Volume 17 Number 28 28 July 2015 Pages 51195330

CrystEngComm
www.rsc.org/crystengcomm

PAPER
Jonas Nyman and Graeme M. Day
Static and lattice vibrational energy differences between polymorphs

CrystEngComm
PAPER
Static and lattice vibrational energy differences
between polymorphs
Cite this: CrystEngComm, 2015, 17,
5154

Jonas Nyman and Graeme M. Day*

A computational study of 1061 experimentally determined crystal structures of 508 polymorphic organic
molecules has been performed with state-of-the-art lattice energy minimisation methods, using a hybrid
method that combines density functional theory intramolecular energies with an anisotropic atomatom
intermolecular model. Rigid molecule lattice dynamical calculations have also been performed to estimate
the vibrational contributions to lattice free energies. Distributions of the differences in lattice energy, free
energy, zero point energy, entropy and heat capacity between polymorphs are presented. Polymorphic
lattice energy differences are typically very small: over half of polymorph pairs are separated by less than
2 kJ mol1 and lattice energy differences exceed 7.2 kJ mol1 in only 5% of cases. Unsurprisingly, vibrational

Received 8th January 2015,

Accepted 23rd March 2015
DOI: 10.1039/c5ce00045a

contributions to polymorph free energy differences at ambient conditions are dominated by entropy
differences. The distribution of vibrational energy differences is narrower than lattice energy differences,
rarely exceeding 2 kJ mol1. However, these relatively small vibrational free energy contributions are large
enough to cause a re-ranking of polymorph stability below, or at, room temperature in 9% of the poly-

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morph pairs.

1 Introduction
Polymorphism, the possibility of a compound to exist in at
least two different crystalline phases,1 has important implications for the development of pharmaceuticals, organic semiconductors,2 explosives and any other material where solid
state properties must be controlled.3 Unexpected polymorphism can have far-reaching economic and medical,4,5 as well
as legal6 consequences. For these reasons, there is a strong
motivation to develop our fundamental understanding of
polymorphism, of property differences between polymorphs
and, ultimately, the ability to predict possible polymorphs a
priori.
The relative free energy determines which polymorph
should be favourable under given thermodynamic conditions.
However, crystallisation does not always lead to the most stable structure, with kinetic factors sometimes leading to an
alternative crystal packing. How large a lattice energy penalty
can be overcome by such kinetic factors? It is important to
understand the energy differences that can exist between
observable polymorphs. This question is particularly relevant

School of Chemistry, University of Southampton, Southampton, UK.

E-mail: [email protected]; Tel: +44 (0)2380599174
Electronic supplementary information (ESI) available: List of included
polymorphs, a description of co-prime splitting for phonon k-point sampling,
additional vibrational energy convergence results, force field parameters and
energy distributions split by hydrogen bonding. See DOI: 10.1039/c5ce00045a

5154 | CrystEngComm, 2015, 17, 51545165

in computational attempts to predict possible polymorphs of

a given molecule. The most commonly adopted approach to
predicting crystal structures involves a search for the lowest
energy crystal packing possibilities, followed by an assessment of which low energy computer-generated structures
might be observed.7,8 Such methods usually lead to many
possible structures and it is necessary to focus one's attention on those potential polymorphs that lie in a limited
energy range from the lowest energy possibility.
Polymorph energy differences are often said to be less
than 10 kJ mol1.3 A rule of thumb can be based on experimental determinations of polymorph relative energies, for
example from sublimation enthalpies,9 melting data,10 differential scanning calorimetry,11 relative solubilities12 or solution microcalorimetry.13 However, experimental collection of
a large quantity of high quality polymorph energy differences
is challenging. An alternative approach to understanding
polymorph energy differences is through computational
modelling.
In computational studies of molecular crystals, the free
energy is commonly approximated with the static lattice
energy, calculated either with force field or electronic structure methods, such as dispersion-corrected periodic DFT14,15
or fragment-based approaches.16 While high quality lattice
energies can be achieved, this ignores the energetic contributions related to the vibration of molecules about their equilibrium positions. Omitting the vibrational contribution to the
free energy is convenient, since it simplifies the calculation,

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and tempting from the computational cost point of view.

This is sometimes justified by a claim that the difference in
vibrational energy between polymorphs is so small that it
never causes a re-ranking of the relative stability. This was
one of the conclusions of Gavezzotti and Filippini's landmark
1995 study of polymorph energy differences.17 The conclusion stands in sharp contradiction to the many experimentally known temperature-dependent polymorphic transitions
and other computational studies that have demonstrated the
importance of vibrational zero-point energy and entropy differences between crystal structures.18 There is a need to
readdress the issue using up-to-date computational methods.
In this study, we present lattice energy and lattice dynamical studies of thermodynamic properties of a set of 1061
experimentally determined crystal structures of 508 polymorphic organic molecules, using state-of-the-art methods for lattice energy evaluation. This is the largest study to date of
energetic differences between polymorphs.

2 Methods
2.1 Selection of polymorph pairs
Crystal structures were obtained from the Cambridge Structural Database (CSD), version 5.35 (Nov. 2013). Reference
code families of polymorphs in van de Streek's best hydrogens list19,20 containing only H/D, C, N, O, F, S, and Cl were
selected, the elements for which the most reliable atomatom
potentials exist. Multicomponent structures and radicals were
removed.
As our lattice dynamical treatment currently only includes
rigid molecule motions, we assume that differences in intramolecular vibrations between polymorphs are negligible. This
approximation may lead to errors when there are significant
molecular geometry differences between polymorphs, such as
in conformational polymorphism. Therefore, we used the
root-mean-square deviation (RMSD) of atomic coordinates for
molecules in different polymorphs (calculated using TORMAT,21
excluding hydrogen atom positions) to exclude structures
with large intramolecular differences. Cruz-Cabeza and Bernstein22 showed that polymorphs tend to have very similar
molecular conformations, and that an RMSD of atomic coordinates of up to 0.2250.3 usually corresponds to slight
adjustments of the same molecular conformer. We observe
essentially the same distribution as Cruz-Cabeza and Bernstein22 (see Fig. S12 in ESI) and set our limit to 0.25 , to
exclude structure pairs where molecular geometry differences
exceeded this value.
The symmetries of structures with non-integer Z were
modified to include whole molecules in the asymmetric unit.
Structures with more than 65 atoms in the asymmetric unit
were excluded to limit the computational cost of the flexible
molecule energy minimisation. Missing hydrogen atoms were
added based on conventional geometric criteria whenever
this could be done unambiguously and deuterium atoms
were substituted by hydrogen in deuterated structures. Structures with disorder or incorrectly placed hydrogen atoms

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were excluded. A small number of structures had to be

excluded because of limitations in the energy-minimisation
method applied here, as described below.
Lattice dynamics calculations require that the Hessian is
positive definite, i.e. that the crystal structure is a true potential energy minimum. For a few structures, this was not the
case and the crystal is thus unstable with respect to symmetry breaking. For these structures, we removed all crystallographic symmetry and performed the lattice dynamics calculations on the P1 unit cell. If the structure was still unstable,
it was discarded.
The final structure set (see list in ESI) consisted of 1061
crystal structures in 508 polymorphic clusters forming 466
polymorph pairs, 39 triplets and 3 quadruplets, yielding 601
pairwise comparisons of polymorph energies. The structures
were analysed for the presence of hydrogen bonds with the
program PLATON.23 654 crystal structures in 310 clusters are
found to contain hydrogen bonds and 507 structures in 198
clusters do not form hydrogen bonds. Structures are referred
to by their CSD reference codes throughout. Our set of structures is three times larger than that used in the largest previous study17 of polymorph energetics that we are aware of.
2.2 Lattice energy minimisation
Lattice energies were calculated from a hybrid model, combining a DFT model for the intramolecular energy with an
atomatom model of intermolecular interactions:
atomatom
.
Elatt = EDFT
intra + E inter

(1)

Intramolecular energies and molecular geometries were

calculated at the B3LYP/6-311Gd,p) level of theory.
The intermolecular interaction energy between molecules
M and N was modelled with an anisotropic model potential
of the form:
intermolecular
EMN
= A exp( B rik ) C rik6 Eikelec
i,k

(2)

where i, k are atoms of type and belonging to molecules M

and N, respectively, separated by the distance rik. The first two
terms model the repulsive and attractive non-electrostatic
intermolecular interactions, with parameters A , B and C
determined through empirical parameterisation. The final
term, describing electrostatic interactions, was calculated from
atom-centered multipoles up to rank 4 (hexadecapole) on all
atoms,24,25 obtained from a distributed multipole analysis26 of
the B3LYP/6-311Gd,p) charge density using GDMA.27 This electrostatic model accurately models the effects of non-spherical
features of electron densities, such as lone pairs and -electron
density, and the resulting directionality of intermolecular interactions such as hydrogen bonding and arenearene interactions. Chargecharge, chargedipole and dipoledipole interactions were calculated using Ewald summation, while repulsion
dispersion interactions and all higher multipolemultipole
interactions were calculated to a cutoff distance of 15 .

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A recently revised28,29 version of the Williams99 exp-6

potential30 was used. The re-parametrisation was performed
to optimise the performance of the potential for use with
atomic multipole electrostatics. Parameters for sulfur were
taken from Abraha and Williams,31 using conventional combining rules for SX interactions. All halogen atoms were
treated as having an anisotropic repulsion, as described previously.25,32 The revised Williams99 parameters, and those
for F and Cl are provided in the supplementary information.
The Williams99 potential requires a foreshortening of all
XH bonds by 0.1 .
All crystal structures were lattice energy-minimised
through the CRYSTALOPTIMIZER program,33,34 which minimises the sum of the intra- and intermolecular energies with
respect to selected intramolecular degrees of freedom, as well
as crystal packing degrees of freedom (molecular orientation,
rotation and unit cell parameters). CRYSTALOPTIMIZER
performs flexible-molecule crystal structure optimisation by
iteratively computing the molecular geometry and energy at the
DFT level of theory with GAUSSIAN 09 (ref. 35) under
the constraints of the crystal packing forces calculated from
the intermolecular potential, using the crystal structure
modelling program DMACRYS25 for intermolecular energy
calculations.
This lattice energy minimisation method includes the
strain on the molecules resulting from the crystal packing
forces on a set of intramolecular degrees of freedom, usually
chosen as flexible torsions and bond angles. These degrees of
freedom are optimised in response to intermolecular interactions. The computational cost increases with the number of
flexible degrees of freedom. To process the large number of
crystal structures, we implemented an algorithm in Python to
automatically select the flexible degrees of freedom that we
considered most important for accurately modelling the
impact of crystal packing on molecular geometry:
All covalent bond lengths are optimised without considering packing forces.;
To accurately model hydrogen bond geometries, bond
angles and dihedrals containing a polar hydrogen atom
(OH, NH, SH) are considered flexible and optimised
under the influence of packing forces.;
All exocyclic bonds are considered rotatable. Dihedral
angles around these bonds are optimised under the influence
of crystal packing forces.;
All dihedrals and angles in rings of 3-coordinated carbon atoms (e.g. phenyl rings) are treated as unaffected by
packing forces.;
All dihedrals and angles, except those with polar H, in
five- or six-membered heterorings of nitrogen and 3-coordinated carbons are optimised without considering packing
forces.;
Any remaining dihedrals (e.g. in heterorings with S or O)
are optimised subject to packing forces.
Since GAUSSIAN requires bond angles to be between 0 and
180 and to prevent angles containing an sp1-hybridized carbon (i.e. CC and CN triple bonds) from exceeding 180, such

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angles were constrained to 179.99. These rules are adequate

for practically all molecules, but fail for GLYCIN, XELLEF
and BEWYUY. Glycine (GLYCIN) crystallizes in zwitterionic
form. During energy minimisation with our method, one proton moves from the amino group to the carboxyl group.
BEWYUY and XELLEF contain triple bonds that are sensitive
to packing forces, so our constraint on near-linear angles is
inappropriate. In this study we have ignored the PV contribution to the (Gibbs) free energy, resulting in errors for highpressure polymorphs with significant differences in density.
Two polymorph pairs (FIGYID, ACRLAC) were identified
where the PV-term is not negligible. These five polymorph
families have therefore been excluded from the current
study.
2.3 Free energy calculations
All vibrational contributions to crystal free energies are calculated from harmonic phonon frequencies calculated at the
optimised crystal structure geometries. Lattice dynamics theory36,37 and its adaptation to the dynamics of rigid molecular
crystals3840 has been described in detail elsewhere. Rigid
molecule lattice dynamics are implemented in the DMACRYS
software for computating phonons using anisotropic atom
atom potentials.41,42
Harmonic phonons can be considered as non-interacting
quantum harmonic oscillators with angular frequencies i.
The resulting partition function is

