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Sarah L. Price - One of the best experts on this subject based on the ideXlab platform.
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can computed Crystal Energy landscapes help understand pharmaceutical solids
Chemical Communications, 2016Co-Authors: Sarah L. Price, Doris E Braun, Susan M ReutzeledensAbstract:Computational Crystal structure prediction (CSP) methods can now be applied to the smaller pharmaceutical molecules currently in drug development. We review the recent uses of computed Crystal Energy landscapes for pharmaceuticals, concentrating on examples where they have been used in collaboration with industrial-style experimental solid form screening. There is a strong complementarity in aiding experiment to find and characterise practically important solid forms and understanding the nature of the solid form landscape.
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The potential of computed Crystal Energy landscapes to aid solid-form development
Drug Discovery Today, 2016Co-Authors: Sarah L. Price, Susan M. Reutzel-edensAbstract:Solid-form screening to identify all solid forms of an active pharmaceutical ingredient (API) has become increasingly important in ensuring the quality by design of pharmaceutical products and their manufacturing processes. However, despite considerable enlargement of the range of techniques that have been shown capable of producing novel solid forms, it is possible that practically important forms might not be found in the short timescales currently allowed for solid-form screening. Here, we report on the state-of-the-art use of computed Crystal Energy landscapes to complement pharmaceutical solid-form screening. We illustrate how Crystal Energy landscapes can help establish molecular-level understanding of the Crystallization behavior of APIs and enhance the ability of solid-form screening to facilitate pharmaceutical development.
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Interpreting computed Crystal Energy landscapes for pharmaceutical molecules
Acta Crystallographica Section A, 2014Co-Authors: Sarah L. PriceAbstract:Crystal Structure Prediction (CSP) algorithms aim to generate the thermodynamically feasible Crystal structures of a molecule from the chemical diagram, ranking their relative stability by a necessarily approximate estimate of the Crystal Energy. Such calculations are becoming feasible for molecules of a size and flexibility of small molecule pharmaceuticals. Contrasting the Crystal Energy landscape, the computer generated structures that are thermodynamically plausible as polymorphs, with the results of experimental polymorph screening, shows that CSP studies are not limited to being a search for the most thermodynamically stable Crystal structure but can play a valuable role in understanding polymorphism and the potential complexity of Crystallisation behaviour.[1] This presentation will illustrate the use of CSP as a complement to industrial-type solid form screening activities. Examples will include olanzapine, [2] tazofelone, two closely related 5-HT2a agonists and 6-[(5-chloro-2-([(4-chloro-2-fluorophenyl)methyl]oxy)phenyl)methyl]-2-pyridinecarboxylic acid (GSK269984B).[3] This illustrates the use of the Crystal Energy landscape to understand disorder, help structurally characterise metastable polymorphs and suggest whether there are additional polymorphs to be targeted. Since Crystal Energy landscapes usually include a wider range of Crystal structures than known polymorphs, it raises the scientific question as to what determines which structures can be observed as metastable polymorphs. Thus both scientific as well as technological challenges need to be overcome before we can predict polymorphs.
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Predicting Crystal structures of organic compounds
Chemical Society Reviews, 2013Co-Authors: Sarah L. PriceAbstract:Currently, organic Crystal structure prediction (CSP) methods are based on searching for the most thermodynamically stable Crystal structure, making various approximations in evaluating the Crystal Energy. The most stable (global minimum) structure provides a prediction of an experimental Crystal structure. However, depending on the specific molecule, there may be other structures which are very close in Energy. In this case, the other structures on the Crystal Energy landscape may be polymorphs, components of static or dynamic disorder in observed structures, or there may be no route to nucleating and growing these structures. A major reason for performing CSP studies is as a complement to solid form screening to see which alternative packings to the known polymorphs are thermodynamically feasible.
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Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate
Crystal Growth & Design, 2013Co-Authors: Doris E Braun, Alastair J. Florence, Rajni M Bhardwaj, Derek A. Tocher, Jean-baptiste Arlin, Volker Kahlenberg, Ulrich J. Griesser, Sarah L. PriceAbstract:The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at aw (water activity) = 0.15 at 25 °C. Structures have been derived from single Crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher Energy structure on a computationally generated Crystal Energy landscape, which has the anhydrate Crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)sorption, and thermo-analytical methods with the computationally generated Crystal Energy landscape and lattice Energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two mono...
Sl Price - One of the best experts on this subject based on the ideXlab platform.
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Computed Crystal Energy Landscapes for Understanding and Predicting Organic Crystal Structures and Polymorphism
ACCOUNTS CHEM RES, 2009Co-Authors: Sl PriceAbstract:The phenomenon of polymorphism, the ability of a molecule to adopt more than one Crystal structure, is a well-established property of Crystalline solids. The possible variations in physical properties between polymorphs make the reliable reproduction of a Crystalline form essential for all research using organic materials, as well as quality control in manufacture. Thus, the last two decades have seen both an increase in interest in polymorphism and the availability of the computer power needed to make the computational prediction of organic Crystal structures a practical possibility.In the past decade, researchers have made considerable improvements in the theoretical basis for calculating the sets of structures that are within the Energy range of possible polymorphism, called Crystal Energy landscapes. It is common to find that a molecule has a wide variety of ways of packing with lattice Energy within a few kilojoules per mole of the most stable structure. However, as we develop methods to search for and characterize "all" solid forms, it is also now usual for polymorphs and solvates to be found. Thus, the computed Crystal Energy landscape reflects and to an increasing extent "predicts" the emerging complexity of the solid state observed for many organic molecules. This Account will discuss the ways in which the calculation of the Crystal Energy landscape of a molecule can be used as a complementary technique to solid form screening for polymorphs.Current methods can predict the known Crystal structure, even under "blind test" conditions, but such successes are generally restricted to those structures that are the most stable over a wide range of thermodynamic conditions. The other low-Energy structures can be alternative polymorphs, which have sometimes been found in later experimental studies. Examining the computed structures reveals the various compromises between close packing, hydrogen bonding, and pi-pi stacking that can result in energetically feasible structures. Indeed, we have observed that systems with many almost equi-energetic structures that contain a common interchangeable motif correlate with a tendency to disorder and problems with control of the Crystallization product. Thus, contrasting the computed Crystal Energy landscape with the known Crystal structures of a given molecule provides a valuable complement to solid form screening, and the examination of the low-Energy structures often leads to a rationalization of the forms found.
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Can the Formation of Pharmaceutical CoCrystals Be Computationally Predicted? I. Comparison of Lattice Energies
CRYST GROWTH DES, 2009Co-Authors: Sl PriceAbstract:A coCrystal is only expected to form if it is thermodynamically more stable than the Crystals of its components. To test whether this can be predicted with a current computational methodology, we compare the lattice energies of 12 coCrystals of 4-aminobenzoic acid, 8 of succinic acid and 6 of caffeine, with the sums of the lattice energies of their components. These three molecules were chosen for their potential use in pharmaceutical coCrystals and because they had sufficient determinations of coCrystals and corresponding partner Crystal structures in the Cambridge Structural Database. The lattice energies were evaluated using anisotropic intermolecular atom-atom potentials, with the electrostatic model and the intramolecular Energy penalty for changes in specified torsion angles derived from ab initio calculations on the isolated molecules. The majority of the coCrystals are calculated to be more stable than their components, but the Energy difference is only large in a few of the cases where the partner molecule, cannot hydrogen bond to itself. More typically, the coCrystal stabilization is comparable to polymorphic Energy differences and some of the specifically identified errors in the computational modeling. The coCrystals will be more stable relative to the observed disordered structures of caffeine and the kinetically preferred polymorph of 4-aminobenzoic acid, highlighting kinetic factors that may be involved in coCrystal formation. Overall, it appears that coCrystal formation should generally be predictable by comparing the relative stability of the most stable coCrystal and its pure components found on the computed Crystal Energy landscapes, but this is often very demanding of the accuracy of the method used to calculate the Crystal Energy.
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Computational prediction of organic Crystal structures and polymorphism
INT REV PHYS CHEM, 2008Co-Authors: Sl PriceAbstract:The development of a robust manufacturing, process for solid organic materials. such as pharmaceuticals, can be complicated when the molecules Crystallize in different solid forms, including polymorphs. The diverse challenges to computational chemistry in computing the relative thermodynamic stability of different potential Crystal structures for a range of organic molecules are outlined. Once the Crystal structures which are thermodynamically feasible have been obtained, then comparison with the experimentally known polymorphs call provide interesting insights into Crystallization behaviour. Although the computational prediction of polymorphism requires modelling the kinetic factors that can influence Crystallization, the computational prediction of the Crystal Energy landscape is already a valuable complement to experimental searches for polymorphs.
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From Crystal structure prediction to polymorph prediction: interpreting the Crystal Energy landscape
PHYS CHEM CHEM PHYS, 2008Co-Authors: Sl PriceAbstract:Many organic molecules are emerging as having many Crystalline forms, including polymorphs and solvates, as more techniques are being used to generate and characterise the organic solid state. The fundamental scientific and industrial interest in controlling Crystallisation is inspiring the development of computational methods of predicting which Crystal structures are thermodynamically feasible. Sometimes, computing this Crystal Energy landscape will reveal that a molecule has one way of packing with itself that is sufficiently more favourable than any other so only this Crystal structure will be observed. More frequently, there will be many Energy minima that are energetically feasible, showing approximately equi- energetic compromises between the various intermolecular interactions allowed by the conformational flexibility. Such cases generally lead to multiple solid forms. At the moment, we usually calculate the lattice Energy landscape, an approximation to the real Crystal Energy landscape at 0 K. Despite its limitations, many studies show that this is a valuable complement to solid form screening, which helps in discovering new structures as well as rationalising the solid forms that are found in experimental searches. The range of factors that can determine which of the thermodynamically feasible Crystal structures are observed polymorphs, shows the many further challenges in developing Crystal Energy landscapes as a tool for control of the organic solid state.
