Journal of Applied Pharmaceutical Science 01 (08); 2011: 01-05

ISSN: 2231-3354
Received on: 15-10-2011
Revised on: 19:10:2011
Accepted on: 23-10-2011

New Trends in the Co-crystallization of Active

Pharmaceutical Ingredients
Veerendra K. Nanjwade, F. V. Manvi, Shamrez Ali. M, Basavaraj K.
Nanjwade and Meenaxi M. Maste

ABSTRACT

Veerendra K. Nanjwade,
F. V. Manvi,
Basavaraj K. Nanjwade,
Meenaxi M. Maste
Department of Pharmaceutics,
KLE University College of Pharmacy,
JN Medical College Campus, Belgaum
590010, Karnataka, India.

Shamrez Ali. M
SimpexPharma Pvt. Ltd, Sigaadi,
Kotdwara 246149.District
PauriGarhwal Uttarakhand,

Pharmaceutical materials science being a fundamental branch that continuously

provides important insights, theories, and technologies to formulation sciences. The recent
advances in this area have brought the possibility to produce pharmaceutical materials by
design. In particular, the formation of co-crystals, i.e. crystalline molecular complexes of twoor more neutral molecules, represents a potential route to achieve pharmaceutical materials with
improved properties of interest, including dissolution rate and stability under conditions of high
relative humidity. Co-crystals consists of API and a stoichiometric amount of a
pharmaceutically acceptable co-crystal former. Pharmaceutical co-crystals are nonionic
supramolecular complexes and can be used to address physical property issues such as
solubility, stability and bioavailability in pharmaceutical development without changing the
chemical composition of the API. These can be constructed through several types of interaction,
including hydrogen bonding, pi-stacking, and van der Waals forces. Phase transformations
induced during processing/storage affects the mechanisms of conversion of crystalline drugs to
co-crystals. Pharmaceutical co-crystals considered better alternatives to optimize drug
properties could play a major part in the future of API formulation and can be employed for
chiral resolution. This review introduces co-crystals as an emerging class of pharmaceutical
materials, focusing on the experimental methods applicable to their crystallization. In addition,
the examples illustrating how the co-crystal approach can be utilized to enhance the specific
properties of pharmaceutical solids, such as dissolution rate of poorly-water soluble APIs and
physical stability of moisture-labile APIs.

Keywords: Co-crystal; API; Phase transformations; Supramolecular complexes; Physical

stability.

INTRODUCTION

For Correspondence
Veerendra K. Nanjwade
Department of Pharmaceutics
KLE University College of Pharmacy,
Belgaum-590010.
Karnataka, India.
Cell No: 00919738173632

Cocrystals are at present the most dynamically developing group of solid pharmaceutical
substances. The definition of the term pharmaceutical cocrystal is still under discussion, but
essentially it is a multi-component compound that is formed between a molecular or ionic API and
a cocrystal former that is a solid under ambient conditions (Vishweshwar, 2006).
Pharmacodynamically, cocrystal former is a ballast molecule (the same applies to salts), and the
GRAS rules apply. Nevertheless even a cocrystal former can be an active molecule. The
stoichiometric ratio of API and cocrystal former in a pharmaceutical cocrystal is mostly simple
(1:1, 1:2, 1:3 or vice versa). Cocrystals are not necessarily binary compounds, ternary and
quarternary cocrystals are known. Cocrystals can be divided into: cocrystal anhydrates, cocrystal
hydrates (solvates), anhydrates of cocrystals of salts and hydrates (solvates) of cocrystals of salts.
The borderline between salts and cocrystals is blurred and can be distinguished by the location of
the proton between an acid and a base.

