Abstract
Single-crystal X-ray diffraction is an extremely powerful technique to characterize small drug molecules in solid form. It is a mature technique that is becoming ever more automated, and it is increasingly viewed as “routine” in both industry and academia. On this basis, it is arguable how much the average formulation scientist needs to know about the technique: is it necessary to understand the inner workings of the “black box”, or is it sufficient just to trust the results produced by an automated analysis system? This chapter provides a brief outline of the principles, then considers some aspects that, in the author’s opinion, should still be understood to measure crystallographic data effectively and to interpret crystallographic results. The focus is on selected topics that are likely to be most relevant to pharmaceutical solid-form characterization.
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Notes
- 1.
“Negative correlations” can be specified. For example, the space group cannot be cubic if the metric symmetry is not cubic. But observing that the metric symmetry is cubic does not prove that the space group is cubic.
- 2.
Numerous unit cells could be chosen to describe a particular lattice. In practice, rules are defined to enable standard choices. The “reduced cell” is based on the three shortest independent distances between lattice points, with all angles either <90° or ≥90°. This defines a primitive cell, which contains only one independent lattice point. Non-primitive cells (containing more than one independent lattice point) might be defined if they better describe the symmetry of the structure. In that case, translational symmetry within the unit cell is defined in the list of space group operators.
- 3.
For example, a structure might be solved and initially refined in a non-centrosymmetric space group, but then it becomes clear from the atomic positions that a centre of inversion is actually present. Software for structure solution might also solve the structure in a lower symmetry space group, then provide a set of possible structures in various space groups for further examination.
- 4.
Newer instruments dispense with opening and closing of the X-ray shutter during data collection, and instead control the measurement and read-out time via electronics on the detector. This gives more precise time-keeping and the cumulative time saving over a long sequence of images can be significant.
- 5.
This section does not refer to the fundamental distinction between nuclear positions and the positions determined for H atoms by X-ray diffraction. See: Allen (1986).
- 6.
The scattering contribution from a particular atom site is reduced either by defining a smaller site occupancy or a larger displacement parameter. Thus, occupancies and displacement parameters are correlated, and it can be necessary to fix one in order to refine the other. The two effects are not entirely indistinguishable, however, since they differ as a function of diffraction angle (Fig. 9.3).
- 7.
This is particularly important when it comes to simulating powder X-ray diffraction patterns. The peak intensities in a pattern simulated from the model with empty regions will be different from the real situation where there is electron density in those regions.
- 8.
Hopefully, the crystals are still available!
- 9.
An interesting question in the pharmaceutical arena is whether submission of a crystal structure to a remote system such as checkCIF amounts to disclosure in the context of intellectual property.
References
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Bond, A.D. (2016). Single-Crystal X-ray Diffraction. In: Müllertz, A., Perrie, Y., Rades, T. (eds) Analytical Techniques in the Pharmaceutical Sciences. Advances in Delivery Science and Technology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-4029-5_9
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