Kale, Bansal, JPS, 2016, Challenges in Development of Pharma Cocrystals

Journal of Pharmaceutical Sciences xxx (2016) 1-14
Contents lists available at ScienceDirect
Journal of Pharmaceutical Sciences

journal homepage: www.jpharmsci.org
Commentary
Challenges in Translational Development of Pharmaceutical Cocrystals

Dnyaneshwar P. Kale, Sandeep S. Zode, Arvind K. Bansal*
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2016
Revised 1 October 2016
Accepted 21 October 2016
The last 2 decades have witnessed increased research in the area of cocrystals resulting in deeper scientic understanding, increase in intellectual property landscape, and evolution in the regulatory
environment. Pharmaceutical cocrystals have received signicant attention as a new solid form on account of their ability to modulate poor physicochemical properties of drug molecules. However, pharmaceutical development of cocrystals could be challenging, thus limiting their translation into viable
drug products. In the present commentary, the role of cocrystals in the modulation of material properties
and challenges involved in the pharmaceutical development of cocrystals have been discussed. The major
hurdles encountered in the development of cocrystals such as safety of coformers, unpredictable performance during dissolution and solubility in different media, difculties in establishing in vitroein vivo
correlation, and polymorphism have been extensively discussed. The inuence of selecting appropriate
formulation and process design on these challenges has been discussed. Finally, a brief outline of cocrystals that are undergoing clinical development has also been presented.
2016 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.
Keywords:
cocrystals
physicochemical properties
preformulation
formulation
crystal engineering
clinical trials
Introduction: Denition and Theoretical Aspects of Cocrystals

Cocrystals, although reported for long in literature, became
popular only after 1990 when M.C. Etter extensively studied the
role of hydrogen bond as a design element in the preparation of
multicomponent crystals.1,2 Attempts have been made to dene
cocrystals by the scientic community as well as by regulatory
bodies. United States Food and Drug Administration (FDA) dened
cocrystals as dissociable API-excipient molecular complexes (with
the neutral guest compound being the excipient called coformers)
wherein both API and excipients are present in the same crystal
lattice.3 This denition by FDA in their guidance document has
been a matter of debate and its consequences were thoroughly
discussed in Indo-US Bilateral Meeting by several leading academic
and industrial groups working in the area of cocrystals.4 In a more
recently published draft guidance by FDA, cocrystals are dened as
crystalline materials composed of two or more different molecules
within the same crystal lattice that are associated by nonionic and
noncovalent bonds.5 It is also stated that if the solid form in a drug
product is a new cocrystal entity, it is considered as a new polymorph (solvate/hydrate) of the active pharmaceutical ingredient
(API). The scientic community has dened cocrystals as solids
* Correspondence to: Arvind K. Bansal (Telephone: 91-172-2214682-2126;

Fax: 91-172-2214692).
E-mail address: akbansal@niper.ac.in (A.K. Bansal).
that are crystalline single-phase materials composed of two or

more different molecular and/or ionic compounds generally in a
stoichiometric ratio, which are neither solvates nor simple salts.4
This denition excludes simple salts, hydrates, and solvates. However, from supramolecular perspective, the solvates or hydrates
could be cocrystals in the case of solvated/hydrated salt cocrystals.6,7 Notably, the multicomponent systems such as solid solutions, inclusion complexes, and dispersions are not encompassed in
this recently proposed denition of cocrystals. European Medicines
Agency has adopted a similar denition in their reection paper,
which dened cocrystals as homogenous (single phase) crystalline
structures made up of two or more components in a denite stoichiometric ratio, where the arrangement in the crystal lattice is not
based on ionic bonds, and components of a cocrystal may nevertheless be neutral as well as ionized.8 Denitions by FDA present a
simplistic view whereas other denitions include additional
supramolecular features of cocrystals.
Cocrystal formation can be designed by applying the principles of
supramolecular chemistry to manipulate solid-state properties of an
API. Design strategies for cocrystals have been presented in many
excellent publications and interested readers can refer them.9-12 It
mainly consists of selecting a suitable coformer based on the presence of compatible supramolecular synthon in the molecule of
interest.6 When same complementary functional groups are present
between 2 molecules, such complexes are called as supramolecular
homosynthons (carboxylic acid-dimer, amide-dimer), whereas
heterosynthons form between different but complementary
http://dx.doi.org/10.1016/j.xphs.2016.10.021
0022-3549/ 2016 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.
D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14
functional groups (carboxylic acid-amide, carboxylic acid-aromatic

nitrogen, alcohol-aromatic nitrogen, and alcohol-amine). Cambridge Structure Database (CSD) helps in identifying hydrogenbonding interactions and synthon competition in organic crystals
of interest. It has been reported through CSD survey that probability
of occurrence of carboxyl-pyridine heterosynthon is more likely
y,14,15 Vishweshwar,16
than that of acid-acid homosynthon.13 Aakero
17
and Almarsson's concept of understanding the hierarchy of supramolecular synthons between the drug and coformer(s) coupled
with the core concept of supramolecular chemistry by Desiraju6 is
the key in the design of cocrystal formation.
Another simple and prominent approach to predict cocrystal
formation is DpKa rule. A salt is formed if the difference between
the pKa base and pKa acid (DpKa) is >3, whereas a DpKa <0 will
generally result in the formation of a cocrystal. On the contrary, a
DpKa of 0-3 can result in complexes containing cocrystals or salts or
shared protons or intermediate ionization states. The latter can be
termed as salt-cocrystal hybrids. For example, salt-cocrystal continuum zone was observed in the pKa region of 0-2.5 in a study
performed using 20 different theophylline (THP)-acid complexes.18
Cruz-Cabeza19 found that DpKa >4 would exclusively result in
ionized acid-base complexes, whereas for DpKa < 1 would result
in nonionized acid-base complexes (cocrystals or solvates or hydrates). Hydrogen-bonding propensity can be helpful in the
rational design of cocrystals. Other design approaches for cocrystals
screening include lattice energy calculations,20 Fabian's method21
(based upon polarity and shape of coformer with respect to drug
molecule), virtual cocrystal screening (based upon molecular
electrostatic potential surfaces [MEPS],22 and the conductor-like
screening model for real solvents [COSMORS].23
Triggers Encouraging Research in the Area of Pharmaceutical
Cocrystals
Pharmaceutical industry has been struggling with critical issues
of poor physicochemical properties such as aqueous solubility,
dissolution rate, permeability, stability, hygroscopicity, and processability of drug molecules.24 Poor aqueous solubility remains one
of the most prominent challenges.25 Traditionally, poor aqueous
solubility has been addressed by use of various solid form modications of a drug such as metastable polymorph(s), solvates/hydrates, amorphous form, and salt formation. Each of the above
approaches has its own advantages and challenges, thus leaving a
scope for the introduction of novel approaches. Metastable polymorphs offer only marginal (commonly 1- to 2-fold) increase in
solubility. Moreover, the poor physical and chemical stability of
metastable polymorph may pose problems in processability and
shelf-life stability.26 Solvates/hydrates are not always preferred on
account of their low thermal stability, variable stoichiometry, and
limited gain in solubility.27-29 Amorphous form increases the solubility of the poorly soluble compounds; however, it has the problem
of physical instability (tends to devitries into crystalline form) as a
result of its higher free energy and entropy.30,31 Increased reactivity
of an amorphous material leads to enhanced hygroscopicity and
susceptibility to chemical degradation. Consequently, relatively few
amorphous drug products are available in the market such as Ceftin
(cefuroxime axetil), Accolate (zarlukast), Rezulin (troglitazone),
and Accupril (quinapril hydrochloride).32 Use of the salt form is a
well-established approach to improve physicochemical properties of
a drug. Nevertheless, a major drawback of salt formation is that they
are limited to those APIs that contain ionizable moieties and is
governed by the DpKa rule.33 Cocrystals have provided a broad
platform for modulation of material properties that are critical
during pharmaceutical development and have emerged as a promising alternative to traditionally used solid forms. Advances in the
area of crystal engineering, diversity of coformers, and regulatory

acceptance have fueled research in the area of cocrystals as novel
materials for pharmaceutical development.
Trend of Cocrystals in Patent and Non-Patent Literatures
Cocrystals are the novel solid forms of an API that have signicant industrial utility and its synthesis involves nonobviousness.
Therefore, cocrystals are patentable inventions, as they satisfy all
the 3 eligibility criteria of novelty, industrial applicability, and
nonobviousness. Speedy ascend in number of patent applications
and publications in peer review journals in the last couple of
decades underlines the attention received by cocrystals from both
academia and pharmaceutical industry. Literature review on the
term cocrystal in the scientic database (PubMed) showed an
increase in number of scientic publications every year (total
>2000 until April 2016; Fig. 1a). Moreover, the WIPO patent database depicted increasing intellectual property (IP) landscape every
year (total >1650 until April 2016; Fig. 1b). The analysis of patent
databases revealed that out of the total patents led for pharmaceutical cocrystals, about 80% lings involved pharmaceutical industry or contract research organization, whereas only 20% of the
lings were from sole academic institution and universities.
Modulation of Material Properties Using Cocrystals
The success of new chemical entity in pharmaceutical industry
is governed by its selectivity, potency, and material (physicochemical) properties.34 Latter includes properties such as solubility, dissolution rate, permeability, stability, hygroscopicity,
melting point, and manufacturability. Poor solubility of a compound can lead to low and variable bioavailability. About 40% of
marketed drugs have low solubility and around 70%-90% of the
drugs in the development pipeline are anticipated to have low
water solubility.25 A recent study conducted on 812 drug candidates from AstraZeneca, Eli Lilly, GlaxoSmithKline, and Pzer
showed that poor pharmacokinetic and bioavailability have
remained the third most common cause of failure of the molecules
in phase I clinical trial.35
There is an increasing interest in crystal structure-property
relationship of pharmaceutical solids as it allows engineering of
supramolecular structure to attain materials with desired properties.36 In the same framework, cocrystals are evolving as a
promising approach to modulate material properties of a molecule by rational use of crystal engineering.37,38 For example,
melting point and aqueous solubility of hexamethylene bisacetamide, an anticancer compound, were systematically customized
using a series of 5 diacids.39 Authors demonstrated that cocrystallization with the diacid of shorter chain length can increase
solubility and decrease the melting point of hexamethylene
bisacetamide. Therefore, higher solubility of cocrystals was
dialed-up by selecting the diacid of lower chain length as
coformers. The strategy of synthesizing the cocrystals of similar
crystal structure so as to maintain organization of individual
building block within crystal lattice coupled with logical changes
to the molecular nature of the coformers (diacids) resulted in
cocrystals with the desired solubility.
Apart from solubility, cocrystals have also been investigated for
modulation of other critical material properties of drugs. For
instance, increased permeability (ux) of furosemide, a Biopharmaceutics Classication System (BCS) class IV drug, was
achieved by cocrystallization with anthranilamide as a
coformer.40 Intrinsic dissolution rate (IDR) of megestrol acetate
was enhanced by 3- to 4-fold as compared to the parent drug by
cocrystallization with saccharin (SAC) as a coformer.41
Figure 1. Trend of cocrystals in (a) scientic database (PubMed) and (b) patent database (*till April 2016).
S-oxiracetam, a drug used in the treatment of cognition

dysfunction, is a highly hygroscopic and deliquescent compound.
Its hygroscopic stability was enhanced by cocrystallization with
gallic acid and 3,4-dihydoxybenzoic acid.42 Lamotrigine exhibits
poor ow properties and undergoes elastic deformation that
causes problems of capping and lamination during tablet
manufacturing. A signicant improvement in powder ow properties and tabletability of lamotrigine was attained by cocrystallization with cinnamic acid and vanillin (VAN).43 The problem of
physical and chemical instability of temozolomide, an anticancer
drug, was successfully solved by cocrystallization with succinic
acid.44 Thus, structural modularity in cocrystals by rational selection of coformer(s) can be successfully used for improving poor
material properties of drugs.
Translational Development of Cocrystals

