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

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.

[1]  Geoff G. Z. Zhang,et al.  The curious case of (caffeine)·(benzoic acid): how heteronuclear seeding allowed the formation of an elusive cocrystal , 2013 .

[2]  Claire S. Adjiman,et al.  Towards crystal structure prediction of complex organic compounds – a report on the fifth blind test , 2011, Acta crystallographica. Section B, Structural science.

[3]  G. Day,et al.  Structure prediction, disorder and dynamics in a DMSO solvate of carbamazepine. , 2011, Physical chemistry chemical physics : PCCP.

[4]  Claude Didierjean,et al.  Crystallization of proteins under an external electric field , 1999 .

[5]  S. Price.  Why don't we find more polymorphs? , 2013, Acta crystallographica Section B, Structural science, crystal engineering and materials.

[6]  Marc-Antoine Perrin,et al.  Energy ranking of molecular crystals using density functional theory calculations and an empirical van der waals correction. , 2005, The journal of physical chemistry. B.

[7]  J. Tardif,et al.  Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib , 2015, Circulation. Cardiovascular genetics.

[8]  H. Okamoto,et al.  bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein. , 2000, Journal of medicinal chemistry.

[9]  M. Neumann.  Tailor-made force fields for crystal-structure prediction. , 2008, The journal of physical chemistry. B.

[10]  T. C. Lewis,et al.  A third blind test of crystal structure prediction. , 2005, Acta crystallographica. Section B, Structural science.

[11]  Gregory J O Beran,et al.  Practical quantum mechanics-based fragment methods for predicting molecular crystal properties. , 2012, Physical chemistry chemical physics : PCCP.

[12]  C. Pulham,et al.  High-pressure studies of pharmaceutical compounds and energetic materials. , 2006, Chemical Society reviews.

[13]  W. G. Marshall,et al.  Putting pressure on elusive polymorphs and solvates , 2009 .

[14]  H. Huppertz.  New synthetic discoveries via high-pressure solid-state chemistry. , 2011, Chemical communications.

[15]  F. Leusen,et al.  Progress in crystal structure prediction. , 2011, Chemistry.

[16]  E. Boldyreva.  High-Pressure Polymorphs of Molecular Solids: When Are They Formed, and When Are They Not? Some Examples of the Role of Kinetic Control , 2007 .

[17]  S. Grimme,et al.  A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. , 2010, The Journal of chemical physics.

[18]  Sarah L Price,et al.  Predicting crystal structures of organic compounds. , 2014, Chemical Society reviews.

[19]  P. W. Cains,et al.  Sonocrystallization: The Use of Ultrasound for Improved Industrial Crystallization , 2005 .

[20]  G. Kresse,et al.  Efficiency of ab-initio total energy calculations for metals and semiconductors using a plane-wave basis set , 1996 .

[21]  Joel Bernstein,et al.  Polymorphism in Molecular Crystals , 2002 .

[22]  Jack,et al.  Disappearing Polymorphs , 2001 .

[23]  M. Probert,et al.  Polymorphism Arising from Differing Rates of Compression of Liquids , 2014 .

[24]  J. Bauer,et al.  Ritonavir: An Extraordinary Example of Conformational Polymorphism , 2001, Pharmaceutical Research.

[25]  S. Moggach,et al.  Incorporation of a new design of backing seat and anvil in a Merrill-Bassett diamond anvil cell , 2008 .

[26]  J. Klimeš,et al.  Perspective: Advances and challenges in treating van der Waals dispersion forces in density functional theory. , 2012, The Journal of chemical physics.

[27]  Paul F. McMillan,et al.  New materials from high-pressure experiments , 2002, Nature materials.

[28]  J. McMahon,et al.  Contrasting Polymorphism of Related Small Molecule Drugs Correlated and Guided by the Computed Crystal Energy Landscape , 2014 .

[29]  A. Otero-de-la-Roza,et al.  A benchmark for non-covalent interactions in solids. , 2012, The Journal of chemical physics.

