A Combined Solid-State NMR and X-ray Powder Diffraction Study of a Stable Polymorph of Paclitaxel

Abstract

Solid-state NMR (SSNMR) and X-ray powder diffraction (XRPD) allow a study of a novel and stable polymorph of paclitaxel (Taxol) with two molecules per asymmetric unit (Z‘) in the P212121 space group. The asymmetric unit volume is 2167 Å3, about four times larger than that previously characterized in combined XRPD/SSNMR studies. The method, employing SSNMR constraints, allows the XRPD Rietveld analysis to establish many of the lattice details that otherwise would be unavailable. NMR structural constraints are provided by isotropic shifts and three-dimensional (3D) chemical shift tensors (CST), which are determined by ab initio quantum mechanical calculations. CST data give highly sensitive information on short-range structural features such as intra-atomic distances (particularly for proton positions that are undetermined with XRPD methods) and short-range valence angles that exhibit relatively poor sensitivity in reasonably large microcrystalline powders. Conversely, space group symmetry, unit cell volumes, long-range cell dimensions, and dihedral angles of extended chains are estimated with XRPD measurements. Corroboration of many structural parameters by combined quantum mechanical, SSNMR, and XRPD results indicate the efficacy of these combined approaches in relatively sizable microcrystalline powders. The population of the asymmetric unit, Z‘ = 2 is clearly observed even in the one-dimensional isotropic 13C spectra, which also confirmed the stability of the polymorph over a three-year period. This structural determination depends specifically on the agreement between previous SSNMR CSTs and single crystal results for baccatin, the rigid part of paclitaxel. Hence, CST data provide a reasonable initial model for the early iterative steps of a Rietveld analysis of XRPD data for a new polymorph of Taxol.

Small Molecule, Big Difference: The Role of Water in the Crystallization of Paclitaxel

“…Anhydrous and hydrated forms of paclitaxel have been investigated most commonly by solid‐state Nuclear Magnetic Resonance (SSNMR),23–25 using X‐ray powder diffraction (XRPD) purely as a tool for phase identification. Although the partial structure of a paclitaxel hydrate has been elucidated by the combined use of SSNMR and synchrotron XRPD data,26 there is, to date, no evidence of a structural investigation using XRPD as the primary technique for crystal structure determination, and no crystal structure of the anhydrous form has been reported so far.…”

Polymorphism and Solvatomorphism 2005

“…The 2005 literature contains a very large number of reports on additional organic compounds that have been shown to exhibit the phenomenon of polymorphism. Many of these substances are probably of limited pharmaceutical interest, but nevertheless some of the reported results71–114 are summarized in Table 1 for those workers who may have a suitably directed interest.…”

Encapsulation of paclitaxel into a bio-nanocomposite. A study combining inelastic neutron scattering to thermal analysis and infrared spectroscopy

“…Paclitaxel (C 47 H 51 NO 14 , hereafter PTX) is an anticancer drug whose effectiveness has been shown against different kinds of tumors [1,2], including breast cancer [3], Fig. 1.…”

“…Nevertheless, concerning the encapsulation, a number of questions remain open. For instance, it is well known that the PTX's anti-cancer activity is driven by its flexible structure [12][13][14], but the encapsulation can induce severe dynamical changes and interactions between the drug and the bio-NCP that may affect the releasing process. This work is the very first attempt to shed light into this particular problem.…”