The journey of a drug substance to a drug product consists of
various steps like preformulation studies, prototype formulation
development, process development, scale-up, and nally
manufacturing of commercial batches. Use of cocrystal as the drug
substance for development of drug product offers challenges, due
to their structural features and unique properties. The proceeding
sections capture the issues involved in preformulation, formulation
development, and process development of cocrystal-based drug
products. The emphasis is on highlighting the issues specic to the
use of cocrystals for product development. The major discussion
revolves around preformulation properties wherein cocrystal
demonstrates the atypical behavior. Preformulation proling helps
in identifying (i) the most suitable cocrystal candidate and (ii)
challenges expected during formulation development. A tiered
approach can be followed during preformulation to achieve these 2
objectives and has been discussed in section Strategy for

Translational Development of Cocrystal Product.
Preliminary Selection of Cocrystal Candidate
Pharmaceutical industry has traditionally relied on the utilization of salts, amorphous form, and polymorphs as the suitable solid
form for product development. This trend is aided by deep scientic
understanding, availability of skilled manpower, and evolved regulatory environment. In contrast, the selection and use of cocrystal
as a solid form is relatively new for pharmaceutical industry that
may cause numerous surprises in its translational development. It
has been discussed in the following sections that cocrystals inuence a number of physicochemical and mechanical properties.
Initial efforts for designing cocrystals were triggered by a strong
need to modulate a particular physicochemical property like
aqueous solubility or stability of API. However, cocrystals may
simultaneously inuence many other physicochemical properties
that were not targeted initially. Hence, investigation on a variety of
physicochemical properties is required before selecting a suitable
cocrystal (see Fig. 2). From preformulation perspective, this is
analogous to the selection of a salt form as it is said to change the
complete prole of a drug substance and is acknowledged as a new
drug. The pharmaceutical scientist is expected to strike a ne balance between the intentionally and unintentionally changed
physicochemical properties due to cocrystal formation.
Another critical concern while selecting cocrystal candidate is
the safety of coformer, which can invite additional regulatory
burden. For marketing authorization of any pharmaceutical product, the safety of active and inactive substances in the product is a
prerequisite. A coformer in the cocrystal candidate (selected for
product development) should be safe or nontoxic in the amount
required for administration of therapeutic doses of the drug as a
Figure 2. General strategy for selection of cocrystal candidate in translational development of cocrystal product (*especially relevant for high-dose drugs). Depending upon triggers
for cocrystal development (bioavailability, stability, or manufacturability), the parameters evaluated for cocrystal may vary. The relative importance of the parameters investigated
depends on BCS class of the molecule, reason for selecting cocrystal as a solid form, and speculated dosage form.
part of the cocrystal. Before designing a cocrystal for a drug, careful

consideration of coformer safety and its amount in cocrystal
product is essential. Use of inactive ingredient database (IID)-listed
excipients as coformers would require less extensive regulatory
review as the safety of their use in particular amount for the specic
route of administration and dosage form may have already been
established. A list of commonly used coformers with their generally
recognized as safe and IID status are presented in Table 1. The
selection of coformer for higher-dose drugs is quite challenging, as
the relatively higher amount of coformer would be required
which may lie beyond the IID limit. For example, the dose of
carbamazepine as an immediate-release tablet (marketed as

Tegretol in the United States) is 400 mg to 1200 mg daily in patients older than 15 years. Assuming a 1:1 stoichiometric ratio of
carbamazepine to coformer in the cocrystal, the equimolar amount
of SAC, urea, or nicotinamide (NCT) as coformers required would be
930.4 mg, 305.0 mg, or 620.3 mg, respectively, for 1200-mg dose.
Although NCT is not listed for oral route, the highest quantity
required for SAC and urea is beyond the IID limit (see Table 1).
Therefore, the marketing authorization of such cocrystal-based
drug products containing these coformers would create an additional regulatory burden.
Table 1
Commonly Reported Coformers Used for Cocrystal Preparation4,9,13,43,45-48 and Their Status in GRAS and IID Database (as per Updated List as on July 31, 2016)
Coformers
Cocrystal Examples
GRAS Status and Max Limit

for Intended Usea
Max IID Limit for Oral Use
Acetylsalicylic acid
4-Aminobenzoic acid
Not listed
Not listed
Not listed
Not listed
Not listed
Not listed
Not listed
Not listed
Not listed
Yes, no max limit other
than cGMP
Not listed
Not
Not
Not
Not
Not
Not
Urea
Sildenal
Carbamazepine, piroxicam,
acetazolamide
Lamotrigine
Lamotrigine
Lamotrigine
Theophylline, caffeine
Naproxen
Carbamazepine, ibuprofen,
theophylline
Carbamazepine, indomethacin,
ethenzamide, indomethacin
piroxicam, spironolactone,
and theophylline
Naproxen
0.018%
Methyl paraben
Propyl gallate
Vanillin
Ezetimibe
Dasatinib
Lamotrigine, danazol
Yes, no max limit other

than cGMP
0.1% (for antimicrobial use)
0.02% (as antioxidants)
Only listed
Cinnamic acid
Salicylic acid
Ferulic acid
Methyl gallate
Thiourea
Nicotinamide
Saccharin
listed
listed
listed
listed
listed
listed for oral use
16 mg
1 gm/5 mL (in syrup)

1.36 mg
65.5 mg
cGMP, current good manufacturing practice; GRAS, generally recognized as safe; IID, inactive ingredients database.
a
GRAS limits listed herein are based on available information in 21 CFR, Chapter I, Subchapter B, Part 18, Part 184, and GRAS Notice Inventory.
Preformulation Studies on Cocrystals

Preformulation studies consist of evaluation of fundamental
properties like solubility, permeability, dissolution, pKa, melting
point, partition or distribution coefcient, stability, and derived
properties such as particle size, morphology, bulk density, ow
properties, and compaction behavior. Although these properties are
a part of any conventional preformulation study, the emphasis is on
highlighting the atypical behavior of cocrystals during the assessment of these preformulation parameters. Preformulation studies
are need based and are guided by the characteristic of the
molecule and intended formulation. These help in rational formulation and process design that can minimize the risk of unexpected
failure in later stages of development. Subsequent sections discuss
some of the important preformulation properties with specic
reference to cocrystals.
Solubility
Measurement of thermodynamic (equilibrium) solubility of
cocrystals is challenging as they may convert to the parent forms
during dissolution. Several reports indicated that cocrystals can
enhance, diminish, or do not change solubility at all (Table 2).
Generally, it is known that solubility of cocrystals increases with

the solubility of the coformers.54
It is well documented that drug release from the cocrystals may
exhibit an initial peak concentration followed by a decline and this
is called as spring-parachute effect.55,56 Such behavior is usually
observed with the coformers having very high solubility compared
to the parent compound.57 For example, uoxetine HCl-succinic
acid (2:1) cocrystal in water gets converted to less soluble parent
form with decline in solubility of uoxetine HCl.49 It is important to
understand the contribution of this phenomenon to overall solubility benet.
Lipinski58 had proposed the triad of dose, solubility, and
permeability to derive the minimum aqueous solubility required
for optimal oral absorption. The peak solubility and duration of
supersaturation level maintained should be assessed in view of
dose, permeability, and required solubility for optimal absorption.
The selection of cocrystal having optimal solubility remains a
challenge as distinct solubility behavior may be observed under
different conditions of pH, temperature, and presence of solubilizing agents (lipids, polymers, surfactants).59 For example, cocrystals of danazol (DNZ) with 4-hydroxybenzoic acid (DNZ-HBA)
and VAN (DNZ-VAN) were much more soluble than DNZ in aqueous
media with solubility advantage (SA Scocrystal/Sdrug) of 770 and
Table 2
Reported Examples of Solubility Study on Cocrystals
APIs
Coformers
Experimental Conditions
Solubility
Inference
References
Fluoxetine HCl
Free base
Benzoic acid
Fumaric acid
Succinic acid
Free base
Caffeine
Free base
Succinic acid
L-Malic acid
Tartaric acid
Free base
Isonicotinamide
Free base
Saccharin
Water, at 20 C
11.4 mg/mL
5.6 mg/mL
14.8 mg/mL
20.2 mg/mL
12.5 g/L
8.64 g/L
e
7 104 M
e
2-Fold decrease
1.3-Fold increase
1.77-Fold increase
e
0.69 Times that of API
e
4-20 Times higher than
crystalline itraconazole
of D90 10 mm
e
2.76-Fold increase
e
No change
49
Sulfacetamide
Itraconazole
Noroxacin
Piroxicam
PBS, phosphate buffer saline.
PBS of pH 7.0
0.1 N HCl, (up to 500 min)
Water
Water
0.21 mg/mL
0.58 mg/mL
<0.01 mg/mL
<0.01 mg/mL
50
51
52
53
370, respectively. However, in the solution of Tween-80, this SA

decreased to 10 for DNZ-HBA and 6 for DNZ-VAN.60
Solution pH is another important parameter that can modulate
thermodynamic stability and solubility of cocrystals of both ionizable and nonionizable drugs.61 Gabapentin-3HBA (1:1) cocrystal
was stable at pH 4.0 and 5.7, whereas it underwent transformation
to its constituents at pH 2.6. On the other hand, the cocrystal
exhibited less solubility at pH 4.0 and 5.7, whereas it was more
soluble at pH less than 2.6.62 This differential effect of pH on cocrystal solubility is governed by ionization of cocrystal constituents.
Thus, cocrystal solubility can be altered by changing the pH of solution. In such cases, rather than using commonly used descriptor
of cocrystal kinetic solubility, SA of the cocrystal over drug can be
ranked unambiguously by determining its eutectic constants value
(Keu).63,64 Keu can be calculated by using Equation 1. The concentration of drug, [drug]eu and that of coformer, [coformer]eu are
determined at a point wherein experimental conditions are such
that the solution is saturated with respect to both drug and cocrystal. Measurement of Keu is valuable in evaluating the effect of
solubilizing agents and pH on solubility and thermodynamic stability of cocrystal. Table 3 summarizes the effect of Keu on solubility
and thermodynamic stability of cocrystals. The important studies
required in the investigation of real SA of cocrystals are captured in
Table 4.
Keu
coformereu
drugeu
(1)
where [coformer]eu is concentration of coformer at eutectic point

