Solid Phases of Cyclopentane:  Combined Experimental and Simulation Study

Torrisi, Antonio; Leech, Charlotte K.; Shankland, Kenneth; David, William I. F.; Ibberson, R. M.; Benet-Buchholz, § Jordi; Boese, Roland; Leslie, Maurice; Catlow, C. Richard A.; Price, Sarah L.

doi:10.1021/jp710017y

Cited by 40 publications

(65 citation statements)

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“…9,22 The tetragonal symmetry suggests the presence of some restriction on the rotational freedom of the molecule, as a completely free rotation would result in a cubic symmetry. 10 The identification of the plastic crystalline phase by X-ray diffraction is corroborated by the DSC analysis. Plastic crystal formation is generally accompanied by a low fusion entropy (∆S fus ) and the ratio ∆S trs /∆S fus is often, but not always, g1.…”

Section: Resultsmentioning

confidence: 83%

Dynamics of the Crystal to Plastic Crystal Transition in the Hydrogen Bonded N-Isopropylpropionamide

et al. 2010

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N-Isopropylpropionamide (NiPPA), which can self-associate via hydrogen bonds, was found to undergo a solid-solid transition as identified by DSC and X-ray diffraction. Below the melting temperature of 51 °C NIPPA adopts a plastic crystalline state with a tetragonal unit cell until it transforms into an ordered crystal with a monoclinic structure at temperatures e10 °C. Dielectric spectroscopy was used to characterize the dynamics of the system, determining the activation parameters for the plastic to crystalline phase transition. The activation enthalpy is relatively high, as expected for a system that involves hydrogen bonds. However, most of the activation energy as the plastic phase assumes a more crystalline state is due to the activation entropy, suggesting that the increased cooperativity observed in the relaxation processes is due to a steric locking of the molecules.

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Section: Resultsmentioning

confidence: 83%

Dynamics of the Crystal to Plastic Crystal Transition in the Hydrogen Bonded N-Isopropylpropionamide

et al. 2010

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Section: What Factors Lead To Different Polymorphs?mentioning

confidence: 99%

“…A common physical manifestation of the effects of entropy in the crystal landscape is the formation of disordered crystal phases which appear in nitrous oxide [143], caffeine [72], and cyclopentane [100] and many other systems. In these disordered phases, the observed crystal structure is energetically less stable than the global lattice minima but observed nevertheless because of entropic favorability.…”

Section: The Need For Ambient Temperature Structuresmentioning

confidence: 99%

“…A complicating factor in the search for commercially viable solid phases is that the stable forms of a material can change based on external factors such as temperature [18,46,[92][93][94][95][96][97][98][99][100][101][102][103], pressure [76][77][78][79][80][81] and humidity [47,82,83,200]. A complete experimental mapping of all possible solid forms for a given material would therefore require screening at every condition the material will encounter.…”

Section: Introductionmentioning

confidence: 99%

“…Structures that can be isolated at one temperature may become kinetically unstable at higher temperatures. Furthermore, the thermodynamically most stable structure can also change with the temperature [18,46,[92][93][94][95][96][97][98][99][100][101][102][103] or pressure [76][77][78][79][80][81] leading to new observable forms.The complete set of all 'observable polymorphs' for a given material therefore consists of all structures that can be produced from any crystallization method in any thermodynamic state of practical interest to the material. The challenge for experimental polymorph screening procedures is to cover a large enough range within this multidimensional space to achieve high confidence that another undiscovered form, which could compromise the performance of the product, will not be observed.…”

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Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dybeck

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AcknowledgementsI would like to acknowledge the guidance and support provided by my advisor MichaelShirts. I would also like to thank Levi Naden, Natalie Schieber, Nate Abraham and the entire Shirts group for their help and technical support during my research. I also would like to acknowledge the UVA high performance computing team for the computational resources necessary to complete this work. Finally, I would like to acknowledge the endless love and support that my friends and family provided me during this challenging Ph.D. journey.iii AbstractThe presence of multiple stable crystal structures in solid organic materials can limit their commercial viability when two or more observable polymorphs exhibit markedly different physical properties. Unintended restructuring events have hindered pharmaceutical solid form development in numerous therapeutic candidates and have led to costly market recalls.Conversely, intentional synthesis of a metastable form has led to significantly more favorable performance in numerous materials.Current computational methods for predicting polymorphic behavior evaluate candidate crystal structures based on the minimized lattice energy. However, these static lattice energybased approaches generate far more lattice energy minima than there are experimentally observed structures. Thermal motion of the crystals under working conditions has the potential to explain why many of these lattice minima are not observed experimentally. Lattice minima that are identified from a static crystal structure prediction can ultimately be unstable at experimental conditions through either temperature-mediated stability reranking, kinetic interconversion of multiple minima, or inaccuracies of the energy function in producing the real crystal ensemble.In this work, we explore the role of thermal motion in eliminating candidate crystal structures using fully atomistic molecular dynamics simulations. Enthalpically favorable structures with low entropy will become unfavorable at high temperatures through temperaturemediated stability reranking. Our simulations correctly identify the high temperature solid form as having a larger entropy than the low temperature form in twelve small molecule organic systems with known temperature-mediated transformations. The estimated entropy differences in the classical point-charge potential are significantly closer to experimental measurements than estimated enthalpy differences. This result suggests that entropy difference estimates are less sensitive to the complexity of the simulation potential than the corresponding enthalpy estimates. We additionally find that a cheaper harmonic approximation provides a sufficient estimate of entropic contributions in small rigid molecules. However, entropies with iv the harmonic approximation diverge from molecular dynamics-derived entropies in systems with multiple rotatable degrees of freedom or dynamically disordered crystalline structures.We additionally probe the sensitivity of the stability estimates to the energy function ...

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Toward Computational Polymorph Prediction

Price

2018

Polymorphism in the Pharmaceutical Industry

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Solid Phases of Cyclopentane: Combined Experimental and Simulation Study

Cited by 40 publications

References 77 publications

Dynamics of the Crystal to Plastic Crystal Transition in the Hydrogen Bonded N-Isopropylpropionamide

Dynamics of the Crystal to Plastic Crystal Transition in the Hydrogen Bonded N-Isopropylpropionamide

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Toward Computational Polymorph Prediction

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