Crystal design approaches for the synthesis of paracetamol Co-crystals

Article abstract of DOI:10.1021/cg300689m

Crystal engineering principles were used to design three new co-crystals of paracetamol. A variety of potential co-crystal formers were initially identified from a search of the Cambridge Structural Database for molecules with complementary hydrogen-bond

Full text of DOI:10.1021/cg300689m

Article
pubs.acs.org/crystal
Crystal Design Approaches for the Synthesis of Paracetamol Co-
Crystals
Vijay K. Srirambhatla,† Arno Kraft,† Stephen Watt,‡ and Anthony V. Powell*,†
†Department of Chemistry, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, U.K.
‡Solid Form Solutions Ltd, The Fleming Building, Edinburgh Technopole, Milton Bridge, Penicuik, EH26 0BE, U.K.
S
* Supporting Information
ABSTRACT: Crystal engineering principles were used to design
three new co-crystals of paracetamol. A variety of potential co-
crystal formers were initially identified from a search of the
Cambridge Structural Database for molecules with complemen-
tary hydrogen-bond forming functionalities. Subsequent screen-
ing by powder X-ray diffraction of the products of the reaction of
this library of molecules with paracetamol led to the discovery of
new binary crystalline phases of paracetamol with trans-1,4-
diaminocyclohexane (1); trans-1,4-di(4-pyridyl)ethylene (2); and 1,2-bis(4-pyridyl)ethane (3). The co-crystals were
1
characterized by IR spectroscopy, differential scanning calorimetry, and H NMR spectroscopy. Single crystal X-ray structure
analysis reveals that in all three co-crystals the co-crystal formers (CCF) are hydrogen bonded to the paracetamol molecules
through O−H···N interactions. In co-crystals (1) and (2) the CCFs are interleaved between the chains of paracetamol molecules,
while in co-crystal (3) there is an additional N−H···N hydrogen bond between the two components. A hierarchy of hydrogen
bond formation is observed in which the best donor in the system, the phenolic O−H group of paracetamol, is preferentially
hydrogen bonded to the best acceptor, the basic nitrogen atom of the co-crystal former. The geometric aspects of the hydrogen
bonds in co-crystals 1−3 are discussed in terms of their electrostatic and charge-transfer components.
the solid state is governed by the precise control of molecular
orientation and stacking sequences in the crystal structures.
This observation paved the way for the further design and
synthesis of new solids based on crystal engineering strategies.
The basic understanding of crystal engineering concepts is
based on analysis of the manner in which molecules are packed
in molecular crystals also considered as supermolecules.20 The
crystal structure of any organic compound may be considered
to be the result of a series of competing, directional, and
predictable interactions between functional groups, giving rise
to recognizable structural building units termed supramolecular
synthons.21 Identifying reliable and robust supramolecular
synthons is key for effective crystal engineering. Shattock et
al.22 have demonstrated that database mining using the
Cambridge Structural Database (CSD) provides valuable
information on the occurrence of a particular supramolecular
synthon in series of closely related structures, which may be
applied to the synthesis of a wide range of co-crystals. The total
number of reported co-crystal structures in the CSD remains
relatively low (8552 entries, ca. 3.3% of all organic entries) in
comparison to the total number of organic structures (254475
entries).23 Database mining has been shown to be an effective
approach to the search for hydrogen-bonded synthons for the
construction of organic crystal structures.24
INTRODUCTION
■
Co-crystals, or multicomponent molecular crystals,1 include
addition compounds,2 organic molecular complexes,3 and solid-
state complexes.4 The definition of a co-crystal is a subject of
debate.1,5,6 While there is no consensus over the precise
definition of what constitutes a co-crystal, a broad generality is
that that they are crystalline materials comprising at least two
different molecular components. Pharmaceutical co-crystals
represent a subset of this broad class, in which at least one of
the components is an active pharmaceutical ingredient (API). It
is well established that different forms of a given pharmaceuti-
cally active compound may have different physical properties,7
salt formation being one of the common approaches to
modifying the physical properties of a drug. However, salt
formation is feasible only when the API possesses a suitable
ionizable site. In contrast, co-crystal formation exploits the very
features that lead to a compound being an API: the presence of
functional groups. Moreover the functional groups may allow
APIs to exhibit polymorphism,8 exist as solvates,9 or form co-
crystals.10 Given the importance of APIs, it is perhaps surprising
that only in recent years have crystal engineering concepts been
applied to APIs11−15 to enhance the range of potentially usable
forms of a given drug substance.
Crystal engineering can be defined as the rational design of
functional molecular solids.16 The concept was introduced by
Pepinsky17 and applied by Schmidt18 to organic solid-state
photochemical reactions. Thomas et al.19 in reviewing the
reactivity of this category of reaction noted that the reactivity in
Received: May 20, 2012
Revised: August 30, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Paracetamol or acetaminophenol is a widely used analgesic
and antipyretic drug that is commonly used for the relief of
fever, headaches, and other minor aches and pains. It belongs to
a class of drugs known as aniline analgesics. In its crystalline
state paracetamol commonly exists in two polymorphic
forms.25 The monoclinic form I (Figure 1a,b) is considered
herringbone pattern to form puckered hydrogen-bonded sheets,
whereas in form II, they form flat hydrogen-bonded sheets.