[30]  G. Day,et al.  Realizing Predicted Crystal Structures at Extreme Conditions: The Low-Temperature and High-Pressure Crystal Structures of 2-Chlorophenol and 4-Fluorophenol , 2005 .

[31]  D. Levendis,et al.  Pharmaceutical hydrates under ambient conditions from high-pressure seeds: a case study of GABA monohydrate. , 2014, Chemical communications.

[32]  Chris J. Pickard,et al.  Structure of phase III of solid hydrogen , 2007 .

[33]  Iain D. H. Oswald,et al.  Exploring the Experimental and Computed Crystal Energy Landscape of Olanzapine , 2013 .

[34]  H. Meekes,et al.  Isonicotinamide self-association: the link between solvent and polymorph nucleation. , 2012, Chemical communications.

[35]  J. McMahon,et al.  A molecular picture of the problems in ensuring structural purity of tazofelone , 2014 .

[36]  Kresse,et al.  Efficient iterative schemes for ab initio total-energy calculations using a plane-wave basis set. , 1996, Physical review. B, Condensed matter.

[37]  Yanming Ma,et al.  Perspective: crystal structure prediction at high pressures. , 2014, The Journal of chemical physics.

[38]  Hafner,et al.  Ab initio molecular dynamics for liquid metals. , 1995, Physical review. B, Condensed matter.

[39]  B. Trout,et al.  Polymorphic control by heterogeneous nucleation - A new method for selecting crystalline substrates , 2011 .

[40]  Sarah L Price,et al.  Successful prediction of a model pharmaceutical in the fifth blind test of crystal structure prediction. , 2011, International journal of pharmaceutics.

[41]  P Verwer,et al.  A test of crystal structure prediction of small organic molecules. , 2000, Acta crystallographica. Section B, Structural science.

[42]  M. Habgood.  Form II Caffeine: A Case Study for Confirming and Predicting Disorder in Organic Crystals , 2011 .

[43]  Yuriy A. Abramov,et al.  Current Computational Approaches to Support Pharmaceutical Solid Form Selection , 2013 .

[44]  A. Myerson,et al.  Polarization switching of crystal structure in the nonphotochemical light-induced nucleation of supersaturated aqueous glycine solutions. , 2002, Physical review letters.

[45]  Yanchao Wang,et al.  Crystal structure prediction via particle-swarm optimization , 2010 .

[46]  A. Cooper,et al.  Modular and predictable assembly of porous organic molecular crystals , 2011, Nature.

[47]  Sarah L Price,et al.  Crystal structure prediction of small organic molecules: a second blind test. , 2002, Acta crystallographica. Section B, Structural science.

[48]  G. Kresse,et al.  From ultrasoft pseudopotentials to the projector augmented-wave method , 1999 .

[49]  S. Price,et al.  Evaluating a Crystal Energy Landscape in the Context of Industrial Polymorph Screening , 2013 .

[50]  Tejender S. Thakur,et al.  Significant progress in predicting the crystal structures of small organic molecules--a report on the fourth blind test. , 2009, Acta crystallographica. Section B, Structural science.

[51]  Many-body dispersion interactions in molecular crystal polymorphism. , 2012, Angewandte Chemie.

[52]  Mario Valle,et al.  Transparent dense sodium , 2009, Nature.

[53]  Chris J Pickard,et al.  Ab initio random structure searching , 2011, Journal of physics. Condensed matter : an Institute of Physics journal.

[54]  Roald Hoffmann,et al.  The chemical imagination at work in very tight places. , 2007, Angewandte Chemie.

[55]  G. Day,et al.  Investigating the latent polymorphism of maleic acid. , 2006, Chemical communications.

[56]  R. Docherty,et al.  Polymorphism in Molecular Crystals: Stabilization of a Metastable Form by Conformational Mimicry , 1997 .

[57]  A. Oganov,et al.  How evolutionary crystal structure prediction works--and why. , 2011, Accounts of chemical research.

[58]  F. Leusen,et al.  A major advance in crystal structure prediction. , 2008, Angewandte Chemie.