Polymorph Predictor

Two new polymorphs of (2E)-2-cyano-3-[4-(diethylamino)phenyl]-prop-2-enethioamide and an acetone solvate were crystallized, and the structures compared to the known nonsolvated form [11]. One of the new forms was found to be considerably more stable than the others, and subsequently the other two new forms became vanishing polymorphs that could only be produced under strictly controlled conditions. The structures of all three polymorphs could be found using polymorph predictor, if the initial molecular structure was obtained from the X-ray data, the molecule held to be rigid during the energy minimization, and both VDW and Coulomb interactions taken into account. 

Figure 10. Crystal structure of quinoxaline showing the unit cell and the C-H—N hydrogen bonded catemer. Top Experimental structure with Z = 5. The symmetry independent molecules are numbered. Bottom Structure determined with the Polymorph Predictor (Cerius2) software and having Z =1. The two structures are nearly equivalent. Would one find other related structures with different values of Z ...

This simulation and other computational studies were carried out with the Polymorph Predictor and Crystal Packer modules in the Cerius2 suite of programs from Molecular Simulations. We thank MSI (Cambridge and San Diego) for their continuing cooperation and assistance. 

Among the currently available methods we quote ZIP-PROMET, which can only handle rigid models and generates the trial structures by a stepwise construction of dimers and layers, UPACK which uses a grid search algorithm, and Polymorph Predictor, which uses a SA search. 

The commercially available Polymorph Predictor program clusters structures by comparing lists of interatomic distances, an approach that is described in more detail in a later section. 

The MSI Polymorph Predictor (PP) is based on a four-step method. " " Sampling via Monte Carlo simulated annealing provides a starting set of trial structures. These are clustered to delete similar structures, minimized to create low energy crystal packings, and once more clustered to remove duplicates. Since the method is under continuous development and the current implementation differs significantly in some places from the procedure originally published, we present it below in relative detail. 

To limit the number of atom-atom interactions to be considered in the calculation of van der Waals and electrostatic interactions, a suitable cutoff radius (UPACK) or an Ewald summation (MPA, Polymorph Predictor) may be used, or both (Gibson and Scheraga ). Finally, the use of lookup tables instead of repeated evaluation of interaction functions may speed up computa-tions. ° ... 

Finally, the ultimate objective of this work is to generate conformations that can be repacked in the correct crystal form. To do this, a limited CSP study was performed on axitinib, as follows. First, we took the structures from the conformational search using each force field with the lowest RMSD to the crystal forms 1, VI, XXV, and XLI. These conformations were used as input for the Polymorph Predictor in an attempt to reproduce the crystal forms in the corresponding space groups. Form IV was not considered in this limited study because it has two molecules in the asymmetric unit cell (termed IV and IV ), which makes the computational CSPs substantially more challenging and time consuming. 

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