X-ray or gamma ray systems or devices – Specific application – Diffraction – reflection – or scattering analysis
Reexamination Certificate
2000-02-10
2003-01-14
Kim, Robert H. (Department: 2882)
X-ray or gamma ray systems or devices
Specific application
Diffraction, reflection, or scattering analysis
C378S073000, C378S208000
Reexamination Certificate
active
06507636
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the characterization of crystalline materials that have been formed on a single substrate surface at predefined positions. More specifically, the invention is directed to the rapid screening of polymorph libraries using X-ray micro-diffraction methods.
BACKGROUND OF THE INVENTION
Polymorphism is the commonly used description for the occurrence of multiple crystal forms of the same chemical compound, distinguishable through physical characterization methods like melting point, rate of dissolution, infra-red and raman spectroscopy, and most pronounced single crystal and powder X-ray diffraction. (W. C. McCrone in “Physics and Chemistry of the Organic Solid State Vol. 2” Eds. D. Fox, M. M. Labes, A. Weissberger, Interscience New York, (1965) 725-767).
Since different crystal forms within one polymorphic system exhibit different physical properties i.e. rate of dissolution (which in turn affects bio-availability), melting point, hygroscopic behavior or pressure stability, identifying different crystal forms is increasingly important in the pharmaceutical industry during the drug product process development stage but also during the drug substance research stage.
Polymorph screens are conducted through crystallization experiments by systematic variation of parameters like solvent, temperature or crystallization method, and crystalline products are characterized using thermo-microscopy, spectroscopic and diffraction methods. The combination of different solvents, crystallization methods and temperatures results in several dozen to several hundred possibly even several thousands of crystallization attempts.
Multi-well plates are the preferred containment for these crystallization experiments, combining the advantage of easy storage and transportability with the option to work with small quantities of substance on the micro-gram scale. With conventional multi-well plates the problem remains however that for crystalline, polycrystalline or amorphous materials, samples have to be removed from the wells and transferred to special sample holders. This procedure is unsuitable for high throughput screening since larger amounts of sample are necessary and only a few samples can be analysed per day and diffractometer.
In the field of combinatorial inorganic and materials chemistry a similar challenge exists for the rapid characterization of crystalline reaction products. Recently, a micro-reactor design was reported for generating combinatorial material libraries through chemical reactions and subsequently analysing these using X-ray diffraction (J. Klein, C. W. Lehmann, H.-W. Schmidt, W. F. Maier, Angew. Chem. Int. Ed. 37, (1998), 3369-3372, and PCT Publication No. EP99/03287).
When using conventional, commercially available multi-well plates for crystallization experiments, then a subsequent diffraction experiment, where the crystalline, polycrystalline or amorphous materials remain in the multi-well plate, faces the following problems. In the case of multi-well plates with permanently affixed side walls the angular range accesssible to the incident and diffracted X-ray beam is determined by the ratio of well diameter to well depths. In most multi-well plates in the prior art this ratio is optimised to place a maximum number of wells onto a given surface area while maintaining a specific volume in each well. Assuming typically diameter to depth ratios between 4:1 and 1:4, it follows that wells with circular cross-section cover at most the angular range of 53 to 180° Bragg-angle 2È and 176 to 180° Bragg-angle 2È respectively, for a reflection geometry diffraction experiment, based on an infinitely small X-ray beam and sample size.
Similar considerations hold for X-ray diffraction experiments in transmission geometry. Here the fixed side wall limits the possible ù-rotation of the sample, while particular requirements must be placed on the properties of the bottom face of the multi-well plates in order to avoid scattering artifacts from the sample support.
SUMMARY OF THE INVENTION
The present invention provides a device in form of a multi-well plate with detachable base plate, for producing an array of crystalline, polycrystalline or amorphous samples. The present invention also provides a method for characterizing such an array that has been formed on a substrate at predefined positions using X-ray micro-diffraction.
More specifically, the invention is directed to the rapid screening of polymorph libraries, prepared using standard crystallization techniques, including but not limited to solvent evaporation, gas phase vapor diffusion, temporal and spatial temperature gradients.
In one embodiment, the multi-well plate is constructed in such a way, that crystalline or polycrystalline precipitates form on the removable substrate, which acts simultaneously as the bottom face to each well, which allows depending on the choice of substrate the characterization of said precipitates by X-ray diffraction in either transmission or reflection geometry.
In a specific configuration the base plate is made of single crystal silicon oriented in the (1 1 1) direction in order to minimise diffuse X-ray scattering originating from the sample support. In this configuration X-ray diffraction analysis is carried out in reflection geometry.
In yet another specific configuration the base plate is made from optically transparent sapphire, shown to be virtually free of X-ray scattering artifacts in the background of the diffractogram. In this configuration X-ray diffraction analysis is also carried out in reflection geometry.
In a further specific configuration the base plate is made from an optically and X-ray transparent polymer film including but not limited to polyacetate for visual inspection of crystalline samples using optical microscopy. X-ray diffraction characterization of the formed crystalline or polycrystalline materials can be carried out either in transmission or in reflection geometry.
X-ray diffractograms from each sample spot deposited are obtained by placing the single substrate into a parallel X-ray beam, by means of a xyz-sample translation stage. Diffracted X-rays are detected by an area detector, for example using a multi-wire gas proportional detector. Diffraction images are converted to diffractograms tabulating intensity versus Bragg angle 2è. The identity of or difference between characterized crystalline forms is established through standard pattern matching procedures.
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Kim Robert H.
Studiengesellschaft Kohle mbH
Yun Jurie
LandOfFree
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