H NMR. In this example, each of the components and the cocrystals share the same space group (P21/c, no. 14). This coincidence is not necessary for the stoichiometry estimation.

The XRPD peak positions of variable hydrates, solvates and/or cocrystals may appear slightly shifted due to minor unit-cell changes, or they may appear at significantly different diffraction angles if the unit-cell changes are large and/or anisotropic. XRPD patterns for a variable composition form may appear to be different and, therefore, may be mistakenly designated as distinct forms when in reality they represent state points in one form with variable properties. Anisotropic cell changes may cause overlapping peaks to become resolved as the cell composition changes, and the "new" peak may be incorrectly sighted as evidence of a new form. Indexing a series of patterns for a variable form may be used to show that a material maintains its symmetry and has continuous changes in unit-cell geometry. This continuity is evidence for a variable form. In contrast, changes in cell symmetry and/or discrete changes in unit- cell parameters are evidence for multiple forms.


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