Optimization of sample preparation conditions for detecting trace amounts of β-tegafur in α- and β-tegafur mixture

We report a semiquantitative method for determining trace amounts (<1%) of thermodynamically stable forms in polymorphic mixtures, focusing on sample preparation effects on solid phase transitions. Tegafur [5-fluoro-1-(oxolan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione] was used as a model material in this study. The amounts of the thermodynamically stable β tegafur were increased to levels detectable by powder X-ray diffractometry by grinding the samples in a ball mill in the presence of water. The limit of detection for this method was as low as 0.0005% of β tegafur in α and β tegafur mixtures. The amount of β tegafur after sample preparation was found to be proportional to the initial weight fraction of β tegafur. The sum of Langmuir and Cauchy-Lorentz equations was used to describe the change in conversion degree due to the added water volume, where Langmuir equation described water sorption during the sample preparation and Cauchy-Lorentz equation described the grinding efficiency.