Docetaxel (Taxotere^® Trihydrate) Forms: Crystal Structure Determination from XRPD & XRSCD Data

Abstract

Docetaxel (form A), a stoichiometric hydrate containing three water molecules per molecule of drug substance (Taxotere®), is thermodynamically stable under ambient conditions of pressure, temperature and relative humidity. In order to gain a better understanding of docetaxel system at the atomic scale a structural study was performed. Due to strong anisotropy of crystals (thin plates), the crystal structure of docetaxel (29 degrees of freedom) was solved and refined using high resolution XRPD data applying an ab initio direct space method. In parallel, an in-depth crystal growth study was carried out until single crystals suitable for XRSCD structural resolution were obtained: surprisingly, a new polymorph of docetaxel, called form B, was isolated.

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

“…The lattice parameters of DOW3 and DOWEt match the two different phases published by Zaske et al (DARGOT, P 2 1 2 1 2 1 , DARGOT01, P 2 1 , see Table ), respectively, and are the only entries for docetaxel shown in the CCDC database to date. No exact comparison between these published structures and DOW3/DOWEt could be carried out, due to the lack of atom coordinates in both the publication and the corresponding CCDC database entries.…”

“…However, while DARGOT and DOW3 have the same chemical composition, DARGOT01 is again reported to be the trihydrate, whereas DOWEt is a different solvated form of docetaxel. Both DARGOT structures have been determined from recrystallizations in ethanol/water . It is therefore difficult, in absence of atomic coordinates, to determine with absolute certainty whether DOWEt and DARGOT01 are truly different solvated crystal forms of docetaxel having very similar cell parameters or whether the published DARGOT01 actually contained some solvated ethanol.…”

“…Both DARGOT structures have been determined from recrystallizations in ethanol/water. 8 It is therefore difficult, in absence of atomic coordinates, to determine with absolute certainty whether DOWEt and DARGOT01 are truly different solvated crystal forms of docetaxel having very similar cell parameters or whether the published DARGOT01 actually contained some solvated ethanol. Both structures DOWEt and DOW3 derive from more complete and precise single-crystal data.…”

“…Therefore, an understanding of the hydrogen-bonding network in docetaxel is imperative if an explanation for its improved solubility over paclitaxel is to be sought. To date, two crystal structures of docetaxel (CSD REF DARGOT and DARGOT01, both reported to be trihydrates) and two derivatives (CSD REF IVIGID and XESVAT) have been reported, although no atomic coordinates are available for the trihydrates.…”

Solving molecular crystal structures from laboratory X-ray powder diffraction data withDASH: the state of the art and challenges

“…Global optimization methods for crystal structure determination from powder diffraction data (SDPD) have become widely available in recent years and have successfully been applied to solve the structures of organic (Harris & Cheung, 2003;Johnston et al, 2004;Rukiah et al, 2004;Zaske et al, 2004), inorganic (Deem & Newsam, 1989;Edgar et al, 2002;Reinaudi et al, 2000) and organometallic (Ivashevskaja et al, 2002;Dinnebier et al, 2000) materials, to cite but a few examples. The basis of global optimization strategies has been fully described elsewhere and software implementing global optimization methods is now widely available [e.g.…”