title: Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening.
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.
authors.affiliation: Avant-garde Materials Simulation Deutschland GmbH, Merzhauser Strasse 177, D-79100 Freiburg, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Neumann
authors.affiliation: Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: van de Streek
authors.affiliation: Department of Crystallography, Georg-August-Universität Göttingen, GZG, Goldschmidtstrasse 1, D-37077 Göttingen, Germany.
authors.forename: F P A
authors.initials: FP
authors.lastname: Fabbiani
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharma Technical Development, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Hidber
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Grassmann
mesh_terms: D000577:Amides; D003198:Computer Simulation; D003460:Crystallization; D004952:Esters; D008956:Models, Chemical; D011312:Pressure; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D000577:Amides; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib