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.

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.

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.