Storey/Solid State Characterization of Pharmaceuticals, 2011
ABSTRACT IntroductionFactors Limiting the Reliability of Computed Energy LandscapesAre Some Cryst... more ABSTRACT IntroductionFactors Limiting the Reliability of Computed Energy LandscapesAre Some Crystal Structures Easier to Predict than Others?Illustrative Examples of Crystal Energy Landscapes for PharmaceuticalsProperty PredictionFuture ProspectsAcknowledgementsReferences
ABSTRACT Computational prediction of the crystal structures of an organic molecule requires suffi... more ABSTRACT Computational prediction of the crystal structures of an organic molecule requires sufficiently accurate models for the forces between the molecules to discriminate between the energies of alternative crystal structures. Such computational predictions are particularly valuable in understanding polymorphism, the ability of some molecules to crystallise in more than one structure. As methods of searching for the most energetically favourable crystal structures have been developed and applied to awide range of organic molecules, reflecting the potential industrial utility of this emerging field of computational chemistry, it has become clear that the force-fields will have to encapsulate many subtleties of intermolecular interactions. We review the development of model potentials for crystal structure prediction and the design of molecular materials, and their role in quantitatively understanding the interplay of thermodynamics and kinetics in crystallisation.
ABSTRACT The structures of Sn(SBut)4 and Sn(SCy)4 have been determined and adopt S4 and D2 confor... more ABSTRACT The structures of Sn(SBut)4 and Sn(SCy)4 have been determined and adopt S4 and D2 conformations respectively; the anion [(PhS)Sn3]−, as its Ph4P+ salt, has a structure approaching Cs symmetry. In all three compounds, there are large variations in the ∠S–Sn–S within the same molecule, which have been rationalised in terms of the C–S–Sn–S–C conformations. For Sn(SR)4, the ∠S–Sn–S increases as the conformations change from trans, trans to trans, gauche and gauche, gauche, as the number of eclipsed lone pairs decreases and this rationale is shown to be applicable to a variety of A(ER)4 (A = C, Si, Ge, Sn; E = O, S, Se) and related [Mo(SR)4, Ga(SR)4−] systems. AM1 calculations have been used to model the ∠S–Sn–S magnitudes and also provide insights into the decomposition mechanisms of these and related species which are relevant to chemical vapour deposition processes.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT Crystallization of 2-fluorophenylacetylene at room temperature using high pressure yield... more ABSTRACT Crystallization of 2-fluorophenylacetylene at room temperature using high pressure yields three different polymorphs. These have distinct supramolecular assemblies despite the only variation in the crystallization protocol employed being the rate of compression.
A series of tin unsymmetric dithiocarbamate complexes have been made from metathesis reaction of ... more A series of tin unsymmetric dithiocarbamate complexes have been made from metathesis reaction of [CH 3 (C 4 H 9 )NSC 2 ]Li and R n SnCl 4 − n ; [R n Sn(S 2 CN(C 4 H 9 )CH 3 ) 4 − n ] [n=3, R =Me (1), Bu (2), Ph (3); n= 2, R = Me (4), Bu (5), Ph (6); n= 1, R = Me , Bu (8), Ph ]. The complexes were characterised by microanalysis, 13 C, 1 H and 119 Sn NMR, Mö ssbauer and, in the case of 3, by X-ray diffraction, which revealed one short Sn S [2.4631(9) A , ] and one long Sn S interaction [3.084(1) A , ] indicative of a weakly chelating dithiocarbamate ligand. Atmospheric pressure chemical vapour deposition using 1 and 8 with H 2 S at 350-550°C produced SnS and Sn 2 S 3 films on glass substrates. The tin sulfides were analysed by Raman, EDAX, SEM and band gap measurements. Growth rates were of the order of 150 nm min − 1 .
