Download Crystal Structure Determination with SXRD

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