XRPD Blog Series on Pharmaceutical Development: Part 3 ‘How Complementary Techniques Enhance the Analysis of Solid Forms’

This four-part blog series introduces how powder X-ray diffraction (XRPD), a form of solid state analysis, assists pharmaceutical developers in optimizing drug solubility and performance.

In this third installment of the series, we explain ‘How to Combine XRPD with Complementary Methods’ to conduct a more comprehensive and efficient evaluation of active pharmaceutical ingredients (APIs). Check out the other parts: Part 1, Part 2, and the Final Part.

Optimizing XRPD Analysis with Transmission Mode

The previous blog explained that XRPD is a powerful and common method for detecting and evaluating polymorphs of APIs. XRPD is the single workflow technique capable of providing a detailed fingerprint of the structures of both crystalline and amorphous APIs. However, characterization of solid forms using XRPD can come with unique challenges, particularly in sample preparation, where two key factors may impact results: (i) crystallite orientation distribution and (ii) particle statistics. For instance, samples may exhibit preferred orientation, causing deviations in measured reflection intensity in diffraction data. This issue is common with powders containing anisotropic crystals (e.g., plate-like or needle-like rather than cubic) (Figure 1). An ideal sample has numerous randomly oriented crystallites and high statistical reproducibility.

So, how can we minimize the preferred orientation effect in XRPD measurements? One of the simplest methods is to switch the geometry of the XRPD experiment from reflection mode to transmission mode. This change in geometry allows for more effective orientation removal by rotating the sample. Although reflection mode has established historical verification and quality control methods, recently, there has been rising popularity in transmission measurement mode to enhance the efficiency of XRPD in solid form analysis.

Enhancing XRPD’s Analytical Potential with Complementary Techniques

While XRPD is a comprehensive method for analyzing the morphology of APIs, using complementary methods alongside it allows for a more detailed understanding of the structure and behavior of solid forms. With a wide range of data, pharmaceutical scientists can make informed, forward-looking decisions in API development. Identifying and excluding unstable, unreliable lead compounds early in the development process saves time and costs and makes subsequent development more reliable.

For example, thermal analysis techniques like Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) are effective for measuring the thermal stability of solid forms. As explained in the previous blog, they are particularly effective when characterizing different polymorphs and conducting stability tests on optimal lead candidates.

DSC measurements and TGA experiments reveal insights on polymorph transition temperatures and energies and formational insights regarding different hydrates. Additionally, XRPD provides insights into crystal structures responsive to temperature and humidity changes. Recently, there has been an increase in performing stability evaluations during development to aid in risk reduction within the development workflow. Moreover, X-ray scattering techniques such as Small-Angle X-ray Scattering (SAXS) and Pair Distribution Function (PDF) enhance understanding of API structures alongside XRPD. SAXS is used for nanoscale material analysis, measuring the intensity of x-rays scattered by samples close to a direct beam. This scattering provides detailed information on nanoparticle size distributions, offering versatility for use on liquid dispersions, porous, and solid samples. On the other hand, PDF evaluates the short-range order of amorphous materials. It is particularly effective for inherently disordered substances and determines the structures of amorphous, low-crystalline, nanocrystalline, and nanostructured materials using complete powder X-ray diffraction patterns.

Conclusion

Proceeding with pharmaceutical development without fully understanding the structure and stability of polymorphs may result in safety, efficacy, and quality issues. Additionally, incomplete polymorph profiling may lead to ambiguous patent filings, potentially resulting in disastrous consequences years later. Although XRPD is a powerful tool for characterizing the solid form of APIs, using complementary tools like thermal analysis, SAXS, and PDF fills these profiling gaps, improving analytical insights.

The final blog of this series, scheduled for publication soon, will give an overview of how to best utilize XRPD in selecting lead compounds during pharmaceutical development.

For more detailed insights on how XRPD aids in pharmaceutical development, please download the FULL guide.

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