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Crystal Structure Determination with SXRD The crystal structure determination is a three-step procedure: Step 1. Crystallisation: Growing suitable single crystals is often the most time and effort requiring step in the whole structure determination procedure with SXRD (Single crystal X-Ray Diffraction). A suitable well-diffracting single crystal must be available. The optimum size is 0.1-0.2 mm in 3-dimensions (3D). b) a) c) a) Solvent evaporation method used to get single crystals. b) The free-interface diffusion method used to get suitable single crystals c) Examples of suitable single crystals for SXRD structure determination. Step 2. Data Collection & Structure Determination: The SXRD method gives results within a few hours when good single-crystals are available. The crystal is mounted on a goniometer head and placed in the X-ray beam of the single-crystal X-ray diffractometer. The unit cell parameters, which describe the repetitive unit in the crystal, are deduced from the diffraction pattern and the reflection intensities are measured by an CCD area detector. Structure determination and Refinment procedure in SXRD Chi-Circle Area Detector X-ray Tube Focussed Beam Primary X-ray Beam 4-Circle Gonoimeter The determined crystal structure (unit cell view) Illustration of a schematic experimental SXRD setup Step 3. Structure Analysis: The final 3-dimensional molecular structure reveals the molecular conformation, crystal packing, absolute configuration, crystal structure stability etc. This information can be used to understand the macroscopic behaviour of a given molecule, enhancing our ability to select a material and predict or tune its properties - i.e. structure informatics. Crystal structure Applications Position modified to increase solubility 3-dimensional Crystal structure supported with theoretical calculations to indicate where the molecule should be modified to decrease the X-X interaction and consequently increase solubility. H H H H H H H H H H H H H O H O H H Experimental XRPD H H O H N O H Cl H O H H H H H H H H H H H O H N H H H H O H O H Cl H XRPD based on the SXRD coordinates H H O H Cl H O H H H With support of the crystal structure, crystallisation problems may be resolved. Up Left: an API not crystallising and up right: the modified API, where crystallisation proceeds without any problems. From the determined crystal structure the theoretical XRPD (powder diffraction) pattern can be calculated. This is used to prove that the bulk substance used for collecting the XRPD-data correspond to the pure substance. The theoretical XRPD is also an important support to patents. •Structure informatics support in formulation, processability and material science •Crystal structure stability (crystal fracture, voids in the crystal structure, mechanical properties) •Solubility improvement (solid state limited solubility) •Understanding of crystallisation and crystallisation properties •Validation/determination of chirality – absolute structure •Solvates - interaction between the drug molecule and solvent •Crystal density and verification of the molecular weight •Unique identification of API’s (Active Pharmaceutical Ingridient) and intermediates •Documentation of API’s and intermediates for patent or NDA •Understanding of crystal habit and crystal surface properties •Structure based drug design support - understanding of conformational space – molecular flexibility •Important support for predictions and simulations •Explanation of solid state properties of different crystal modifications i.e. polymorphs