In addition to the reported polymorphic forms, a number of
research groups have synthesized and characterized several co-
crystal/solvate forms of paracetamol. Karki et al.29 synthesized
four co-crystals of paracetamol involving theophylline, oxalic
acid, naphthalene, and phenazine as CCFs. They also
demonstrated that the co-crystal forms possess better
compression properties compared to that of form II. In
addition to these pharmaceutically acceptable co-crystals, multi-
component crystalline forms (both two-component co-crystals
and solvates) of paracetamol containing N,N-dimethylpiper-
azine, 4,4′-bipyridine, N-methylmorpholine, morpholine,
1,4,8,11-tetraazacyclotetradecane, 1,4-diazabicyclo[2.2.2]-
octane, ethanol, water, piperazine, and 1,4-dioxane as CCFs
or solvate have been reported.30 In all the reported multi-
component crystals of paracetamol the hydrogen bonds
involving the donor groups, i.e., the phenolic O−H and the
amidic N−H participate in conventional hydrogen bonds
through O−H···N/O and N−H···O/N interactions involving
acceptors from either the paracetamol molecules or CCFs.
Similarly the acceptor groups are involved in O···H−O/N type
intermolecular interactions.
If we consider form I, the strongest hydrogen bonds are
formed between the phenolic O−H donor and the amide
oxygen acceptor (d(H···O) = 1.77 Å), while those between the
N−H donor and O−H acceptor are weaker (d(H···O) = 2.00
Å). Therefore, in order to make co-crystals of paracetamol, it is
necessary to break these hydrogen bonds and introduce
interactions with the CCF that are of comparable strength. In
seeking to identify suitable co-crystal formers (CCFs) to
promote such interactions, we performed a search of the
Cambridge Structural Database (CSD) for molecules contain-
ing functional groups that form hydrogen bonds with similar
geometrical parameters. The results of this targeted search
suggested a series of molecules in which these functional groups
are present. These molecules were then screened for co-crystal
formation. This led ultimately to the synthesis of the three new
co-crystals of paracetamol with trans-1,4-diaminocyclohexane,
1,2-bis(4-pyridyl)ethane, and trans-1,4-di(4-pyridyl)ethylene
(Figure 2) reported here.
Figure 1. The packing arrangement of form I of paracetamol viewed
along (a) [010] and (b) [100] and (c) form II viewed along [001].
Solid red lines represent intermolecular hydrogen bonds. Key:
nitrogen, blue circles; oxygen, red circles; carbon, black circles;
hydrogen, small white circles.
EXPERIMENTAL SECTION
■
CSD Analysis. Identification of candidate co-crystal formers
suitable for paracetamol was achieved by carrying out an analysis of
structural information contained in the Cambridge Structural Database
to be the thermodynamically stable form. Form II which
crystallizes in the orthorhombic system (Figure 1c) is of
interest in formulations because of its superior compression
properties compared to that of form I. Although a third
polymorph (form III) has been identified,26 until recently its
crystal structure27 remained elusive. The paracetamol molecule
consists of a benzene ring substituted with hydroxyl and
acetamide groups in the para (1,4) positions. Both of the
structurally characterized forms of paracetamol exhibit a similar
pattern of hydrogen bonds involving the phenolic O−H group,
which acts an acceptor in N−H···O interactions and as a donor
in O−H···OC interactions, to generate in both forms I and
II, a two-dimensional network. Using the graph set approach to
hydrogen bonding of Bernstein et al.28 both forms I and II may
be described as having C(7) and C(9) motifs. However, the
two polymorphs of paracetamol differ in the orientation of the
molecules. In form I paracetamol molecules are arranged in a
Figure 2. Chemical structures of the active pharmaceutical ingredient
and cocrystal formers investigated in this work.
B
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Table 1. The Potential Co-Crystal Formers Used for Screening with Paracetamol
C
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Table 1. continued
(CSD). The search was performed using CSD version 5.33
(November 2011) + 2 updates. The following search criteria were
applied: only those organic structures for which three-dimensional
structural coordinates have been determined were considered; only
those crystal structures for which R ≤ 7.5% were retained in the results
of the search; structures which showed evidence of disorder or had
been shown to contain errors were excluded, as were those for
polymeric species.
All starting materials were obtained from Sigma-Aldrich and were
used as obtained. The solvent-drop grinding method31 was used to
screen for co-crystal formation. Stoichiometric amounts of para-
cetamol and potential CCF were ground together with a mortar and
pestle for ca. 5 min following addition of solvent (15 μL of solvent per
50 mg of starting materials). The grinding experiments were
performed in seven different solvents, methanol, ethanol, acetonitrile,
chloroform, acetone, tetrahydrofuran, and n-propanol, representing a
wide range of dielectric constants (4.8−37.5) and containing at least
one representative from each of the polar protic, polar aprotic, and
nonpolar solvent categories. The resulting solid material was analyzed
by powder X-ray diffraction (PXRD). A total of 168 liquid assisted
grinding experiments were conducted. The CCFs and solvent systems
investigated are presented in Table 1.
Analysis of the X-ray diffraction data of the polycrystalline materials
arising from these solvent drop-grinding experiments revealed that for
critical paracetamol/CCF ratios, reflections arising from the starting
materials are absent, indicating the presence of new phases, when
trans-1,4-diaminocyclohexane, 1,2-bis(4-pyridyl)ethane, and 1,2-di(4-
pyridyl)ethylene are used as CCFs. These molecules were
subsequently used to prepare single-crystal samples by solvent
evaporation methods, using the ratios for which reflections arising
from the starting materials were absent from PXRD data.
Crystallization experiments were conducted in various combinations
of commonly occurring organic solvents; however, only those
experiments which led to diffraction quality crystals are detailed
below. Single crystals of paracetamol/trans-1,4-diaminocyclohexane
(1) were prepared from a solution of paracetamol (302 mg, 2.00
mmol) and trans-1,4-diaminocyclohexane (114 mg, 1.00 mmol) in 3
mL of methanol. The solution was heated for 3 min before being
allowed to stand at room temperature. After 4 days colorless crystals of
(1) appeared. Pale yellow colored crystals of paracetamol:1,2-di(4-
pyridyl)ethylene (2) were obtained by evaporation, over 3 days, of
solvent from a solution containing 2 mmol (302 mg) of paracetamol
and 1 mmol of 1,2-di(4-pyridyl)ethylene (182 mg) in 5 mL of
methanol. A similar method was used for the preparation of
paracetamol/1,2-bis(4-pyridyl)ethane (3) from a 1:1 molar ratio of
paracetamol (151 mg, 1 mmol)/1,2-bis(4-pyridyl)ethane (184 mg,
1.00 mmol) in 2 mL of dimethyl sulphoxide. Crystals emerged after
allowing the solution to stand at room temperature for 5 days.
Polycrystalline materials obtained from the crystallization experi-
ments were analyzed by PXRD and compared with powder diffraction
patterns generated from the structures determined by single-crystal
methods. Diffraction data for the powders resulting from the use of
trans-1,4-diaminocyclohexane and 1,2-bis(4-pyridyl)ethane as CCFs
are consistent with a bulk phase of co-crystals (1) and (3) respectively,
irrespective of the solvent used. In the case where trans-1,4-di(4-
pyridyl)ethylene was used as a CCF the PXRD pattern matches the
simulated powder diffraction pattern generated from the single crystal
structure of (2) when the solvent of crystallization is methanol.
However, the powder diffraction data for products of crystallization
experiments in other solvents do not correspond to the simulated
pattern of (2) and show a dependence on the solvent used. This may
indicate formation of alternative solvated co-crystal phases, although
diffraction quality crystals could not be obtained.
PXRD data for the polycrystalline products of screening for CCF
formation were collected using a Bruker D8 Discover diffractometer,
operating in transmission geometry with Cu Kα radiation (λ = 1.5418
Å) and fitted with a Gobel X-ray focusing mirror and a LynxEye linear
̈
detector. Finely ground samples of each of the products of screening
were contained in a 96-well plate. Data for each sample were collected
over the angular range 4 ≤ 2θ/° ≤ 50, counting for 0.25 s at each
0.02019 increment of the detector position.
Single crystal X-ray diffraction data for the co-crystals were collected
using a Bruker Nonius X8-Apex2 CCD diffractometer operating with
graphite-monochromatized Mo Kα radiation (λ = 0.710173 Å). An
Oxford Cryosystems Cryostream was used to cool the crystals to 100
K prior to data collection. Data were processed using the
manufacturer’s standard routines.32 The crystal structures were solved
by direct methods using the program SHELXS,33 and subsequent
Fourier calculations and least-squares refinements were performed on
F using the program CRYSTALS.34 All non-hydrogen atoms were
refined with anisotropic displacement parameters. All hydrogen atoms
bonded to the carbon atoms were placed geometrically and refined
with the isotropic displacement parameter fixed at 1.5 times Ueq of the
atoms to which they are attached. Protons involved in hydrogen
bonding were located directly via inspection of difference Fourier maps
and were refined isotropically.
Infrared spectroscopic data for co-crystals 1−3 were obtained using
a Perkin-Elmer 100 ATR spectrometer. Ground crystals of co-crystals
1−3 were placed on the crystal plate of the infrared instrument and
the spectrum was recorded in diffuse reflectance geometry. Differential
scanning calorimetric data for the samples 1−3 were obtained using a
Seiko model DSC-6200 instrument. The samples were weighed into
aluminum DSC pans and crimped with a pinhole on the lid. The
samples were analyzed over the temperature range 25−280 °C, using a
heating rate of 10 °C. The data were processed using Muse
Measurement v. 5.4 (Build 263) software.
Samples for 1H NMR were dissolved in DMSO-d6 and spectra
obtained using a Bruker 300 MHz spectrometer. The 1H NMR
spectrum was recorded to confirm the API/CCF ratio in the bulk
1
1
material. H chemical shift values are reported on the δ scale . H
NMR (300 MHz, DMSO-d6) of the co-crystal (1): δ 9.64 (s, 2H), 7.32
and 6.66 (AA′XX′, 2 × 4H), 3.97 (br. s, 6H), 2.45 (m, 2H), 1.97 (s,
D
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
1
6H), 1.68 (m, 4H), 1.00 (m, 4H). H NMR (DMSO-d6) of co-crystal
(2): 9.65 (s, 2H), 9.16 (br. s, 2H), 8.60 and 7.60 (AA′XX′, 2 × 4H),
7.53 (s, 2H), 7.34 and 6.68 (AA′XX′, 2 × 4H), 4.13 (s, 1H), 3.17 (s,
1
3H), 1.97 (s, 6H). H NMR (DMSO-d6) of co-crystal (3): δ 9.66 (s,
2H), 9.15 (s, 2H), 8.44 and 7.25 (AA′XX′, 2 × 4H), 7.33 and 7.25
(AA′XX′, 2 × 4H), 2.94 (s, 8H), 1.97 (s, 6H).
RESULTS AND DISCUSSION
■
A summary of the results of the search of the CSD is presented
in Table 2. The database search was conducted to find
complementary co-crystal formers targeting the phenolic OH−
group of paracetamol. The results of the CSD search are
presented in two categories: raw and refined. The former refers
to the search results for a specified functional group(s)
including those occurrences where other functional groups
may be present, whereas the latter contains those results for
which there are no additional functional group(s) in the
immediate vicinity of those for which the search was conducted.
The CSD search reveals 8009 crystal structures containing at
least one phenolic O−H moiety of which 13% exhibit the
OH···OH supramolecular homosynthon. However, the remain-
der of the crystal structures in the search results are dominated
by supramolecular heterosynthons. The CSD analysis reveals
that of those structures containing a phenolic hydroxyl group
together with functional groups such as aromatic nitrogen
atoms and amines, 42−52% involve supramolecular hetero-
synthon formation, even in the presence of other functional
groups. In the absence of other hydrogen bond donors or
acceptors the percentages rise to 54% and 64% for aromatic
nitrogen atoms and amines respectively. The search also reveals
that for interactions of phenols with amides, in those cases
where homosynthons are observed, the CONH2···CONH2
homosynthon dominates over the OH···OH homosynthon, in
both the raw and refined data. However, heterosynthons
involving O−H/amide interactions are predominant in the
refined data. For the interactions of phenols with carboxylic
acids, OH···OC(OH) supramolecular heterosynthons exhibit
56% reliability in the presence of competing functional groups,
which increases to 67% in the absence of competing functional
groups, while the analysis of phenol−amine interactions
indicates that the OH···NH2 supramolecular heterosynthon is
more common than the OH···OH supramolecular homosyn-
thon. In summary, analysis of the CSD for structures in which
there are noncovalent interactions between phenolic and other
complementary functional groups reveals a marked preference
for supramolecular heterosynthons over supramolecular homo-
synthons. Taking into account the percentage occurrence of
supramolecular heterosynthons observed in the refined
searches, molecules containing at least one of the functional
groups of aromatic nitrogen group, amides, carbonyl groups,
carboxylic acids, and amines were selected as potential co-
crystal formers for screening studies (Table 1).
PXRD of the solids obtained from the liquid assisted
grinding method of screening revealed physical mixtures of
starting materials in most cases. In such cases the liquid phase
may merely serve as a lubricant, which would be consistent with
the lack of any dependence of the nature of the solid product
on the choice of solvent. However, the reflections arising from
the starting materials were absent when trans-1,4-diaminocy-
clohexane, 1,2-bis(4-pyridyl)ethane, and 1,2-di(4-pyridyl)-
ethylene are used as CCFs. PXRD data for the products of
solvent-drop grinding experiments using 1,2-di(4-pyridyl)-
ethylene as CCF reveal that while reflections of the starting
E
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
materials are absent regardless of the solvent used, a different
solid phase is produced with each solvent. However, it has not
been possible to obtain suitable single crystals of these new
phases to study the detailed hydrogen bonding arrangement
(see Supporting Information for experimental PXRD data).
The DSC data of the co-crystals reveal single sharp
endotherms at 157.9, 113.1, and 116.6 °C for products 1−3
respectively. These endotherms, which correspond to the
melting point of the solids, occur at significantly different
temperatures to those of paracetamol (168−172 °C) or the co-
crystal former (trans-1,4-diaminocyclohexane, 68−72 °C; trans-
1,2-di-(4-pyridyl)-ethylene, 148−152 °C; 1,2-bis(4-pyridyl)-
ethane, 110−112 °C), indicating the formation of co-crystals
and not simple physical mixtures. All three co-crystals described
here have melting temperatures reduced from that of
paracetamol, suggesting that the cohesive energy of co-crystals
1−3 is reduced from that of pure paracetamol form I.
Full crystallographic details for crystal structure determi-
nations of the co-crystals 1−3 are presented in Table 3. The
Table 3. Crystallographic Data for Co-Crystals 1−3
1
2
3
chemical
formula
C11H16N2O2
C29H32N4O5
C40H42N6O4
formula
weight
208.26
516.59
670.8
crystal system triclinic
triclinic
triclinic
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
5.0174(5)
9.0546(2)
10.6241(2)
14.3162(3)
82.97(3)
89.69(3)
73.85(3)
8.9707(4)
12.8633(6)
16.8305(2)
106.06(2)
95.27(2)
95.13(3)
8.8907(9)
12.7562(1)
106.21(4)
91.40(5)
90.15(5)
space group
V/Å3
P1
P1
P1
̅
̅
̅
546.2 (1)
1312.3 (5)
1844.8 (1)
Z
2
2
2
Nreflection
/
4141/136
4904/343
4389/469
Nparameter
ρcalc/g cm−3
1.266
1.307
1.208
radiation type Mo Kα (λ =
Mo Kα (λ =
0.710173 Å)
Mo Kα (λ =
0.710173 Å)
0.710173 Å)
T/K
100
100
293
θ range/°
range of h
range of k
range of l
Rmerge
2−40
1−27
2−27
−8 to 8
−15 to 15
−18 to 21
0.019
−9 to 11
−17 to 18
−13 to 11
0.023
−11 to 11
−16 to 16
−16 to 21
0.028
R1 (%)
3.75
4.18
5.44
Figure 3. Local coordination of the non-hydrogen atoms in the co-
crystals of paracetamol with (a) trans-1,4-diaminocyclohexane, (1);
(b) trans-1,4-di(4-pyridyl)ethylene, (2); 1,2-bis(4-pyridyl)ethane, (3).
The displacement ellipsoids are drawn at the 50% probability level and
atoms in the asymmetric unit are labeled.
