Imidazole Hidden Polar Phase

Paliwoda, Damian; Dziubek, Kamil; Katrusiak, Andrzej

doi:10.1021/cg300852t

Cited by 44 publications

(56 citation statements)

References 31 publications

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Section: What Factors Lead To Different Polymorphs?mentioning

confidence: 99%

“…In this instance, polarity of the solvent kinetically biases the molecule in to one specific molecular packing. Other environmental factors that can influence the synthesized crystal structure include temperature [26,29,44,75], pressure [76][77][78][79][80][81], humidity [47,56,82,83], impurities [84][85][86], impeller speed, and other shear forces [27,52,75,85,87].…”

Section: Improving Materials Performance Through Crystal Polymorphismmentioning

confidence: 99%

“…Polarization is also suggested to explain the high pressure-high temperature polymorphs of multiple common compounds [78][79][80]302]. Capturing these effects with a computer model will require a Hamiltonian that incorporates at least polarization and possibly quantum effects as well.…”

Section: Conclusion and Future Outlookmentioning

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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confidence: 99%

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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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