Crystal structure prediction for organic molecules requires both the fast assessment of thousands... more Crystal structure prediction for organic molecules requires both the fast assessment of thousands to millions of crystal structures and the greatest possible accuracy in their relative energies. We describe a crystal lattice simulation program, DMACRYS, emphasizing the features that make it suitable for use in crystal structure prediction for pharmaceutical molecules using accurate anisotropic atom-atom model intermolecular potentials based on the theory of intermolecular forces. DMACRYS can optimize the lattice energy of a crystal, calculate the second derivative properties, and reduce the symmetry of the spacegroup to move away from a transition state. The calculated terahertz frequency k = 0 rigid-body lattice modes and elastic tensor can be used to estimate free energies. The program uses a distributed multipole electrostatic model (Q, t = 00,...,44s) for the electrostatic fields, and can use anisotropic atom-atom repulsion models, damped isotropic dispersion up to R(-10), as well as a range of empirically fitted isotropic exp-6 atom-atom models with different definitions of atomic types. A new feature is that an accurate model for the induction energy contribution to the lattice energy has been implemented that uses atomic anisotropic dipole polarizability models (alpha, t = (10,10)...(11c,11s)) to evaluate the changes in the molecular charge density induced by the electrostatic field within the crystal. It is demonstrated, using the four polymorphs of the pharmaceutical carbamazepine C(15)H(12)N(2)O, that whilst reproducing crystal structures is relatively easy, calculating the polymorphic energy differences to the accuracy of a few kJ mol(-1) required for applications is very demanding of assumptions made in the modelling. Thus DMACRYS enables the comparison of both known and hypothetical crystal structures as an aid to the development of pharmaceuticals and other speciality organic materials, and provides a tool to develop the modelling of the intermolecular forces involved in molecular recognition processes.
RSC Publishing Logo View PDF VersionView Previous ArticleView Next Article DOI:10.1039/B806763E (... more RSC Publishing Logo View PDF VersionView Previous ArticleView Next Article DOI:10.1039/B806763E (Paper) New J. Chem., 2008, 32, 1761-1775. The observed and energetically feasible crystal structures of 5-substituted uracils†. ...
Novel, volatile (fluoroalkylthiolato)tin(IV) precursors have been synthesised and (CF 3 CH 2 S) 4... more Novel, volatile (fluoroalkylthiolato)tin(IV) precursors have been synthesised and (CF 3 CH 2 S) 4 Sn used to deposit tin sulfide films under APCVD (atmospheric pressure chemical vapour deposition) conditions. H 2 S is, however, required as co-reactant. Films deposited at ...
Bulk materials (SnS, SnS 2 ) have been prepared by direct reaction of the elements,1214 solid-st... more Bulk materials (SnS, SnS 2 ) have been prepared by direct reaction of the elements,1214 solid-state metathesis reactions15 and pyrolysis of organotin precursors [(R 2 SnS) 3 or (R 3 Sn) 2 S; R = Ph, PhCH 2 ].1618 Crystalline materials have been prepared by chemical5 ...
ABSTRACT Aerosol-assisted chemical vapour deposition of SnS has been achieved on glass substrates... more ABSTRACT Aerosol-assisted chemical vapour deposition of SnS has been achieved on glass substrates from the single source precursor [Sn(SCH2CH2S)2] at 400–550°C. In the presence of H2S the precursor produces films of SnS2 at 350°C, Sn2S3 at 400°C and SnS at 500°C. The tin sulfides were analysed by Raman (SnS2 312 and 215 cm−1; Sn2S3 307, 251, 234, 183, 87, 71, 60, 52 and 36 cm−1 and SnS 288, 220, 189, 163 and 96 cm−1), EDAX, SEM and band gap measurements (SnS 1.15 eV, SnS2 2.20 eV). Growth rates were of the order of 15 nm min−1.
An extensive experimental search for solid forms of the antipsychotic compound olanzapine identif... more An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three non-solvated 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 responsible for all the observed structures being based on the dimer. Thus this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization.
A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (f... more A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (form V) to be selectively formed by templating the growth of carbamazepine from the vapour phase onto the surface of a crystal of dihydrocarbamazepine form II.
Following on from the success of the previous crystal structure prediction blind tests (CSP1999, ... more Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories – a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.
