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

Neumann MA, van de Streek J, Fabbiani FP, Hidber P, Grassmann O - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Avant-garde Materials Simulation Deutschland GmbH, Merzhauser Strasse 177, D-79100 Freiburg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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f4: 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.

Mentions: The two experimental forms A and B both belong to the structure 1 family. The ordered low-temperature form B actually matches structure 1. Figure 3 shows an overlay of the two structures that is representative for the excellent agreement between experimental low-temperature structures and computer-generated structures at the DFT-D level. The atomic coordinates of the disordered high-temperature form A are compatible with a mixture of structure 1 and structure 22; however, lattice energy calculations presented in the Supplementary Note 1 suggest that the true nature of the disorder in form A is probably much more complex. The relative stability of crystal forms is determined by their free energies, to which the lattice energies reported here are only an approximation. In addition, various flavors of DFT-D yield somewhat different energy-ranking results. When Perdew-Burke-Ernzerhof (PBE)–Neumann–Perrin is used instead of BLYP-D3 (see Supplementary Note 1), structure 1 is predicted to be less stable than structures 2 and 3, which were therefore perceived as potential candidates for the true thermodynamically stable form. Pressure-dependent lattice energy calculations (see Fig. 4) indicate that at high pressure a form belonging to the structure 2 family would be significantly more stable than the experimentally observed forms A or B, thus providing a straightforward recipe for the crystallization of a new crystal form to be verified experimentally.


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

Neumann MA, van de Streek J, Fabbiani FP, Hidber P, Grassmann O - Nat Commun (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525153&req=5

f4: 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.
Mentions: The two experimental forms A and B both belong to the structure 1 family. The ordered low-temperature form B actually matches structure 1. Figure 3 shows an overlay of the two structures that is representative for the excellent agreement between experimental low-temperature structures and computer-generated structures at the DFT-D level. The atomic coordinates of the disordered high-temperature form A are compatible with a mixture of structure 1 and structure 22; however, lattice energy calculations presented in the Supplementary Note 1 suggest that the true nature of the disorder in form A is probably much more complex. The relative stability of crystal forms is determined by their free energies, to which the lattice energies reported here are only an approximation. In addition, various flavors of DFT-D yield somewhat different energy-ranking results. When Perdew-Burke-Ernzerhof (PBE)–Neumann–Perrin is used instead of BLYP-D3 (see Supplementary Note 1), structure 1 is predicted to be less stable than structures 2 and 3, which were therefore perceived as potential candidates for the true thermodynamically stable form. Pressure-dependent lattice energy calculations (see Fig. 4) indicate that at high pressure a form belonging to the structure 2 family would be significantly more stable than the experimentally observed forms A or B, thus providing a straightforward recipe for the crystallization of a new crystal form to be verified experimentally.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Avant-garde Materials Simulation Deutschland GmbH, Merzhauser Strasse 177, D-79100 Freiburg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus