Structure determination of (pseudo)polymorphic pharmaceuticals by pattern recognition and global optimization techniques (NFC.6216)

Project nummer: nfc6216

Omschrijving van het onderzoek

Single-crystal diffraction yields a detailed and accurate picture of molecular and crystal structures and is a widely applied technique. For most compounds it is relatively easy to produce crystalline material. However, such material is often not suitable for single-crystal diffraction. Structure determination from diffraction data of microcrystalline powders is therefore an interesting and challenging alternative. An attractive aspect of powder diffraction is the possibility to collect data at varying temperature and humidity. Pharmaceuticals often have the tendency to crystallize in various polymorphs or hydrates as a function of the crystallization medium, temperature and humidity. The possibility to monitor, and understand solid-state inter-conversion of polymorphs and hydrates at the molecular level, is very appealing. It critically depends, however, on the availability of powerful structure elucidation methods. The current powder methods are tedious and need very high quality data in order to successfully pass the so called "indexing" step, i.e. the determination of the crystallographic unit cell. As a result, attempted structure determination from powder diffraction data fails in more than half of all cases. The aim of this project is the realization of a more efficient and generally applicable method for optimal extraction of structural information from powder diffraction data. The key to this method is a combination of pattern recognition and global optimization techniques, recently developed at the University of Nijmegen, which already proved to be very successful in the analysis of laser-induced fluorescence spectra. In the analysis of powder diffraction data it allows for a simultaneous determination of both unit cell and structural parameters. Such integration of indexing and structure solution is a new concept. It is expected to enhance the applicability of powder diffraction and to afford a basic tool to understand and control polymorphism and hydrate formation of pharmaceuticals in detail.
Utilization
For pharmaceutical industries structure analysis plays an important role in the development of both drug substances and drug products. It is an essential step in the understanding of physico chemical properties (like color, melting point, morphology, dissolution kinetics, resorption and physical and chemical stability), structure-activity relationships (SAR) and in the evaluation of polymorphism and hydrate formation. Polymorphism and hydrate formation are particularly important with respect to patenting of drugs. In screening of polymorphism and hydrate formation, many crystal modifications ((pseudo)polymorphs) are being produced in small quantities, often of moderate quality. It would be highly desirable to obtain the crystal structures of these crystalline materials in a fast and reliable way, but current methods are usually not up to the job. The present investigation should provide a new methodology for routine determination of a crystal structure from powder diffraction data.

Gebruikers

Six companies are involved in this project.

Projectleider

Dr. R. de Gelder

Radboud Universiteit Nijmegen
Natuurwetenschappen, Wiskunde en Informatica
NSRIM

Postbus 9010
6500 GL Nijmegen

Status van het project

Gestart	: 01-11-2004
Einddatum	: 28-11-2007

Trefwoorden

Crystallography, Structure determination, X-ray diffraction.

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