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Crystallization and Crystal Energy landscape of hydrochlorothiazide
CRYST GROWTH DES, 2007Co-Authors: Sl PriceAbstract:A search for physical forms of the diuretic compound hydrochlorothiazide, utilizing automated parallel Crystallization, identified two polymorphs and seven novel organic solvates (1:1 with aniline, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, and methyl acetate and 1:2 with N,N-dimethylacetamide and N-methyl-2-pyrrolidone). The majority of Crystallizations produced the well-known polymorphic form I, with the recently reported metastable form II obtained from a subset of Crystallization conditions. An accompanying computational search found that five rigid body conformations generated ca. 60 Crystal structures, including the two polymorphs, within 12 kJ mol(-1) of the global minimum. This is a consequence of the abundant hydrogen-bonding opportunities that arise from the functional groups present in the molecule. In particular, a range of bimolecular hydrogen-bonding motifs is predicted, and these motifs are also prevalent among the solvated Crystal structures. The value of the Crystal structure predictions is, therefore, not restricted to nonsolvated forms but has been extended to provide a more complete view of the favorable motifs that underpin solvate formation, a phenomenon that remains largely unexplained at present. While this is an encouraging step along the way to understanding solvate formation, this investigation also highlights important elements of the prediction methodology that require further development.
Alastair J. Florence - One of the best experts on this subject based on the ideXlab platform.
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Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate
Crystal Growth & Design, 2013Co-Authors: Doris E Braun, Alastair J. Florence, Rajni M Bhardwaj, Derek A. Tocher, Jean-baptiste Arlin, Volker Kahlenberg, Ulrich J. Griesser, Sarah L. PriceAbstract:The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at aw (water activity) = 0.15 at 25 °C. Structures have been derived from single Crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher Energy structure on a computationally generated Crystal Energy landscape, which has the anhydrate Crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)sorption, and thermo-analytical methods with the computationally generated Crystal Energy landscape and lattice Energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two mono...
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exploring the experimental and computed Crystal Energy landscape of olanzapine
Crystal Growth & Design, 2013Co-Authors: Rajni M Bhardwaj, Sarah L. Price, Blair F. Johnston, Susan M Reutzeledens, Louise S. Price, Gary J Miller, Iain D H Oswald, Alastair J. FlorenceAbstract:An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 Crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental Crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The Crystal Energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are respo...
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complex polymorphic system of gallic acid five monohydrates three anhydrates and over 20 solvates
Crystal Growth & Design, 2013Co-Authors: Doris E Braun, Alastair J. Florence, Rajni M Bhardwaj, Derek A. Tocher, Sarah L. PriceAbstract:We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate Crystal Energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity.
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Experimental and predicted Crystal Energy landscapes of chlorothiazide
Crystal Growth & Design, 2011Co-Authors: Andrea Johnston, Sarah L. Price, Julie Bardin, Blair F. Johnston, Philippe Fernandes, Alan R. Kennedy, Alastair J. FlorenceAbstract:An experimental search for physical forms of the thiazide diuretic compound chlorothiazide comprising 402 different Crystallizations identified one nonsolvated form and ten Crystalline solvates. There are five distinct conformations in the experimental Crystal structures which are in good agreement with the conformational minima found by ab initio optimization of the isolated molecule structure. An approximate rigid-body Crystal Energy landscape using these five conformations produced a diverse range of low Energy Crystal structures, with the anhydrous structure among the most stable. Inspection of the molecular packing adopted in both the experimental and predicted structures highlighted a number of chlorothiazide···chlorothiazide motifs that result from packing the different conformers. Specifically, four bimolecular face-to-face motifs were observed in most of the predicted structures and all of the experimental structures. The role of these robust intermolecular packing motifs and of the organic solvent molecules in stabilizing the experimental solvate structures of chlorothiazide is discussed. The results highlight the value of the approximate Crystal Energy landscape for flexible organic molecules in assisting with the interpretation of solid-state diversity in chlorothiazide Crystal structures and identifying key stabilizing packing features.
Andrew I Cooper - One of the best experts on this subject based on the ideXlab platform.
