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

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• 作者：James K. Harper ; Dewey H. Barich ; Elizabeth M. Heider ; David M. Grant ; Roland R. Franke ; James H. Johnson ; Yuegang Zhang ; Peter L. Lee ; Robert B. Von Dreele ; Brian Scott ; Darrick Williams ; and Gerald
• 刊名：Crystal Growth & Design
• 出版年：2005
• 出版时间：September 2005
• 年：2005
• 卷：5
• 期：5
• 页码：1737 - 1742
• 全文大小：150K
• 年卷期：v.5,no.5(September 2005)
• ISSN：1528-7505

文摘

Solid-state NMR (SSNMR) and X-ray powder diffraction (XRPD) allow a study of a novel and stablepolymorph of paclitaxel (Taxol) with two molecules per asymmetric unit (Z') in the P2₁2₁2₁ space group. Theasymmetric unit volume is 2167 ų, 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 manyof the lattice details that otherwise would be unavailable. NMR structural constraints are provided by isotropicshifts and three-dimensional (3D) chemical shift tensors (CST), which are determined by ab initio quantum mechanicalcalculations. CST data give highly sensitive information on short-range structural features such as intra-atomicdistances (particularly for proton positions that are undetermined with XRPD methods) and short-range valenceangles that exhibit relatively poor sensitivity in reasonably large microcrystalline powders. Conversely, space groupsymmetry, unit cell volumes, long-range cell dimensions, and dihedral angles of extended chains are estimatedwith 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 dependsspecifically on the agreement between previous SSNMR CSTs and single crystal results for baccatin, the rigid partof paclitaxel. Hence, CST data provide a reasonable initial model for the early iterative steps of a Rietveld analysisof XRPD data for a new polymorph of Taxol.