How complementary techniques boost XRPD in solid form analysis
In this four-part blog series, we explore how one type of solid form analysis – X-ray powder diffraction (XRPD) – is helping drug developers optimize the solubility and performance of drug products. In this third part of the series, we discuss how XRPD can be paired with complementary techniques for a more comprehensive and efficient characterization of active pharmaceutical ingredients (APIs). Parts one and two can be found here.
Optimizing XRPD analysis with transmission mode
In the last blog, we discussed how X-ray powder diffraction (XRPD) is a powerful and popular technique to detect and characterize polymorphic forms of APIs. XRPD is the only single-workflow technique that gives a detailed fingerprint of the structure of crystalline and amorphous API forms.
However, characterization of solid forms using XRPD can sometimes hold its own challenges. There are two key factors related to the preparation of the sample that can affect the results: (i) the orientation distribution of the crystallites, and (ii), the particle statistics. The sample can, for example, exhibit preferred orientations that cause deviations in reflection intensities measured in diffraction data. This can be quite a common issue in powders that include anisotropic crystallites (i.e., plate or needle-like crystals, rather than cuboid – figure 1). An ideal sample has a large number of randomly-oriented crystallites, which has high statistical reproducibility.
So how can we minimize preferred orientation effects in XRPD measurements? One of the simplest ways is to switch the geometry of the XRPD experiment from reflection mode to transmission mode. This change of geometry makes spinning the sample more effective in removing orientation. In recent years, there has been a growing popularity for transmission measurement modes to increase the effectiveness of using XRPD in solid form analysis, despite historical validation and quality control methods having been established using reflection mode.
Complementary techniques improve the analysis potential of XRPD
Whilst XRPD is a comprehensive method to analyze the morphological forms of an API, complementary techniques can be used in combination to provide a more complete picture of the structure and behavior of the solid forms. Having a wider breadth of data types enables pharmaceutical scientists to make well-informed and future-proof choices for API development. Less stable and, therefore, less reliable lead candidates can then be eliminated early in the development process, which saves time and cost, and ensures that consequent development follows a more secure route.
For example, thermal analysis techniques such as differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA) can be useful to determine the thermal stability of solid forms. As discussed in the previous blog, this is particularly useful when characterizing different polymorphs, and performing stability testing on the most promising lead candidates.
DSC measurements and TGA experiments can help elucidate the transition temperatures and energies of polymorphs, providing insight into the formation of different hydrates. XRPD then provides insight on crystalline structures that may change with temperature or humidity. Increasingly, stability assessments are conducted throughout development, which helps derisk the development workflow.
In addition, X-ray scattering techniques like Small-angle X-ray scattering (SAXS) and Pair-distribution function (PDF) can be utilized along with XRPD to improve the structural insight for APIs. SAXS is used for analysis of nanomaterials and measures the intensity of X-rays scattered by a sample close to the direct beam. The scattering provides detailed information on particle size distribution in the nanometer range. This technique is extremely versatile and can be used for liquid dispersions, porous materials and solid samples. PDF, on the other hand, is a method for assessing short-range order in amorphous materials. It is particularly useful for intrinsically-disordered materials and uses the complete powder XRD pattern to determine the structure of amorphous, poorly-crystalline, nano-crystalline or nano-structured substances.
Conclusions
Progressing drug development without fully understanding the structure and stability of polymorph variants can quickly lead to potential safety, efficacy or quality issues. Gaps in polymorph profiling can also lead to ambiguity in patent applications, which can have disastrous consequences even years into a drug product’s lifecycle. Whilst XRPD is a powerful tool to characterize API solid forms, complementary tools like thermal analysis, SAXS and PDF can be used to improve analytical insight by filling in these profiling gaps.
In the final blog of this series, coming soon, we will provide an overview of how XRPD can be best utilized in drug development to select lead candidates.
Download the full guide here to discover how XRPD can increase your API analysis potential.
Read other blogs in this series