Review

Cocrystallization for successful

drug delivery
Changquan Calvin Sun
1. Introduction University of Minnesota, College of Pharmacy, Department of Pharmaceutics, Minneapolis,
MN, USA
2. Nature of cocrystal
3. Impact of cocrystallization on Introduction: Cocrystallization is an effective crystal engineering approach
drug properties and for modifying the crystal structure and properties of drugs. The number of
performance examples of solving drug formulation and manufacture problems by cocrystal-
lization is rapidly growing. An updated review that systematically examines
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4. Preparation methods
the cocrystal research in the context of drug delivery is timely and valuable.
5. Future trend in cocrystal
Areas covered: Topics covered in this review include nature of cocrystal,
research
impact of cocrystallization on key pharmaceutical properties (both enhance-
6. Conclusions
ment and deterioration), cocrystal preparation method and future directions
7. Expert opinion in this field. The focus of this review is on the crystal engineering and pharma-
ceutical literature in the last 5 years. However, classical literature is also
examined when relevant.
Expert opinion: The most effective cocrystal research relies on both in-depth
understanding of structure--property relationship and efficient preparation
of desired cocrystals. The future cocrystal research will see growth in the areas
of designing ternary and higher-order structures, cocrystals between
For personal use only.

neutral and ionic species, cocrystal polymorphism, cocrystal glasses and

thermodynamics of cocrystallization.

Keywords: cocrystal, crystal engineering, crystallization, drug delivery, performance,

pharmaceutical property, polymorph, solid-state, solubility, stability

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

The successful delivery of any active pharmaceutical ingredient (API) to patients

requires the ability to manufacture effective drug products. Common problems
that challenge the successful drug delivery and manufacture include deficiencies in
their properties, such as solubility, stability, bioavailability, organoleptic properties
and mechanical properties. Cocrystallization is one of the emerging crystal engineer-
ing techniques for modulating pharmaceutical performance through controlling
solid-state properties of APIs. This is possible because cocrystallization significantly
expands the access to new solid forms differing in structures [1]. Recognizing the
growing interest in using cocrystals for drug product development, the United
States Food and Drug Administration (FDA) released draft guidance on the subject
of regulatory classification of pharmaceutical cocrystals [2].
Because of its importance to drug delivery, the topic of pharmaceutical cocrystals
has been examined in several reviews, with a focus on opportunities in property
enhancement by cocrystallization [3-7]. In this discussion, the author will review
recent progress in cocrystal research with equal considerations on both property
deterioration and enhancement in the context of drug delivery. The author will
also discuss common cocrystal preparation methods and suggest future directions
in cocrystal research.

10.1517/17425247.2013.747508 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1

