The Power of Synchrotron X-Ray Powder Diffraction

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The power of synchrotron X-ray powder diffraction

A state-of-the-art technology opening doors to new horizons for the characterisation of pharmaceuticals and other complex materials…

-Ray Powder Diffraction (XRPD) is a radiation damage of organic compounds powerful technique that exploits and perform kinetic studies of structural Xthe interaction between X-rays changes during chemical reactions or and matter to study the structural and under temperature and pressure variations. microstructural properties of materials. Its power lies in the direct and unique Synchrotron radiation facilities have relationship between the X-ray powder traditionally been accessible only to expert diffraction pattern of a given substance and scientists due to their intrinsic complexity, its structural order and/or disorder. The and are characterised by long waiting position and intensity of the peaks in a times not compatible with the speed diffraction pattern (so-called Bragg peaks) requested by private companies. Excelsus reflect in fact the solid state symmetry of Swiss Light Source Powder Diffraction Station Structural Solutions SPRL (ESS) is a the substance and, in powder mixtures, spin-off company of the Paul Scherrer XRPD can determine the percentage in In the field of pharmaceutical powders, Institute founded in March 2012 with the weight of the components. Furthermore, XRPD is thus considered as the gold mission of providing industry with fast the diffraction peaks’ width and shape standard method for the identification and easy access to SR-XRPD, including unveils further precious information on the and quantification of solid forms (i.e. poly- data interpretation and design of substance microstructure. morphs, solvates, hydrates, salts, co-crystals, non-standard experiments. amorphous).1 However, it is the quality of The high brightness of an XRPD pattern that defines the accuracy SR-XRPD is a key tool to support research, synchrotron radiation and reliability of the technique, and there- development, manufacturing and sources enables X-ray fore the wealth of information that can be life cycle management activities for characterisation of phar- maceutical products and extracted. When it comes to data quality, (bio)pharmaceuticals. Drug substances chemical compounds nothing competes with Synchrotron X-Ray can exist in different crystalline forms with a quality much supe- powder diffraction (SR-XRPD), which is (polymorphs), solvates/hydrated forms rior to that achievable widely superior to laboratory XRPD in terms (pseudo-polymorphs) and amorphous with lab-based X-ray sources. The Paul Scherrer Institute is home of the of angular resolution, counting statistics, forms, as a result of the manufacturing and Swiss Light Source ( www.psi.ch/sls ), providing energy tunability and fast acquisition time. storage conditions. These different forms unique facilities and services for single-crystal, can have a profound effect on the quality powder diffraction and chemical analysis to both In SR-XRPD, X-rays are generated by a syn- or performance (e.g. solubility, bioavailabil- academic and industrial users. We have a long tra- 3 dition in providing services to industry and are chrotron facility and are at least five orders ity, efficacy, safety) of the drug products. proud supporters of our spin-off companies of magnitude more intense than the best For example, therapeutic failure has been Dectris, Eulitha, Expose and Excelsus Structural X-ray laboratory source. When combining attributed to uncontrolled hydrate forma- Solutions (ESS). With the advent of ever more SR-XRPD with the new generation of tion in tablets during storage.4 For this sophisticated X-ray detectors with fast readout, 2 detailed in-situ kinetic of phase transformation solid-state ultra-fast and efficient detectors, reason, it is now a regulatory requirement studies of chemical processes have become possi- level of detection (LoD) smaller than 0.05% to conduct a detailed analysis of the poly- ble. It is my prediction that the volume of industrial wt are obtainable even when only micro- morphism of the drug substance and drug analytical services at synchrotron radiation sources grams of powder are available. Such an product during technical development, will grow significantly during the coming years. efficient data collection with acquisition including screening, characterisation, prop- J Friso van der Veen, Head of Research Department Synchrotron Radiation and Nanotechnology, Paul Scherrer times ranging from milliseconds to few erty determination and setting of accept- Institut, CH-5232 Villigen PSI, Switzerland minutes allows one to control the inevitable ance criteria for the different forms. Typical 2

