Powerful analytical solutions for the Pharmaceutical Industry

Synchrotron X-Ray Powder & Electron Diffraction

STRUCTURAL SOLUTIONS AND SERVICESSR-PXRD Sample preparation (mgr quantity) and performance of SR-PXRD synchrotron experimentsSR-PXRD angular resolution down to 0.003° in 2q and access to wide d - spacing values (0.2 – 500 Å)SR-PXRD Pair distribution function (PDF)SR-PXRD Characterization and phase quantification of all polymorphic forms in the drug substance and product, including in fully opaque blistersSR-PXRD Structure solution from powder data of unknown structures with Rietveld refinementSR-PXRD quantification of amorphous contentSR-PXRD Stability studies of polymorphic forms and troubleshooting activities /nvestigations du-ring commercial ManufacturingSR-PXRD Patent application for new materials and patent life extensionSR-PXRD Detection of counterfeits even with minute differencesSR-PXRD Cell parameter determination of protein structures and their polymorphsSR-PXRD Crystal structure of proteins and ligands-proteins complex structure formation

ED (Electron Diffraction) tomography solution for poorly crystalline drugs (not well defined or presence of many overlapping peaks at SR -PXRD)ED Tomography solution for cell parameter determination of drug APIs and their polymorphs

ED Tomography solution for crystal structure determination of drug APIs and their polymorphsED tomography solution for study of nm size crystals (“X-Ray amorphous”)

Nanometer scale mapping of amorphous –crystalline areas using ED techniques

Advanced State of the art Synchrotron Radiation facilities and specialized Electron Microscopy Laboratories over the world are usually only ac-

cesible to expert scientists due to their intrinsic com-pexity, long waiting times and expensive access.

NanoMEGAS SPRL is a leading European Company in the field of advanced electron crystallography solu-

tions in combination with X-Ray diffraction techniques.

Through our partnership with unique research labora-tories we provide to the Pharmaceutical Industry with fast and easy access to most advanced Synchrotron powder X-Ray facilities (SR-PXRD), including data in-terpretation and design of non –standard experiments.

contact: pharma@nanomegas.com

Combination of Synchrotron X-Ray Powder Diffraction and Electron Diffraction Tomography

X-Ray Powder Diffraction (PXRD) is a gold standard technique for crystal structure identification and structu-ral solution. In the field of phar-maceutical powders, PXRD is used

for identification and quantification of solid forms (polymorphs,solvates, hydrates, salts, co-crystals, amor-phous). When it comes to data quality , Synchrotron X-Ray pow-

der diffraction (SR-PXRD) is widely superior from laboratory PXRD in terms of angular resolution, coun-ting statistics , energy tunability and ultra fast acquisition time.

In PXRD, X-Rays are generated by a Synchrotron facility and are at least five orders of magnitude more intense than the best X-Ray labo-ratory source . With SR-PXRD a le-vel of detection (LoD) smaller than 0,05% wt is obtainable even when only micrograms of powder are available and Synchrotron acquisi-tion times range from milliseconds to few minutes allowing to control radiation damage of organic com-pounds and perform kinetic studies. Drug substances can exist in diffe-rent crystalline forms (polymorphs), solvates/ hydrated forms (pseudo-polymorphs) and amorphous forms as a result of the manufacturing and storage conditions. These different forms can have a profound effect on the quality of performance (e.g. solubility,bioavailability,efficacy,safety) of the drug products. For this reason, it is now a regulatory requi-rement to conduct a detailed analy-sis of the polymorphism of the drug

substance and drug product during technical development, including screening, characterization, pro-perty dissemination and setting of acceptance criteria for the different forms.

SR-PXRD data quality is appropria-te for both qualitative analysis (e.g. structural identification, structural solution and refinement, detection of crystalline traces in amorphous , microstructural analysis) and quan-titative analysis of complex mixtures of active pharmaceutical ingredients (APIs) and finished products.

SR-PXRD is a powerful technique also for the study of protein-ligand complexes, where it offers a distinct advantage over single crystal work due to complete immunity to crystal fracture and where protein lattice parameters can be determined with 2 orders of magnitude more preci-se than those obtained from single

crystal experiments. Changes of the lattice parameters of less than 0,5% can be detected easily and SR –PXRD data that can be used to locate the position of the ligand, at the protein-ligand structure can be refined to determine the details of complex formation.

Electron Diffraction Tomography in a Transmission Electron microscope (TEM) is perfectly complementary to SR-PXRD technique in case of poorly crystalline samples, crystals of nm size (which appear as “X-Ray amorphous”) and also in case of very small quantity of sample avai-lable.

REFERENCESBeckers D. Pharmaceutical technology Europe (2010) pp 29-30Bernstein J : Polymorphism in molecular crystals, IUCr Monographs on Crystallography (2002) Oxford science publicationsVon Dreele, RB J.Applied Crystallography 1999, 32, 1084-1089

I.Margiolaki & J.P Wright Acta Cryst A , 2008 , Jan 64 (Pt 1) : 169-80Kolb U., Mugnaioli E., Gorelik T. E. Automated electron diffraction tomography – a new tool for nano crystal

structure analysis. Crystal Research and Technology 46 (2011) 542–554 (10.1002/crat.201100036)Anna Bergamaschi et al J. Synchrotron Rad. (2010). 17, 653–668 , The MYTHEN detector for X-

ray powder diffraction experiments at the Swiss Light Source

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