Storey/Solid State Characterization of Pharmaceuticals, 2011
ABSTRACT IntroductionFactors Limiting the Reliability of Computed Energy LandscapesAre Some Cryst... more ABSTRACT IntroductionFactors Limiting the Reliability of Computed Energy LandscapesAre Some Crystal Structures Easier to Predict than Others?Illustrative Examples of Crystal Energy Landscapes for PharmaceuticalsProperty PredictionFuture ProspectsAcknowledgementsReferences
ABSTRACT Computational prediction of the crystal structures of an organic molecule requires suffi... more ABSTRACT Computational prediction of the crystal structures of an organic molecule requires sufficiently accurate models for the forces between the molecules to discriminate between the energies of alternative crystal structures. Such computational predictions are particularly valuable in understanding polymorphism, the ability of some molecules to crystallise in more than one structure. As methods of searching for the most energetically favourable crystal structures have been developed and applied to awide range of organic molecules, reflecting the potential industrial utility of this emerging field of computational chemistry, it has become clear that the force-fields will have to encapsulate many subtleties of intermolecular interactions. We review the development of model potentials for crystal structure prediction and the design of molecular materials, and their role in quantitatively understanding the interplay of thermodynamics and kinetics in crystallisation.
ABSTRACT The structures of Sn(SBut)4 and Sn(SCy)4 have been determined and adopt S4 and D2 confor... more ABSTRACT The structures of Sn(SBut)4 and Sn(SCy)4 have been determined and adopt S4 and D2 conformations respectively; the anion [(PhS)Sn3]−, as its Ph4P+ salt, has a structure approaching Cs symmetry. In all three compounds, there are large variations in the ∠S–Sn–S within the same molecule, which have been rationalised in terms of the C–S–Sn–S–C conformations. For Sn(SR)4, the ∠S–Sn–S increases as the conformations change from trans, trans to trans, gauche and gauche, gauche, as the number of eclipsed lone pairs decreases and this rationale is shown to be applicable to a variety of A(ER)4 (A = C, Si, Ge, Sn; E = O, S, Se) and related [Mo(SR)4, Ga(SR)4−] systems. AM1 calculations have been used to model the ∠S–Sn–S magnitudes and also provide insights into the decomposition mechanisms of these and related species which are relevant to chemical vapour deposition processes.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ABSTRACT Crystallization of 2-fluorophenylacetylene at room temperature using high pressure yield... more ABSTRACT Crystallization of 2-fluorophenylacetylene at room temperature using high pressure yields three different polymorphs. These have distinct supramolecular assemblies despite the only variation in the crystallization protocol employed being the rate of compression.
A series of tin unsymmetric dithiocarbamate complexes have been made from metathesis reaction of ... more A series of tin unsymmetric dithiocarbamate complexes have been made from metathesis reaction of [CH 3 (C 4 H 9 )NSC 2 ]Li and R n SnCl 4 − n ; [R n Sn(S 2 CN(C 4 H 9 )CH 3 ) 4 − n ] [n=3, R =Me (1), Bu (2), Ph (3); n= 2, R = Me (4), Bu (5), Ph (6); n= 1, R = Me , Bu (8), Ph ]. The complexes were characterised by microanalysis, 13 C, 1 H and 119 Sn NMR, Mö ssbauer and, in the case of 3, by X-ray diffraction, which revealed one short Sn S [2.4631(9) A , ] and one long Sn S interaction [3.084(1) A , ] indicative of a weakly chelating dithiocarbamate ligand. Atmospheric pressure chemical vapour deposition using 1 and 8 with H 2 S at 350-550°C produced SnS and Sn 2 S 3 films on glass substrates. The tin sulfides were analysed by Raman, EDAX, SEM and band gap measurements. Growth rates were of the order of 150 nm min − 1 .