Z vib

i , k
exp

2kBT ,
=
i , k
i,k
1 exp

kBT

(3)

where kB is Boltzmann's constant and is the reduced Planck

constant. The product is over all vibrational modes, i, and all
points in reciprocal space, k. A crystal with Z rigid molecules
in the unit cell has 6Z vibrational modes at each k-point. Our
sampling of reciprocal space is described below.
The vibrational contribution to the free energy Fvib is then
Fvib(T) = kBT ln Zvib,

(4)

which can be calculated directly from the phonon spectrum

as
Fvib (T ) =

i , k
1
ln 1 exp
i , k kBT

2 i,k
i,k
kBT

(5)

The first term is the vibrational zero point energy, ZPE, while
the second term is the thermal contribution to the free
energy. The Helmholtz free energy A is obtained as
A(T) = Elatt + Fvib(T),

(6)

and the entropy S is obtained from the derivative of the free

energy with respect to temperature:

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i , k
S (T ) = kB ln 1 exp

i,k
kBT

Paper

i , k
exp

1
kBT
i , k

T i,k
i , k
1 exp

kBT

(7)

The heat capacity is calculated as:


exp i , k
2
i , k
kBT
Cv (T ) = kB

2
i , k k BT
i , k
exp
1
kBT

(8)

The accuracy of calculated vibrational energy contributions depends on how well the calculations reproduce the
true vibrational frequencies, and on the sampling of reciprocal space used in calculating the partition function (eqn (3)).
Phonon calculations using the form of anisotropic atom
atom potentials employed here have previously been shown
to reproduce observed frequencies from terahertz spectroscopy with good accuracy,43,44 so that errors due to inaccuracies of the model potential should be small. The lattice
dynamics implementation in DMACRYS only provides phonons calculated at the Brillouin zone centre (k = 0). Non-zero
k-vectors were sampled by generating supercells of the original unit cell; the vibrational modes of a (N, M, P) supercell
include N M P distinct k-points of the original cell. To
ensure that our calculated energies are converged with
respect to sampling of k-points, it is important to sample as
widely as possible between k = 0 and the edge of the first
Brillouin zone. However, to obtain k-points close to 0 using
the supercell method can require very large supercells and
prohibitively long computational times. To keep computational costs manageable, we sampled k-points using combinations of linear supercells, each expanded along a single
lattice vector. Phonon frequencies from a series of supercells
are then combined. For cubic, tetragonal and orthorhombic
unit cells, the linear supercell expansion leads to k-point
sampling along the reciprocal unit cell axes a*, b*, c*. In
lower symmetry crystal systems, the sampling is not necessarily along the reciprocal lattice vectors, but should adequately
sample the dependence of phonon frequency on orientation
in reciprocal space.
In testing the convergence of calculated thermodynamic
properties with respect to k-point sampling, we set target
k-point distances along each reciprocal space direction
(length in reciprocal space per k-point). A particular target
length defined a number of k-points in that direction and,
thus, the length of the supercell. Elongated supercells were
split into several smaller supercells that sample approximately the same number of unique k-points (see ESI for a
description), providing a nearly equivalent k-point sampling
at a reduced computational cost. The individual supercells in
each direction are chosen to have mutually co-prime supercell

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expansion coefficients, ensuring that each supercell samples a

unique set of k-points (apart from k = 0, whose duplicates were
removed prior to computing thermodynamic properties).
Ambient conditions are most relevant for understanding
the energetic aspects of polymorphism, so all thermodynamic
properties reported here are calculated at T = 300 K. So as
not to exclude weakly bound crystal structures, we did not
attempt to excude structures with melting points below
300 K.

3 Results and discussion

3.1 Free energy convergence with phonon sampling
The convergence of Helmholtz energy, entropy, zero point
energy and heat capacity with respect to k-point sampling
was studied to decide on a sampling density that gives sufficiently small errors in calculated thermodynamic quantities,
while maintaning the computational efficiency required to
evaluate properties of all 1061 crystal structures. In his investigation of vibrational energy contributions in crystal structure prediction, van Eijck18 found that 50 randomly chosen
k-points provided converged thermodynamic properties.
However, the number of k-points necessary for convergence
is not the same for different crystal structures, but depends
on the size and contents of the unit cell. Therefore, instead
of targetting a set number of k-points, we studied convergence with respect to the distance (in reciprocal space)
between sampled k-points. We believe that this provides a
uniform treatment of crystal structures.
Convergence of thermodynamic properties was investigated for a set of four polymorph pairs of theophylline (CSD
refcode family BAPLOT), two polymorph pairs of maleic
hydrazide (MALEHY) and the pair of 3,4-cyclobutylfuran
(XULDUD) polymorphs (Fig. 1), chosen to represent crystal
structures with varying types and strengths of intermolecular
interactions. The structures for theophylline polymorphs VI
and VII were taken from Eddleston et al.45 and Eddleston
et al.46 The crystal structures were geometry optimised, as
described above, before the lattice dynamics calculation were
performed for a series of k-point sampling densities.

Fig. 1 Chemical diagrams of selected molecules: a) theophylline (CSD

refcode: BAPLOT); b) maleic hydrazide (MALEHY); c) 3,4-cyclobutylfuran
(XULDUD); d) meso-1,2-diacetoxy-1,2-bis9-anthryl)ethane (JARXUV); e)
3,5-diphenyl-4-amino-1,2,4-triazole (UKANOJ); f) dimethyl-4,4-1,3,4oxadiazole-2,5-diyl)diphenylenedicarboxylate (BEBMAX) and g) 2-amino5-nitropyrimidine (PUPBAD).

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Fig. 2 shows the convergence of the difference in heat

capacity and entropy for the 7 polymorph pairs. The error is
measured relative to the best estimate of S and Cv calculated at a very dense k-point sampling of 0.08 1.
At the largest k-point distance, only k = 0 is sampled,
clearly giving unacceptable results and errors in relative
entropies exceeding 10 J mol1 K1 (corresponding to errors
of 23 kJ mol1 in A). We find that it is necessary to sample
several, but not very many, k-vectors to achieve sufficiently
converged thermodynamic properties. Heat capacity differences converge relatively easily (Fig. 2a), while entropy differences converge more slowly (Fig. 2b).
Based on these, and additional convergence tests
described elsewhere,47 we have chosen a target k-point distance of 0.12 1 for the polymorph pair calculations, corresponding to 15 k-vectors on average per structure, though

with a large variance. With this sampling, we estimate that

the errors caused by the finite k-point sampling should usually be less than 1 J mol1 K1 in S and 1 kJ mol1 for the difference in total vibrational energy between polymorphs.

Fig. 2 Convergence of a) relative heat capacities and b) relative

entropies with respect to the k-point sampling for a set of polymorphs
of theophylline (indicated by Roman numerals), maleic hydrazide and
3,4-cyclobutylfuran. The x-axis indicates the target k-point sampling
distance (smaller values indicating a denser sampling). Errors in relative
values are calculated relative to the densest k-point sampling (0.08 1).

Fig. 3 Distributions of the absolute value of calculated differences in

a) lattice energies, b) vibrational energies and c) Helmholtz free
energies between polymorphs. Vibrational energies and free energies
are calculated at a temperature of 300 K. One data point (the
polymorph pair UKANOJ/01), at Elatt = 18.5 kJ mol1 and A = 18.2 kJ
mol1 is off the scale of plots (a) and (c).

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3.2 Overall energetic contributions

We first inspect the distribution of lattice energy differences
between polymorphs (Fig. 3a). These are the total differences
in the sum of intermolecular and intramolecular energies,
calculated for the static, lattice energy minimised structures.
Our results confirm the validity of the rule-of-thumb that

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polymorph lattice energy differences are less than 10 kJ mol1

(ref. 3); only 1.5% of polymorph pairs included in this study
exceed 10 kJ mol1 in relative lattice energy. Indeed, most lattice energy differences are much smaller: over half (52.7%) of
polymorph pairs are separated by less than 2 kJ mol1 and
95% by less than 7.2 kJ mol1. Measured in percent, the lattice energy difference is less than 8% in all but a few cases
(see Fig. S1 in ESI).
Lattice energy differences are generally dominated by differences in intermolecular interactions, with 68.5% of polymorph pairs differing in intramolecular energy by less than 1
kJ mol1 (see Fig. S12 in the ESI). This is, in part, due to our
selection of polymorphs with small intramolecular geometry
differences. The range in intramolecular energies that we
find is in broad agreement with our recent study of conformational energies in molecular crystals.48 In rare cases, intramolecular energy differences reach 1520 kJ mol1, where a
high energy conformation is found in one polymorph. The
largest intramolecular energy differences that we find are
associated with changes in hydrogen atom positions that lead
to a switch between inter- and intramolecular hydrogen
bonding. This type of conformational polymorphism is a particularly difficult challenge for computational methods.49 In
all cases of large intramolecular energy differences, the intramolecular penalty is compensated by improved intermolecular interactions in the polymorph containing the
higher energy molecular conformation.
Differences in the total vibrational contribution to free
energy at 300 K are generally smaller in magnitude (Fig. 3b).
|Fvib| is calculated to be less than 1 kJ mol1 in more than
70% of polymorph pairs and is greater than 2 kJ mol1 in
fewer than 6% of cases. Due to the small magnitude of Fvib
between polymorphs, and recalling that A = Elatt + Fvib,
the overall distribution of free energy differences (Fig. 3c)
closely resembles the distribution of lattice energy differences: 56.6% of pairs are separated by less than 2 kJ mol1 in
calculated free energy, 95% are below 6.4 kJ mol1 and the
free energy difference of only 0.5% of polymorph pairs
exceeds 10 kJ mol1.
Despite the small contributions of Fvib to polymorph free
energy differences, these results should not be interpreted as
demonstrating the unimportance of lattice vibrational contributions to polymorph relative stabilities. Fig. 4 shows the lattice energy difference and Fvib data together for all polymorph pairs, and demonstrates that there is only a weak
correlation between the two quantities.
As a consequence, there are cases where Fvib reinforces the
static lattice energy difference (the shaded red region in
Fig. 4), as well as cases where Fvib and Elatt have opposite
sign (the yellow and green shaded regions in Fig. 4). The latter case, where Fvib counteracts Elatt, is more common:
dynamical energy contributions (Fvib) reduce the energy difference between polymorphs in 69% of pairs included in this
study. The free energy curves of these pairs will cross at some
temperature, leading to an enantiotropic phase transition if
the crossing temperature falls below their melting point. The

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Fig. 4 Differences in lattice energy, Elatt, and total vibrational

contributions to the free energy, Fvib, between polymorphs. The order
of polymorphs is defined so that Elatt is positive in all cases. Fvib is
calculated at T = 300 K. The shading indicates areas where Elatt and
Fvib are the same sign (red), Elatt and Fvib are of opposite sign
(yellow and green) and where Fvib causes a re-ordering of polymorph
stability at 300 K (green). Green and red data points denote structures
with and without hydrogen bonds, respectively.

shaded green area in Fig. 4 highlights those polymorph pairs

where Fvib is greater than, and of opposite sign, to Elatt at
300 K, leading to a change in order of stability of the polymorph pair; this is the case for 9% of polymorph pairs.
3.3 Contributions to Fvib
The total vibrational contribution to the free energy difference between polymorphs is a sum of the zero point energy,
thermal contribution to the internal energy and entropic
contribution:
Fvib = ZPE +

RT
0Cv(T)dT TS.

(9)

Vibrational zero point energy is a minor contribution to

the relative stability of polymorphs (Fig. 5a). ZPE is less
than 0.33 kJ mol1 in 95% of polymorph pairs and the largest
calculated difference is just over 0.7 kJ mol1.
Molar heat capacities do not vary greatly from their
expected equipartition value. Since our lattice dynamical
treatment excludes intramolecular vibrations, each molecule
has six vibrational degree of freedom (3 translational and 3
rotational) and the calculated Cv 6R (Fig. 6). This is the
expected result at room temperature, since the entire phonon
density of states for almost all crystal structures falls below
kBT (208.5 cm1 at 300 K), so that there is significant thermal
population of energy levels for all vibrational modes. As a
consequence, heat capacity differences between polymorphs
are very small (Fig. 5b): in 95% of polymorph pairs, Cv differs
by less than 0.46 J mol1 K1.
Entropy differences are, at room temperature, an order of
magnitude larger than the thermal contribution to internal
energy (Fig. 5c) and entropy is by far the most important

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Fig. 6 Distribution of heat capacities calculated at 300 K for all 1061

crystal structures. Only intermolecular vibrational mode contributions
are included.

Fig. 5 Distributions of the differences in vibrational a) zero point

energy, b) heat capacity and c) entropy between polymorphs. Heat
capacities and entropies are calculated at 300 K. One data point (the
polymorph pair BEBMAX/01), at S = 20.0 J mol1 K1 is off the scale of
plot (c). This value is discussed in the text.

Two caveats to these results are that i) vibrational energy

contributions have been calculated in the rigid molecule
approximation, and ii) non-vibrational contributions to the
entropy have not been included. While molecular flexibility
and intramolecular energy differences are fully accounted for
during geometry optimisation and in our lattice energy calculations, the rigid molecule lattice dynamical treatment means
that intramolecular vibrational frequencies are ignored. This
approximation will affect the absolute thermodynamic quantities; for example, heat capacities (Fig. 6) will be significantly
underestimated for molecules where intramolecular vibrations are near or below kBT. However, the focus here is on differences in thermodynamic quantities between polymorphs
and we expect that intramolecular vibrational energy differences will only be important in specific cases, such as conformational polymorphism. For this reason, inclusion of intramolecular vibrations using the hybrid energy model (eqn (1))
will be a focus of future work. In terms of non-vibrational
entropy contributions, disorder is expected to be the other
main source of entropy differences between polymorphs.
Greater static or dynamic disorder in one polymorph than
another can easily lead to entropy differences that match or
exceed the vibrational entropy differences.5052 These contributions must be considered when disorder is present in one
or more polymorphs.

3.4 Physical origins of entropy differences

vibrational contribution to polymorph free energy differences. As with all of our observed distributions, entropy differences are often small: 50.7% of calculated S are below 2 J
mol1 K1, corresponding to only 0.6 kJ mol1 at 300 K. However, S is greater than 5.4 J mol1 K1 in 10% of polymorph
pairs and exceeds 6.8 J mol1 K1 in 5% of pairs, corresponding to a 2 kJ mol1 contribution to the room temperature
free energy difference. These largest entropy differences are
important when compared to the static lattice energy differences, which are less than 2 kJ mol1 in over half the polymorph pairs. Vibrational effects are most important in the
cases where large entropy differences are coupled with small
lattice energy differences.

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The thermodynamic properties described in this section are

functions of the phonon density of states, and differences in
entropy, heat capacity and zero point energy arise from variations in the distribution of lattice vibrational frequencies
between polymorphs. Calculated phonon frequencies fall in
the range between 4 and 220 cm1 a wider frequency band
than was observed by Gavezzotti and Filippini17 and the
distribution of frequencies in this range can vary significantly
between polymorphs. As an example, Fig. 7a shows the vibrational frequency distributions in theophylline forms I and II.
Form II is favoured by lattice energy and is known to be the
thermodynamically more stable of forms I and II at low temperatures.53 However, form I displays a lower frequency distribution

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Fig. 7 The phonon density of states for a) theophylline polymorphs I

and II and b) the two monoclinic polymorphs of maleic hydrazide. The
target k-point sampling is 0.12 1 in all cases. The densities of states
have been normalized to 1.

than form II. This leads to a relatively large difference in

entropy (S = 6.5 J mol1 K1) favouring form I and an
enantiotropic phase transition between these structures,
which is known to occur at high temperatures.53 By contrast,
many pairs of polymorphs have very similar distributions of
vibrational frequencies, leading to smaller differences in
entropy: for example, Fig. 7b shows the density of states of

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the two monoclinic polymorphs of maleic hydrazide, whose

vibrational entropies differ by only 0.84 J mol1 K1 (polymorph
MH3,54 MALEHY12, having the slightly higher entropy).
A pertinent question is what causes these differences in
vibrational frequencies. In the examples quoted above, the
theophylline polymorphs I and II differ in which atoms are
involved in hydrogen bonding, while maleic hydrazide forms
the same hydrogen bonding in both polymorphs. Differences
in strong intermolecular interactions undoubtedly lead to different vibrational spectra and, sometimes, differences in
thermodynamic properties. However, a detailed analysis of
interactions in 1061 crystal structures is not possible.
Instead, we ask if a coarser description of structural differences is useful.
Our results demonstrate a weak (R 2 = 0.09), but statistically significant, correlation between lattice energy and density differences between polymorphs (Fig. 8a). The denser
polymorph tends to have a lower (i.e. more stable) lattice
energy. Structures with lower density are often assumed to
vibrate with lower frequencies, due to molecules having more
free space to move, and hence might be expected to have
higher entropy. There is indeed such a trend in our findings
(Fig. 8b). As with lattice energy, the correlation is extremely
weak (R 2 = 0.06), but statistically significant. A lower density
polymorph tends to have more vibrational entropy. Both correlations represent trends across a large set of polymorph
pairs and are not predictive for individual cases. In terms of
free energy, the trends in lattice energy and vibrational
entropy compensate each other, contributing to the finding
that Fvib usually lowers polymorph energy differences. However, the scatter in Fig. 8 shows that other factors, such as
detailed structural features and specific intermolecular interactions, often dominate the bulk trend. Nevertheless, entropy
can be expected to contribute a stabilising effect for poorly
packed crystal structures, such as clathrates and inclusion
compounds.
Strong directional interactions, and hydrogen bonds in
particular, might interfere with the close-packing of crystals
and cause differences in density and entropy between polymorphs. We have therefore examined if there are any differences in the distributions of Fvib and S between polymorphs for molecules with and without hydrogen bonds
(green and red data points, respectively, in Fig. 4, 8, 9 and
additional figures in the ESI). We find no evidence for a difference in distribution of thermodynamic property differences between polymorphs based on the presence or absence of
hydrogen bonding.

3.5 Outliers and particular observations

The largest lattice and free energy difference (Elatt = 18.5, A =
18.2 kJ mol1) is between the polymorphs of 3,5-diphenyl-4amino-1,2,4-triazole (UKANOJ/01, Fig. 1e). The reason is the
dramatically different hydrogen bonding motifs in these structures. The more stable UKANOJ01 has a stable 3-dimensional
network of strong NHN hydrogen bonds, while UKANOJ

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than the other at 300 K. BEBMAX has very anisotropic unit cell
dimensions and turns out to be particularly sensitive to the
phonon k-point sampling. S is still large (9.14 J mol1 K1),
but less extreme with a finer 0.08 1 sampling.
3,4-Cyclobutylfuran (XULDUD, Fig. 1c) was a target in the
first blind test of crystal structure predictions.55 It was later
discovered that XULDUD was highly unstable and a disappearing polymorph. Our calculations show that the XULDUD
structure is located at a saddle point on the potential energy
surface and symmetry breaking results in a stable Z = 2
structure. The lowering in energy is small and the observed
structure is probably a thermal average over the symmetrybroken minima. A similar phenomenon was found for only a
handful of crystal structures.
The polymorphs of 2-amino-5-nitropyrimidine (PUPBAD/
01/02, Fig. 1g), have attracted some interest before. An
attempt to calculate their relative stability and to rationalize
their polymorphic behaviour was reported by Aakery et al.56
They concluded that the orthorhombic form III (PUPBAD)
has the lowest lattice energy, but quantification of energy differences was limited by difficulties in treating molecular flexibility with their computational methods. Thermal (DSC) studies were also inconclusive. Indeed, by lattice energy, we find
that form III (PUPBAD) is much more stable than forms I
(PUPBAD01, Elatt = 6.7 kJ mol1) and II (PUPBAD02, Elatt =
7.4 kJ mol1). However, neglecting vibrational effects in these
polymorphs is misleading. The entropy differences are exceptionally large (S = 12 J mol1 K1 and 14 J mol1 K1 respectively) so that by 330 K, all three have essentially the same
free energy. This helps explain why the three polymorphs
crystallise concomitantly.56
3.6 Implications for crystal structure prediction
Fig. 8 Differences in a) lattice energy and b) entropy vs. density
differences between polymorphs. Polymorphs in each pair are ordered
such that the density difference is positive. Green and red data points
denote structures with and without hydrogen bonding. The correlation
in both cases is statistically significant to p < 109.

forms an unfavourable structure with unusually long hydrogen bonds.

We also calculate a large difference in lattice energy Elatt =
14.5 kJ mol1 for the polymorph pair JARXUV/01 (Fig. 1d).
This is one of the largest molecules in our set, so the lattice
energies are large in magnitude. While the percentage lattice
energy difference (8%) for this pair is also one of the largest
in our set, the value is less exceptionally large. In discussing
polymorphs of molecules of different size, percentage lattice
energy differences may be more meaningful than absolute
differences. Also, for this pair, the vibrational energy stabilises
the higher energy polymorph (JARXUV01) by 1.55 kJ mol1,
so the free energy difference is less extreme than the lattice
energy difference.
For the polymorph pair BEBMAX/01 (Fig. 1f), we calculate
one polymorph (BEBMAX) to have 20 J mol1 K1 higher entropy

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The results of this study should be valuable for discussion

and analysis of polymorphism in general. An understanding
of the expected energy differences between polymorphs forms
a foundation for examinations of the influence of specific
structural features and particular interactions on polymorph
relative stabilities.
One area where an understanding of polymorph energies
is crucial is the ab initio prediction of crystal structures,
which is usually performed by ranking computer-generated
crystal structures by their calculated lattice energies.7,8,57 The
fact that lattice energy differences tend to be so small demonstrates the challenge involved in correctly ranking the energies of predicted structures. The differences in calculated
energies between observed and unobserved predicted crystal
structures are typically as small as the polymorph energy differences seen here. Furthermore, given that observed polymorphs can differ by up to 10 kJ mol1 in lattice energy, all
predicted crystal structures within this energy range from the
most stable structure can be seen as potentially observable
polymorphs. Such an energy range frequently includes large
numbers of putative crystal structures.58 In fact, our distribution of polymorph lattice energy differences closely matches
the relative lattice energies of observed crystal structures in

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crystal structure prediction studies of small organic molecules.59 The reasons why predicted polymorphs outnumber
observed polymorphs have recently been discussed by Price.60
A further observation relates to the use of lattice energy
versus free energy in predicting relative stabilities of predicted
polymorphs. Free energies should be used to assess the true
thermodynamic stabilities of structures, but are often approximated by calculated lattice energies, due in large part to the
added complexity and computational expense of free energy
calculations. However, the small magnitude of lattice energy
differences that we find between known polymorphs highlights the fact that it takes very little vibrational energy to
cause a re-ranking of polymorph stability. While a small number of studies have shown promising results from the inclusion of dynamical effects in crystal structure prediction, either
through a lattice dynamics18,6163 or molecular dynamics6466
approach, lattice energy-based predictions are still the norm.
Our results show why lattice energies have achieved good
success, particularly as the quality of lattice energy calculations has improved.14,16,67,68 The correlation between A and
Elatt is strong (R 2 = 0.85, see Fig. 9), demonstrating that lattice energy is the dominant contribution to free energy differences. However, the slope of the regression line is 0.86, not
1, reflecting our finding that Elatt and Fvib are of opposite
sign in the majority of cases; vibrational contributions in
general decrease the energy differences between polymorphs.
Furthermore, some pairs are re-ranked by the vibrational
energy, which contradicts Gavezzotti and Filippini's conclusion that free energy differences always have the same sign
as enthalpy differences.17 Differences in our conclusions may
be due to their simpler force field model, lack of intramolecular energy in their assessment of lattice energies, as well as
our different Brillouin zone sampling methods.
The green triangle in Fig. 9 marks the area where the vibrational contribution causes a discordant ranking of polymorph

Fig. 9 The correlation between Elatt and A between polymorphs.

Each polymorph pair is ordered such that the lattice energy difference
is positive. The green area highlights those structures where reranking occurs between lattice energy and free energy at 300 K. Green
and red data points denote structures with and without hydrogen
bonds, respectively.

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stability relative to lattice energy; this area covers 9% of the

polymorph pairs. This fraction is large enough to justify the
computational effort of free energy calculations, since this
rate of mis-ranking over an entire landscape of predicted crystal structures can have a significant influence on the outcomes of a prediction.

4 Conclusions
Lattice energy minimisation and rigid-molecule harmonic lattice dynamics have been applied to understand thermodynamic property differences for a large set of experimentally
determined, non-disordered, packing polymorphs of organic
molecules. Our principle results are those summarised in
Fig. 3 and 4, showing the distribution of static and vibrational energy differences between polymorphs. While our
study is restricted to single-component crystal structures of
molecules containing the elements C, N, O, H, F, Cl and S,
given the large size of the structure set (1061 crystal structures in 508 polymorph families), and quality of the energy
model, we believe that these faithfully reflect true energy differences and, thus, are of great value in discussing and
understanding polymorphism.
Unsurprisingly, the lattice energy differences between
polymorphs are typically very small and are less than 7.2 kJ
mol1 in 95% of polymorph pairs. Entropies dominate the
vibrational contribution to relative free energies and, while these
contributions to relative free energies are typically small (|Fvib|
< 2 kJ mol1 in most cases), they can be large enough to significantly affect the calculated relative stability of polymorphs.
Fvib and Elatt are of opposite sign in 69% of the polymorph pairs, so that polymorph free energies usually converge with increasing temperature and will eventually cross.
By T = 300 K, we find that vibrational contributions swap the
stability order of 9% of polymorph pairs.
Correlations of energy and entropy differences with density
are weak, and there is no evidence that polymorphs of hydrogen bonding and non-hydrogen bonding molecules show different trends in thermodynamic differences. Therefore, it is
difficult to predict relative stability or thermodynamic behaviour based on these coarse descriptions of structure.
Based on the evidence presented here, computational
studies of polymorph stability, including crystal structure prediction, should not be restricted to static lattice energy calculations. The influence of lattice vibrations is important in
judging the true stability difference between polymorphs and
a necessary consideration for the anticipation of temperaturedriven phase transitions. Since the errors introduced by
restricting lattice dynamics to a single k-point are large, the
energy methods that are developed for use in the context of
crystal structure prediction should be sufficiently efficient to
allow adequate sampling of phonons without an unacceptably large computational expense. Currently, only atomatom
potentials meet these criteria and we believe that the continued development of accurate atomatom models for such
studies is necessary.

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Acknowledgements
We thank Dr Manolis Vasileiadis for support and problem
solving our use of the CrystalOptimizer program. The
research leading to these results has received funding from
the European Research Council under the European Union's
Seventh Framework Programme (FP/2007-2013)/ERC Grant
Agreement no. 307358 ERC-stG-2012-ANGLE). The authors
acknowledge the use of the IRIDIS High Performance Computing Facility at the University of Southampton.

References
1 J. Haleblian and W. McCrone, J. Pharm. Sci., 1969, 58,
911929.
2 T. Siegrist, C. Besnard, S. Haas, M. Schiltz, P. Pattison, D.
Chernyshov, B. Batlogg and C. Kloc, 20792082, Adv. Mater.,
2007, 19.
3 J. Bernstein, Polymorphism in Molecular Crystals, Oxford
University Press, 2002.
4 S. R. Chemburkar, J. Bauer, K. Deming, H. Spiwek, K. Patel,
J. Morris, R. Henry, S. Spanton, W. Dziki, W. Porter, J. Quick,
P. Bauer, J. Donaubauer, B. A. Narayanan, M. Soldani, D. Riley
and K. McFarland, Org. Process Res. Dev., 2000, 4, 413417.
5 J. Bauer, S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter, J.
Quick, P. Bauer, J. Donaubauer, B. A. Narayanan, M. Soldani,
D. Riley and K. McFarland, Pharm. Res., 2001, 18, 859866.
6 W. Cabri, P. Ghetti, G. Pozzi and M. Alpegiani, Org. Process
Res. Dev., 2007, 11, 6472.
7 G. M. Day, Crystallogr. Rev., 2011, 17, 352.
8 S. L. Price, Chem. Soc. Rev., 2014, 43, 20982111.
9 J. S. Chickos and W. E. Acree, J. Phys. Chem. Ref. Data,
2002, 31, 537698.
10 L. Yu, J. Pharm. Sci., 1995, 84, 966974.
11 L. Yu, G. A. Stephenson, C. A. Mitchell, C. A. Bunnell, S. V.
Snorek, J. J. Bowyer, T. B. Borchardt, J. G. Stowell and S. R.
Byrn, J. Am. Chem. Soc., 2000, 122, 585591.
12 C.-H. Gu and D. J. W. Grant, J. Pharm. Sci., 2001, 90, 12771287.
13 J. K. Guillory and D. M. Erb, Pharm. Manuf., 1985, 2(9), 2833.
14 M. A. Neumann, F. J. Leusen and J. Kendrick, Angew. Chem.,
Int. Ed., 2008, 47, 24272430.
15 A. Otero-de-la-Roza and E. R. Johnson, J. Chem. Phys.,
2012, 137, 054103.
16 G. J. O. Beran and K. Nanda, J. Phys. Chem. Lett., 2010, 1,
34803487.
17 A. Gavezzotti and G. Filippini, J. Am. Chem. Soc., 1995, 117,
1229912305.
18 B. P. van Eijck, J. Comput. Chem., 2001, 22, 816826.
19 J. van de Streek and S. Motherwell, Acta Crystallogr., Sect. B:
Struct. Sci., 2005, 61, 504510.
20 J. van de Streek, Acta Crystallogr., Sect. B: Struct. Sci.,
2006, 62, 567579.
21 Z. F. Weng, W. S. Motherwell and J. M. Cole, J. Appl.
Crystallogr., 2008, 41, 955957.
22 A. J. Cruz-Cabeza and J. Bernstein, Chem. Rev., 2013, 114,
21702191.

5164 | CrystEngComm, 2015, 17, 51545165

CrystEngComm

23 A. L. Spek, J. Appl. Crystallogr., 2003, 36, 713.

24 A. J. Stone and S. L. Price, J. Phys. Chem., 1988, 92,
33253335.
25 S. L. Price, M. Leslie, G. W. A. Welch, M. Habgood, L. S.
Price, P. G. Karamertzanis and G. M. Day, Phys. Chem. Chem.
Phys., 2010, 12, 84788490.
26 A. Stone and M. Alderton, Mol. Phys., 2002, 100, 221233.
27 A. J. Stone, Distributed Multipole Analysis of Gaussian
wavefunctions, GMDA version 2.2.02.
28 H. P. Thompson, E. O. Pyzer-Knapp and G. M. Day, 2015,
Manuscript in preparation.
29 E. O. Pyzer-Knapp, Ph.D. thesis, University of Cambridge,
2014.
30 D. E. Williams, J. Comput. Chem., 2001, 22, 11541166.
31 A. Abraha and D. E. Williams, Inorg. Chem., 1999, 38,
42244228.
32 G. M. Day and S. L. Price, J. Am. Chem. Soc., 2003, 125,
1643416443.
33 A. Kazantsev, P. Karamertzanis, C. Pantelides and C.
Adjiman, CrystalOptimizer: An Efficient Algorithm for Lattice
Energy Minimization of Organic Crystals Using IsolatedMolecule Quantum Mechanical Calculations, 2010.
34 A. V. Kazantsev, P. G. Karamertzanis, C. S. Adjiman and C. C.
Pantelides, J. Chem. Theory Comput., 2011, 7, 19982016.
35 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.
Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F.
Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin,
V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N.
Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S.
Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V.
Ortiz, J. Cioslowski and D. J. Fox, Gaussian 09 Revision A.02,
2009, Gaussian Inc. Wallingford CT, 2009.
36 B. Fultz, Prog. Mater. Sci., 2010, 55, 247352.
37 M. Born and K. Huang, Dynamical theory of crystal lattices,
Clarendon Press Oxford, vol. 188, 1954.
38 S. Califano, Lattice dynamics and intermolecular forces,
Academic Press, vol. 55, 1975.
39 N. Neto, R. Righini, S. Califano and S. Walmsley, Chem.
Phys., 1978, 29, 167179.
40 S. Califano, V. Schettino and N. Neto, Lattice dynamics of
molecular crystals, Springer-Verlag Berlin, vol. 26, 1981.
41 G. M. Day, S. L. Price and M. Leslie, J. Phys. Chem. B,
2003, 107, 1091910933.
42 G. M. Day, Ph.D. thesis, University College London, 2003.
43 G. M. Day, J. A. Zeitler, W. Jones, T. Rades and P. F. Taday,
J. Phys. Chem. B, 2006, 110, 447456.

This journal is The Royal Society of Chemistry 2015

CrystEngComm

44 R. Li, J. A. Zeitler, D. Tomerini, E. P. J. Parrott, L. F. Gladden

and G. M. Day, Phys. Chem. Chem. Phys., 2010, 12,
53295340.
45 M. D. Eddleston, K. E. Hejczyk, E. G. Bithell, G. M. Day and
W. Jones, Chem. Eur. J., 2013, 19, 78747882.
46 M. D. Eddleston, K. E. Hejczyk, A. M. C. Cassidy, G. M. Day,
H. P. G. Thompson and W. Jones, Manuscript in
preparation.
47 J. Nyman, In Silico Predictions of Porous Molecular Crystals
and Clathrates, 2014, M. Phil thesis, University of
Southampton.
48 H. P. Thompson and G. M. Day, Chem. Sci., 2014, 5,
31733182.
49 P. G. Karamertzanis, G. M. Day, G. W. A. Welch, J. Kendrick,
F. J. J. Leusen, M. A. Neumann and S. L. Price, J. Phys. Chem.
B, 2008, 128, 244708.
50 B. P. van Eijck, Phys. Chem. Chem. Phys., 2002, 4, 47894794.
51 M. Habgood, R. Grau-Crespo and S. L. Price, Phys. Chem.
Chem. Phys., 2011, 13, 95909600.
52 A. J. Cruz-Cabeza, G. M. Day and W. Jones, Phys. Chem.
Chem. Phys., 2011, 13, 1280812816.
53 B. Legendre and S. L. Randzio, Int. J. Pharm., 2007, 343,
4147.
54 A. Katrusiak, Acta Crystallogr., Sect. B: Struct. Sci., 2001, 57,
697704.
55 J. P. M. Lommerse, W. D. S. Motherwell, H. L. Ammon, J. D.
Dunitz, A. Gavezzotti, D. W. M. Hofmann, F. J. J. Leusen,
W. T. M. Mooij, S. L. Price, B. Schweizer, M. U. Schmidt,
B. P. van Eijck, P. Verwer and D. E. Williams, Acta
Crystallogr., Sect. B: Struct. Sci., 2000, 56, 697714.
56 C. B. Aakery, M. Nieuwenhuyzen and S. L. Price, J. Am.
Chem. Soc., 1998, 120, 89868993.
57 D. A. Bardwell, C. S. Adjiman, Y. A. Arnautova, E.
Bartashevich, S. X. M. Boerrigter, D. E. Braun, A. J. CruzCabeza, G. M. Day, R. G. Della Valle, G. R. Desiraju, B. P. van
Eijck, J. C. Facelli, M. B. Ferraro, D. Grillo, M. Habgood,

This journal is The Royal Society of Chemistry 2015

Paper

58
59
60
61
62

63
64
65
66
67
68

D. W. M. Hofmann, F. Hofmann, K. V. J. Jose, P. G.

Karamertzanis, A. V. Kazantsev, J. Kendrick, L. N. Kuleshova,
F. J. J. Leusen, A. V. Maleev, A. J. Misquitta, S. Mohamed,
R. J. Needs, M. A. Neumann, D. Nikylov, A. M. Orendt, R.
Pal, C. C. Pantelides, C. J. Pickard, L. S. Price, S. L. Price,
H. A. Scheraga, J. van de Streek, T. S. Thakur, S. Tiwari, E.
Venuti and I. K. Zhitkov, Acta Crystallogr., Sect. B: Struct.
Sci., 2011, 67, 535551.
G. M. Day, J. Chisholm, N. Shan, W. D. S. Motherwell and
W. Jones, Cryst. Growth Des., 2004, 4, 13271340.
G. M. Day, W. D. S. Motherwell and W. Jones, Cryst. Growth
Des., 2005, 5, 10231033.
S. L. Price, Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng.
Mater., 2013, 69, 313328.
A. T. Anghel, G. M. Day and S. L. Price, CrystEngComm,
2002, 4, 348355.
G. M. Day, T. G. Cooper, A. J. Cruz-Cabeza, K. E. Hejczyk,
H. L. Ammon, S. X. M. Boerrigter, J. S. Tan, R. G. Della Valle,
E. Venuti, J. Jose, S. R. Gadre, G. R. Desiraju, T. S. Thakur,
B. P. van Eijck, J. C. Facelli, V. E. Bazterra, M. B. Ferraro,
D. W. M. Hofmann, M. A. Neumann, F. J. J. Leusen, J.
Kendrick, S. L. Price, A. J. Misquitta, P. G. Karamertzanis,
G. W. A. Welch, H. A. Scheraga, Y. A. Arnautova, M. U.
Schmidt, J. van de Streek, A. K. Wolf and B. Schweizer, Acta
Crystallogr., Sect. B: Struct. Sci., 2009, 65, 107125.
A. J. Cruz-Cabeza, G. M. Day and W. Jones, Chem. Eur. J.,
2008, 14, 88308836.
A. Gavezzotti, J. Am. Chem. Soc., 2000, 122, 1072410725.
P. Raiteri, R. Martonk and M. Parrinello, Angew. Chem., Int.
Ed., 2005, 44, 37693773.
P. G. Karamertzanis, P. Raiteri, M. Parrinello, M. Leslie and
S. L. Price, J. Phys. Chem. B, 2008, 112, 42984308.
P. J. Bygrave, N. L. Allan and F. R. Manby, J. Phys. Chem.,
2012, 137, 164102.
J. Yang, W. Hu, D. Usvyat, D. Matthews, M. Schtz and
G. K.-L. Chan, Science, 2014, 345, 640643.

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