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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

Molecular structure of Dalcetrapib.Chemical structure of Dalcetrapib highlighting the 10 torsional degrees of freedom.
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f1: Molecular structure of Dalcetrapib.Chemical structure of Dalcetrapib highlighting the 10 torsional degrees of freedom.

Mentions: Dalcetrapib19 (Fig. 1) was originally discovered by Japan Tobacco Inc., which reported in 2000 that the molecule inhibited cholesterol ester transferase protein activity. Dalcetrapib was in clinical development at Roche until 2012. It has been recently demonstrated that the drug compound has significant potential in treatment of cardiovascular diseases for a genetic subgroup20.


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)

Molecular structure of Dalcetrapib.Chemical structure of Dalcetrapib highlighting the 10 torsional degrees of freedom.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Molecular structure of Dalcetrapib.Chemical structure of Dalcetrapib highlighting the 10 torsional degrees of freedom.
Mentions: Dalcetrapib19 (Fig. 1) was originally discovered by Japan Tobacco Inc., which reported in 2000 that the molecule inhibited cholesterol ester transferase protein activity. Dalcetrapib was in clinical development at Roche until 2012. It has been recently demonstrated that the drug compound has significant potential in treatment of cardiovascular diseases for a genetic subgroup20.

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