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predicted Crystal Energy landscapes of porous organic cages
Chemical Science, 2014Co-Authors: Edward O Pyzerknapp, Hugh P G Thompson, Florian Schiffmann, Kim E Jelfs, Samantha Y Chong, Marc A Little, Andrew I CooperAbstract:In principle, the development of computational methods for structure and property prediction offers the potential for the in silico design of functional materials. Here, we evaluate the Crystal Energy landscapes of a series of porous organic cages, for which small changes in chemical structure lead to completely different Crystal packing arrangements and, hence, porosity. The differences in Crystal packing are not intuitively obvious from the molecular structure, and hence qualitative approaches to Crystal engineering have limited scope for designing new materials. We find that the Crystal structures and the resulting porosity of these molecular Crystals can generally be predicted in silico, such that computational screening of similar compounds should be possible. The computational predictability of organic cage Crystal packing is demonstrated by the subsequent discovery, during screening of Crystallisation conditions, of the lowest Energy predicted structure for one of the cages.
Doris E Braun - One of the best experts on this subject based on the ideXlab platform.
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Experimental and computational approaches to rationalise multicomponent supramolecular assemblies: dapsone monosolvates.
Physical Chemistry Chemical Physics, 2019Co-Authors: Doris E BraunAbstract:The monosolvate Crystal Energy landscapes of dapsone (DDS) including the solvents carbon tetrachloride, acetone, cyclohexanone, dimethyl formamide, tetrahydrofuran, methyl ethyl ketone, 1,2-dichloroethane, 1,4-dioxane, dichloromethane and chloroform were established using experimental and computational approaches. To rationalise and understand solvate formation, solvate stability and desolvation reactions a careful control of the experimental Crystallisation and storage conditions, a range of thermoanalytical methods and Crystal structure prediction were required. Six of the eight DDS monosolvates are reported and characterised for the first time. Structural similarity and diversity of the at ambient conditions unstable monosolvates were apparent from the computed Crystal Energy landscapes, which had the experimental packings as lowest Energy structures. The computed structures were used as input for Rietveld refinements and isostructurality of four of the monosolvates was confirmed. Packing comparisons of the solvate structures and molecular properties of the solvent molecules indicated that both size/shape of the solvent molecule and the possible DDS⋯solvent interactions are the important factors for DDS solvate formation. Through the combination of experiment and theory solvate stability and structural features have been rationalised.
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can computed Crystal Energy landscapes help understand pharmaceutical solids
Chemical Communications, 2016Co-Authors: Sarah L. Price, Doris E Braun, Susan M ReutzeledensAbstract:Computational Crystal structure prediction (CSP) methods can now be applied to the smaller pharmaceutical molecules currently in drug development. We review the recent uses of computed Crystal Energy landscapes for pharmaceuticals, concentrating on examples where they have been used in collaboration with industrial-style experimental solid form screening. There is a strong complementarity in aiding experiment to find and characterise practically important solid forms and understanding the nature of the solid form landscape.
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Computational and Experimental Characterization of Five Crystal Forms of Thymine: Packing Polymorphism, Polytypism/Disorder, and Stoichiometric 0.8-Hydrate
Crystal Growth & Design, 2016Co-Authors: Doris E Braun, Thomas Gelbrich, Klaus Wurst, Ulrich J. GriesserAbstract:New polymorphs of thymine emerged in an experimental search for solid forms, which was guided by the computationally generated Crystal Energy landscape. Three of the four anhydrates (AH) are homeoenergetic (A° – C), and their packing modes differ only in the location of oxygen and hydrogen atoms. AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Analysis of the Crystal Energy landscape for alternative AH C hydrogen bonded ribbon motifs identified a number of different packing modes, whose three-dimensional structures were calculated to deviate by less than 0.24 kJ mol–1 in lattice Energy. These structures provide models for stacking faults. The three anhydrates A° – C show strong similarity in their powder X-ray diffraction, thermoanalytical, and spectroscopic (IR and Raman) characteristics. The already known anhydrate AH A° was identified as the thermodynamically most stable form at ambient conditions; AH B and AH C are metastable but show high kinetic stability. Th...
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Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate
Crystal Growth & Design, 2013Co-Authors: Doris E Braun, Alastair J. Florence, Rajni M Bhardwaj, Derek A. Tocher, Jean-baptiste Arlin, Volker Kahlenberg, Ulrich J. Griesser, Sarah L. PriceAbstract:The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at aw (water activity) = 0.15 at 25 °C. Structures have been derived from single Crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher Energy structure on a computationally generated Crystal Energy landscape, which has the anhydrate Crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)sorption, and thermo-analytical methods with the computationally generated Crystal Energy landscape and lattice Energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two mono...
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complex polymorphic system of gallic acid five monohydrates three anhydrates and over 20 solvates
Crystal Growth & Design, 2013Co-Authors: Doris E Braun, Alastair J. Florence, Rajni M Bhardwaj, Derek A. Tocher, Sarah L. PriceAbstract:We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate Crystal Energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity.