The Power of Synchrotron X-Ray Powder Diffraction for the Characterization of Pharmaceuticals

X-ray powder diffraction (XRPD) is a powerful technique that exploits the interaction between x-rays and matter to study the structural and microstructural properties of materials. Its power lies in the direct and unique relationship between the powder diffraction pattern of a given substance and its structural order and/or disorder. The position and relative intensity of the peaks in a powder diffraction pattern (i.e., the Bragg peaks) reflect the chemical composition and the arrangement in space of the atoms of the substance under investigation. In powder mixtures, XRPD can determine the percentage in weight of the components. Furthermore, the width and shape of the diffraction peaks unveil further information on the substance microstructure, such as the domain size and shape, strain, and defects. In the field of pharmaceutical powders, XRPD is considered the gold standard method for the identification and quantification of solid forms (i.e., polymorphs, solvates, hydrates, salts, co-crystals, amorphous forms) (1). It is, however, the quality of an XRPD pattern that defines the accuracy and reliability of the technique, and therefore, the wealth of information that can eventually be extracted (2).

Synchrotron x-ray powder diffraction (synchrotron-XRPD), which uses a synchrotron x-ray source, offers better data quality than laboratory XRPD for angular resolution, counting statistics, energy tunability, and fast acquisition time (3). In synchrotron-XRPD, x-rays are generated by a synchrotron facility and are at least five orders of magnitude more intense than the best x-ray laboratory source. The photon wavelength can, furthermore, be continuously tuned over a wide range of values, allowing one, for example, to hit or avoid specific absorption edges, or to tailor the absorption by the sample under investigation. When combining synchrotron-XRPD with the new generation of solid-state, ultra-fast, efficient detectors (4) and unconventional optics set-ups, level of detections (LOD) of the order of 0.01% weight can be obtained even when only micrograms of polycrystalline pharmaceutical powder are available. Figure 1 shows the LOD improvement from 0.1% down to 0.01% in weight in an ad-hoc pharmaceutical mixture when the synchrotron optics is fine-tuned. Furthermore, efficient data collection with acquisition times ranging from milliseconds to a few minutes allows one to control the radiation damage of organic compounds and/or perform kinetic studies of structural changes during chemical reactions or under temperature and pressure variations (3).

Figure 1: Synchrotron x-ray powder diffraction patterns recorded on pharmaceutical binary mixtures of similar elemental composition ranging from 0.01% to 1% weight of minority phase. By carefully fine-tuning the synchrotron optics, the smallest signal directly detectable drops down to 0.01% weight. LOD is level of detection. Figure 1 is courtesy of the author.

When dealing with pharmaceutical organic powders, there are two major challenges related to their structural analyses. Firstly, these powders are made up of low-Z elements that are intrinsically poorer scatterers than inorganic high-Z materials, therefore, requiring substantially longer acquisition times for sufficient signal-to-noise ratios. Secondly, pharmaceutical organic powders are very sensitive to radiation damage, which is dose dependent. Counting longer is thus often not a workable solution to improve the signal-to-noise ratio.

Before the advent of the efficient detection systems, the use of synchrotron-XRPD for the study of pharmaceuticals was often hampered by radiation damage (4). Today, however, synchrotron-XRPD is a powerful tool to support research, development, manufacturing, and lifecycle management activities for bio/pharmaceuticals. APIs can exist in different crystalline forms (polymorphs), solvates/hydrated forms (pseudo-polymorphs), and amorphous forms. These different forms can have a profound effect on the quality or performance (e.g., solubility, bioavailability, efficacy, safety) of the drug products (5). For example, therapeutic failure has been attributed to uncontrolled hydrate formation in tablets during storage. For this reason, it is a regulatory requirement to conduct a detailed analysis of the polymorphism of the drug substance and drug product during development, which includes screening, characterization, property determination, and setting of acceptance criteria for the different forms.

Synchrotron-XRPD can be a key support analytical tool for:

• Structural solution of a new solid form

• Development of formulation and screening of excipients, including co-crystals

• Characterization and accurate quantification of polymorphic forms in drug substances and products, including in fully opaque blisters

• Detection and quantification of impurities down to trace levels

• Optimization of manufacturing processes, in particular crystallization, formulation, drying, lyophilization, wet granulation, tableting, and packaging operations.

• In-situ non-ambient kinetic studies at millisecond scale

• Stability studies of polymorphic forms

• Troubleshooting activities and investigations during commercial manufacturing

• Patent application for new materials and patent-life extension

• Detection of counterfeits even with minute differences.

Synchrotron-XRPD data quality is useful for both qualitative and quantitative analyses at trace levels in complex mixtures of APIs as well as finished products. Accurate and precise quantification of traces of APIs in formulated drugs remains, however, a challenge that requires the control of both the instrumental background and the signal from excipients. The direct detection of API traces in synchrotron-XRPD patterns is instrumental to the success of quantification in formulated drugs as the quality of the quantitative refinements can be validated by qualitative and semi-quantitative direct inspection of experimental data.

References

1. D. Beckers, Pharmaceutical Technology Europe 22 (7) 29–30 (2010).

2. F. Gozzo et al., Z. Kristallogr. 225, 616–624 (2010).

3. F. Gozzo, Synchrotron X-Ray Powder Diffraction in Uniting Electron Crystallography and Powder Diffraction, pp. 65–82 (Springer, 2011).

4. A. Bergamaschi et al., J. Synchrotron Rad. 17, 653–668 (2010).

5. J. Bernstein, Polymorphism in Molecular Crystals (Oxford Science Publications, 2002).

About the Author

Fabia Gozzo, PhD, is CEO of Excelsus Structural Solutions. With more than 25 years of experience at synchrotron facilities, she has constructed and developed a state-of-the-art powder diffractometer at the Swiss Light Source before founding Excelsus Structural Solutions, a spin-off company that provides synchrotron radiation based analytical services to the pharmaceutical and chemical industry.

Article Details

Pharmaceutical Technology
Vol. 42, No. 2
February 2018
Page: 18

Citation

When referring to this article, please cite it as F. Gozzo, “The Power of Synchrotron X-Ray Powder Diffraction for the Characterization of Pharmaceuticals,” Pharmaceutical Technology 42 (2) 2018.