Pushing Detection Limits in Pharmaceutical XRPD:

Industrial Success at ALBA Synchrotron

Excelsus Structural Solutions, established in 2012 as a spin-off of the Paul Scherrer Institute, is a company of highly specialized synchrotron scientists providing cutting-edge, customizable, and cost-effective synchrotron-based structural characterization services for the pharmaceutical industry across all stages of the product lifecycle —from selection and development to stability studies, manufacturing, and intellectual property protection.

Their capabilities extend well beyond those of conventional laboratory techniques, while remaining cost competitive. Through Excelsus, industrial clients gain access to exceptional angular resolution and ultra-sensitive detection, enabling the accurate quantification of complex polymorphic mixtures.

Given the high standards required for their synchrotron-based analytical services, Excelsus carefully evaluate and fully characterize any facility before deploying industrial projects. Historically, most of their activities have been conducted at the Swiss Light Source (SLS), with additional facilities used as backup. In preparation for the long shutdown of SLS planned for September 2023, alternative facilities with comparable performance were evaluated. The ALBA Synchrotron was identified as the most suitable option to ensure continuity of service.

Several months prior to the SLS shutdown, Excelsus progressively transferred industrial projects to ALBA while simultaneously assessing beamline performance for advanced applications, including accurate quantification via mass-controlled approaches. With the support of TamaTA-INNOV, a programme of the LEAPS-INNOV EU project, the company was able to carry out a comprehensive performance evaluation and validate their advanced methodologies at ALBA. The support from the Industrial Liaison Office team and the BL04-MSPD, Materials Science Powder Diffraction beamline scientists was instrumental to the success of this process.

Following this validation phase, Excelsus conducted approximately 450 hours of proprietary industrial access at the ALBA Materials Science Powder Diffraction beamline, leading to multiple successful projects. As a representative example, it is worth to highlight a collaboration with Novartis (Arnaud Grandeury and team, Basel) focused on the purity assessment of a highly potent compound in both drug substance (API) and drug product (DP). The API was known to exist in three crystalline polymorphic forms with very closely spaced, intense diffraction peaks.

In such cases, the level of detection —critical for purity assessment— is strongly influenced by peak overlap. Beyond high signal-to-noise ratio, which remains essential, angular resolution (i.e., the ability to resolve closely spaced peaks) proved to be the determining factor, and a key limitation for conventional laboratory X-ray powder diffraction (XRPD). Equally critical was the ability to calibrate the 2θ angular scale to within a few hundredths of a degree.

Figure 1 presents the synchrotron XRPD patterns recorded at the ALBA Powder Diffraction beamline for the three crystalline reference forms (Forms I, II, and III), with Form II being the target phase. Although each form exhibits at least one characteristic Bragg peak, these peaks are so closely spaced that they cannot be resolved using laboratory XRPD. While pure phases can still be distinguished by secondary features, this becomes infeasible in drug products with API loadings below 1 wt%.

Using high-resolution synchrotron XRPD, these phases were clearly distinguished, as illustrated in Figure 2. Furthermore, through careful signal-to-noise analysis, a limit of detection better than 0.08 wt% was estimated.

This study provides a clear demonstration of the power of synchrotron XRPD for investigating pharmaceutical polymorphism, combining high counting statistics, 2q angular resolution, and precise calibration of the instrument 2θ scale to within a few thousandths of a degree.

Figure 1 – Synchrotron X-ray powder diffraction (XRPD) patterns of three crystalline polymorphic forms of a Novartis active pharmaceutical ingredient (API): Forms I, II, and III, with Form II as the target phase in the drug product. The characteristic Bragg peaks of the three forms are so closely spaced that they cannot be resolved by laboratory XRPD, but are clearly distinguished using high-resolution synchrotron XRPD combined with precise angular calibration.

Figure 2 – Overlay of synchrotron XRPD patterns of Novartis drug products, crystalline API reference forms, and excipients. The high data quality enables straightforward identification of the target crystalline form of the active ingredient. The limit of detection was estimated to be better than 0.08 wt%.