and [drug]eu is concentration of drug at eutectic point.
In addition to nature of the coformer, cocrystals with different
stoichiometry of the same coformer can also inuence the thermodynamic stability and solubility. Hornedo et al. demonstrated
that thermodynamic stability and solubility are inversely related to
each other, that is, the thermodynamically most stable form of
cocrystal had the lowest solubility, whereas thermodynamically
unstable forms had higher solubilities.65 Thermodynamically unstable forms have initial high solubility (kinetic solubility) but may
undergo phase transformation resulting in lower supersaturation
level. For instance, 2:1 urea-succinic acid cocrystal was stable in 2propanol, ethanol, and water, whereas the 1:1 cocrystal studied
under the same conditions was found to be unstable and underwent phase transformation to the 2:1 cocrystal.66 Similarly, 1:4
stoichiometric carbamazepine:p-aminobenzoic acid cocrystal was
found to be thermodynamically unstable, but the 1:1 and 2:1
cocrystals were found to be relatively more stable.67
Apart from using conventional tools, it is prudent to use
advanced tools such as biorelevant dissolution media, dynamic
dissolution experiments, and further prediction by physiologically
based pharmacokinetic modeling for realistic assessment of capability of cocrystal to address solubility-related challenges.68,69
Intrinsic Dissolution Rate
Sometimes, cocrystallization of a drug may not always result in
solubility enhancement, but instead it could increase dissolution
rate. Faster dissolution of cocrystals reduces time to absorb drug
from gastrointestinal tract (decreased Tmax), which can reduce
intersubject variability and minimize the effect of food on oral
absorption. The representative examples of IDR studies on cocrystals are captured in Table 5. It can be seen that in case of cocrystals,
IDR can increase, decrease, or remain same as that of the API. For
example, febuxostat cocrystals with urea, acetamide, NCT,
p-aminobenzoic acid, and SAC in 60% v/v ethanol showed
24.1-, 52.5-, 36.6-, 34.1-, and 29.4-fold faster IDR, respectively, as
compared to parent API.71 However, a decrease in IDR was observed
Table 3
Effect of Keu on Solubility of a 1:1 Cocrystal63
keu Value
Impact on Solubility
Impact on Thermodynamic
Stability
<1
Cocrystal is less soluble

than parent drug
Solubility of drug and that

of cocrystal is same
Cocrystal is more soluble
than parent drug
Cocrystal is
thermodynamically
more stable
Stability of drug and that of
cocrystal is same
Cocrystal is
thermodynamically less
stable
>1
for cocrystals of sulfacetamide with isonicotinamide (0.64 times

that of the API) in pH 7.0 phosphate buffer saline.50 Lower IDR of the
cocrystal as compared to the parent drug was attributed to its faster
dissociation followed by phase transformation to less soluble form.
Diffusion/Membrane Permeability
Permeability is a major barrier in achieving desired absorption
and distribution of a drug through biological membrane.73 It is also
crucial to understand the interplay of solubility and permeability
and their contribution to overall bioavailability of a drug. Membrane permeability can be optimized mainly by structural modication of a compound or prodrug approach and sometimes using
permeation enhancers. Latter has the drawback of causing membrane toxicity owing to disturbance in the normal integrity of the
biological membrane. Cocrystals have opened a new avenue to
modulate permeability of drugs without adopting covalent modication. For example, improved diffusion/membrane permeability
of cocrystals of hydrochlorothiazide with nicotinic acid, NCT,
4-aminobenzoic acid, and resorcinol as coformers was observed as
compared to hydrochlorothiazide using the modied Franz diffusion cell apparatus through a dialysis membrane (MW, 14000 Da).
However, a cocrystal of hydrochlorothiazide with succinamide
showed poor solubility and ux, which was ascribed to the formation of primary sulfonamide dimer synthon.74
Similarly, modulation of diffusion/membrane permeability was
observed in the cocrystals of THP with isomeric aminobenzoic acids
(o-ABA, m-ABA, and p-ABA) as coformers using dialysis membrane135.75 Cocrystals of THP with o-ABA prepared with different stoichiometric ratios (2:3, 2:2, 3:2, and 2:1) showed higher cumulative
amount of drug release and faster ux density. However, cocrystallization with m-ABA and p-ABA (1:1) showed slow cumulative
amount of drug release and lower ux density. All the cocrystals of
THP exhibited improved solubility compared to parent THP. This
study emphasized that interplay of solubility and permeation
behavior of the cocrystal depends on the presence of different
hydrogen bond synthons and solute-solvent interactions.
The optimal permeability of a drug is vital not only in the successful development of oral but also for topical/transdermal dosage
Table 4
Important Studies Required in the Investigation of True Solubility Advantage of
Cocrystals64
Parameters or Studies
Application/Relevance
Keu determination
Effect of additive(s)
and pH on solubility
Real solubility advantage can be judged

Helps to understand how solubility of cocrystal
can be tailored by use of appropriate
additive(s) and using suitable pH
Whether obtained solubility value from
cocrystal can achieve optimal absorption
within the physiologically relevant time
frame (bioavailability)
Extent and duration of

supersaturation
Table 5
Representative Examples of Reported IDR Study on Cocrystals
API
Coformer
Dissolution Medium
IDR of Cocrystal
Reference
2-[4-(4-Chloro-2-uorphenoxy)phenyl]pyrimidine-4-carboxamide
Glutaric acid
Water (over 90 min)
70
Exemestane
Febuxostat
Maleic acid
Urea
Acetamide
Nicotinamide
p-Aminobenzoic acid
Saccharin
Caffeine
Isonicotinamide
Theophylline
Saccharin
Urea
p-Aminobenzoic acid
NF-L-arginine-H2O (salt)
FaSSIF
Ethanol:water (60% v/v)
18 Times faster than parent

compound
Same as that of parent API
24.1-Fold faster
52.5-Fold faster
36.6-Fold faster
34.1-Fold faster
29.4-Fold faster
Comparable to API
3-4 Times higher than API
1.32-Fold faster
2.71-Fold faster
Sulfacetamide
Megestrol acetate
Nitrofurantoin
PBS of pH 7.0
FaSSIF
Water (initial 30 min)
41
71
50
41
72
FaSSIF, fasted state simulated intestinal uid; IDR, intrinsic dissolution rate.
forms. Acyclovir (ACV) is used in the treatment of recurrent herpes

labialis (cold sores); however, its therapeutic effectiveness is
limited on account of poor skin permeability. Cocrystallization has
been used for the simultaneous improvement in both permeability
and solubility of ACV.76 In vitro skin permeation of polyethylene
glycol-400 ointment containing ACV-fumaric acid and ACV-glutaric
acid cocrystals showed higher in vitro skin permeability, whereas
ACV-maleic acid salt exhibited lower permeability when compared
to ACV form V.
Stability
Moisture Stability. Several studies have demonstrated that stability
of drugs toward moisture (hydration stability) can be improved,
deteriorated, or remain unaltered on cocrystallization. Anhydrous
caffeine and THP are not stable and they readily convert to their
respective hydrated forms. Hydration stability of anhydrous THP77
and caffeine78 was improved by cocrystallization with oxalic acid.
The stability of caffeine-maleic acid cocrystals (1:1 and 1:2) was
comparable to caffeine, whereas that of caffeine-glutaric acid (1:1)
was found to be worse than caffeine exhibiting conversion to
caffeine-glutaric acid (1:1) form II even at lower humidity condition of 43% relative humidity (RH) on day 1 which was followed by
dissociation into caffeine hydrate.78 Caffeine-glutaric acid cocrystal
may exhibit serious problem of processability and storage stability
and hence should not be selected for product development.
The stoichiometry of cocrystal could also have an impact on
physical stability. For instance, cocrystals of imatinib mesylate with
5-uorouracil (1:1) and hydroxyurea (2:1) were found to be
nonhygroscopic and chemically stable for 8 weeks when exposed to
40 C/75% RH. However, a cocrystal with different stoichiometry of
imatinib mesylate-hydroxyurea (1:2) was hygroscopic and unstable
under similar conditions.79
Cocrystals of THP with acidic coformers such as malonic, maleic,
or glutaric acids did not convert to the hydrate form. However, they
dissociated at high humidity (98% RH), as the water replaces the
acidic coformer to form hydrogen bond with THP, thereby forming
a crystalline THP monohydrate.77 Such dissociation (instability) of
the cocrystals can be prominent at higher humidity (>75%) in the
coformer whose solubility differs by about 30% as compared to the
drugs. The phenomenon was only observed at higher humidity,
indicating the role of water in the dissociation of the cocrystals.
Therefore, this can be a widespread issue and is particularly likely
to occur during processes that involve the addition of water such as
wet granulation and wet milling.80
ACV-tartaric acid (1:1) was stable only at 0% RH and room
temperature when studied for 3 weeks.81 While under the
humidity conditions of 43%, 75%, and 98% RH, the cocrystal was
highly hydroscopic and formed the sticky substance with a color
changing to light pink. The cocrystal was stable for only 7 and 3
days at RH of 43% and 75%, respectively. These cocrystal candidates
having very poor physical stability under normal storage conditions
are very difcult to manufacture and cannot be stabilized by
packaging and formulation approaches. Therefore, they should not
be taken forward for the product development.
Chemical Stability. The importance of selecting right coformers
based on degradation pathway of a drug to prevent its chemical
degradation has been recently illustrated in the case of adefovir
dipivoxil (AD). During storage, AD undergoes degradation by 2
pathways, hydrolysis and dimerization. Considering these degradation pathways, cocrystals of AD formed with SAC, a weakly acidic
coformer, exhibited a signicantly greater chemical stability than
the cocrystals formed using NCT, a basic coformer. This varying
behavior of the cocrystals of AD was attributed to differences in
microenvironment pH, crystal packing style, and hydrogen bond
formation.82
Thermal Stability. Cocrystal should remain stable at temperature
encountered during unit operations like drying, melt granulation,
and accelerated storage conditions. Thermal stress is commonly
used to assure both physical and chemical stability of drug product.
However, only a few studies have been reported in the context of
effect of thermal stress on cocrystal stability. Cocrystals of paracetamol (PCA) with 1,4-dioxane, N-methylmorpholine, morpholine,
N,N-dimethylpiperazine, and piperazine were found to be unstable
during heating run differential scanning calorimetry experiment.
On heating, initial loss of the coformers (guest) followed by a
melting endotherm attributed to the monoclinic form of PCA was
observed. Only PCA-4,4 bipyridine cocrystal was found to be relatively stable during the heating.83
Cocrystal can exist as hydrates.84-87 However, they have been
found to be unstable at higher temperature and converted to
anhydrate with loss of water molecule(s) around 88 C-110 C. For
example, temperature induced phase transformation of cocrystal
hydrates of acetazolamide with 2-aminobenzamide and NCT. These
cocrystals showed water loss around 93 C-104 C followed by
coformer elimination on further heating.86 In case of etoricoxibsuberic acid trihydrate cocrystal, loss of water was observed at
87.5 C.87 Nevertheless, instability of the cocrystal hydrate at higher
temperature could not pose a major challenge in product development as most of the manufacturing processes are usually carried
out at a relatively lower temperature.
Photostability. Few studies have demonstrated the role of cocrystallization in improving photostability of light-sensitive drugs.
Nitrofurantoin is known to be a photosensitive drug and shows
about 27.7% degradation after 168 h of UV irradiation. Cocrystals of
nitrofurantoin with 3-aminobenzoic acid, 4-aminobenzoic acid,
and 4-hydroxybenzamide as coformers degraded to a minor extent
(<3%) under the same conditions, demonstrating that signicant
stabilization can be achieved through cocrystallization approach.
However, physical mixtures of nitrofurantoin and the coformers
revealed degradation similar to the parent drug.88
The biological performance and applicability of menadione are
greatly limited by its poor photostability in the solid state. Three
cocrystals of menadione with 1-hydroxy-2-naphthoic acid, 6hydroxy-2-naphthoic acid, and sulfamerazine showed signicant
improvement in photostability. This improvement in photostability
after cocrystallization was attributed to the alternate stacking between menadione and the corresponding coformers via pp
interaction.89
As discussed above, cocrystals can improve photostability of
drugs; nonetheless, reverse is also possible as they may deteriorate
photostability. Therefore, photostability of cocrystals should be
carefully evaluated during its preformulation proling.
Mechanical Properties
Mechanical properties of a material are of paramount importance in the development of solid dosage forms. A good tablet
formation requires (i) development of interparticulate bonding
area that should subsequently be retained upon ejection of the
tablet from the die cavity and (ii) plastic deformation of material
during the tablet compaction. The presence of slip planes facilitates
plastic deformation and shows ability to form large interparticulate
bonding area during compaction.90 Therefore, the internal structure of any crystalline material plays an important role in tabletability. Following sections illustrate on how cocrystallization can
tailor the mechanical properties of the compounds.
Improved Mechanical Properties. PCA is the most commonly prescribed high-dose antipyretic drug. However, polymorphic form I of
PCA, which is commercially used and thermodynamically stable
form, has poor mechanical properties causing difculties in
manufacturing tablet of adequate tensile strength. Cocrystal of PCA
with 5-nitroisophhthalic acid exhibited improved mechanical
properties that can be successfully manufactured into the tablets of
desired tensile strength without compromising the dissolution
prole.91 This was attributed to the presence of slip planes and
superior bonding strength in the cocrystals as compared to PCA.
Other examples with improved mechanical properties include
cocrystals of PCA with oxalic acid, naphthalene, THP, and phenazine
as coformers,92 cocrystals of VAN isomers,93 and cocrystal of carbamazepine with NCT.94
Deterioration of Mechanical Properties. Cocrystals of piroxicam-SAC
(1:1) exhibited less plasticity compared to individual components
resulting in poor plastic deformation and tabletability.95 The tabletability followed the order of SAC > physical mixture > piroxicam
> cocrystal. Interestingly, the cocrystals of THP and methyl gallate
(MG) showed an improvement in tabletability of 1 component, that
is, MG, and deterioration of the other, that is, THP. The order of
tableting performance investigated was THP > cocrystal >> MG.96
The deterioration in compaction behavior of caffeine on cocrystallization with oxalic acid as coformer (2:1) has also been
reported.97 Compaction behavior of different compacts was in the
order, caffeine > caffeine-oxalic acid cocrystal prepared using
solvent cooling > caffeine-oxalic acid cocrystal prepared by
ultrasound-assisted solution cocrystallization. The cocrystals
prepared by 2 different techniques exhibited dissimilar mechanical properties despite their similar crystal habit, indicating the
inuence of methods of cocrystal generation on the alteration in
mechanical properties. Authors suspected that difference in
behavior of the cocrystals could be due to different surface
properties caused by different processing conditions encountered
in the 2 techniques.
Phase Transformation During Mechanical Stress. Like other solid
forms of a drug, cocrystals can undergo phase transformation when
subjected to mechanical stress. Mechanical stress is encountered
during different stages of manufacturing such as grinding, milling,
and compaction. For example, caffeine:4-chloro-3-nitrobenzoic
acid (1:1) cocrystal exists in 2 polymorphic forms, that is, form I
and II, which showed different mechanical behavior.98 Notably,
form I (metastable) of the cocrystal showed shear-induced phase
instability and converted to form II when subjected to mechanical
grinding for 1 h. The transformation from form II (thermodynamically stable form) to form I was unfavorable owing to the resistance
offered due to high energy barrier.
Polymorphism
Previously, it was thought that cocrystals are less prone to
polymorphism and could be used to minimize polymorphism.
However, Aitipamula et al.99 in their review claried that the percentage of polymorphs in cocrystals is comparable to the percentage of polymorphs in crystals that contain a single solid
component. Cruz-Cabeza et al.100 further veried this justication
by doing a statistical analysis of all the cocrystal polymorphs in the
literature and he suggested, Cocrystals were found to be just as likely
of being polymorphic as single component systems. Hence, cocrystallization should not, as it has been suggested in the literature, be
regarded as a cure to polymorphism.100 Polymorphs are well
known for their distinct pharmaceutical behavior and the same is
applicable to the polymorphic cocrystals. For example, in dissolution study of sulfacetamide-acetamide (1:1) cocrystals, dissolution
rates of the metastable form I was 1.6 times and of stable form II
was 1.3 times faster than that of sulfacetamide in aqueous buffer
medium of pH 7.101 Like single-component systems, it is necessary
to conduct polymorphic screening of cocrystal and thermodynamically most stable form should be selected for subsequent
development. Nevertheless, the identication of polymorphs of a
cocrystal and subsequent investigation on its physicochemical
properties to select the most appropriate form may extend the
product development timeline.
Effect of Microenvironment pH
A thin saturated layer formed at the dissolving surface of the
solid particle represents microenvironment and the pH at this
region is called as microenvironment pH. It is well known that
microenvironment pH may vary from bulk pH in case of ionizable
drugs and it can inuence dissolution rate102,103 and stability.104
Nonionizable drugs have same microenvironment and bulk pH.
However, a cocrystal of even a nonionizable drug can modulate
microenvironment pH owning to the presence of ionizable
coformer. Similarly, contribution of ionizable drug and ionizable
coformer on overall microenvironment pH should be clearly
understood.
The role of microenvironment pH in altering solubility and
chemical stability of cocrystal has been illustrated by cocrystals of
AD with SAC and NCT.82 AD exhibits much higher degradation in
weakly alkaline buffer solution (pH 7.2) than that in pure water and
acidic buffer solution (pH 2). Cocrystals of AD formed with SAC
exhibited a signicantly greater chemical stability than the cocrystals formed using NCT. This was attributed to acidic
microenvironment pH resulting in stabilization of AD whereas

basic microenvironment contributed by NCT triggered hydrolytic
degradation of AD.
The solubility of AD-SAC cocrystals was much higher than
AD-NCT, which was partly attributed to acidic microenvironment
provided by dissociated SAC (pH changes from 6.7 to 3.1) that
facilitated the dissolution process of a weakly basic AD. pH value
was determined to be 6.93 for AD-NCT cocrystal at the end of solubility experiment, indicating unfavorable environment caused by
the basic coformer.82 Thus, unexpected modulation of solubility or
dissolution of cocrystals may be understood by measurement of
microenvironment pH after the end of the experiment. Knowledge
of pKa of drug and coformers (acidic and basic nature) can be
helpful in the prediction of microenvironment pH effect, thereby
selecting the suitable coformers that help in designing of cocrystals
with the desired dissolution and stability.
Cocrystal-Excipient Compatibility
Drug-excipient compatibility is an important part of preformulation activities as it helps in the selection of a particular
excipient. It is likely that the components of a cocrystal (coformer
or drug) may not always be compatible with the excipients. For
example, dibasic calcium phosphate dihydrate is known to undergo
hydrolysis during storage to release water that may trigger dissociation of the cocrystal leading to physical instability. A very
commonly used diluent, lactose (except anhydrous lactose), shows
Maillard reaction by reacting with an amine functional group in the
drug and excipients leading to chemical incompatibility. A similar
incompatibility may occur with the coformers that contain primary
and secondary amine groups (e.g., amino acid coformers). Thus,
beyond the traditional drug-excipient compatibility study,
compatibility of the cocrystal with excipients should be performed
in the development of drug product containing cocrystal. Incompatibility between drug and coformer would lead to exclusion
of the cocrystal from product development.
Formulation Development of Pharmaceutical Cocrystals
Generally, pharmaceutical development of a drug product consists of 3 major stages, that is, formulation development, process
development, and selection of container closure system (CCS).
Being a relatively new solid form of a drug, the development of a
cocrystal offers distinct challenges in addition to traditional hurdles. These challenges can be minimized or eliminated by (a)
selecting the most suitable cocrystal candidates for the development, (b) rational formulation and process design, (c) selection of
appropriate CCS, and (d) environment control. The knowledge
gained in the preformulation studies of the cocrystals aids in the
further product development. General strategies for selection of
excipients and other approaches in cocrystal product development
are summarized in Table 6. These suggestions can be applied to
improve product performance of cocrystal-based product, when
the selected cocrystal candidate does not possess optimum physicochemical properties.
Prototype Formulation Development
Generally, formulation development activity is aimed at
investigating the additional impact of excipients on performance,
safety, and manufacturability of the product. It consists of optimization of material properties to consistently achieve desired
performance of the product. Following sections cover literature
reports on the development of cocrystal formulations and illustrate how rational formulation development could help in
achieving a robust formulation.
Table 6
General Strategies for Selection of Excipients and Other Approaches in Cocrystal
Product Developmenta
Formulation Challenges
Excipient Selection or Other Approaches
Solubility and
thermodynamic stability
pH-modifying agents
Use of surfactants
Use of polymers
Combined use of both surfactant
and polymer
Particle size reduction
Permeation enhancer
Dissolution
Permeability
Stability
Chemical stability
Physical stability (moisture)
Microenvironment pH effect
Compaction-mediated
phase transformation
pH-modifying agents
Use of desiccants
(moisture-adsorbing agents)
Selection of suitable manufacturing
process
Control of manufacturing
environment (humidity)
Packaging strategy
pH-modifying agents or buffers
Choice of alternative formulation
(e.g., tablet vs. capsule)
Selection of cushioning agents
a
The above suggestions can be applied to improve product performance of
cocrystal-based product when the selected cocrystal candidate does not possess
optimum physicochemical properties.
Modulating Apparent Solubility, Dissolution, and In Vivo Performance

of Cocrystal by Formulation Approach. Excipients are pharmacologically inactive but may affect the overall performance of the drug
product. Remenar et al.105 illustrated dependency of solubility of
celecoxib-nicotinamide cocrystals (Cel-Nic) on types and amount of
excipients. Cel-Nic rapidly converted into large aggregates of Cel-III
(celecoxib form III) that dissolved more slowly than commercial
Cel-III in the presence of low concentration (1%) of sodium lauryl
sulfate (SLS) in the medium. However, formulation of Cel-Nic
containing both 1%-10% solid SLS and polyvinylpyrrolidone (PVP)
dissolved more rapidly by virtue of its conversion to a mixture of
amorphous celecoxib and micron-sized celecoxib form IV, which is
up to 4 times more bioavailable than a commercial form of celecoxib, that is, Cel-III. The importance of use of a suitable concentration of polymer (PVP) or surfactant (SLS) to inhibit
transformation and increase solubility of the cocrystal was also
demonstrated by a study on indomethacin-SAC (1:1) cocrystal.56
Childs et al.48 demonstrated the impact of formulation manipulation on apparent solubility, in vitro dissolution, and ultimately
in vivo bioavailability of DNZ-VAN cocrystal. DNZ-VANeformulated
cocrystals consisted of a solubilizer (1% D-a-tocopherol polyethylene glycol succinate) and a crystallization inhibitor (2% Klucel
LF Pharma hydroxypropylcellulose), a simple supersaturated drug
delivery system intended to enhance bioavailability in SpragueDawley rats following 20 mg/kg doses of DNZ. Nonformulated
cocrystal (neat aqueous suspension) showed a modest in vivo
improvement of 1.7 times higher area under the curve compared to
the crystal form of DNZ API under identical conditions. Interestingly, the formulated cocrystal exhibited a 10-fold increase in area
under the curve as compared to poorly soluble DNZ polymorph,
demonstrating the role of formulation in the modulating performance of the cocrystal. Similarly, other studies illustrating the role
of additives on in vitro and in vivo performance of solutionbased106,107 and tablet-based cocrystal formulations108,109 have also
been reported in literature. Thus, it is noteworthy that a thorough
understanding of the impact of excipients on the performance of a
cocrystal formulation is essential to overcome the challenges of
undesirable solubility/dissolution, solution-mediated phase transformation, and poor in vivo performance.
10
Optimal in vivo biopharmaceutical performance of a cocrystalbased product requires selection of the appropriate cocrystal
candidate and formulation development strategy. One of the most
important aspect in cocrystal-based products is to prevent
supersaturation-triggered precipitation of the drug. Polymers like
polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropylcellulose, and polyethylene glycol act as
precipitation inhibitors. Those enabling supersaturation for physiologically relevant timeframe are selected for formulation development. In most of the cases, polymers have been selected based on
their precipitation inhibition capacity toward drug and
cocrystals.48,106,107
Surfactants play a vital role in solubilization and thermodynamic stabilization of cocrystals in aqueous media by forming
micelles and thereby preventing the solution-mediated phase
transformation.63,110 A suitable surfactant can be selected based on
attainment of maximum apparent solubility of cocrystal achieved
by its varying concentrations.48 Alternatively, a combination of
both surfactant and polymer can be selected to achieve the required
supersaturation level.
Cocrystal eutectic constant (Keu) and transition points
(i.e., pHmax, pH at the transition point; S*, solubility at the transition
point; and CSC, critical stabilization concentration) can be valuable
parameters for selection and optimization of suitable excipients in
the formulation development.56,59,63,64 Increase in solubilizing
agent concentration above CSC will not enhance SA of cocrystal as
S* is the upper limit of solubility. Solubility at the transition point
(S*) can be either experimentally measured or calculated from
aqueous solubility of cocrystal and drug.59 pH stabilization to attain
desired supersaturation level is a valuable strategy in solution or
suspension-based formulation development of cocrystals. pHmax is
a crucial parameter used in the selection of optimal pH to gain
maximum SA.61 A cocrystal is more soluble than a drug at pH lower
than the pHmax (pH > pHmax).62,64
Furthermore, a formulation usually consists of diverse excipients, and the effect of all excipients on the product performance has
to be investigated using statistically sound experiments.
Establishment of In VitroeIn Vivo Correlation for Cocrystal-based
Drug Product. Difculty in establishing in vitroein vivo correlation
(IVIVC) is another major challenge in cocrystal product development. In vitro testing of cocrystal may not be easily correlated with
in vivo performance owing to change in its solubility in the varying
gastrointestinal tract conditions due to the presence of endogenous
surfactants, lipids, and pH. For example, a cocrystal of lamotrigine
with NCT showed signicantly enhanced dissolution but resulted in
unexpected decrease in in vivo oral bioavailability when dosed in
rats compared to the parent drug.111 Another major reason for failure
of IVIVC could be improper selection of in vitro dissolution conditions. Sun et al.112 recommended nonsink dissolution as an in vitro
tool for predicting product quality control and in vivo performance of
amorphous solid dispersion (ASD), a supersaturating drug delivery
system. United States Pharmacopeia and US-FDA recommend
dissolution media for marketed ASD-based drug products which
mostly consist of nonsink dissolution conditions.112 Just like ASDs,
cocrystals are also an example of supersaturating drug delivery
system; knowledge generated for ASDs can be extrapolated to cocrystal and nonsink dissolution conditions, along with the use of
biorelevant media, may be helpful in the prediction of in vivo performance of cocrystals. However, additional scientic understanding is necessary to validate the usefulness of this approach.
Selecting Appropriate Excipients to Improve Mechanical Properties.
Cocrystal approach although mainly used for the improvement in
solubility or stability can also affect the mechanical properties.113
Use of a formulation strategy such as particle engineering

can help in achieving the desired mechanical properties.
5-Fluorocytosine (FC) is available as only capsules and cannot be
prepared as a more preferred tablet dosage form on account of its
high dose, physical instability, and poor mechanical properties.
Conjugate acid base cocrystals of FC with acesulfame (FCAS21) and
with hydrogen chloride (FCHCl21) exhibited improved physical
stability, but their tabletability was not suitable for manufacturing
the tablets of acceptable quality. FCAS21 and FCHCl21 cocrystals
formulated using silica-coated Avicel PH105, which has excellent
compaction properties, exhibited adequate tabletability along with
sufcient owability to enable commercial manufacturing of tablets by direct compression.113
Formulation Strategies to Minimize Phase Transformation of Cocrystals During the Mechanical Stress. As discussed earlier, cocrystals
may undergo mechanical stresseinduced polymorphic phase
transformation (e.g., caffeine:4-chloro-3-nitrobenzoic acid cocrystal98). Compaction-induced phase transformation can be overcome
by preparing tablets using cushioning agent. Latter possesses a
good elastic deformation property, which can absorb the mechanical shock (e.g., microcrystalline cellulose pellets, carrageenans,
chitosans, polyethylene oxides, and alginates).114,115 An alternative
approach is to prepare a capsule dosage form instead of a tablet.
However, it is advisable to use the most stable polymorphic form of
the cocrystal to avoid surprises in later stages of the development.
Process Development
The aim of process development is to identify critical process
parameters to ensure consistent quality of the product. Choice of
the manufacturing process, equipment, and in-process controls is
dictated by the material properties of cocrystals. Among the material properties, stability of cocrystals is of paramount importance
in the selection of manufacturing process and deciding the control
measures (temperature, humidity, and pressure). Like any traditional solid forms of APIs, it is also perceived that unit processes like
drying, milling, mixing, grinding, wet granulation, compression,
encapsulation, and coating may trigger phase transformation of
cocrystals. The underlying mechanism of phase transformation in
case of cocrystals can be hydrate/anhydrate conversion, solid-state
transition, solution-mediated phase transformation, and cocrystal/
amorphous conversion. Thus, rational selection of the process
together with environment control, appropriate excipient selection, and packaging approach may minimize process-induced
phase transformation and poor physical stability of cocrystals.
Cocrystals of THP with acidic coformers such as malonic, maleic,
or glutaric acids undergo dissociation in the presence of water.77
Therefore, unit operations like wet granulation and wet milling
are likely to dissociate the cocrystals.80 This problem can be
resolved by selecting an alternative unit operation such as dry
granulation or direct compression. Anhydrous THP-citric acid cocrystal at higher humidity condition (at 98% RH) was found to
convert into cocrystal hydrate within just 3 days.116 Control measure such as manufacturing in low humidity condition would tackle
the problem. Cocrystal of caffeine:4-chloro-3-nitrobenzoic acid
undergoes polymorphic phase transformation under mechanical
stress encountered during grinding.98 Particle size control by
adopting suitable crystallization conditions rather than using size
reduction means can avoid milling-induced transition. Sodium
naproxen-lactose-tetrahydrate cocrystal was found to undergo
transformation into coamorphous system on heating from 60 C to
120 C due to loss of water molecules from crystal structure.117
Similar transition is likely during drying of sodium naproxenlactose-tetrahydrate cocrystal; however, this can be overcome by
maintaining the drying temperature below the transition temperature. Physical and chemical stability of the cocrystals may vary in
different solvents and hence the solvent(s) used during
manufacturing should be critically selected.
Therefore, selection of manufacturing process should consider
these needs and traditional approaches of circumventing the
issues described in the literature should be adopted.118
Selection of Container Closure System
The judicious choice of CCS can help in the protection of cocrystal products against oxygen, moisture, and light. Strategy adopted for packaging should be based on resistance offered by cocrystal
against the stressors. For example, nitrofurantoin is a photosensitive drug (sold under the brand name of Furadantin as an oral
suspension in United States), which is supplied in the ambercolored bottle. Cocrystals of nitrofurantoin with 3-aminobenzoic
acid, 4-aminobenzoic acid, and 4-hydroxybenzamide as coformers
exhibited improved photostability.88 This can eliminate the need of
using the amber-colored bottle for the nitrofurantoin cocrystal
product.
Adopting water-free process, humidity control of manufacturing
area, use of moisture adsorbent excipients (e.g., amorphous silica,
microcrystalline cellulose), and protective packaging can overcome
challenges faced by slightly hygroscopic cocrystals. For example, a
cocrystal of AMG 517:2-hydroxycaproic acid was found to be
slightly hygroscopic at 80% RH/25 C, in moisture absorption
experiments.119 The above combined approach can be helpful in the
product development of this cocrystal.
Although rational formulation design, proper process development, environment control, and the selection of CCS may overcome
the challenges in the translational development of cocrystal, it is
advisable to select the most appropriate cocrystal candidate during
the preformulation screening.
Strategy for Translational Development of Cocrystal Product
Figure 2 represents a general strategy for selection of cocrystal
candidate in the translational development of cocrystal product. A
2-tiered approach can be adopted for preformulation activities
conducted for the development of cocrystal-based product and
which can be divided into 2 categories, viz. critical preformulation
parameters (essential properties) and additional preformulation
parameters (desirable properties). Critical preformulation parameters are those that must be carried out early, in order to develop a
cocrystal product. These are critical for decision making and help in
deciding the suitability of the cocrystal in further development.
Additional preformulation parameters are those that usually are
less critical and challenges posed by them can be circumvented by
using conventional approaches. However, the relative importance
of a particular parameter investigated depends on BCS class of the
molecule, the reason for selecting the cocrystal as the solid form,
and intended nal dosage form.
Cocrystals in Clinical Development and Market
Translational development of cocrystals to successful drug
products can be judged by analyzing the progression of cocrystals to
different stages of clinical development. Few examples of cocrystals
in clinical trials are briey discussed in the following sections.
Ertugliozin:L-Pyroglutamic Acid (1:1) Cocrystal
Ertugliozin is a sodium glucose cotransporter-2 inhibitor that
promotes urinary glucose excretion and prevents hyperglycemia in
11
type-2 diabetes mellitus. The candidate drug is in phase 3 of clinical

development in the form of cocrystal.120 Initially, in spite of
extensive screening studies, large-scale synthesis of ertugliozin to
get kilograms quantity of compound, which is usually required for
late clinical trials and further developmental activities, resulted in
the formation of hygroscopic amorphous solid with a low glass
transition temperature. Salt formation strategy was not applicable,
as the compound is nonionizable near physiological pH.
Ertugliozin:L-pyroglutamic acid (1:1) cocrystal was developed to
overcome these critical challenges and taken for further
development.121
Tramadol-Celecoxib (1:1) Cocrystal
E-58425 comprising celecoxib and tramadol (1:1) developed by
Enantia and Esteve R&D, Spain, and patented by Laboratorios Del.
Dr S.A. Esteve, is an example of multidrug cocrystal, which is under
clinical development. Synergistic action between its components
will help to achieve therapeutic benet at lower and tolerable doses
of each component. A phase II proof-of-concept study in acute
postoperative pain has shown that the cocrystals demonstrated
superior efcacy and safety over both placebo and a standard.122
Presently, phase II clinical trial is ongoing in Europe for establishing the effective dose of E58425 for moderate to severe dental
pain.123 In the view of signicant therapeutic benet, moderate to
less risk of development, comparatively low cost of investment,
strong IP protection, and favorable European regulatory environment shall attract pharmaceutical industry to develop novel
multidrug cocrystals.
TAK-020 Cocrystal
TAK-020 is Bruton's tyrosine kinase inhibitor developed for the
potential treatment of rheumatoid arthritis, which is currently in
the phase I clinical trial. In the rst part of the clinical study,
sponsor Takeda wishes to assess the relative bioavailability of
different oral tablet formulations of TAK-020, that is, cocrystal
tablet, solid dispersion tablet, and immediate-release tablet in
comparison with oral solution formulation containing Captisol
(sulfobutylether betacyclodextrin). The formulations showing better or comparable bioavailability shall be assessed further for the
food effect.120 This study outlines emphasis laid by the pharmaceutical industry on the potential of cocrystals in developing
effective drug products.
A Recently Approved Pharmaceutical Cocrystal: ENTRESTOTM
Multidrug cocrystal containing sacubitril (angiotensin receptor
blocker), disodium valsartan (neprilysin inhibitor), and water
termed as supramolecular complex (CSD refcode: NAQLAU) has
been approved by FDA in July 2015 and by European Medicines
Agency in November 2015. It is indicated in adult patients for the
treatment of symptomatic chronic heart failure with reduced
ejection fraction and is being sold under the brand name
ENTRESTOTM.124
Conclusions
Pharmaceutical cocrystals as a new solid form have gained
extensive attention by virtue of their capability to modulate clinically relevant material properties. This is further corroborated by
expanding IP landscape and emergence of regulatory guidelines.
Preclinical and clinical studies have established a proof-of-concept
on utility of cocrystals. Commercial launch of ENTRESTOTM has
further strengthened this view. However, cocrystals may pose
12
signicant challenges in their translational development to

drug products. This mainly includes lower than expected
supersaturation solubility (spring-parachute effect), safety of
coformer, difculties in the manufacturing of high-dose drug,
polymorphism, atypical behavior of cocrystal in the formulation,
and difculty in establishing an IVIVC. For successful development
of cocrystal-based drug product, the maximum emphasis should be
laid on understanding the material properties during preformulation stage. This may help in rational formulation and process design, thereby helping subsequent product development.
Enhanced scientic understanding on crystal engineering and
biopharmaceutical performance of cocrystals shall open new opportunities for introduction of drug products containing cocrystals.
References
1. Etter MC, Frankenbach GM. Hydrogen-bond directed cocrystallization as a
tool for designing acentric organic solids. Chem Mater. 1989;1(1):10-12.
2. Etter MC. Hydrogen bonds as design elements in organic chemistry. J Phys
Chem. 1991;95(12):4601-4610.
3. U.S. Food and Drug Administration. Guidance for Industry: Regulatory Classication of Pharmaceutical Co-crystals; 2013. Available at: http://www.fda.gov/
downloads/Drugs/.../Guidances/UCM281764.pdf. Accessed April 5, 2016.
4. Aitipamula S, Banerjee R, Bansal AK, et al. Polymorphs, salts, and cocrystals:
what's in a name? Cryst Growth Des. 2012;12(5):2147-2152.
5. U.S. Food and Drug Administration. Guidance for Industry: Regulatory Classication of Pharmaceutical Co-crystals; 2016. Available at: http://www.fda.gov/
downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM516813.pdf. Accessed August 18, 2016.
6. Desiraju GR. Supramolecular synthons in crystal engineering-A new organic
synthesis. Angew Chem Int Ed. 1995;34(21):2311-2327.
7. Walsh RDB, Bradner MW, Fleischman S, et al. Crystal engineering of the
composition of pharmaceutical phases. Chem Commun. 2003;(2):186-187.
8. European Medicines Agency. Reection Paper on the Use of Cocrystals of Active
Substances in Medicinal Products; 2015. Available at: http://www.ema.europa.
eu/docs/en_GB/document_library/Scientic_guideline/2015/07/WC50018
9927.pdf. Accessed April 6, 2016.
9. Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical
cocrystals: an overview. Int J Pharm. 2011;419(1):1-11.
10. Wood PA, Feeder N, Furlow M, Galek PTA, Groom CR, Pidcock E. Knowledgebased approaches to co-crystal design. CrystEngComm. 2014;16(26):58395848.
Zaworotko MJ. Pharmaceutical coc11. Duggirala NK, Perry ML, Almarsson O,
rystals: along the path to improved medicines. Chem Commun. 2016;52(4):
640-655.
12. Thipparaboina R, Kumar D, Chavan RB, Shastri NR. Multidrug co-crystals:
towards the development of effective therapeutic hybrids. Drug Discov
Today. 2016;21(3):481-490.
13. Shan N, Zaworotko MJ. The role of cocrystals in pharmaceutical science. Drug
Discov Today. 2008;13(9):440-446.
y CB, Salmon DJ. Building co-crystals with molecular sense and
14. Aakero
supramolecular sensibility. CrystEngComm. 2005;7(72):439-448.
y CB. Crystal engineering: strategies and architectures. Acta Crystallogr
15. Aakero
Sect B Struct Sci. 1997;53(4):569-586.
16. Vishweshwar P, McMahon JA, Peterson ML, Hickey MB, Shattock TR,
Zaworotko MJ. Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients. Chem Commun. 2005;(36):46014603.
Zaworotko MJ. Crystal engineering of the composition of
17. Almarsson O,
pharmaceutical phases. Do Pharmaceutical Co-crystals Represent A New Path
Improved Medicines? Chem Commun. 2004;(17):1889-1896.
18. Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: the inuence of
crystal structure on ionization state. Mol Pharm. 2007;4(3):323-338.
19. Cruz-Cabeza AJ. Acidebase crystalline complexes and the pKa rule. CrystEngComm. 2012;14(20):6362-6365.
20. Karamertzanis PG, Kazantsev AV, Issa N, et al. Can the formation of pharmaceutical cocrystals be computationally predicted? 2. Crystal structure
prediction. J Chem Theor Comput. 2009;5(5):1432-1448.
bi
21. Fa
an L. Cambridge structural database analysis of molecular complementarity in cocrystals. Cryst Growth Des. 2009;9(3):1436-1443.
22. Musumeci D, Hunter CA, Prohens R, Scuderi S, McCabe JF. Virtual cocrystal
screening. Chem Sci. 2011;2(5):883-890.
23. Abramov YA, Loschen C, Klamt A. Rational coformer or solvent selection for
pharmaceutical cocrystallization or desolvation. J Pharm Sci. 2012;101(10):
3687-3697.
24. Gardner CR, Walsh CT, Almarsson O. Drugs as materials: valuing physical form
in drug discovery. Nat Rev Drug Discov. 2004;3(11):926-934.
25. Thayer AM. Finding solutions-custom manufacturers take on drug solubility
issue to help pharmaceutical rms move products through development.
Chem Eng News Archive. 2010;88(22):13-18.
26. Brittain HG, David JRG, Paul BM. Effects of polymorphism and solid-state
solvation on solubility and dissolution rate. In: Brittain HG, ed. Polymorphism in pharmaceutical solids. 2nd ed. New York: CRC Press; 2009:
436-480.
27. Khankari RK, Grant DJW. Pharmaceutical hydrates. Thermochim Acta.
1995;248:61-79.
28. Braun DE, Kahlenberg V, Gelbrich T, Ludescher J, Griesser UJ. Solid state
characterisation of four solvates of R-cinacalcet hydrochloride. CrystEngComm. 2008;10(11):1617-1625.
29. Tong HHY, Chow ASF, Chan HM, et al. Process-induced phase transformation
of berberine chloride hydrates. J Pharm Sci. 2010;99(4):1942-1954.
30. Hancock BC, Zogra G. Characteristics and signicance of the amorphous state
in pharmaceutical systems. J Pharm Sci. 1997;86(1):1-12.
31. Yu L. Amorphous pharmaceutical solids: preparation, characterization and
stabilization. Adv Drug Deliv Rev. 2001;48(1):27-42.
32. Rele SM. Editorial [Hot topic: new paradigms in drug formulation and
phytotherapeutics (guest editor: Shyam M. Rele)]. Curr Bioact Compd.
2008;4(4):200.
y CB, Fasulo ME, Desper J. Cocrystal or salt: does it really matter? Mol
33. Aakero
Pharm. 2007;4(3):317-322.
34. Di L, Kerns EH. Proling drug-like properties in discovery research. Curr Opin
Chem Biol. 2003;7(3):402-408.
35. Waring MJ, Arrowsmith J, Leach AR, et al. An analysis of the attrition of drug
candidates from four major pharmaceutical companies. Nat Rev Drug Discov.
2015;14(7):475-486.
36. Sun CC. Materials science tetrahedron- a useful tool for pharmaceutical
research and development. J Pharm Sci. 2009;98(5):1671-1687.
37. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950-2967.
38. Bolla G, Nangia A. Pharmaceutical cocrystals: walking the talk. Chem Commun.
2016;52(54):8342-8360.
y CB, Forbes S, Desper J. Using cocrystals to systematically modulate
39. Aakero
aqueous solubility and melting behavior of an anticancer drug. J Am Chem Soc.
2009;131(47):17048-17049.
40. Banik M, Gopi SP, Ganguly S, Desiraju GR. Cocrystal and salt forms of furosemide: solubility and diffusion variations. Cryst Growth Des. 2016;131(47):
17048-17049.
41. Shiraki K, Takata N, Takano R, Hayashi Y, Terada K. Dissolution improvement
and the mechanism of the improvement from cocrystallization of poorly
water-soluble compounds. Pharm Res. 2008;25(11):2581-2592.
42. Wang Z-Z, Chen J-M, Lu T-B. Enhancing the hygroscopic stability of
S-oxiracetam via pharmaceutical cocrystals. Cryst Growth Des. 2012;12(9):
4562-4566.
43. Thipparaboina R, Kumar D, Mittapalli S, Balasubramanian S, Nangia A,
Shastri NR. Ionic, neutral, and hybrid acidebase crystalline adducts of lamotrigine with improved pharmaceutical performance. Cryst Growth Des.
2015;15(12):5816-5826.
44. Babu NJ, Sanphui P, Nangia A. Crystal engineering of stable temozolomide
cocrystals. Chem Asian J. 2012;7(10):2274-2285.
45. Sun CC. Cocrystallization for successful drug delivery. Expert Opin Drug Deliv.
2013;10(2):201-213.
46. Rajurkar VG, Gite RD, Ghawate VB. Development of naproxen cocrystal formation: an efcient approach to enhance aqueous solubility. Anal Chem Lett.
2015;5(4):229-238.
47. Sugandha K, Kaity S, Mukherjee S, Isaac J, Ghosh A. Solubility enhancement of
ezetimibe by a cocrystal engineering technique. Cryst Growth Des. 2014;14(9):
4475-4486.
48. Childs SL, Kandi P, Lingireddy SR. Formulation of a danazol cocrystal with
controlled supersaturation plays an essential role in improving bioavailability.
Mol Pharm. 2013;10(8):3112-3127.
49. Childs SL, Chyall LJ, Dunlap JT, Smolenskaya VN, Stahly BC, Stahly GP.
Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of uoxetine hydrochloride
with benzoic, succinic, and fumaric acids. J Am Chem Soc. 2004;126(41):
13335-13342.
50. Goud NR, Khan RA, Nangia A. Modulating the solubility of sulfacetamide by
means of cocrystals. CrystEngComm. 2014;16(26):5859-5869.
51. Remenar JF, Morissette SL, Peterson ML, et al. Crystal engineering of novel
cocrystals of a triazole drug with 1, 4-dicarboxylic acids. J Am Chem Soc.
2003;125(28):8456-8457.
m D, Velaga SP. Pharmaceutical cocrystal and salts of nor52. Basavoju S, Bostro
oxacin. Cryst Growth Des. 2006;6(12):2699-2708.
53. Banerjee R, Bhatt PM, Ravindra NV, Desiraju GR. Saccharin salts of active
pharmaceutical ingredients, their crystal structures, and increased water
solubilities. Cryst Growth Des. 2005;5(6):2299-2309.
54. Good DJ, Rodriguez-Hornedo N. Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des. 2009;9(5):2252-2264.
55. Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst Growth Des. 2011;11(7):2662-2679.
56. Alhalaweh A, Ali HRH, Velaga SP. Effects of polymer and surfactant on the
dissolution and transformation proles of cocrystals in aqueous media. Cryst
Growth Des. 2014;14(2):643-648.
57. Childs SL, Rodrguez-Hornedo N, Reddy LS, et al. Screening strategies based on
solubility and solution composition generate pharmaceutically acceptable
cocrystals of carbamazepine. CrystEngComm. 2008;10(7):856-864.

58. Lipinski CA. Drug-like properties and the causes of poor solubility and poor
permeability. J Pharmacol Toxicol Methods. 2000;44(1):235-249.
59. Lipert MP, Rodrguez-Hornedo N. Cocrystal transition points: role of cocrystal
solubility, drug solubility, and solubilizing agents. Mol Pharm. 2015;12(10):
3535-3546.
60. Lipert MP, Roy L, Childs SL, Rodriguez-Hornedo N. Cocrystal solubilization in
biorelevant media and its prediction from drug solubilization. J Pharm Sci.
2015;104(12):4153-4163.
61. Bethune SJ, Huang N, Jayasankar A, Rodrguez-Hornedo N. Understanding and
predicting the effect of cocrystal components and pH on cocrystal solubility.
Cryst Growth Des. 2009;9(9):3976-3988.
62. Reddy LS, Bethune SJ, Kampf JW, Rodrguez-Hornedo N. Cocrystals and salts of
gabapentin: pH dependent cocrystal stability and solubility. Cryst Growth Des.
2008;9(1):378-385.
63. Good DJ, Rodriguez-Hornedo N. Cocrystal eutectic constants and prediction of
solubility behavior. Cryst Growth Des. 2010;10(3):1028-1032.
64. Kuminek G, Cao F, Da Rocha ABDO, Cardoso SG, Rodrguez-Hornedo N. Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5.
Adv Drug Del Rev. 2016;101:143-166.
65. Jayasankar A, Reddy LS, Bethune SJ, Rodraguez-Hornedo N. Role of cocrystal
and solution chemistry on the formation and stability of cocrystals with
different stoichiometry. Cryst Growth Des. 2009;9(2):889-897.
m D, Velaga SP. 1: 1 and 2: 1 urea-succinic acid
66. Alhalaweh A, George S, Bostro
cocrystals: structural diversity, solution chemistry, and thermodynamic stability. Cryst Growth Des. 2010;10(11):4847-4855.
67. Li Z, Matzger AJ. Inuence of coformer stoichiometric ratio on pharmaceutical
cocrystal dissolution: three cocrystals of carbamazepine/4-aminobenzoic acid.
Mol Pharm. 2016;13(3):990-995.
68. Hisada N, Takano R, Takata N, et al. Characterizing the dissolution proles of
supersaturable salts, cocrystals, and solvates to enhance in vivo oral absorption. Eur J Pharm Biopharm. 2016;103:192-199.
69. Tomaszewska I. In Vitro and Physiologically Based Pharmacokinetic Models for
Pharmaceutical Cocrystals. UK: University of Bath; 2013.
70. McNamara DP, Childs SL, Giordano J, et al. Use of a glutaric acid cocrystal to
improve oral bioavailability of a low solubility API. Pharm Res. 2006;23(8):
1888-1897.
71. Maddileti D, Jayabun SK, Nangia A. Soluble cocrystals of the xanthine oxidase
inhibitor febuxostat. Cryst Growth Des. 2013;13(7):3188-3196.
72. Cherukuvada S, Babu NJ, Nangia A. Nitrofurantoinep-aminobenzoic acid
cocrystal: hydration stability and dissolution rate studies. J Pharm Sci.
2011;100(8):3233-3244.
73. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery
and development settings. Adv Drug Del Rev. 2001;46:3-26.
74. Sanphui P, Devi VK, Clara D, Malviya N, Ganguly S, Desiraju GR. Cocrystals of
hydrochlorothiazide: solubility and diffusion/permeability enhancements
through drugecoformer interactions. Mol Pharm. 2015;12(5):1615-1622.
75. Saikia B, Bora P, Khatioda R, Sarma B. Hydrogen bond synthons in the interplay of solubility and membrane permeability/diffusion in variable stoichiometry drug cocrystals. Cryst Growth Des. 2015;15(11):5593-5603.
76. Yan Y, Chen JM, Lu TB. Simultaneously enhancing the solubility and permeability of acyclovir by crystal engineering approach. CrystEngComm.
2013;15(33):6457-6460.
77. Trask AV, Motherwell WDS, Jones W. Physical stability enhancement of
theophylline via cocrystallization. Int J Pharm. 2006;320(1):114-123.
78. Trask AV, Motherwell WDS, Jones W. Pharmaceutical cocrystallization:
engineering a remedy for caffeine hydration. Cryst Growth Des. 2005;5(3):
1013-1021.
79. Veverka M, Simon P, Gallovic J, Jorik V, Veverkova E, Dubaj T. Imatinib
mesylate cocrystals: synthesis, screening, and preliminary characterization.
Monatsh Chem. 2012;143(10):1405-1415.
80. Eddleston MD, Thakuria R, Aldous BJ, Jones W. An investigation of the
causes of cocrystal dissociation at high humidity. J Pharm Sci. 2014;103(9):
2859-2864.
81. Sarkar A, Rohani S. Cocrystals of acyclovir with promising physicochemical
properties. J Pharm Sci. 2015;104(1):98-105.
82. Gao Y, Gao J, Liu Z, et al. Coformer selection based on degradation pathway of
drugs: a case study of adefovir dipivoxilesaccharin and adefovir dipivoxilenicotinamide cocrystals. Int J Pharm. 2012;438(1-2):327-335.
83. Oswald IDH, Allan DR, McGregor PA, Motherwell WDS, Parsons S,
Pulham CR. The formation of paracetamol (acetaminophen) adducts with
hydrogen-bond acceptors. Acta Crystallogr Sect B Struct Sci. 2002;58(6):
1057-1066.
84. Jayasankar A, Roy L, Rodrguez-Hornedo N. Transformation pathways of
cocrystal hydrates when coformer modulates water activity. J Pharm Sci.
2010;99(9):3977-3985.
85. Aitipamula S, Vangala VR, Chow PS, Tan RBH. Cocrystal hydrate of an antifungal drug, griseofulvin, with promising physicochemical properties. Cryst
Growth Des. 2012;12(12):5858-5863.
p H. Interrelation of
86. Arenas-Garcia JI, Herrera-Ruiz D, Morales-Rojas H, Ho
the dissolution behavior and solid-state features of acetazolamide cocrystals.
Eur J Pharm Sci. 2016;96:299-308.
87. Mittapalli S, Bolla G, Perumalla S, Nangia A. Can we exchange water in a
hydrate structure: a case study of etoricoxib. CrystEngComm. 2016;18(16):
2825-2829.
13
88. Vangala VR, Chow PS, Tan RBH. Characterization, physicochemical and photostability of a co-crystal involving an antibiotic drug, nitrofurantoin, and
4-hydroxybenzoic acid. CrystEngComm. 2011;13(3):759-762.
89. Zhu B, Wang JR, Zhang Q, Mei X. Improving dissolution and photostability of
vitamin K3 via cocrystallization with naphthoic acids and sulfamerazine. Cryst
Growth Des. 2016;16(1):483-492.
90. Sun CC. Decoding powder tabletability: roles of particle adhesion and plasticity. J Adhes Sci Technol. 2011;25(4-5):483-499.
91. Hiendrawan S, Veriansyah B, Widjojokusumo E, Soewandhi SN, Wikarsa S,
Tjandrawinata RR. Physicochemical and mechanical properties of paracetamol cocrystal with 5-nitroisophthalic acid. Int J Pharm. 2016;497(1):
106-113.
92. Karki S, Frisic T, Fabian L, Laity PR, Day GM, Jones W. Improving mechanical
properties of crystalline solids by cocrystal formation: new compressible
forms of paracetamol. Adv Mater. 2009;21(38-39):3905-3909.
93. Krishna GR, Shi L, Bag PP, Sun CC, Reddy CM. Correlation among crystal
structure, mechanical behavior, and tabletability in the co-crystals of vanillin
isomers. Cryst Growth Des. 2015;15(4):1827-1832.
94. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and
stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS
PharmSciTech. 2011;12(2):693-704.
95. Chattoraj S, Shi L, Chen M, Alhalaweh A, Velaga S, Sun CC. Origin of deteriorated crystal plasticity and compaction properties of a 1: 1 cocrystal between
piroxicam and saccharin. Cryst Growth Des. 2014;14(8):3864-3874.
96. Chattoraj S, Shi L, Sun CC. Understanding the relationship between crystal
structure, plasticity and compaction behavior of theophylline, methyl gallate,
and their 1: 1 co-crystal. CrystEngComm. 2010;12(8):2466-2472.
97. Aher S, Dhumal R, Mahadik K, Ketolainen J, Paradkar A. Effect of cocrystallization techniques on compressional properties of caffeine/oxalic acid 2: 1
cocrystal. Pharm Dev Technol. 2013;18(1):55-60.
98. Ghosh S, Mondal A, Kiran M, Ramamurty U, Reddy CM. The role of weak
interactions in the phase transition and distinct mechanical behavior of two
structurally similar caffeine co-crystal polymorphs studied by nanoindentation. Cryst Growth Des. 2013;13(10):4435-4441.
99. Aitipamula S, Chow PS, Tan RBH. Polymorphism in cocrystals: a review and
assessment of its signicance. CrystEngComm. 2014;16(17):3451-3465.
100. Cruz-Cabeza AJ, Reutzel-Edens SM, Bernstein J. Facts and ctions about
polymorphism. Chem Soc Rev. 2015;44(23):8619-8635.
101. Goud NR, Nangia A. Synthon polymorphs of sulfacetamideacetamide cocrystal based on NH$$$OS and NH$$$OC hydrogen bonding. CrystEngComm. 2013;15(37):7456-7461.
102. Serajuddin A, Jarowski CI. Effect of diffusion layer pH and solubility on the
dissolution rate of pharmaceutical acids and their sodium salts II: salicylic
acid, theophylline, and benzoic acid. J Pharm Sci. 1985;74(2):148-154.
103. Mooney KG, Mintun MA, Himmelstein KJ, Stella VJ. Dissolution kinetics of
carboxylic acids I: effect of pH under unbuffered conditions. J Pharm Sci.
1981;70(1):13-22.
104. Zannou EA, Ji Q, Joshi YM, Serajuddin ATM. Stabilization of the maleate salt of
a basic drug by adjustment of microenvironmental pH in solid dosage form.
Int J Pharm. 2007;337(1-2):210-218.
105. Remenar JF, Peterson ML, Stephens PW, Zhang Z, Zimenkov Y, Hickey MB.
Celecoxib: nicotinamide dissociation: using excipients to capture the cocrystal's potential. Mol Pharm. 2007;4(3):386-400.
106. Guo M, Wang K, Hamill N, Lorimer K, Li M. Investigating the inuence of
polymers on supersaturated ufenamic acid cocrystal solutions. Mol Pharm.
2016;13(9):3292-3307.
107. Wang C, Tong Q, Hou X, Hu S, Fang J, Sun CC. Enhancing bioavailability of
dihydromyricetin through inhibiting precipitation of soluble cocrystals by a
crystallization inhibitor. Cryst Growth Des. 2016;16(9):5030-5039.
108. Li M, Qiu S, Lu Y, Wang K, Lai X, Rehan M. Investigation of the effect of
hydroxypropyl methylcellulose on the phase transformation and release
proles of carbamazepine-nicotinamide cocrystal. Pharm Res. 2014;31(9):
2312-2325.
109. Ullah M, Hussain I, Sun CC. The development of carbamazepine-succinic acid
cocrystal tablet formulations with improved in vitro and in vivo performance.
Drug Dev Ind Pharm. 2015;42(6):969-976.
110. Huang N, Rodrguez-Hornedo N. Effect of micellar solubilization on cocrystal
solubility and stability. Cryst Growth Des. 2010;10(5):2050-2053.
111. Cheney ML, Shan N, Healey ER, et al. Effects of crystal form on solubility and
pharmacokinetics: a crystal engineering case study of lamotrigine. Cryst
Growth Des. 2009;10(1):394-405.
112. Sun DD, Wen H, Taylor LS. Non-sink dissolution conditions for predicting
product quality and in vivo performance of supersaturating drug delivery
systems. J Pharm Sci. 2016;105(9):2477-2488.
113. Perumalla SR, Paul S, Sun CC. Enabling the tablet product development of 5uorocytosine by conjugate acid base cocrystals. J Pharm Sci. 2016;105(6):
1960-1966.
114. Picker KM. Soft tableting: a new concept to tablet pressure sensitive materials. Pharm Dev Technol. 2004;9(1):107-121.
115. Schmidt AG, Wartewig S, Picker KM. Potential of carrageenans to protect
drugs from polymorphic transformation. Eur J Pharm Biopharm. 2003;56(1):
101-110.
116. Karki S, Fris
ci
c T, Jones W, Motherwell WDS. Screening for pharmaceutical
cocrystal hydrates via neat and liquid-assisted grinding. Mol Pharm.
2007;4(3):347-354.
14
117. Sovago I, Wang W, Qiu D, et al. Properties of the sodium naproxen-lactosetetrahydrate co-crystal upon processing and storage. Molecules. 2016;21(4):509.
118. Zhang GGZ, Law D, Schmitt EA, Qiu Y. Phase transformation considerations
during process development and manufacture of solid oral dosage forms. Adv
Drug Del Rev. 2004;56(3):371-390.
119. Stanton MK, Bak A. Physicochemical properties of pharmaceutical
co-crystals: a case study of ten AMG 517 co-crystals. Cryst Growth Des.
2008;8(10):3856-3862.
120. Search for Ertugliozin j Diabetes Mellitus, Type 2 on ClinicalTrials.gov.
Washington, DC: National Institutes of Health; 2016. Available at: https://
clinicaltrials.gov/ct2/results?term=Ertugliozin&cond=%22DiabetesMellitus
%2CType2%22. Accessed April 5, 2016.
121. Bowles P, Brenek SJ, Caron S, et al. Commercial route research and development for SGLT2 inhibitor candidate ertugliozin. Org Process Res Dev.
2014;18(1):66-81.
122. E-58425. Esteve R&D. Barcelona, Spain: Laboratorios del Dr. Esteve, S.A.U.;
2016. Available at: http://www.esteve.es/EsteveFront/es/en/jsp/idi_rd_
portfolio_E-58425.jsp. Accessed August 18, 2016.
123. Clinical trials for E-58425. EU Clinical Trials Register. Canary Wharf, London:
European Medicines Agency; 2016. Available at: https://www.clinical
trialsregister.eu/ctr-search/search?query=E-58425. Accessed April 5, 2016.
124. Newsroom Press Announcements. Silver Spring, MD: US Food and Drug
Administration; 2016. Available at: http://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm453845.htm. Accessed April 6, 2016.

Kale, Bansal, JPS, 2016, Challenges in Development of Pharma Cocrystals

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Kale, Bansal, JPS, 2016, Challenges in Development of Pharma Cocrystals

Uploaded by

Copyright:

Available Formats

Journal of Pharmaceutical Sciences xxx (2016) 1-14

Contents lists available at ScienceDirect

Journal of Pharmaceutical Sciences

Challenges in Translational Development of Pharmaceutical Cocrystals

Introduction: Denition and Theoretical Aspects of Cocrystals

* Correspondence to: Arvind K. Bansal (Telephone: 91-172-2214682-2126;

that are crystalline single-phase materials composed of two or

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

functional groups (carboxylic acid-amide, carboxylic acid-aromatic

area of crystal engineering, diversity of coformers, and regulatory

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

S-oxiracetam, a drug used in the treatment of cognition

Translational Development of Cocrystals

objectives and has been discussed in section Strategy for

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

part of the cocrystal. Before designing a cocrystal for a drug, careful

carbamazepine as an immediate-release tablet (marketed as

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

GRAS Status and Max Limit

Max IID Limit for Oral Use

Yes, no max limit other

1 gm/5 mL (in syrup)

Preformulation Studies on Cocrystals

Generally, it is known that solubility of cocrystals increases with

PBS, phosphate buffer saline.

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

370, respectively. However, in the solution of Tween-80, this SA

where [coformer]eu is concentration of coformer at eutectic point

Cocrystal is less soluble

Solubility of drug and that

for cocrystals of sulfacetamide with isonicotinamide (0.64 times

Real solubility advantage can be judged

Extent and duration of

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

Water (over 90 min)

18 Times faster than parent

forms. Acyclovir (ACV) is used in the treatment of recurrent herpes

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

microenvironment pH resulting in stabilization of AD whereas

Excipient Selection or Other Approaches

Modulating Apparent Solubility, Dissolution, and In Vivo Performance

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

Use of a formulation strategy such as particle engineering

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

type-2 diabetes mellitus. The candidate drug is in phase 3 of clinical

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

signicant challenges in their translational development to

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

D.P. Kale et al. / Journal of Pharmaceutical Sciences xxx (2016) 1-14

You might also like