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. 2015 Jul 22:6:7793.
doi: 10.1038/ncomms8793.

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

M A Neumann  1 , J van de Streek  2 , F P A Fabbiani  3 , P Hidber  4 , O Grassmann  5
Affiliations

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

M A Neumann et al. Nat Commun. .

Abstract

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

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Conflict of interest statement

M.A.N. is the founder, owner and director of the company Avant-garde Materials Simulation that develops the GRACE software for crystal structure prediction. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Molecular structure of Dalcetrapib.
Chemical structure of Dalcetrapib highlighting the 10 torsional degrees of freedom.
Figure 2
Figure 2. Energy-density diagram generated from the crystal structure prediction of Dalcetrapib.
Energy-density diagram for the 30 computer-generated and three experimentally observed crystal structures of Dalcetrapib. Two of the experimental crystal forms are disordered and match several similar computer-generated structures. The computer-generated structures are numbered 1–30 in order of increasing lattice energy and families of similar structures are named according to their member with the lowest lattice energy. The average lattice energy was calibrated to zero.
Figure 3
Figure 3. Structural overlay of experimental and computer-generated Dalcetrapib form B.
Overlay of the experimental crystal structure of Dalcetrapib form B at 100 K (red) with the computer-generated crystal structure 1 (blue).
Figure 4
Figure 4. Relative lattice energies as a function of pressure.
Relative lattice energies as a function of pressure for computer-generated structure 1 (green dashed line), structures 2 and 3 (red dotted lines) and all other computer-generated structures (continuous grey lines) of Dalcetrapib. Lattice energy optimizations were carried out from 0.0 to 1.0 GPa in steps of 0.2 GPa. For every pressure the average lattice energy was calibrated to zero.
See this image and copyright information in PMC

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