REVIEW

Pharmaceutical Co-Crystals
PEDDY VISHWESHWAR, JENNIFER A. McMAHON, JOANNA A. BIS, MICHAEL J. ZAWOROTKO
Department of Chemistry, University of South Florida, CHE205, 4202 East Fowler Avenue, Tampa, Florida 33620

Received 12 July 2005; revised 11 September 2005; accepted 21 December 2005

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20578

ABSTRACT: Crystal engineering has evolved in such a manner that it is now

synonymous with the paradigm of supramolecular synthesis, that is, it invokes selfassembly of existing molecules to generate a wide range of new solid forms without the
need to break or form covalent bonds. This review addresses how crystal engineering has
been applied to active pharmaceutical ingredients, APIs, with emphasis upon how
pharmaceutical co-crystals, a long known but little explored alternative to the four
traditionally known forms of API, can be generated in a rational fashion. Case studies on
Carbamazepine (CBZ) and Piracetam are presented which illustrate the relative ease
with which pharmaceutical co-crystals can be prepared and their diversity in terms of
composition and physical properties. 2006 Wiley-Liss, Inc. and the American Pharmacists
Association J Pharm Sci 95:499516, 2006

Keywords: crystal engineering; hydrogen bond; pharmaceutical co-crystal; polymorphism; supramolecular synthesis

INTRODUCTION
Crystalline forms of active pharmaceutical ingredients, APIs, have traditionally been limited
to salts, polymorphs, and solvates (including
hydrates).1 Given the high intrinsic value of APIs
and the importance of structure and composition
in the context of both intellectual property
and bioavailability, it is perhaps surprising
that systematic approaches to the development
of a new broad class of API, pharmaceutical cocrystals, have only been attempted in recent
years.216 Co-crystals represent a long known
class of compounds, a prototypal example of
which is quinhydrone, which was reported at
least as early as 1844 and 1893.17,18 However,
how narrowly or broadly one defines the term cocrystal remains a matter of topical debate. For
Correspondence to: Michael J. Zaworotko (Telephone: 813974-4129; Fax: 813-974-3203; E-mail: xtal@usf.edu)
Journal of Pharmaceutical Sciences, Vol. 95, 499516 (2006)
2006 Wiley-Liss, Inc. and the American Pharmacists Association

example, a broad definition is that a co-crystal

is a mixed crystal or crystal that contains two
different molecules.19 An alternative approach
that arises conceptually from applying the
concepts of supramolecular chemistry and crystal
engineering is that a co-crystal is the consequence
of a molecular recognition event between different
molecular species.20,21 Aakeroy clarified the situation further by suggesting that co-crystals are
made from reactants that are solids at ambient
temperature.22 He also stated that all hydrates
and other solvates are excluded which, in principle, eliminates compounds that are typically
classified as clathrates or inclusion compounds
(where the guest molecule is a solvent or a gas
molecule). That there is such debate concerning
the definition of a co-crystal more than 160 years
after they were first reported clarifies a need for
distinguishing between multi-component crystalline materials that are comprised of two or more
solids versus those composed of one or more solids
and a liquid. The latter have been called solvates
or pseudopolymorphs, an issue that has also

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provoked recent discussion by Seddon, Desiraju,