WR2 (%)
4.24
4.34
5.67
goodness-of-
fit
1.072
1.117
1.102
local coordination and atom numbering scheme for each of the
three co-crystals is presented in Figure 3. Selected bond
distances and angles are presented as Supporting Information
while geometric parameters of the hydrogen bonds are reported
in Table 3, together with those for paracetamol. Co-crystal (1)
contains one molecule of paracetamol and half a molecule of
trans-1,4-diaminocyclohexane in the asymmetric unit (Figure
3a). N(2)−H(2)···O(2) hydrogen bonding interactions
between paracetamol molecules lead to the formation of
infinite chains, which may be denoted C(4), directed along
[100] (Figure 4)]. These chains are then cross-linked in the
[110] direction through O(1)−H(1)···N(1) and N(1)−
H(16)···O(1) hydrogen bonding interactions to create a two-
dimensional (2D) hydrogen bonded network (Figure 4). Along
with several weak interactions there is an additional N(1)−
H(15)···O(2) interaction between the 2D networks which
extend the structure into the third dimension.
Co-crystal (2) contains in the asymmetric unit two molecules
of paracetamol, one molecule of trans-1,2-di-(4-pyridyl)-
ethylene, and one molecule of methanol (Figure 3b). Pairs of
crystallographically distinct paracetamol molecules are linked
F
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Table 4. Geometric Parameters for the Hydrogen Bonds in
Paracetamol (PAC) and the Co-Crystals 1−3
(H···A) vdW
d
d
θ (D−
cutoff
contraction
(%)
(H···A) (D···A) H···A)
compound hydrogen bond
(Å)
(Å)
(°)
PAC
PAC
(1)
N−H···O
2.00
1.77
2.06
2.91
2.66
2.96
163.8
166.1
174.1
26
36
23
O−H···OC
N(2)−
H(2)···O(2)
(1)
(1)
(1)
(2)
(2)
(2)
(2)
(2)
(3)
(3)
(3)
(3)
O(1)−
1.81
2.26
2.32
1.85
1.93
1.85
1.99
1.76
1.75
2.02
1.77
1.98
2.68
3.15
3.16
2.78
2.83
2.71
2.90
2.72
2.71
2.99
2.75
2.96
169.9
169.9
158.0
177.9
162.9
169.8
173.8
173.8
166.6
166.4
175.8
175.5
33
17
15
33
29
33
27
35
36
26
35
28
H(1)···N(1)
N(1)−
H(16)···O(1)
N(1)−
H(15)···O(2)
O(1)−
H(1)···N(1)
N(3)−
H(2)···O(5)
O(3)−
H(3)···N(2)
Figure 4. The structure of cocrystal (1) viewed along [001]. Key: as
for Figure 1.
N(4)−
H(4)···O(2)
O(5)−
H(5)···O(4)
through N(4)−H(4)···O(2) intermolecular hydrogen bonding
interactions to form dimeric units, neighboring pairs of which
are connected through N(3)−H(2)···O(5) and O(5)−
H(5)···O(4) hydrogen bonds involving the methanol solvent
incorporated in the co-crystal. This produces paracetamol-
O(1)−
H(1)···N(4)
N(6)−
H(6)···N(3)
O(3)−
H(44)···N(2)
methanol chains directed approximately along [110]. The co-
̅
N(5)−
crystal former trans-1,2-di-(4-pyridyl)-ethylene serves to cross-
link these chains through O(1)−H(1)···N(1) and O(3)−
H(3)···N(2) hydrogen bonds (Figure 5, Table 4). The
neighboring aromatic rings of trans-1,2-di-(4-pyridyl)-ethylene
are arranged in a face to face35 stacking fashion with a slip angle
of 18.2° with a centroid to centroid distance of around 3.32 Å.
Aromatic interactions of this kind are known to generate
supramolecular synthons and have been exploited for co-crystal
synthesis.36 These paired units are then linked through several
weak interactions between the 2D networks to stabilize the co-
crystal to extend into the third dimension.
H(45)···N(1)
a
D refers to the proton donor, A refers to the proton acceptor, d are
distances in Å. The atom numbering scheme is that presented in
Figure 3.
of paracetamol are involved in hydrogen bonding. While in co-
crystals (1) and (2) it is only the phenolic −OH that is
hydrogen bonded to the CCF, here the amidic N−H is also
hydrogen bonded to the CCF. However, the carbonyl groups of
paracetamol are not involved in conventional hydrogen bonds
but participate in weak C−H···O interactions between
molecules related by an inversion center. The paracetamol
molecules are linked to two 1,2-bis(4-pyridyl)ethane molecules,
through O(1)−H(1)···N(4) and N(6)−H(6)···N(3) interac-
The asymmetric unit of the co-crystal (3) consists of four
independent molecules, two each of paracetamol and the co-
crystal former 1,2-bis(4-pyridyl)ethane (Figure 3c). Analogous
to co-crystals (1) and (2) the phenolic −OH and amidic −NH
Figure 5. The structure of cocrystal (2) viewed along [001]. Key: as for Figure 1.
G
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 6. The structure of co-crystal (3). Key: as Figure 1.
Table 5. Bond Stretching Frequencies in Paracetamol and the Three Co-Crystals, Determined by Infrared Spectroscopy
assignment
paracetamol in gas-phase42
paracetamol Form I
(1)
3326
(2)
(3)
ν(O−H)/cm−1
3653
3465
3034
1721
3160
3324
2895
1651
3070
3290
2870
1653
3195
3246
2950
1673
ν(N−H)/cm−1
3326, 3273
3049
ν(C−H)aromatic/cm−1
ν(CO)/cm−1
1636
tions in one crystallographically independent molecule and
O(3)−H(44)···N(2) and N(5)−H(45)···N(1) interactions in
the other (Table 3). This produces two crystallographically-
distinct stepped chains of molecules (Figure 6). The CH2
groups in one of the crystallographically independent 1,2-bis(4-
pyridyl)ethane molecules were found to be disordered over two
sites and were refined anisotropically with occupancies of 0.47
and 0.53. Several weak C−H···O interactions between these
one-dimensional chains extend the structure into a three-
dimensional structure.
in the co-crystals 1−3 which is in accord with the empirical
rules proposed by Etter.37
Complexes with hydrogen bonds are stabilized by electro-
static, polarization, induction, and dispersion energy terms.