BASF has been working with Excelsus Structural SR-XRPD patterns Solutions (ESS) since its recorded on pharma- inception. Synchrotron ceutical binary X-Ray Powder Diffraction has always been an ele- mixtures of similar mental part of our analyti- elemental composition cal toolbox, but in the ranging from 0.05% to past the effort of access- 5% weight (wt) of the ing beam time and collecting data was exorbitant. minority phase. The Since our collaboration with ESS, this has become as simple as a phone call. We do not have to small XRPD signal is concern ourselves with all the details of the experi- directly detectable mental setup, which can be impressively, but also down to 0.05% wt dauntingly, complex. It is a great pleasure for us to with a signal-to-noise work with a company so dedicated and profes- better than 10, allow- sional as ESS has proven to be. ESS is our first choice when it comes to accessing SR-XRPD Data. ing the quantification Bernd Hinrichsen, Research Scientist, BASF SE, of the minority phase Ludwigshafen, Germany applications include: • Structural solution of a new solid form; identification, structural solution and performance of products are dependent refinement, detection of crystalline traces on their crystalline structure and relative • Development of formulation and screen- in amorphous, microstructural analyses) distribution of their polymorphic forms, ing of excipients, including co-crystals; and quantitative analyses of complex such as: food and aroma compounds, mixtures of active pharmaceutical cosmetics, pigments, catalysts, cement. • Characterisation and quantification of all ingredients (APIs) and finished products. polymorphic forms in a drug substance Acknowledgements and product, including in fully opaque SR-XRPD is a powerful technique in several Arturo Araque, Christoph Quitmann, Phil Willmott, Friso blisters; other areas where the properties and van der Veen, Joel Mesot, Stefan Mueller and Cinzia Giannini instantly believed in this project and strongly supported it.

• Detection of impurities down to a trace Novartis owns strong level (<0.05% wt); technical and scientific 1 Beckers D: Pharmaceutical Technology Europe (2010), capabilities allowing us pp. 29-30 • Optimisation of manufacturing processes; rapidly assess and resolve 2 Bergamaschi A, Cervellino A, Dinapoli R, Gozzo F, Henrich problems that might arise. Each material has the B, Johnson I, Kraft P, Mozzanica A, Schmitt B and Shi X: • In situ non-ambient kinetic studies at potential to present differ- J Synchrotron Rad, 17 (2010) 653-668 the millisecond scale; ent challenges and tech- 3 Bernstein J: Polymorphism in Molecular Crystals, IUCr nical features. Some may Monographs on Crystallography (2002), Oxford Science be straightforward and routine, others may be • Stability studies of polymorphic forms; complex. We have further enhanced our analytical Publications capability by forming a partnership with Excelsus 4 Law D, Schmitt EA, Marsh KC, Everitt EA,Wang W, Fort JJ, • Troubleshooting activities and investiga- Structural Solutions (ESS). For complex tasks requir- Krill SL, Qiu Y. J. Pharm. Sci. 2004; 93 (3): 563–567 tions during commercial manufacturing; ing a creative, technical or logistical solution, a spe- cialist service such as SR-XRPD was not available worldwide. Faced with exceptionally challenging • Patent application for new materials and deadlines our partnership with ESS has been very patent-life extension; successful in improving our ability to deliver quick solutions. ESS brings energy, pride and passion on everything they do, they innovate and improve. This • Detection of counterfeits even with partnership has been found to ensure a smooth minute differences. transition of products during drug product develop- Fabia Gozzo PhD ment, underpinning more conventional routes. Excelsus Structural Solutions SPRL SR-XRPD data quality is appropriate for Arnaud Grandeury, Fellow, Pharmaceutical and Analytical [email protected] both qualitative analyses (e.g. structural Development, Novartis Campus Basel, Switzerland www.excels.us