Bernstein, and Nangia.2326 We agree that the
time has come to abandon the term pseudopolymorph in favor of solvate and recommend that
the term pharmaceutical co-crystal be applied in
the context of APIs in which all components
are solids when pure. Pharmaceutical co-crystals,
co-crystals that are formed between a molecular
or ionic API and a co-crystal former that is a solid
under ambient conditions, represent a clearly
defined subset of multi-component crystals, a
group that also includes salts, solvates, clathrates, inclusion crystals and hydrates.5 Although
such definitions lessen the level of ambiguity,
there would still be an overlap between these
classes. For example, if a crystalline material
consists of two or more components that are solids
under ambient conditions and a liquid component
then it might be called a co-crystal solvate or, if
appropriate, a co-crystal hydrate. However, a
multi-component system made of molecular cocrystal former and an ionic API would simply be
classified as a pharmaceutical co-crystal.9
It is important to note that from a supramolecular perspective solvates and pharmaceutical cocrystals can be regarded as being closely related to
one another since components within the crystal
interact by hydrogen bonding or other directional
noncovalent interactions. The primary difference
between solvates and pharmaceutical co-crystals
is simply the physical state of the isolated pure
components: if one component is a liquid at room
temperature, a compound is a solvate; if both
components are crystalline solids at room temperature, they are pharmaceutical co-crystals.
These differences may seem inconsequential but
they can profoundly affect the stability, processing, and physical properties of APIs. The stability
of solvates (including hydrates) at different temperatures and pressures differ from those of the
unsolvated forms. These differences can influence
formulation, procession, and stability under various storage conditions of the drug compound, as
well as the pharmaceutical product. Whereas
solvates are commonplace because they often
occur as a serendipitous result of crystallization
from solution. Co-crystals, especially pharmaceutical co-crystals, represent a relatively unexplored
but broad ranging class of compounds.
A literature review reveals that co-crystals in
which both components are solids under ambient
conditions are long known as addition compounds,27 organic molecular compounds,18,28
mixed binary molecular crystal,29 molecular comJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 3, MARCH 2006

plexes,30 or solid-state complexes31 or heteromolecular crystals.32 However, a survey of the 355071

crystal structures deposited in the August 2005
release of the Cambridge Structural Database
(CSD),33 indicates that such co-crystals remain
relatively unexplored. Indeed there are few entries
prior to 1960 and even today there are only ca. One
thousand four hundred eighty seven hydrogen
bonded co-crystals versus 35882 hydrates. Therefore, it would be fair to summarize co-crystals as
being long known but little studied. However,
interest in co-crystals is increasing with potential
applications in nonlinear optics (NLO),34 solventfree organic synthesis,35,36 host-guest chemistry,3739 and photographic film formulation.40
Figure 1 reveals the rapid increase in the number
of co-crystals reported from 19902003, a time
period which coincided with the emergence of the
paradigm of crystal engineering.
The concept of crystal engineering was introduced by Pepinsky41 in 1955 and implemented by
Schmidt in the context of organic solid-state
photochemical reactions.42 Desiraju subsequently
defined crystal engineering as the understanding
of intermolecular interactions in the context of
crystal packing and in the utilization of such
understanding in the design of new solids with
desired physical and chemical properties.43 Crystal engineering has now matured into a paradigm
for the preparation or supramolecular synthesis of
new compounds. A salient feature of crystal
engineered structures is that they are designed
from first principles using the principles of
supramolecular chemistry44 and self-assembly.
They can therefore consist of a diverse range of

Figure 1. Occurrence of H-bonded co-crystals in the

CSD from 19902003.
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PHARMACEUTICAL CO-CRYSTALS

chemical components as exemplified by coordination polymers (i.e., metals and organic

ligands),4550 polymers sustained by organometallic linkages51 and networks sustained by noncovalent bonds.45,52 54 This contribution will focus
upon pharmaceutical co-crystals with special
emphasis upon the following: design, methods of
preparation, and polymorphism in co-crystals.

HOW ARE CO-CRYSTALS DESIGNED?

That pharmaceutical co-crystals are susceptible
to design by crystal engineering distinguishes
them from other crystalline forms of API. Analysis of existing crystal structures represents the
first step in a crystal engineering experiment.
This is typically executed via the CSD, which
facilitates statistical analysis of packing motifs
and thereby provides empirical information concerning common functional groups and how they
engage in molecular association, that is, how they
form supramolecular synthons.55 The potential of
the CSD in the context of design was envisaged at
least 22 years ago when Allen and Kennard
noted56 that the systematic analysis of large
numbers of related structures is a powerful
research technique, capable of yielding results
that could not be obtained by any other method.
Two decades later it has become clear that crystal
engineering is in many ways synonymous with
supramolecular synthesis and herein we present
case studies that address how pharmaceutical cocrystals can be prepared from first principles.

501

USA.60 Carboxylic acids therefore represent an

excellent starting point for crystal engineering of
pharmaceutical co-crystals. Their complementary
hydrogen bond donor and acceptor sites makes
supramolecular homosynthon I favorable. However, formation of I is unlikely in competitive
situations. Allen et al.61 determined the probability of formation of 75 bimolecular hydrogen bonded
ring synthons in organic crystal structures. The
probability of formation of I was found to be only
33%. This relatively low probability was attributed
to competition with other hydrogen-bonded acceptors (e.g., COO
, pyridine N, Amide C O, S O, P
O, etc.). A recent CSD study by Steiner62 on
carboxyl donors indicated that carboxylic acid
pyridine interactions through O
H    N hydrogen
bonding, II, is more favored than I. Indeed, II is a
highly reliable supramolecular heterosynthon2
that has been widely exploited in crystal engineering.6371 Ab initio calculations support the idea
that the II is energetically favored over I and that
the acid-amide supramolecular heterosynthon
IV7275 is favored over I and III.64,65 These
observations are particularly relevant for design
of co-crystals since robust supramolecular heterosynthons represent perhaps the most reliable and
rational route to co-crystals. Furthermore, complementary supramolecular heterosynthons that
seem to clearly favor formation of co-crystals are
not limited to carboxylic acids. The alcoholamine7678 and alcohol-pyridine7981 supramolecular heterosynthons are also well established in
crystal engineering.

HOW ARE CO-CRYSTALS PREPARED?

Carboxylic acid moieties represent one of the

most commonly studied functional groups in
crystal engineering43,5759 and they exist in 30 of
the 100 top-selling prescription drugs in the
DOI 10.1002/jps

Synthesis of a co-crystal from solution might be

thought of as counterintuitive since crystallization is such an efficient and effective method of
purification and as such it is used widely in the
pharmaceutical industry for isolation of single
component crystals. However, if different molecules with complementary functional groups
result in hydrogen bonds that are energetically
more favorable than those between like molecules
of either component, then co-crystals are likely to
be thermodynamically (although not necessarily
kinetically) favored. Co-crystals involving these
supramolecular synthons are usually synthesized
by slow evaporation from a solution that contains
stoichiometric amounts of the components (cocrystal formers); however, sublimation, growth
from the melt, slurries, and grinding two solid
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co-crystal formers in a ballmill are also suitable

methodologies. More often than not, the phase
that is obtained is independent of the synthetic
methodology. The recently reported technique
of solvent-drop grinding, addition of a small
amount of suitable solvent to the ground mixture
to accelerate co-crystallization appears to be a
particularly promising preparation method.15,82
Jones et al.83 reported that grinding of cyclohexane-1,3cis,5cis-tricarboxylic acid and 4,40 -bipyridine does not afford a co-crystal whereas grinding
the two components with few drops of MeOH
facilitates complete conversion within minutes.
Solvent drop grinding avoids excessive use of
crystallization solvent and hence it can be regarded as a green process. Solvent-drop grinding
could also prove useful for polymorph control15
and selective polymorph transformation.84
That co-crystals can often be prepared in a facile
manner does not mean that their synthesis and
isolation is routine. A detailed understanding of
the supramolecular chemistry of the functional
groups present in a given molecule is a prerequisite for designing a co-crystal since it facilitates
selection of appropriate co-crystal formers. However, when multiple functional groups are present
in a molecule, as is often the case for APIs, the CSD
rarely contains enough information to address the
hierarchy of the possible supramolecular synthons. Furthermore, the role of solvent in nucleation of crystals and co-crystals remains poorly
understood, yet solvent can be critical in obtaining
a particular co-crystal from solution.