All rights reserved: reproduction in whole or in part not permitted
 C. C. Sun
Article highlights.
. Pharmaceutical cocrystals are similar to pharmaceutical
salts in several ways. The transition from salt to cocrystal
is a smooth rather than abrupt process.
. A pharmaceutical cocrystal can exhibit either improved
or deteriorated properties when compared with its
parent active pharmaceutical ingredient (API).
. Cocrystal formation from a solution is most favored
when concentration ratio of the coformers corresponds
to their solubility ratio in the crystallizing solvent.
. Solid-state cocrystallization by grinding is more effective
and efficient when facilitated by solution-mediated
phase transition.
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. Cocrystal research will advance in the areas of
polymorphic cocrystal, higher-order cocrystal, cocrystal,
salt cocrystal, glassy cocrystal and thermodynamics
of cocrystallization.
This box summarizes key points contained in the article.
2. Nature of cocrystal
The definition of cocrystal has been a subject of intense
debate. In absence of a commonly accepted definition and
to facilitate the organization of this review, the author defines
For personal use only.
cocrystals as Crystals with structure constituted of multicom-
ponents, generally in a stoichiometric ratio, among which one
or more components are neutral compounds. The constitut-
ing compounds (either ionic or neutral) are also termed
coformers, which is derived from the initial term cocrystal for-
mer, in this discussion. A point of debate is whether mole-
cules that are volatile at room temperature should be
considered as coformers. Their inclusion or not does not fun-
damentally change the nature of cocrystal but have some
impact on properties of cocrystals, such as solid-state stability
at ambient conditions and weight loss during processing and
handling. The author excludes those molecules as coformers
because such crystals belong to a class of well studied materials
already widely known as hydrates or solvates. This definition
allows a cocrystal to be hydrated (Figure 1). It also allows ionic
components to be present in the structure of a cocrystal but
easily distinguished from a pure salt where a non-
volatile neutral compound is absent from the crystal structure
(Figure 1). Moreover, it includes the possible, although rare,
non-stoichiometric cocrystals, where excess amount of one
of the coformers fill the spaces, for example, channels, in the
crystal structure formed by the coformers in stoichiometric
ratio [8]. Simple solid solutions, where the guest molecularly
distributes in the host crystal, are not considered as cocrystals
by this definition if the crystal is formed by a single compo-
nent. However, it is possible that a molecular solute can
form a solid solution in a host cocrystal.
2.1Racemic cocrystals
Since enantiomers are structurally distinct molecules, racemic
compounds between two opposite enantiomers are cocrystals [9].
2 Expert Opin. Drug Deliv. [Early Online]
Some examples of drugs marketed in the form of racemic
cocrystals include: atenolol, atropine, certirazine, disopyramide,
fluoxetine, ketoprofen, loratadine, modafinil, omeprazole,
warfarin and zopiclone. With the technological development
in chiral separation, single enantiomer synthesis and analysis,
the development of individual stereoisomers has been preferred
over racemic compounds by the pharmaceutical industry [10].
This trend in chiral drug development has been driven by
both economical incentives and regulatory guidance on the
basis of the potentially different pharmacokinetics and pharma-
cological effects of different enantiomers [11]. The switch from
a racemic compound to a pure enantiomer, termed chiral
switching, highlights the possible deteriorative effects of cocrys-
tallization in drug properties and performance. Such racemic
cocrystals have been extensively studied and are well known
to pharmaceutical scientists [12,13]. The author will therefore
not focus on this special class of cocrystals to limit the length
of this discussion.
2.2 Cocrystal--salt continuum
A clear distinction between a neutral drug molecule and its
ionic counterparts is whether or not complete proton transfer
has taken place. Hence, discerning a cocrystal from a salt
may seem straightforward. However, the transfer of proton
between two compounds in a crystal depends on their
chemical nature, that is, the acidity of proton donor and
basicity of the proton acceptor. The position of proton
between two components can be continuous, ranging from
covalently bonded to the donor molecule to covalently
bonded to the acceptor molecule. Partial proton transfer, or
shared proton, between a donor and an acceptor has been
observed [14]. The position of a proton can also shift with
temperature between the same pair of acid and base [15].
Moreover, the extent of proton transfer is affected by the
packing patterns of molecules in the crystal of polymorphs
and hydrates [16,17]. Clearly, the transition from salt to cocrys-
tal is a smooth rather than abrupt process [16]. This leads to
the difficulty in defining complete proton transfer and classi-
fying certain crystals as cocrystal or salt. Moreover, piroxicam
is in either neutral or zwitterionic forms in the two poly-
morphs of its 1:1 cocrystal with 4-hydroxybenzoic acid [18].
The discovery of a class of crystals formed between API conju-
gated acid--base pairs (CAB), that is, two compounds differring
by one proton, at a defined stoichiometric ratio further
discredits any attempt to separate cocrystal from salt [19,20].
There will necessarily be an overlap between the definition
of salts and cocrystals, which may be termed salt cocrystal
(Figure 1). Salt cocrystal here refers to a crystal formed
between a neutral compound and a salt, which may or may
not be the salt of the neutral compound. It includes the
CAB cocrystals and cocrystals formed between an inorganic
salt and a neutral coformer, known as ionic cocrystals [21].
Consistent with the structural continuity, properties of
cocrystals and salts are similar in many ways. For example,
both salts and cocrystals generally have defined stoichiometries

