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Crystal Structure Determination from Conventional Powder Diffraction Data: Application to Hydrates, Hydrochloride Salts, and Metastable Polymorphs

The Powder Solve method, available within Accelrys' Reflex Plus product, has been used by Gregory A. Stephenson at Eli Lilly to re-determine the crystal structures of papaverine hydrochloride and erythromycin A dihydrate, and to solve the crystal structure of the metastable polymorph B of acetohexamide [1].

Crystal structure solution is not always possible by traditional single crystal X-ray diffraction techniques. In particular metastable polymorphic forms, isolated by rapid crystallization or growth, can be obtained as micro-crystalline aggregates or crystals too small for single-crystal diffraction techniques. Twinning can also cause severe problems in single crystal work. In such cases, techniques for structure solution from powder diffraction data, such as Powder Solve, provide a useful alternative. The Powder Solve methodology is widely used in pharmaceutical industry and has been thoroughly validated since its introduction in 1998 [2].

The limited number of observations in powder diffraction patterns means that only a limited number of variables can be studied in the structure solution procedure. All bond distances and angles within molecular fragments are fixed to values reported for similar structures or conformations obtained by molecular modeling methods. Thus, in the Monte Carlo Simulated Annealing (MC/SA) search for the correct crystal structure, only the translation and rotation of the molecules in the unit cell, plus selected torsion angles, are considered as degrees of freedom.

Dr G. A. Stephenson has applied Powder Solve to the structure solution of the previously reported structures of papaverine hydrochloride and erythromycin A dihydrate. In addition to the rotational and translational degrees of freedom, six torsions were explored for papaverine hydrochloride with the initial conformation being obtained by force field minimization (Dreiding 2.21 with Qeq charges). In the case of erythromycin A dihydrate (see molecular diagram), several structurally similar molecules were known to adopt the same conformation. This conformation was used as a template and the whole molecule defined as a rigid body. In both cases Powder Solve provided solutions in good agreement with the reported structures.

Erythromycin A dihydrate

In addition, the Powder Solve method was successfully applied to the structure solution of the metastable polymorph B of acetohexamide, for which numerous attempts to grow single crystals suitable for single crystal structure determination had been unsuccessful. Several molecular fragments were kept rigid in conformations corresponding to reported structures of similar compounds, while three torsional degrees of freedom were explored. The structure solution was validated by the high degree of reproducibility in the MC/SA search, by solid-state spectroscopic data (FTIR and NMR), and by close inspection of the crystal packing (close contacts, hydrogen bonding pattern, and consistency with known crystal structures of similar compounds).

In all three examples, laboratory CuK a powder diffraction patterns were used, demonstrating that - if the initial hurdle of powder indexing can be overcome - high quality synchrotron powder data is not required for structure solution with Powder Solve.


1) G. A. Stephenson, J. Pharm. Sci. , 2000, 89 , 958-966.

2) G. E. Engel, S. Wilke, O. K├Ânig, K. D.M. Harris, and F. J.J. Leusen, J. Appl. Crystallogr ., 1999, 32 , 1169-1179.

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