WHY ARE PHARMACEUTICAL CO-CRYSTALS

OF RELEVANCE IN THE CONTEXT OF APIs?
The crystalline form of an API profoundly affects
physical properties such as solubility, stability,
dissolution rate, and bioavailability. Pharmaceutical co-crystals should be attractive to the
pharmaceutical industry because they offer multiple opportunities to modify the chemical and/or
physical properties of an API without making or
breaking covalent bonds. Indeed, the physical
properties of the pharmaceutical co-crystals that
have been studied in detail indicate differences
from those of the pure APIs. The inherent nature
of APIs, that is, molecules that contain exterior
hydrogen bonding moieties, means (unfortunately
to some) that they are predisposed towards the
existence of polymorphs and solvates but it also
makes them ideally suited for formation of
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pharmaceutical co-crystals. The polymorphic tendency of APIs varies greatly, but the consensus
seems to be that most APIs are at some time or
another going to display polymorphic behavior.
However, the extent of polymorphism of APIs is
almost certainly going to be limited to a handful of
crystal forms. Solvates (including hydrates) can
be more numerous, and in certain cases very large
numbers of solvates can be observed. Indeed,
sulfathiazole is inordinately promiscuous in
terms of solvate formation, with over one hundred
solvates found.85 Salt forms can also be numerous, with over 90 acids and 30 bases considered
suitable for pharmaceutical salt selection.86
Examples of compounds possessing a dozen or
more crystalline salt forms have been published.87,88 However, it is important to remember
that salt formation is generally directed at one
acidic or basic functional group. In contrast, cocrystals can simultaneously address multiple
functional groups in an API, including those that
are not acidic or basic enough to form a salt. In
addition, the space is not limited to binary
combinations since tertiary68 and quaternary89
co-crystals are realistic possibilities. Co-crystal
formers that are suitable for pharmaceutical use
remain to be enumerated fully, but there are over
a hundred solid materials with generally
regarded as safe (GRAS) status (including food
additives and other well-accepted substances) and
sub-therapeutic amounts of eminently safe drug
substances, such as aspirin and acetaminophen,
are also legitimate co-crystal formers. The space
of pharmaceutical co-crystals would therefore
appear to be large with thousands of possibilities
for any given drug, especially when at least two
hydrogen bonding moieties are present in an API.
Furthermore, it is unlikely that applications of cocrystals in the context of the pharmaceutical
industry will be limited to form and formulation.
For example, a co-crystal might be used to isolate
or purify an API during its processing and the cocrystal former could be discarded prior to formulation. In addition, co-crystallization with
homochiral co-crystal formers might be used to
separate enantiomers.

POLYMORPHISM IN SINGLE COMPONENT

CRYSTALS VERSUS CO-CRYSTALS
Mitscherlich recognized the phenomenon of polymorphism as long ago as 1822 and in 1965
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503

Table 1. CSD Statistics of Polymorphic Single Component and Co-Crystal

Crystal Structures

Organic crystal structures

Hydrates
Single component molecular organic structures
Single component polymorphic structures
Co-crystals
Polymorphic co-crystals

No. of Entries

130448
9621
94900
1600a
1487b
21a

100c
7.3c
72.7c
1.7d
1.1c
1.5d

The CSD searches were conducted with only organic crystal structures. A CSD search with only
organics as a parameter also retrieves structures containing metals like Na, K, Ca etc. Such entries
were excluded from the statistics quoted above (CSD Conquest 1.7, Aug05 update, 355,071 entries).
a
Only one refcode was counted for each polymorphic compound.
b
Co-crystals sustained by strong hydrogen bonds.
c
Percentages with respect to organic crystal structures only.
d
Percentages with respect to 94,900and 1,487 sub-totals, respectively.

McCrone defined polymorphism as a solid crystalline phase of a given compound resulting from
the possibility of at least two different arrangements of the molecules of that compound in the
solid state.90 McCrones definition is particularly
appropriate in the context of APIs since they
manifest themselves via multiple modes of selforganization or self-assembly. Similar issues face
agrochemicals, explosives, dyes, pigments, flavors, and confectionery products.
As revealed by Table 1,91 polymorphism92 95
has been observed in ca. Single component
crystals (1.7%) versus ca. 1.5% of co-crystals.
These numbers are likely to be significantly
underreported. However, there are so few examples of polymorphic co-crystals that it would be
appropriate to address such structures individually in order to determine the origin of the
polymorphism. There are 21 hydrogen bonded
co-crystals in the CSD that exhibit polymorphism
but there are only 11 for which atomic coordinates
are available for all the forms: (CSD refcodes)
AJAJEA, 01; EXUQUJ, 01; HADKUT, 01; JICTUK01, 10; MACCID, 01, 02; MUROXA, 01;
PDTOMS10, 11; PTZTCQ, 01; QUIDON, 02;
TECCAF01, 02; and ZIGPAG, 01. A detailed
analysis96 of the crystal packing in these 11
compounds indicates that their polymorphism is
not linked to the supramolecular synthons that
sustain the co-crystal. Rather, it appears to be the
result of subtle conformational or packing
changes. Indeed, to our knowledge there have
not yet been any examples of supramolecular
isomerism45 in co-crystals. If these observations
hold true over a broader range of compounds it
would suggest that co-crystals represent a desirDOI 10.1002/jps

able class of compound from the perspectives of

both design and phase stability.

CASE STUDIES OF PHARMACEUTICAL

CO-CRYSTALS
Whereas there are early examples of pharmaceutical co-crystals in the scientific literature they
tend to be more the result of serendipity than
design, and we are unaware of any examples
that have been approved for use by the FDA.
Perhaps the earliest literature that in the context
of APIs relates to a series of studies conducted in
the 1950s by Higuchi. They studied complex
formation between macromolecules and certain
pharmaceuticals; for example complexes of polyvinylpyrrolidone with procaine hydrochloride,
caffeine, cortisone, chloramphenicol, benzylphenicillin, sulfathiazole, phenobarbital, etc. were
isolated. However, these would not be classified as
pharmaceutical co-crystals according the criteria
applied herein.97100 Perhaps the first application
of crystal engineering to the generation of
pharmaceutical co-crystals was a series of studies
by Whitesides et al. concerning the use of
substituted barbituric acid, including barbital
and melamine derivatives to generate supramolecular linear tape, crinkled tape, and rosette
motifs sustained by robust three-point N
H    O
and N
H    N hydrogen bonds (Fig. 2).11,101105
Ironically the focus of these studies was not
so much the physical properties of the resulting
co-crystals but rather the supramolecular functionality of barbitals106 and their complementarity with melamine. Nevertheless, these studies
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Figure 2. Crystal packing of 1:1 co-crystals of 5,5-diethylbarbituric acid (barbital)

with melamine derivatives. (a) Crinkled tape motif formed by barbital and 2-amino-4,6bis(t-butylamino)-1,3,5-triazine co-crystal. (b) Rosette motif of barbital and N,N0 -bis(4-tbutylphenyl)melamine co-crystal.

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505

illustrated very well the potential diversity of

forms that can exist for a particular API as more
than 60 co-crystals were structurally characterized in this series of studies. We have chosen to
herein focus upon two case studies that involve
two APIs that are polymorphic in their pure
forms and are therefore more directly relevant to
issues that face the pharmaceutical industry.
Pharmaceutical Co-Crystals and Solvates of
Carbamazepine (CBZ), 1
Carbamazepine (CBZ) [5H-dibenz(b,f) azepine-5carboxamide], 1, is known to exist as four well
characterized polymorphs,107 114 a dihydrate,115
an acetone solvate,109 and two ammonium
salts.116 CBZ has been in use for over 30 years
to treat epilepsy and trigeminal neuralgia even
though it poses multiple challenges to oral drug
delivery, including a small therapeutic window,
autoinduction of metabolism, and dissolutionlimited bioavailability.117 From a supramolecular
perspective, CBZ is a simple molecule with only
one hydrogen bonding group, a primary amide.
The self-complementary nature of the amide
moiety manifests itself in a predictable manner
since all forms of CBZ exhibit supramolecular
homosynthon III118120 (Fig. 3). CBZ therefore
represents an excellent candidate for a case study
that addresses how APIs can be converted to
pharmaceutical co-crystals and whether or not
pharmaceutical co-crystal forms offer physical,
chemical, or biochemical advantages over existing
forms of an API.121,122