1. Hydrate of cocrystal
2. Salt cocrystal
3. Hydrate of salt
Cocrystal 4. Hydrate of salt cocrystal
1 A key challenge in drug delivery is the poor bioavailability
2
4
Hydrate
Salt
3 dissolution rate of a poorly soluble drug [23,27-32]. For exam-
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Figure 1. Relationship among cocrystal, hydrate and salt.
and their solubility is sensitive to the common-component effects
(common ion effects for salts and common coformer effects
for cocrystals). They are both characterized by the solubility
product (Ksp) and a pHmax [22,23]. These similarities support
the view that pharmaceutical cocrystals and salts should be clas-
sified and regulated in similar way during new drug product
review and approval [24]. In the search for superior solid forms
of a drug, ones mind should be free from the artificial divide
between salt and cocrystal set by criteria, such as DpKa between
the two reacting species. Instead, the focus should be put on
For personal use only.
discovering multicomponent solid forms of a drug with all
suitable chemicals in hand. Such a practice will lead to the
discovery of a larger number of solid forms of a given drug.
Consequently, it is more likely to find an optimum solid
form for drug formulation and development.
3.Impact of cocrystallization on drug
properties and performance
Each new cocrystal of any drug will exhibit a unique set of
properties as expected by the structure--property relationship
in materials science [25]. Recent research has focused on
demonstrating the advantages of cocrystals in the context of
clinical performance and manufacturability. However, the
changes in physical, chemical and mechanical properties of a
drug introduced by cocrystallization are not always beneficial.
Of course, whether or not a change is useful to drug delivery
depends on various factors, such as intended route of admini-
stration, drug release profiles and manufacturing process. For
example, high solubility is desired for fast release of a drug.
However, a cocrystal with lower solubility may be desired
for slow and sustained release of a drug. Most case studies
have shown the improvement by cocrystallization in certain
pharmaceutical properties that are problematic for product
development of individual APIs. However, if the solution
to one problem leads to deterioration in other properties,
the fix is not practically meaningful. In this sense, the
pharmaceutical industry will benefit from work focusing
on simultaneous improvement, or at least lack of deteriora-
tion, of all key properties by cocrystallization [26]. The
following discussion provides a summary of recent work
Expert Opin. Drug Deliv. [Early Online]
Cocrystallization for successful drug delivery
concerning the impact of cocrystallization on key drug
properties and performance.
3.1 Solubility, dissolution rate and bioavailability
caused by solubility and dissolution limited drug absorption.
Cocrystallization may either enhance or reduce solubility or
ple, cocrystallization with benzoic acid reduces the solubility
of fluoxetine HCl but succinic acid and fumaric acid cocrys-
tals exhibit enhanced solubility [32]. The aqueous solubility
of the coformers (organic acids) qualitatively correlates with
the aqueous dissolution rates of the cocrystals [32]. This trend
is consistent with the observation that solubility of cocrystals
to parent drug increases with the solubility ratio of the
coformer to drug for several APIs [27]. It is important to point
out that cocrystals can be less soluble than their parent drugs.
A unique example of the deteriorated solubility by cocrystalli-
zation is the melamine and cyanuric acid 1:1 cocrystal.
Neither compounds are toxic when digested separately even
at high doses. However, a single dose exposure of 32 mg/kg
of each coformer leads to acute kidney problem because the
two coformers react to form the 1:1 cocrystal, which is poorly
soluble [33]. This is the reason of the acute renal failures in pets
when foods contaminated with both compounds were con-
sumed. Although not yet widely investigated, there is the
potential for similar problems to occur in humans, especially
for patients taking multiple drugs to battle several chronic
clinical conditions. It is possible that drugs and drug meta-
bolites may form cocrystals with extremely low solubility,
which may lead to kidney stone formation and other
health problems.
In parallel to the dual effects on solubility and dissolution
rate, cocrystallization may similarly lead to either negative or
positive effects on bioavailability of APIs. However, literature
examples generally show improved bioavailability by cocrys-
tals [8,29,34]. For example, the bioavailability of a sodium
channel blocker in dogs was significantly improved by a gluta-
ric acid cocrystal [34]. This trend is likely driven by the general
desire to enhance the bioavailability of poorly soluble com-
pounds. Hence, only cocrystals exhibiting higher solubility
and faster dissolution are tested for bioavailability. This
practice is at least partially driven by the high costs involved
in conducting an appropriately designed pharmacokinetic
study.
3.2 Physical and chemical stability
The ability of cocrystals to address physical instability prob-
lems of drugs, such as hydrate formation on exposure to
high relative humidities (RH), is one of the earliest demon-
strated advantages of cocrystallization [35,36]. The chemical
stability of an API may be different from its cocrystals simply
because of the different spatial arrangements of reacting func-
tional groups in the crystals. The different melting points of
the cocrystal (either lower or higher) and coformers [37] may
3
 C. C. Sun
HO
O NH2
O O
S Cl
O NH
NH
S H
HO
O O
O O
OH
A B
Figure 2. Molecular structures of A) saccharine, B) acesulfame, C) sucralose and D) aspartame.
also contribute to different stability behaviors at elevated
temperatures. Literature examples generally favor chemical
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stability enhancement by cocrystallization. For example,
nitrofurantoin under stressed conditions (elevated RH and
temperature) or ultraviolet light exposure was improved on
cocrystallizing with 4-hydroxybenzoic acid [38]. The stability
of adefovir dipivoxil was improved through cocrystallization
with saccharin [30]. Chemical stability deterioration by
cocrystallization has been rarely reported in pharmaceutical
literature. Such observations are likely treated as negative
outcomes that dampen the enthusiasm of industrial scientists
in publishing them. However, cocrystals have been used as
intermediates for solid-state synthesis of molecules that
are difficult to obtain through solution chemistry [39]. For
For personal use only.
example, templated cocrystals undergo highly efficient
photodimerization for the synthesis of ladderane [40]. It is
perceivable that some of pharmaceutical compounds may
form cocrystals that are open to this and other types of
solid-state reaction. If so, the chemical stability of the drug
is impaired on cocrystallization.
3.3 Mechanical properties
Mechanical properties of APIs affect key industrial manufac-
turing processes, such as milling and compaction [41-43].
Deficient mechanical properties often lead to problems in
tablet formulation and manufacture. Tablet tensile strength is
controlled by both bonding area and bonding strength between
particles [44]. A crystal with very low plasticity suffers from poor
tabletability because very small bonding area is developed by
compaction. In that case, improved crystal plasticity by cocrys-
tallization usually leads to better tabletability. This is shown by
a 1:1 cocrystal between caffeine and methyl gallate, which
exhibits better tableting performance than both coformers [45].
Cocrystallization also improved compaction properties of acet-
aminophen and two profens [26,46]. However, if an API crystal
is more plastic than corresponding cocrystals, cocrystallization
may lead to deteriorated tableting performance. For example,
the cocrystallization with methyl gallate deteriorated tableting
performance of theophylline [47]. It is also possible that poor
tabletability is caused by low bonding strength, even if bonding
area is large for a plastic API. If so, cocrystals with lower
plasticity but much higher bonding strength can still be used
to improve powder tabletability of the API. Hence, the effects
of cocrystallization on tableting performance depend on
the relative crystal plasticity and bonding strength between
4 Expert Opin. Drug Deliv. [Early Online]
O
OH
HO
O
O Cl
N
OCH3
O O OH
Cl
C D
the coformers and the cocrystal. The effects of cocrystallization
on crystal mechanical properties may be assessed based on
several known structure--property relationships. A crystal with
a flat-layered structure tends to be plastic and larger inter-
layer distance usually leads to higher plasticity [25,48-50]. Crystals
with layers formed by stacking hydrogen bonded molecular
columns, which can take different shapes, for example, V
and Z, are generally more plastic than those with rigid two-
dimensional hydrogen bonded layers [26,47]. On the other
hand, crystals with extensive three-dimensional hydrogen
bond network or interwoven rigid layers generally exhibit low
plasticity and poor tabletability [50]. The studies of mechanical
properties of a series of structurally related cocrystals will
be extremely useful in the quest for a clear understanding
of the relationship between crystal structure and mechanical
properties.
3.4 Sweet cocrystals
Saccharine is an artificial sweetener commonly used in foods
and drinks. As a relatively strong organic acid, with a pKa of
1.6 [51], it has been used for preparing pharmaceutical salts
and cocrystals [52]. A number of saccharine cocrystals with
poorly ionizable drugs, such as carbamazepine [53], ethenza-
mide [54], indomethacin [55], piroxicam [56], spironolactone [57]
and theophylline [58] have been reported. It is possible that
saccharine cocrystals exhibit better taste profiles than their
parent drugs alone, especially if the cocrystal has lower
aqueous solubility. If so, one can prepare sweet cocrystals to
alleviate the problem of delivering bitter, or other unpleasant
tastes, APIs to non-compliant patients, such as infants and
young children. Sweet cocrystals are beneficial for developing
chewable tablets, oral suspensions or solutions with the poten-
tial for new intellectual properties. In the same direction,
other effective artificial sweeteners fit for human consump-
tions may also be used. Some other artificial sweeteners, for
example, aspartame, acesulfame and sucralose, are also poten-
tially good coformers for preparing sweet cocrystals because of
the multiple hydrogen bond acceptors and donors on these
molecules (Figure 2).
3.5Other opportunities
Cocrystals formed between two or more drugs offer a conve-
nient way for combo therapy and intellectual property
opportunities [59-61]. Although therapeutic efficacies of both
drugs have been individually demonstrated, a product using

