Crystallization Features
of the Chiral Drug Timolol
Precursor: The Rare Case of Conglomerate with Partial Solid Solutions
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Abstract
A synthetic precursor of the chiral
drug timolol, 4-[4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]-morpholine
(<b>2</b>) represents a rare case of conglomerate with partial
solid solution. This fact was established by inspection of an original
solubility test, by the originally developed IR spectra analysis,
and by construction of a binary phase diagram which is totally based
on thermochemical measurements. The special procedure was developed
for quantitative analysis of complex differential scanning calorimetry
traces for incongruently melting samples of intermediate enantiomeric
composition. The X-ray analyses were performed on a single crystal
of <b>2</b> grown from the enantiopure feed material and on
a single crystal picked out from the racemic polycrystalline sample.
The structure of the enantiopure crystal was solved and refined in
the <i>P</i>2<sub>1</sub>2<sub>1</sub>2<sub>1</sub> space
group with the only symmetry independent molecule in the unit cell.
The structure of the crystal picked out from the racemic <b>2</b> sample was solved and refined in the <i>P</i>1 space group
with four symmetry independent molecules in the unit cell. The epoxy
moieties of the independent molecules in this crystal were found to
be disordered over two positions with almost equal relative occupancies
of opposite enantiomers for all the molecules. The quantitative characteristics
of the disorder, 0.78(0.02):0.22(0.02), are close to those found by
an independent method of the Tammann diagram