The primary amide dimer, like the carboxylic

acid dimer, is well-documented in the CSD. Of the
1231 crystal structures that contain at least one
primary amide functional group, the dimer is
exhibited in 428 structures (35%). In most of these
structures, the peripheral NH moiety forms a
hydrogen bond to an adjacent amide, thereby
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Figure 3. The CBZ amide dimer III that exists in all

previously reported forms of CBZ.

generating tapes or sheets, or it hydrogen bonds

to a different functional group. However, this is not
the case for CBZ, in which the peripheral H-bond
donors and acceptors are unused, presumably due
to steric constraints imposed by the azepine ring of
CBZ. That the CBZ dimer does not engage its
peripheral H-bonding capabilities represents one
avenue for crystal engineering and CBZ forms a
number of co-crystals and solvates that retain the
primary amide dimer. Figure 4 presents the
crystal structures of five pharmaceutical co-crystals of CBZ that maintain the amide dimer, 1ae.
In the benzoquinone (1a) and terephthalaldehyde
(1b) co-crystals, the ketone and aldehyde, respectively, H-bond with the anti N
H    O hydrogen
bond of the CBZ dimers and sustain 1-D hydrogen
bonded chains. A similar result occurs in 1c, in
which the aromatic amines of 4,40 -bipyridine
molecules act as H-bond acceptors to the antioriented NH of CBZ. Structure 1d is a pharmaceutical co-crystal of CBZ and nicotinamide that
exists as more complex 1-D hydrogen bonded
chain. CBZ dimers H-bond to the syn positions of
the nicotinamide amide group through an exterior
translation-related pattern. The anti-oriented Hbonding sites of the nicotinamide amide group
form a catemer motif with adjacent nicotinamide
molecules. In 1e saccharin molecules serve as Hbond donors by forming N
H    O hydrogen bonds
with CBZ carbonyl groups. They also serve as Hbond acceptors: the S O group of the saccharin
bonds to the exterior N
H moiety of CBZ. CBZ also
forms several solvates in which homosynthon III is
retained. The solvent molecules in 1fh all interact with the anti N
H of the CBZ dimers to form
N
H    O C/S hydrogen bonds.
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Figure 4. The supramolecular interactions that occur in pharmaceutical co-crystals

1ae. 1ad can be described a 1-D tapes whereas 1e is a discrete structure.

A second strategy for co-crystal formation

involving CBZ involves breakage of homosynthon
III and formation of a supramolecular heterosynthon. This would be expected to occur with a
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functional group that is complementary with the

amides, that is, a moiety with both an H-bond
donor and an H-bond acceptor. Carboxylic acids fit
this criterion and 71 of the 153 structures in the
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507

Figure 5. Illustrations of the four molecule supramolecular complexes formed by CBZ:

carboxylic acid solvates 1oq.

CSD that contain both a carboxylic acid and a

primary amide are sustained by supramolecular
heterosynthon IV. Co-crystal formation between
CBZ and carboxylic acids occurs, and Figure 5
presents three examples of solvates that are
sustained by supramolecular heterosynthon IV,
1oq. All three solvates exhibit four molecule
supramolecular adducts that are sustained by the
unused anti N
H of IV. Co-crystallization of CBZ
with other carboxylic acids affords pharmaceutical
co-crystals that are sustained by synthon IV.
Details of their crystal packing are presented
elsewhere.3,4
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Pharmaceutical Co-Crystals of Piracetam, 26

Piracetam, (2-oxo-1-pyrrolidinyl)acetamide, 2, is
a nootropic drug that enhances learning and

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Figure 6. Carboxamide dimer (a) and catemer (b)

motifs as exhibited in Piracetam polymorphs.

memory by stimulating the central nervous

system.123 It is considered virtually nontoxic as
acute toxicity studies on Piracetam have shown
no measurable LD50 rate for rats, mice, and
dogs.124,125 Four polymorphic forms of 2 have
been deposited in the CSD.126129 Two forms, a
triclinic and a monoclinic modification, crystallize
via III, while the other two are monoclinic forms,
crystallizes in a catemeric fashion (Fig. 6). In all
four forms, the ring carbonyl is involved in
hydrogen bonding to the anti-NH of the primary
amide. The are no co-crystals of piracetam in the
CSD, however one hydrate is reported recently.129
One study suggests that 2 may exhibit six
polymorphs.130
Gentisic acid, 2,5-dihydroxybenzoic acid is an
aspirin metabolite that exhibits NSAID activity.131133 Gentisic acid exhibits two polymorphic
forms,134 two co-crystals and a clathrate hydrate
are reported.135 137 Single crystals of the 1:1 cocrystal of piracetam and gentisic acid, 2a were
obtained via slow evaporation from acetonitrile
and Figure 7 reveals that 2a is sustained by
heterosynthon IV. The 5-hydroxy group of gentisic
acid serves as a hydrogen bond donor to the ring
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carbonyl of piracetam, resulting in a 4,4-topology

network that is twofold interpenetrated. Piracetam also forms a 1:1 co-crystal with p-hydroxybenzoic acid, 2b. Co-crystal 2b crystallizes from
acetonitrile and its crystal structure also reveals
the presence of IV which in turn dimerizes to form
a tetrameric motif sustained by anti N
H    O
hydrogen bonding (Fig. 7). This tetrameric motif is
found in 10 (14%) of the 71 structures in the CSD
that contain acid-amide supramolecular heterosynthons.138 The ring carbonyl of piracetam
molecules and the hydroxy group of p-hydroxybenzoic acid also form hydrogen bonds which link
each tetramer to four others at the corners,
thereby affording a threefold interpenetrated
network.
2a and 2b were screened for the existence of
polymorphs using solvent-drop grinding, a technique that has been shown to be able to generate and
control polymorphism.15 Mechanical grinding
experiments were conducted in reaction vessels
by adding gentisic acid or p-hydroxybenzoic acid to
solid piracetam form A. Twenty-three solvents
(water, acetone, methanol, ethanol, ethyl acetate,
n-hexane, toluene, acetonitrile, tetrahydrofuran,
isopropyl acetate, benzyl alcohol, nitromethane,
dimethyl amine, 2-butanol, ethyl formate, acetic
acid, methyl ethyl ketone, methyl tertiary butyl
ether, chlorobenzene, N-methyl pyrrolidone, 1,2dichloroethane, dimethylsulfoxide, and dimethoxy
ethane) was evaluated by adding a different
solvent to each well. The samples were ground
for 20 min and characterized using powder X-ray
diffraction. Co-crystals 2a or 2b were obtained
from all conditions as a mixture with one or both of
the starting materials, that is, 2a and 2b do not
exhibit polymorphism based on a series of solventmediated grinding experiments. That a wide range
of pharmaceutical crystals can be crystal engineered is suggested by our observations with CBZ
and piracetam, and is further supported by recent
studies from other groups that have focused
upon Triazole,7 Fluoxetine hydrochloride,9 Trimethoprim,10 Barbital11,101106, Paracetamol,14
and Caffeine15,16. However, there remain several
important issues that will only be resolved
by further experimentation. For example, can
pharmaceutical co-crystals lead to formulations
with superior bioavailability when compared to
conventional forms of APIs and are they more or
less prone to polymorphism? Almarsson et al.139
have investigated the CBZ and saccharin cocrystal (1e) in terms of performance attributes,
including scale-up, polymorphism, physical stabiDOI 10.1002/jps

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509

Figure 7. Views of the intermolecular hydrogen bonding in 2a (a) and 2b (b). Note the
carboxylic acid-amide supramolecular heterosynthon, IV in both the co-crystals and
tetrameric motif in 2b.

lity, in vitro dissolution, and oral bioavailability,

with the goal of comparing the novel composition
with known polymorphs and solvates of the drug.
1e was synthesized in 30 g scale through cooling a
saturated alcohol solution and the physical stability of the co-crystal is superior to that of solvates.
DOI 10.1002/jps