From an electrostatic viewpoint, the interaction may be
considered to have contributions from interactions between
monopoles, dipoles, quadrupoles, etc., each of which has a
different characteristic cutoff in terms of distance. One
common means of assigning the character of the hydrogen
bond is the contraction, with respect to the sum of the van der
Waals’ radii, of the H···A distance. Proton-centered hydrogen
bonds typically exhibit a contraction of between 40 and 55% of
the sum of the van der Waals’ radii.38 In co-crystals 1−3 the van
der Waals’ cutoff contraction lies between 20 and 40% (Table
3), which suggests these hydrogen bonds may be classed as
being of moderate strength38 in which the electrostatic
interaction terms are dominant. It has been empirically
established that hydrogen bonds become increasingly linear
with increasing strength, as linearity optimizes the electrostatic
component (dipole−monopole, dipole−dipole) of the inter-
action. The electrostatic contribution to the intermolecular
interaction tends to dominate and imparts directionality on
hydrogen bonds. This is particularly significant in short and
proton-centered hydrogen-bonds, whose typical angular range
is 160 ≤ θ/° ≤ 180, but also applies to longer bonds of
electrostatic nature. According to Reed et al.,39 charge transfer
between donor and acceptor groups has a strong influence on
the geometrical and spectral properties of the co-crystals. In
particular, in a D−H···A hydrogen bond there is charge transfer
from lone pairs or π-molecular orbitals of the electron donor
(proton acceptor) to the antibonding orbitals of the D−H
bond of the electron acceptor (proton donor). An increase of
electron density in the antibonding orbitals elongates the D−H
bond, which causes the red-shift of the D-H stretching
frequency. Therefore charge transfer and hence hydrogen-
bond formation may be inferred from comparison of
characteristic vibrational frequencies of a free R-D-H group
The paracetamol molecule contains two hydrogen bond
donors; the phenolic O−H and the amidic N−H groups and
two acceptors; the amidic and phenolic oxygen atoms. A
reasonable expectation would be for the strongest hydrogen
bonds to be formed between the best donor and best acceptor.
During co-crystal formation the donors and acceptors of
paracetamol are in competition with those of the co-crystal
former and the structure adopted is that which optimizes the
donor−acceptor interactions in the co-crystal. Geometric
parameters of the hydrogen bonds in co-crystals 1−3 are
presented in Table 3. The strong O−H···OC interactions
(d(D···A) = 2.66 Å) present in paracetamol are absent in the
co-crystals. However, they are replaced by O−H···N
interactions which operate over a similar distance and are
therefore of comparable strength. This is supported by the
similarity in the contraction of the H···A van der Waals’ cutoff
and red shift of the ν(D-H) stretching frequencies (vide infra).
The geometric and spectroscopic data are consistent with the
strongest hydrogen bonds in the co-crystals resulting from
these O−H···N interactions. Consistent with the suggestions of
Etter37 all of the remaining proton donors and acceptors also
participate in hydrogen bond formation, as evidenced in all
three co-crystals by the N−H···OC interactions between
paracetamol molecules, which are of similar strength to those in
paracetamol itself. Co-crystal (2) has additional hydrogen
bonds N−H···O and O−H···OC due to the incorporation of
solvent molecules. This suggests a hierarchy of hydrogen bonds
H
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
with that of the same group in the presence of a hydrogen bond
acceptor. The characteristic vibrational frequencies of the three
co-crystals 1−3 and of crystalline paracetamol form I may be
compared with those observed in the gas phase infrared
spectrum of paracetamol (Table 5). The frequencies of the
ν(O−H), ν(N−H), and ν(CO) stretching vibrations in co-
crystals 1−3 and in paracetamol form I are red-shifted by up to
16% relative to the equivalent vibrations in the gas-phase
spectrum of paracetamol. From the crystal structure determi-
nation, it can be deduced that the lone pair of the nitrogen
atom of each of the co-crystal formers is aligned along the axis
of the O−H bond of the hydroxyl group of paracetamol,
thereby facilitating charge transfer between the donor and
acceptor pair. Therefore, we conclude that both electrostatic
and charge transfer terms influence the directional behavior of
the hydrogen bonds in co-crystals 1−3.
that neither the amine nor pyridyl CCFs investigated are
sufficiently basic to form a salt with paracetamol through
complete proton transfer. Calculated values ΔpKa of <0 are
thus consistent with the formation of a neutral complex.
CONCLUSIONS
■
Analysis of structural data in the Cambridge Structural
Database resulted in the identification of a range of potential
co-crystal formers compatible with paracetamol. Subsequent
screening using solvent-drop grinding in conjunction with high-
throughput PXRD led to the discovery of three new co-crystals
of paracetamol. All the three co-crystals presented here utilize
the O−H···N supramolecular heterosynthon. The ability of
phenols to form this heterosynthon is consistent with the
results of the analysis of the structural database, suggesting the
approach may be applicable to a wider range of phenol
derivatives. Comparison of the geometric and spectroscopic
parameters of the hydrogen-bonds in co-crystals 1−3 with
those for paracetamol reveals that they are of similar strength,
irrespective of the chemical identity of the synthon. The study
shows that a balance between the retrosynthetic approach
(synthon method) and database screening of supramolecular
synthons provides a useful approach to the targeted synthesis.
