The Devil is in the Detail: A Rare H‑Bonding Motif in New Forms of Docetaxel

Docetaxel is a semisynthetic analog
of the taxane paclitaxel, pivotal
for the treatment of various types of cancer. Minor differences in
its chemical structure give docetaxel a slightly better water solubility
profile when compared to paclitaxel. An understanding of the hydrogen-bonding
network in docetaxel is therefore imperative if an explanation for
its improved solubility over its predecessor is to be sought. New
crystalline forms for solvated (ethanol), hydrated, and anhydrous
docetaxel are reported. The crystal structures were determined by
single crystal synchrotron and laboratory powder X-ray diffraction
experiments on crystalline materials resulting from polymorph screening
tests in various solvents. Variable-temperature experiments were carried
out over ranges between 20 and 130 °C, with subsequent loss of
crystal water at 70 and 90 °C. The resulting structures are discussed
in terms of their intermolecular interactions, molecular conformations,
and packing motifs. A rare hydrogen-bonding motif, observed between
carbamate and tetracyclic ether groups, was found in the packing of
all phases of docetaxel. Subtle but significant changes in structural
hydrogen bonding motifs are discussed and their differences supported
and visualized by Hirshfeld surface calculations and related two-dimensional
fingerprint plots.