A comparison of oral bioavailability of 1e with

Tegretol1 tablets in dogs established that 1e could
serve as a practical alternative to anhydrous CBZ
in oral formulation. Other observations concerning 1e include the following: (i) chemical stability
appears to be similar to other forms of CBZ, (ii)
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 3, MARCH 2006

510

VISHWESHWAR ET AL.

following over 700 experiments that included

high-throughput screening, neat grinding, solvent-drop grinding with several solvents, and
slurry conversion in different solvents.
In summary, if CBZ and piracetam represent a
microcosm of the issues one faces during form
selection of APIs then pharmaceutical co-crystals
would appear to represent a significant opportunity for improving the diversity and performance
of API forms.

BUT BEWARE OF FAKE

PHARMACEUTICAL CO-CRYSTALS!

Figure 8. Examples of fake pharmaceutical cocrystals found in the literature: (a) HEKRUK, Trimethoprim sulfametrole, a salt. (b) JATMEW, 3-[2(N0 , N0 -dimethylhydrazino)-4-thiazolylmethylthio]-N2sulfamoylpropionamidine maleic acid. Structural parameters suggest formation of a salt. (c) SAGQEWa
propionic acid solvate of mebendazole.

physical stability of 1e is greater than that of

solvates and similar to the marketed forms of CBZ;
(iii) 1e exhibits good pK performance; (iv) polymorphism was not observed in the co-crystal
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 3, MARCH 2006

Before we conclude, it should be emphasized

that there can sometimes be ambiguity concerning whether or not a compound is a co-crystal,
a solvate or a salt. The distinction between a cocrystal and a salt can be especially problematic
if X-ray crystallography is the only method
of characterization and the difference between
in a hydrogen atom
the two extremes is ca. 1 A
position. For example, a recent publication9 cited
a number of co-crystals of APIs, however several
are questionable in terms of whether or not
they are salts or co-crystals. For instance, trimethoprim sulfametrole (CSD refcode: HEKRUK), even though reported under the
misleading title 1:1 Molecular complex of trimethoprim and sulfametrole was described by
the primary authors as an ionic complex (Fig. 8).140
JATMEW, 3-[2-(N0 , N0 -dimethylhydrazino)-4thiazolylmethylthio]-N2-sulfamoylpropionamidine maleic acid (1:1) was reported as a neutral
complex.141 However, the structural parameters
(C
O bond lengths, C
N
C bond angles) suggest the formation of a maleate anion and a
propionamidinium cation. The physical state of
the components must also be taken into consideration. For instance, SAGQEW is the crystal
structure of Mebendazole and propionic acid.142
The latter exists as a liquid phase at ambient
temperatures (M.p.
218C). Therefore, SAGQEW
should be classified as a solvate rather than a cocrystal.
We have also experienced that CSD searches
retrieve ionic compounds despite limiting the
search to neutral components. For example,
salts EBIBEW, PIKLEA, QAWNAD, VAPBAP,
VENLUV, etc. are all retrieved as neutral compounds.143 147 One should therefore not rely solely
on the CSD for the identification of co-crystals. The
database findings should be supported by inspection of the structural parameters of co-crystal
DOI 10.1002/jps

PHARMACEUTICAL CO-CRYSTALS

components, and/or revision of the corresponding

publications.
6.

CONCLUSIONS
Whereas there is a clear need for greater understanding and control of crystalline forms in the
context of pharmaceutical development, the concepts of supramolecular synthesis, and crystal
engineering remain largely underexploited. This
contribution highlights the need to think supramolecularly for structural analysis of APIs. In
particular, applying the concepts of supramolecular synthesis and crystal engineering to the
development of pharmaceutical co-crystals represents a paradigm that offers many opportunities
related to drug development and delivery. It
seems inevitable that pharmaceutical co-crystals
will gain a broader foothold in drug formulation.

7.

8.

9.

ACKNOWLEDGMENTS
We are grateful for financial support from Transform Pharmaceuticals, 29 Hartwell Avenue, Lexington, MA 02421.

10.

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