A.
Cocrystal solubility curve
API concentration, mM
Evaporation line
CS,A
1
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CS,B
Coformer B concentration, mM
Figure 3. Phase solubility diagram of a cocrystal in relation to saturation solubility of the two coformers. Solubility lines of
the two coformers cross at a point A) below, or B) above, the solubility curve of the cocrystal. The cocrystal is always
metastable in A). The cocrystal is stable in the shaded stable cocrystal zone (SCZ) in B), but metastable outside of SCZ.
the new solid form between two drugs still needs to be
rigorously tested to ensure safety, bioavailability, stability
and manufacturability. Other than marketed drugs,
compounds exhibiting pharmacological effects sold as nutra-
ceuticals have also been investigated for cocrystal formation
For personal use only.
with both common coformers and marketed drugs [62-64].
Not surprisingly, solubility of the nutraceutical compounds
can either increase or decrease depending on coformers
used [63,64].
4. Preparation methods
With the widespread acceptance of cocrystals in drug develop-
ment because of their potential advantages to drug delivery, it
is becoming a routine exercise in the pharmaceutical industry
to screen for new cocrystals of APIs under development. For
pharmaceutical cocrystals, coformers must not be toxic.
Hence, a simple default routine is to crystallize a drug with
compounds classified as generally recognized as safe (GRAS)
for use as food additives.
4.1 Solvent-mediated cocrystallization
The solution crystallization is a prevailing approach in
preparing commercial scale pharmaceutical cocrystals, in
part, because of the availability of solution crystallization
equipments in pharmaceutical manufacturing plants. Typi-
cal cocrystal screening is performed by solution crystalliza-
tion in pharmaceutical industry, especially when single
crystals are desired for crystal structure elucidation. How-
ever, the outcomes of cocrystallizing from a solution are
not always predictable. A frustrating aspect of solution
crystallization is, sometimes, its inability to prepare a
cocrystal that has been observed by other means, for
example, thermal treatment and grinding. To understand
the mechanism of success or failure of cocrystallization
Expert Opin. Drug Deliv. [Early Online]
Cocrystallization for successful drug delivery
B.
API concentration, mM
SCZ 1
Coformer B concentration, mM
from solutions, a consideration of the phase solubility
diagram of cocrystals is required [22].
In the solution saturated with a cocrystal between an API
(A) and a coformer (B), the processes of dissociation of
the cocrystal and association between A and B are in
equilibrium (1):
(1)
A a Bb ( solid ) aA ( solution ) + b B(solution)
Where a and b are the respective stoichiometric numbers of A
and B in the cocrystal AaBb. In this system, concentrations of A
and B, [A] and [B], can vary but the solubility product, Ksp, is
approximately constant at a given temperature as shown in (2):
(2)
a b
K sp [A] [B]
It follows from (2) that [A] decreases with increasing [B] for a
given cocrystal following a cocrystal solubility curve as illus-
trated in Figure 3. The cocrystal will dissolve if the solution
composition is below the cocrystal solubility curve and grow
if above the solubility curve.
Let the saturation solubility of A and B be Cs,A and Cs,B,
respectively. Point 1 defined by Cs,A and Cs,B falls below the
solubility curve in Figure 3A. This means that a solution satu-
rated with the cocrystal is supersaturated with one or both of
the coformers. In this case, cocrystal is unstable and tends to
convert into pure A, pure B or both when suspended in the
solvent. When Point 1 is on or above the solubility curve
(Figure 3B), the cocrystal is stable if the solution composition
is within the stable cocrystal zone (SCZ, shaded), where
the solution is undersaturated to both pure A and B phases
but is supersaturated to the cocrystal. The API or the
coformer precipitates out if the solution composition lies
outside of SCZ and above the solubility of either the API or
5
 C. C. Sun
the conformer (Figure 3B). This explains the phenomenon
of cocrystal disproportionation, where one or both coformers
are spontaneously formed when a cocrystal is suspended in
a solvent. The solution concentration of the precipitating
coformer(s) is the same as its saturation solubility under
these conditions. It is possible that solubility of one coformer is
affected by the presence of the other coformer in solution.
However, this effect does not affect the use of the phase diagram
in understanding the process of solution cocrystallization.
In the case of cocrystallization by solvent evaporation, for
example, for growing single crystals, the cocrystal is formed
if the drying curve passes the shaded SCZ. However, if
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the drying line misses the SCZ, either A or B will precipitate
out before cocrystal is formed. The slope of the drying line is
determined by the ratio of the two coformers in the initial
solution. It is immediately clear that, regardless of the size of
SCZ, the drying line will always reach SCZ if the initial
concentration ratio between A and B is equal to Cs,A/Cs,B. It
follows that the most favorable experiment for growing phase
pure cocrystals is to start with a solution with the coformer
concentrations at the ratio of Cs,A/Cs,B. This is especially
important when the area of SCZ is very small, where a small
deviation leads to the potential crystallization of one of the
coformers. It is also clear that the use of a solution with the
For personal use only.
coformers at the stoichiometric composition of the cocrystal
is justified only if it corresponds to the solubility ratio of the
two coformers in the solvent of crystallization, which is usu-
ally not the case. To reliably grow cocrystal between a poorly
soluble drug and a soluble coformer, the initial concentration
of the coformer should be accordingly higher than that of the
drug to avoid the crystallization of the drug. If one prefers to
use 1:1 ratio for cocrystallization, the solvent should be care-
fully selected so that the solubility of the two components is
approximately the same. If a solvent mixture is used, it should
be made aware that different vapor pressures of the consti-
tuting solvents may lead to change in the composition of
the solvent over the course of solvent evaporation, which
may lead to a change in solubility ratio of the coformers.
Similarly, the initial concentration ratio between the cofor-
mers should also be the same as Cs,A/Cs,B when preparing a
cocrystal by cooling a solution of the two coformers.
When suspending both coformers in the same solvent,
the cocrystal can be formed as long as point 1 is above the
cocrystal solubility curve. This situation is analogous to the
preparation of the most stable polymorph by suspending
the metastable polymorph in an appropriate solvent [65]. The
thermodynamic certainty makes it an excellent method for
screening cocrystals by slurrying [66]. The scalability of
this simple process also makes it an appealing option for
large-scale manufacture of cocrystal API. This process may
not work well if the conversion kinetics is very slow because
one or both coformers exhibit very low solubility in the
chosen solvent.
For a system where point 1 is below cocrystal solubility
curve, the cocrystal is metastable. Hence, cocrystallization is
6 Expert Opin. Drug Deliv. [Early Online]
possible only by manipulating kinetic factors. The key to pro-
ducing metastable cocrystal is to induce the condition of high
supersaturation, similar to the successive crystallization of
polymorphs described by the Ostwalds rule of stage. This
may be achieved by rapid cooling, fast solvent removal or
anti-solvent addition. If the concentrations of the two
coformers can be elevated, for example, by heating, above
the cocrystal solubility curve at the lower temperature, rapid
cooling may lead to the formation of the metastable cocrystal.
On the other hand, if the solvent can be rapidly removed so
that the individual coformers do not have sufficient time to
crystallize, the metastable cocrystal may be produced. This
strategy has been successfully used to prepare metastable
cocrystals [26,67]. In this direction, supercritical fluid (SCF)
serves as anti-solvent for an API, when mixed with an organic
solvent. When sprayed, the rapid expansion of SCF leads to
rapid removal of solvent to further increase the degree of
supersaturation in the solution [68].
Similar to the observed solvent effects on salt formation,
where a HCl salt of weakly ionizable drugs can be formed
when crystallized from less polar organic solutions but not
from water [19], outcomes of cocrystallization experiments
are also expected to be affected by solvent. The crystallization
of a stable cocrystal is likely favored when the two cocrystal
formers, A and B, interact more strongly than the interactions
between A-solvent, B-solvent, A-A or B-B.
4.2 Solid-state cocrystallization
If solution-based cocrystallization fails for some reasons, one
can use solvent-free methods, such as solid-state cogrinding
and thermal treatment, to prepare cocrystals.
Cocrystallization by grinding, or mechanochemical reac-
tion, is mediated by mechanisms such as the formation of
amorphous phase, vapor diffusion and eutectic melting [69-71].
Each of these mechanisms leads to increased molecular mobi-
lity of coformers. When the vapor diffusion is the mechanism,
cocrystal can form on the surfaces even without grinding if the
vapor pressure of the coformer is high. Of course, the more
intimate contact between coformers by grinding enhances
the rate of reaction.
Mechanical treatment can lead to amorphization of many
organic crystals [72]. If the amorphous phase mediates
the reaction, the presence of a small amount of residual
solvent expedites the cocrystal formation rate by increasing
molecular mobility of the amorphous phase through the
effect of depressed Tg [69]. In a process termed liquid-assisted
grinding (LAG), some solvent is added to the powder
mixture during grinding. Although the exact mechanism
is still not known, LAG is significantly more effective in
generating new cocrystals than neat grinding [73,74]. LAG is
different than the simple plasticizing effects by residual
solvent in that liquid solvent is present in the system to
form a solution on the coformer particles. The LAG may
be viewed as a milling-facilitated slurry process, that is, the
combination of neat grinding and solution-mediated

