Download detecting trace amounts of the thermodynamically stable

DETECTING TRACE AMOUNTS OF THE THERMODYNAMICALLY STABLE
POLYMORPH IN A MIXTURE OF POLYMORPHS
Raitis Bobrovs, Andris Actiņš
University of Latvia, Department of Chemistry, Kr. Valdemara iela 48, Riga, LV-1013, Latvia
About two thirds of organic compounds and about 80% of active pharmaceutical ingredients
under certain conditions can exist in more than one polymorphic form. The most
thermodynamically stable form is usually chosen for pharmaceutical use, but sometimes a
metastable form has a better solubility or bioavailability, and is selected for manufacturing. In
this case it becomes very important that the final manufactured product is free from the
thermodynamically stable form, because even trace amounts of it can facilitate a phase transition
to the unwanted thermodynamically stable form.
Semi-quantitative method for determining trace amounts (<1%) of thermodynamically stable
forms in polymorphic mixtures using powder X-ray diffractometry has been developed by using
the  and  crystalline forms of tegafur (5-fluoro-1-(tetrahydro-2-furyl)-uracil) as a model
system.
The fraction of the thermodynamically stable  tegafur was increased to levels detectable by
powder X-ray diffractometry by grinding the samples in a ball mill in the presence of water. The
amount of  tegafur after sample preparation was found to be proportional to the initial weight
fraction of  tegafur. The limit of detection for this method was as low as 0.0005 % of  tegafur
in a mixture of  and  tegafur.
For the initial  tegafur fraction from 2.0 % to ~0.05 %, the best correlation was achieved when
samples were ground for 5 minutes at 20 oC with 10 Hz frequency. At a lower weight fraction of
 tegafur, the grinding frequency of 15 Hz was preferred. The optimum results were achieved
when 0.06 mL of water was added to 0.50 g of tegafur. A sum of Langmuir and Cauchy–Lorentz
equations could be used to describe the change in conversion degree depending on the added
water volume. The indirectly determined surface areas and the dependence of conversion degree
on water additive volume demonstrated that increasing the added the water volume above 0.06
mL did not improve the effectiveness of  to  tegafur phase conversion. The conversion degree
to  tegafur was highly dependent on sample drying time after grinding.