In all three co-crystals presented here, the structural and
spectroscopic data indicate that the hydrogen bonds formed
between the API and the CCF are of comparable strength to
those originally present in the API. All three co-crystals studied
here have the same, i.e., O−H···N supramolecular hetero-
synthon between the API and CCF. However in structure (3)
in addition to the O−H···N there is a N−H···N supramolecular
interaction observed between the API and CCF. Our
investigations show that difunctional CCFs, able to form
chain-like structural motifs through distinct hydrogen bonds,
are necessary for co-crystal formation with paracetamol. This is
in accordance with previously reported CCFs in multi-
component crystalline forms of paracetamol. Although CSD
analysis suggests carboxylic acids and amides as potential co-
crystal formers, our experiments demonstrate that they are not
effective for paracetamol. This may be due to the self-
complementary hydrogen bonding nature of these functional
groups, which favors homosynthon formation. A hierarchical
arrangement between the best donor of paracetamol to the best
acceptor in CCF is observed in all the co-crystals presented
here and is indeed observed in almost all of the previously
reported co-crystal forms of paracetamol. Of the reported co-
crystals of paracetamol, only those involving theophylline and
bipyridine29 do not follow the hierarchical arrangement of
hydrogen bonding. In the case of the paracetamol-bipyridine
co-crystal, strong π−π interactions (at a distance of ca. 3.4 Å)
between the pyridine moieties of bipyridine stabilize the crystal
structure in co-operation with the hydrogen bonds. In the case
of the paracetamol-theophylline co-crystal, the best acceptor of
theophylline, the imidazole nitrogen atom, does not participate
in conventional hydrogen bonds. The two molecules are
arranged such that they form flat hydrogen bonded sheets.
A generally accepted guideline40 is that proton transfer will
occur from an acid to a base when the difference in pKa (where
ΔpKa refers to the difference between the pKa value of a
protonated base and that of the acid) is >3.5, and a neutral co-
crystal will form when the ΔpKa < 0. A co-crystal to salt
continuum30d exists between 0 ≤ ΔpKa ≤ 3.5. The ambiguity in
this range of ΔpKa values may be a problem when applying
crystal engineering principles to co-crystal formation, as the
charge separation resulting from salt formation leads to the
dominance of electrostatic interactions over the noncovalent
interactions, on which crystal engineering is based. Moreover,
the prediction of the degree of proton transfer in the solid-state
form based on the pKa difference remains imprecise and may
also show variations with the solvent of crystallization.
Calculated pKa values41 of the CCFs used in this work indicate
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic information files, CSD search details, DSC,
NMR and IR spectra, powder diffraction patterns of screening
experiments using trans-1,2-di-(4-pyridyl)-ethylene as CCF,
comparison plot between single crystal simulated and bulk
powder patterns, calculated pKa values of paracetamol and
CCFs. This information is available free of charge via the
Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*Tel: +44 131 451 8034. Fax: +44 (0)131 451 3180. E-mail: a.
v.powell@hw.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors wish to thank the Scottish Funding Council-
SPIRIT programme and Heriot-Watt University for funding.
■
REFERENCES
(1) Bond, A. D. CrystEngComm 2007, 9, 833.
(2) Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1931, 53, 2784.
■
(3) Anderson, J. S. Nature 1937, 140, 583.
(4) Hall, B.; Devlin, J. P. J. Phys. Chem. 1967, 71, 465.
(5) Desiraju, G. R. CrystEngComm 2003, 5, 466.
(6) Jack, J. D. CrystEngComm 2003, 5, 506.
(7) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid State Chemistry of
Drugs, 2nd ed.; SSCI Inc.: IN, 1999.
(8) (a) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon
Press: Oxford, 2002. (b) Davey, R. J. Chem. Commun. 2003, 13, 1463.
(c) Rogers, R. D. Cryst. Growth Des. 2004, 4, 1085.
(9) (a) Vishweshwar, P.; Beauchamp, D. A.; Zaworotko, M. J. Cryst.
Growth Des. 2006, 6, 2429. (b) Mondal, R.; Howard, J. A. K.; Banerjee,
R.; Desiraju, G. R. Cryst. Growth Des. 2006, 6, 2507. (c) Banerjee, R.;
Bhatt, P. M.; Desiraju, G. R. Cryst. Growth Des. 2006, 6, 1468.
(d) Barnett, S. A.; Tocher, D. A.; Vickers, M. CrystEngComm 2006, 8,
313. (e) Hosokawa, T.; Datta, S.; Sheth, A. R.; Brooks, N. R.; Young,
V. G.; Grant, D. J. W. Cryst. Growth Des. 2004, 4, 1195.
I
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(10) (a) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M.
J. J. Pharm. Sci. 2006, 95, 499. (b) Vishweshwar, P.; McMahon, J. A.;
Peterson, M. L.; Hickey, M. B.; Shattock, T. R.; Zaworotko, M. J.
Chem. Commun. 2005, 4601. (c) Fleischman, S. G.; Kuduva, S. S.;
McMahon, J. A.; Moulton, B.; Bailey Walsh, R. D.; Rodriguez-
Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909.
(d) Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369.
(e) Childs, S. L.; Hardcastle, K. I. Cryst. Growth Des. 2007, 7, 1291.
(f) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.;
Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335.
(11) (a) Stahl, P. H.; Nakano, M. In Handbook of Pharmaceutical
Salts: Properties, Selection, and Use; Stahl, P. H.; Wermuth, C. G., Eds.;
Wiley-VCH: New York, 2002; Ch. 4. (b) Berge, S. M.; Bighley, L. D.;
Monkhouse, D. C. J. Pharm. Sci. 1977, 66, 1.
