X-ray diffractometric determination of micro amounts of ß tegafur in the a and ß polymorph mixture
Sanita Petkune Department of Chemistry,
University of Latvia
Riga
LV 1586, Latvia
Abstract:
For stability concerns the thermodynamically most stable crystalline form is normally chosen for development into the final dosage product, but more recently, metastable forms have been utilized due to enhanced dissolution or bioavailability profiles. However, the metastable polymorphic form may be inadvertently generated due to the stress produced by temperature, mechanical treatment and moisture during processing or storage of the drug product. Contamination by polymorphic impurities can influence both the stability and performance of the final product therefore during the last decade, the requirement on identification, specification and control of polymorphs for a drug substance has become as a part of the quality assurance process. Therefore it has become necessary to develop quantification methods for low level physical impurities of separate crystalline phase. Ever-growing quality requirements of pharmaceutical active substance demand the rapid and simple quantification method of low levels (<1%) of unwanted solid forms in the developed one.
The purpose of this study was to develop a suitable analytical method for determining micro amounts of the thermodynamically stable polymorphic form (<1%) in the mixture of thermodynamically stable and metastable polymorphic modifications. α and β forms of tegafur - 5-fluoro-1-(tetrahydro-2-furyl)-uracil, a chemotherapy drug used in the treatment of cancer and primarily - bowel cancer [7], were selected as a model material in this study. The content of β tegafur was increased in the analysed samples by promoting the phase transition from α to β form to such β form amount that can be determined with the quantitative PXRD analysis. Samples were grinded for fixed time, temperature and grinding frequency and the phase transition was stimulated by adding some water to samples before grinding. The calibration line was constructed using the less-square method.
