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

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.