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

Abstract

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 hydrogenbonding 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.

DOPE/CHEMS-Based EGFR-Targeted Immunoliposomes for Docetaxel Delivery: Formulation Development, Physicochemical Characterization and Biological Evaluation on Prostate Cancer Cells

“…The encapsulation of the nanoparticles was monitored through PXRD analysis ( Figure 5 A). The diffraction pattern of the pure drug is in a good agreement with the crystalline structure reported by Vella-Zarb and coworkers (2013) [ 66 ]. It is not possible to observe any peaks derived from DTX in any of the liposomes and immunoliposomes.…”

Polymorphism observed in dapsone–flavone cocrystals that present pronounced differences in solubility and stability

“…Hirshfeld surface analysis is a valuable tool for characterizing various types of intermolecular contacts and gaining additional insight into crystal structures. [33][34][35] This method has been applied to quantify intermolecular interactions and elucidate similarities and differences in polymorphs, [36][37][38][39][40][41][42] solvates, 43,44 and cocrystals 33,[45][46][47] of active pharmaceutical ingredients. The 3D Hirshfeld surfaces and 2D fingerprint plots are unique for any crystal structure, therefore the 2D fingerprint plots can present a quantitative summarization of the nature and type of intermolecular contacts in the crystal.…”

A Critical Review of Properties and Analytical Methods for the Determination of Docetaxel in Biological and Pharmaceutical Matrices

“…But, compared to paclitaxel (PTX), it is quickly absorbed, it is less toxic and the water solubility is better, due to differences in their chemical structures at two positions, the C-13 tert-butoxy group instead of the benzamide phenyl group and the C-10 hydroxy group replacing the acetyl group. [26][27][28] The pharmacokinetic profile of DTX is well characterized, composed of three compartments, with half-lives of 4.5 min, 38.3 min, and 12.2 h for the alpha, beta, and gamma phases, respectively. [26] The standard dose varies according to the type of cancer and the treatment used, however the recommended dose is between 75 and 100 mg/m 2 with infusion once every 3 weeks for 1 h, unlike PTX whose recommended dose varies from 200 to 250 mg/m 2 .…”