(12) Oswald, I. D. H.; Allan, D. R.; McGregor, P. A.; Motherwell, W.
D. S.; Parsons, S.; Pulham, C. R. Acta Crystallogr., Sect. B 2002, 58,
1057.
(13) Almarsson, O; Zaworotko, M. J. Chem. Commun. 2004, 1889.
(14) Rodriguez-Spong, B.; Price, C. P.; Jayasankar, A.; Matzger, A. J.;
Rodriguez-Hornedo, N. Adv. Drug Delivery Rev. 2004, 56, 241.
(15) Blagden, N.; De Matas, M.; Gavan, P. T.; York, P. Adv. Drug.
Delivery Rev. 2007, 59, 617.
(37) Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
(38) Gilli, G.; Gilli, P. The Nature of the Hydrogen Bond Outline of a
Comprehensive Hydrogen Bond Theory; Oxford University Press:
Oxford, 2009.
(39) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88,
899.
(40) Johnson, S. L.; Rumon, K. A. J. Phys. Chem. 1965, 69, 74.
(41) The SPARC program (http://archemcalc.com/sparc) uses
computational algorithms based on fundamental chemical structure
theory to estimate a variety of reactivity parameters. For some
examples of the use of the SPARC program for pKa calculations, see
(a) Erdemgil, F. Z.; Sanli, S.; Sanli, N.; Ozkan, G.; Barbosa, J.;
Guiteras, J.; Beltran, J. L. Talanta 2007, 72, 489. (b) Hilal, S. H.;
Karickhoff, S. W.; Carreira, L. A. Quant. Struct. Act. Rel. 1995, 14, 348.
(c) Hilal, S. H.; ElShabrawy, Y.; Carreira, L. A.; Karickhoff, S. W.;
Toubar, S. S. Talanta 1996, 43, 607. (d) Hilal, S. H.; Carreira, L. A.;
Baughman, G. L.; Karickhoff, S. W.; Melton, C. M. J. Phys. Org. Chem.
1994, 7, 122.
(42) NIST Standard Reference Database 35, NIST/EPA Gas-Phase
Infrared Database; National Institute of Standards and Technology:
Gaithersburg, MD.
(16) Desiraju, G. R. Crystal Engineering. The Design of Organic Solids;
Elsevier: Amsterdam, 1989.
(17) Pepinsky, R. Phys. Rev. 1955, 100, 971.
(18) Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647.
(19) Thomas, J. M. Phil. Trans. R. Soc. Lond. A 1974, 277, 251.
(20) Dunitz, J. D. Pure Appl. Chem. 1991, 63, 177.
(21) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311.
(22) Shattock, T. S.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J.
Cryst. Growth Des. 2008, 8, 4533.
(23) The method of search for existing cocrystals: The search was
conducted using the parameters option “number of chemical units” as
more than or equal to two. Hydrates and solvates were excluded from
the search.
(24) (a) Allen, F. H.; Raithby, P. R.; Shields, G. P.; Taylor, R. Chem.
Commun. 1998, 1043. (b) Allen, F. H.; Motherwell, W. D. S.; Raithby,
P. R.; Shields, G. P.; Taylor, R. New. J. Chem. 1999, 23, 25.
(25) (a) Drebushchak, T. N.; Boldyreva, E. V. Z. Kristallogr. 2004,
219, 506. (b) Wilson, C. C. Z. Kristallogr. 2000, 215, 693.
(26) Burger, A. Acta Pharm. Technol 1982, 28, 1.
(27) Perrin, M-A; Neumann, M. A.; Elmaleh, H.; Zaska, L. Chem.
Commun. 2009, 3181.
(28) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew.
Chem. Int. Ed. 1995, 34, 1555.
(29) Karki, S.; Friscic, T.; Fabian, L.; Laity, P. R.; Day, G. M; Jones,
W. Adv. Mater. 2009, 21, 3905.
(30) (a) Oswald, I. D. H.; Allan, D. R.; McGregor, P. A.; Motherwell,
W. D. S; Parsons, S.; Pulham, C. R.. Acta Crystallogr. Sect. B 2002, 58,
́
1057. (b) Andre, V.; Piedade, M. F. M; da; Duarte, M. T..
CrystEngComm 2012, 14, 5005. (c) Vrcelj, R. M.; Clark, N. I. B.;
Kennedy, A. R.; Sheen, D. B.; Shepherd, E. E. A.; Sherwood, J. N. J.
Pharm. Sci. 2003, 92, 2069. (d) Oswald, I. D. H.; Motherwell, W. D. S;
Parsons, S.; Pulham, C. R. Acta Crystallogr. Sect. E 2002, 58, O1290.
(d) Oswald, I. D. H..; Pulham, C. R. CrystEngComm 2008, 10, 1114.
(e) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4,
323.
(31) Trask, A. V.; Motherwell, W. D. S; Jones, W. Chem Commun.
2004, 890.
(32) APEX-2 software, Version 1.27; Bruker AXS Inc.: Madison,
Wisconsin, USA, 2005.
(33) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
(34) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.;
Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487.
(35) Collings, J. C.; Roscoe, K. P.; Thomas, R. Ll.; Batsanov, A. S.;
Stimson, L. M.; Howard, J. A. K.; Marder, T. B. New J. Chem. 2001, 25,
1410.
(36) Salonen, L. M.; Ellermann, M.; Diedrich, F. Angew. Chem., Int.
Ed. 2011, 50, 4808.
J
dx.doi.org/10.1021/cg300689m | Cryst. Growth Des. XXXX, XXX, XXX−XXX