Crystal structure prediction for organic molecules requires both the fast assessment of thousands... more Crystal structure prediction for organic molecules requires both the fast assessment of thousands to millions of crystal structures and the greatest possible accuracy in their relative energies. We describe a crystal lattice simulation program, DMACRYS, emphasizing the features that make it suitable for use in crystal structure prediction for pharmaceutical molecules using accurate anisotropic atom-atom model intermolecular potentials based on the theory of intermolecular forces. DMACRYS can optimize the lattice energy of a crystal, calculate the second derivative properties, and reduce the symmetry of the spacegroup to move away from a transition state. The calculated terahertz frequency k = 0 rigid-body lattice modes and elastic tensor can be used to estimate free energies. The program uses a distributed multipole electrostatic model (Q, t = 00,...,44s) for the electrostatic fields, and can use anisotropic atom-atom repulsion models, damped isotropic dispersion up to R(-10), as well as a range of empirically fitted isotropic exp-6 atom-atom models with different definitions of atomic types. A new feature is that an accurate model for the induction energy contribution to the lattice energy has been implemented that uses atomic anisotropic dipole polarizability models (alpha, t = (10,10)...(11c,11s)) to evaluate the changes in the molecular charge density induced by the electrostatic field within the crystal. It is demonstrated, using the four polymorphs of the pharmaceutical carbamazepine C(15)H(12)N(2)O, that whilst reproducing crystal structures is relatively easy, calculating the polymorphic energy differences to the accuracy of a few kJ mol(-1) required for applications is very demanding of assumptions made in the modelling. Thus DMACRYS enables the comparison of both known and hypothetical crystal structures as an aid to the development of pharmaceuticals and other speciality organic materials, and provides a tool to develop the modelling of the intermolecular forces involved in molecular recognition processes.
RSC Publishing Logo View PDF VersionView Previous ArticleView Next Article DOI:10.1039/B806763E (... more RSC Publishing Logo View PDF VersionView Previous ArticleView Next Article DOI:10.1039/B806763E (Paper) New J. Chem., 2008, 32, 1761-1775. The observed and energetically feasible crystal structures of 5-substituted uracils†. ...
Novel, volatile (fluoroalkylthiolato)tin(IV) precursors have been synthesised and (CF 3 CH 2 S) 4... more Novel, volatile (fluoroalkylthiolato)tin(IV) precursors have been synthesised and (CF 3 CH 2 S) 4 Sn used to deposit tin sulfide films under APCVD (atmospheric pressure chemical vapour deposition) conditions. H 2 S is, however, required as co-reactant. Films deposited at ...
Bulk materials (SnS, SnS 2 ) have been prepared by direct reaction of the elements,1214 solid-st... more Bulk materials (SnS, SnS 2 ) have been prepared by direct reaction of the elements,1214 solid-state metathesis reactions15 and pyrolysis of organotin precursors [(R 2 SnS) 3 or (R 3 Sn) 2 S; R = Ph, PhCH 2 ].1618 Crystalline materials have been prepared by chemical5 ...
ABSTRACT Aerosol-assisted chemical vapour deposition of SnS has been achieved on glass substrates... more ABSTRACT Aerosol-assisted chemical vapour deposition of SnS has been achieved on glass substrates from the single source precursor [Sn(SCH2CH2S)2] at 400–550°C. In the presence of H2S the precursor produces films of SnS2 at 350°C, Sn2S3 at 400°C and SnS at 500°C. The tin sulfides were analysed by Raman (SnS2 312 and 215 cm−1; Sn2S3 307, 251, 234, 183, 87, 71, 60, 52 and 36 cm−1 and SnS 288, 220, 189, 163 and 96 cm−1), EDAX, SEM and band gap measurements (SnS 1.15 eV, SnS2 2.20 eV). Growth rates were of the order of 15 nm min−1.
An extensive experimental search for solid forms of the antipsychotic compound olanzapine identif... more An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three non-solvated 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 responsible for all the observed structures being based on the dimer. Thus this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization.
A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (f... more A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (form V) to be selectively formed by templating the growth of carbamazepine from the vapour phase onto the surface of a crystal of dihydrocarbamazepine form II.
Following on from the success of the previous crystal structure prediction blind tests (CSP1999, ... more Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories – a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.
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