transformation. Here, milling not only directly leads to coc-
rystallization via the solid-state amorphization route but also
facilitates the solution-mediated reaction because of the large
surface area of fragmented coformer crystals. This may be a
reason why LAG is much more efficient and effective than
dry milling.
When the eutectic melting mechanism is in effect,
cocrystal may be produced by heating the mixtures to above
eutectic point but below melting point of the cocrystal.
Eutectic melting results in a liquid phase containing reac-
ting coformers, where molecules have sufficient mobility
to cocrystallize. This property is the basis of an empirical
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cocrystal screening method using differential scanning
calorimetric (DSC) method [58]. If two compounds form
a cocrystal, DSC thermogram will show a eutectic melting
endotherm followed by a cocrystal melting endotherm on
heating. The cocrystallization exotherm is likely masked
by the concurrent eutectic melting. Such phase transition
events can be visualized by employing the hot stage micros-
copy [75]. From the industrial point of view, cocrystalliza-
tion based on this mechanism can be realized using
scalable processes such as hot melt extrusion using a twin
screw extruder, which has the ability to perform mixing at
elevated temperatures [76].
For personal use only.
4.3 High-throughput cocrystal screening
High-throughput screening was once a leading approach
for discovering new cocrystals. Unfortunately, a platform
required for the high-throughput screening is expensive
to acquire. The capital investment on high-throughput
screening was justified in early period of pharmaceutical
cocrystal research when the science had not been well devel-
oped to guide cocrystal screening. Hence, the chance of
discovering a new cocrystal is increased statistically by
conducting a large number of experiments. High-
throughput remains a useful tool to pharmaceutical industry
at the present. However, it will lose its appeal when the
science pertaining to cocrystallization is more mature.
Instead, cocrystal design using the supramolecular synthon
and retrosynthetic approach is expected to grow [77]. In this
approach, a crystal, also termed supramolecule, is assembled
from molecules through specific intermolecular interactions
dictated by both chemical and geometric properties of the
molecules. The future of cocrystallization research will
significantly benefit from the discovery of new synthons,
which are structural units for building a crystal. Such
knowledge and the ever improved computational power
are expected to bring us closer to the goal of delineating
cocrystal landscape of a drug in silico. When the ability in
crystal structure design and prediction improves, the high-
throughput approach will be gradually marginalized. Never-
theless, the diverse crystallization conditions provided by
high-throughput screening experiments sometimes lead
to exciting serendipitous discoveries. One example is the
discovery of the elusive polymorphs of aspirin during
Expert Opin. Drug Deliv. [Early Online]
Cocrystallization for successful drug delivery
a high-throughput cocrystal screening study [78]. Such
serendipities remind us of the complexity of the crystalliza-
tion processes and the beauty of crystallization research.
Mechanistic understanding of crystal nucleation and
growth is a direction for crystallization in general and for
cocrystallization in particular.
5. Future trend in cocrystal research
5.1 Polymorphism of cocrystal
One proposed advantage concerning cocrystallization is
their lower tendency to polymorphism than respective
coformers [61,79]. However, such a proposition was merely
speculated based on a selected set of compounds. Just like
salts, which can be polymorphic, cocrystal can also exhibit
polymorphism. In certain cases, it may be possible that a coc-
rystal may exhibit more complex polymorphism than individ-
ual coformers because of a larger number of possible spatial
arrangements of multiple molecules in the crystal. An increas-
ing number of polymorphic cocrystals have been discovered in
recent years [18,53,60,80-82], some of which are trimorphic [60,82].
The emerging polymorphism of cocrystals is a natural out-
come of the growing number of cocrystallization experiments
made. Whether the coformers or the cocrystal is more
polymorphic depends on which one gives higher structural
flexibility when crystallizing. Thus, tendency to polymor-
phism is linked to the total number of energy minima readily
accessed by molecules but not to whether the crystal is
composed of single or multiple components. In this context,
it is advisable to screen, characterize and control polymorphs
of a drug cocrystal similar to that for single component
polymorphs [83].
5.2 Higher-order cocrystals
The screening of cocrystals for an API is usually targeted for
two component crystals, that is, the drug and one coformer.
The formation of hydrates or solvates, sometimes serendipi-
tously, of two component cocrystals [11] suggest the possibility
of preparing ternary [84,85], quaternary [86] and possibly even
higher-order cocrystals. Such structures can, in theory, signi-
ficantly expand the solid-state landscape of drugs. However,
research in this direction is still in the nascent stage and few
examples have been reported, perhaps because of the relatively
fewer attempts in preparing them. One strategy is to cogrind
multiple compounds employing LAG [73,87]. This approach
allows the use of coformers without the challenge of dissolving
multiple compounds in a solvent, which is a prerequisite for
solution-based crystallization. Hence, a much larger space is
accessible for exploration than what solution crystallization
can afford. Some design strategies have also been proposed,
which can be used to guide the LAG experiments. One
strategy is based on hydrogen bonding preference, where a
ditopic base with two potential H-bond accepting sites to
react with two acids of different strengths. A ternary cocrystal
is formed when the stronger H-bond donor in the acid
7
 C. C. Sun
interacts with the stronger hydrogen bond acceptor site in the
base and the weaker donor (acid) interacts with the weaker H-
bond acceptor site [88]. Another design strategy is to replace a
weakly bonding molecule in a binary cocrystal with a mole-
cular mimic. When a molecule in a binary cocrystal does
not interact strongly with other molecules, that is, a space
filler, another molecule that is similar in size and shape can
replace it to form a ternary cocrystal without significantly
disrupting the crystal structure [89].
5.3 Salt cocrystals
The charge-facilitated strong H-bonds hold the potential for
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Sussex Library on 01/17/13
preparing cocrystals between a CAB pair [20]. Wide applicabi-
lity of this approach in API cocrystal design is expected in
light of the recent examples of salt formation of molecules
that had been traditionally thought as non-ionizable [19,48].
Unlike the cocrystals formed with a chemically distinct
neutral coformer, CAB cocrystals of an API have the advan-
tages of high potency. This will likely favor the formulation
and manufacturing of drug products because of the extra for-
mulation space available to excipients when delivering a
desired dose. CAB cocrystals can also mitigate hygroscopicity
problem of a salt due to the incorporation of hydrophobic
drug molecules in the crystal of the salt. One example is the
For personal use only.
valproate hemi sodium salt [90,91]. Other possible examples
likely come from CAB cocrystals between hygroscopic salts,
for example, HCl and sodium salts, and corresponding neu-
tral bases or acids. Typical API CAB cocrystals require the
presence of both neutral and ionized drug molecules in the
crystal structure. In absence of crystal structure data, vibra-
tional spectroscopy can be used to identify the formation of
CAB cocrystals since spectroscopic signatures of both the neu-
tral molecule and salts can be observed, though with slight
modifications due to the hydrogen-bonding interactions
between them [92,93]. The CAB cocrystals of an API should
not be confused with cocrystals where coformer, instead
of the API, is present in both ionic and neutral forms in
the cocrystal [94-96]. Moreover, CAB cocrystal should also be
distinguished from cocrystals between a neutral molecule
and inorganic salts [21,97].
5.4 Other aspects
It has been known that chemical impurities can act as nucle-
ation and growth inhibitors and hence promoting the forma-
tion of stable glasses [98]. Studies on vitrification of cocrystal
melts may yield interesting insights that help to better under-
stand the crystallization of organic molecules since one
coformer is effectively a chemical impurity to the other. It is
likely that cocrystal glasses are more resistant to crystallization
than the pure drug in general. This can potentially translate
into a new strategy for delivery poorly soluble drugs, taking
advantage of the higher free energy of amorphous solids.
When cocrystal glasses are used for drug delivery, the mecha-
nical properties of cocrystal glasses are of importance because
the solubility advantage of amorphous glasses can be realized
8 Expert Opin. Drug Deliv. [Early Online]
only for oral solid dosage forms. The unintended cocrystal
formation during formulation [99] and storage [100] is another
topic of pharmaceutical importance. A common feature
among examples of unintended cocrystallization is the phase
transition mediated by a liquid phase, either formulation
vehicle or water. Water may come from the deliquescence or
dehydration of one of the formulation components during
storage [100,101]. Similarly, cocrystal disproportionation may
also occur when a liquid phase is present during the life
time of a cocrystal. Both problems can be avoided by imple-
menting proper strategies, for example, protective packaging,
to isolate drug product from liquids. Thermodynamics of
cocrystallization is another direction that is important for a
clear understanding of cocrystals. Besides solubility phase
diagram, the direct measurement of enthalpy of cocrystalliza-
tion is expected to play an important role in this direction
since it is required for deriving free energy of cocrystalliza-
tion [102]. Finally, as a key element for achieving the ultimate
goal of in silico design of new cocrystal with desired pharma-
ceutical properties, computational cocrystal screening and
structure prediction will continue to advance following
the recent significant progress [103,104]. A more rewarding
direction is likely the development of reliable computational
methods capable of yielding accurate relative lattice energy.
6. Conclusions
The cocrystal is a class of materials holding potential to address
problems in drug delivery. The new crystal structures of an
API cocrystal may lead to either enhanced or deteriorated
pharmaceutical properties. The cocrystallization is useful only
when it improves the problematic property without impairing
other properties. Hence, all key pharmaceutical properties
must be considered during cocrystal screening and evaluation.
The solubility phase diagram of the cocrystal and coformers
can be used to explain stability of cocrystal in presence of a
solution and guide robust preparation of a cocrystal by solution
crystallization. The effectiveness of liquid-assisted grinding in
cocrystallization is a result of the combined advantages of
solid-state grinding and solution-mediated phase transforma-
tion. Future advancement in cocrystal research will occur in
the areas of cocrystal polymorphism, higher-order cocrystal,
salt cocrystal and glassy cocrystal.
7. Expert opinion
Cocrystals is a class of material that has been known for a long
time by the science community. Despite the relatively recent
interest in pharmaceutical applications of cocrystals, numer-
ous examples have well established its potential in overcoming
drug delivery problems, ranging from drug stability to
bioavailability and to manufacturing. A current challenge in
cocrystal research is the empiricism in discovery and produc-
tion of cocrystals despite significant progress in cocrystal
design in the recent decade. It is highly desired to move

cocrystal discovery from screening against a large number of
coformers to reliable design of new cocrystals based on inter-
molecular interactions, for example, hydrogen bond-based
synthon approach. A discovery of new and robust synthons
for designing new cocrystals will be extremely useful. To
that end, salt cocrystals formed between CAB pairs through
charge-assisted strong hydrogen bonding interaction promises
to expand solid-state landscape of ionizable drugs and will see
a rapid expansion in their synthesis and characterization in the
near future.
Because the structural diversity created by cocrystallization
leads to either improved or deteriorated properties, the effi-
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Sussex Library on 01/17/13
cient design of cocrystal for solving drug delivery problems
rests on understanding the structure--property--performance
relationships of cocrystals, which is critical for reaching the
ultimate goal of computer-based design of new cocrystals
with desired pharmaceutical properties. Progress toward this
goal is hindered by the relatively few reports, especially those
authored by industrial scientists, on property deterioration by
cocrystallization. A strategic shift from property enhancement
to property modulation and from simple case report of new
cocrystals, sometime discovered serendipitously, to systematic
design of cocrystals will greatly benefit the future cocrystal
research. Another hindrance is general requirement of high
For personal use only.
quality single crystals for structure elucidation of cocrystals.
Advances in structure elucidation by powder X-ray diffraction
will accelerate cocrystal research as well as other areas of
crystal engineering. Progress in computer-based structure
prediction of cocrystal will also be extremely useful.
For cocrystals to be industrially useful, the robust prepara-
tion of bulk cocrystal powders is a prerequisite. Research
on bulk cocrystallization must address the issues of preparation
Expert Opin. Drug Deliv. [Early Online]
Cocrystallization for successful drug delivery
efficiency, environmental impact, purity and stability. A clear
understanding of both kinetic factors and thermodynamics
underpinning the stability of cocrystals relative to coformers,
both in solution and in solid state, is a key to successful
preparation of bulk cocrystals.
Being only in their nascent stage, research in the design and
preparation of ternary and higher-order cocrystals will be both
fruitful and impactful. A systematic study of polymorphism in
cocrystal is another important area, which will elevate not
only cocrystal research but also crystal engineering as a whole.
To that end, strategies or methods capable of reliably produc-
ing metastable polymorphs of a cocrystal will be extremely
valuable. Studies on glassy cocrystals will further expand our
understanding in the formation, growth and structure--
property relationship of cocrystals. As the cocrystal research
matures and drug cocrystals move through the development
process, a clear framework for the review and approval of
cocrystal-based drug product by the regulatory authority
is critically important. Any policy regulating cocrystal
drug product approval will have a far-reaching impact on
cocrystal research.
Acknowledgements
The author would like to thank S Chattoraj, SR Perumalla
and L Shi for useful discussion during the course of the
manuscript preparation.
Declaration of interest
The author states no conflict of interest and has received no
payment in preparation of this manuscript.
9
 C. C. Sun
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Affiliation
Changquan Calvin Sun PhD
University of Minnesota,
College of Pharmacy,
Department of Pharmaceutics,
9-127B Weaver-Densford Hall,
308 Harvard Street S.E.,
Minneapolis, MN 55455, USA
Tel: +1 612 624 3722;
Fax: +1 612 626 2125;
E-mail: sunx0053@umn.edu
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