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Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph
M A Neumann1, J van de Streek2, F P A Fabbiani3
1Avant-garde Materials Simulation Deutschland GmbH, Merzhauser Strasse 177, D-79100 Freiburg, Germany.
Nature Communications
|July 23, 2015
Summary
Computational screening and planned experiments successfully identified new crystal forms of Dalcetrapib. High pressure enabled crystallization of a stable polymorph, reducing risks in pharmaceutical development.
Area of Science:
- Crystallography
- Materials Science
- Computational Chemistry
Background:
- Organic molecules, including pharmaceuticals, often exhibit polymorphism, leading to varied physicochemical properties.
- Discovering crystal polymorphs has traditionally relied on time-consuming, empirical trial-and-error methods.
- The flexibility of pharmaceutical compounds can complicate polymorphism studies.
Purpose of the Study:
- To investigate the polymorphism of the pharmaceutical compound Dalcetrapib using a combined in silico and experimental approach.
- To identify thermodynamically more stable polymorphs of Dalcetrapib that may not be accessible through standard crystallization techniques.
- To assess the feasibility of using high pressure to induce the crystallization of novel polymorphs.
Main Methods:
- In silico polymorph screening was performed to map the lattice energy landscape of Dalcetrapib.
- Rationally planned crystallization experiments were designed based on computational predictions.
- Pressure-dependent stability calculations were conducted to predict polymorph behavior under varying pressures.
- Crystallization experiments were carried out in a high-pressure range (0.02–0.50 GPa).
Main Results:
- Experimental crystal polymorphs of Dalcetrapib were located at the lowest energy points in the calculated landscape.
- Two predicted crystal structures were identified as candidates for a missing, more stable polymorph.
- High-pressure crystallization successfully yielded one of the predicted, more stable polymorphs.
- The newly crystallized polymorph was found to be metastable at ambient pressure.
Conclusions:
- The integrated computational and experimental strategy is effective for polymorph screening of flexible molecules.
- High pressure is a viable method for accessing and crystallizing thermodynamically more stable polymorphs.
- Identifying and controlling polymorphs, especially under pressure, can mitigate risks in pharmaceutical development and manufacturing.