Journal of Applied Pharmaceutical Science 01 (08); 2011: 01-05

the proton between an acid and a base. In salts, carboxyl proton is

moved to the hydrogen of the base while in cocrystals the proton
remains on the 5 carboxyl of the acid. In cases when D pKa = pKa
(base) pKa (acid) = 0 3, the transfer of proton is ambiguous and
we talk about the salt-cocrystal continuum (Childs and Stahly,
2007).
The cocrystallization potential of some active molecules is
studied in detail, e.g.carbamazepine, itraconazole, piroxicam,
norfloxacin, fluoxetin, caffein and others (Schultheiss and
Newman, 2009). The reason is to achieve a wide variation in solidstate properties of APIs. These efforts stem from principles of
supramolecular chemistry and crystal engineering to affect the
properties of API through the bottom up approach. This is
illustrated in the following examples. By the cocrystallization of
antifungal drug itraconazole with 1, 4-dicarboxylic acids (succinic
acid, L-tartaric acid or L-malic acid) a modification of the
dissolution profile is achieved compared to the amorphous form of
itraconazole (Sporanox, Janssen-Cilag) (Morissete et al., 2004). A
1:1 carbamazepine/saccharin cocrystal compared to polymorph III
of carbamazepine (Anticonvulsant Tegretol, Novartis) shows no
polymorphous behaviour and is not prone to hydration (Morissete
et al., 2007). The cocrystallization of pregabalin with S- mandelic
acid separates from the mixture of R and S isomers only the (1:1)
cocrystal (S)-pregabalin/(S)-mandelic acid. This technology is used
by Pfizer in manufacturing daosage form Lyrica ( Zaworotko M,
2008). The cocrystals of paracetamol show improved tablet
formation ability than free paracetamol, polymorph I (Panadol,
GlaxoSmithKline) (Jones, 2009). Caffein tends to form hydrates at
high RH (relative humidity) while its cocrystals with oxalic acid or
malonic acid do not have this unwanted property (never form
hydrates) (Jones, 2009). However, general trends of variation of
properties during the transition from APIs to their cocrystals are
not so far evident because fundamental causes of cocrystallization
are not known so far. The preparation of cocrystals involves a
number of techniques, in gas, liquid or solid phase. The most
important is the joint cocrystal growth from solution or joint solid
state grinding.
Often with the addition of a small amount of a molecular
lubricant (methanol, cyclohexan, chlorophorm etc.). Furthermore,
co-crystals can be synthesized by evaporation, sublimation,
melting, sonication etc. It often holds that identical starting
components may not yield the same product under different
cocrystallization techniques. Although cocrystals are intensively
studied and patented by both academic institutions and R&D
departments of pharmaceutical companies, there is no medicament
on the market formulated from a cocrystal. Nevertheless it turns
out that some pharmaceutical salts should be re-classified as cocrystals. This is also important for patent litigation.
Polymorphs, solvates, salts, and co-crystals are
schematically depicted in Fig. 1. We will use the term drug
substance for the therapeutic moiety, which may be a solvate, salt
or a co-crystal, while the single, uncharged molecule will be called
the active molecule.

The brief chronological scheme outlines the progress of

crystal engineering during the last 50 years, and more so since the
late 1980s from when onwards the attention of the chemical
community has become more fully focused on it. The work of
Schmidt on topochemistry is considered by many to represent the
formal beginnings of crystal engineering.

Fig 1. Schematic depiction of various types of solid forms.

CO-CRYSTAL VERSUS SOLVATES

The main difference between solvates and co-crystals is
the physical state of the isolated pure components: if one
component is a liquid at room temperature, the crystals are
designated as solvates; if both components are solids at room
temperature, the crystals are designated as co-crystals.
SALT VERSUS CO-CRYSTAL FORMATION
Co-crystal and salts may sometimes be confused. The
understanding of the fundamental difference between a salt
formation and a co-crystal is very important to both preformulation activities and chemical/pharmaceutical development
aspects. Indeed, salts and co-crystals can be considered as opposite
ends of multi-component structures (Stahly, 2007; Childs, 2007).
Salt are often chosen instead of the free acid or base as these can
improve crystallinity, solubility and stability of a pharmaceutical
compound. Co-crystals are an alternative to salts when these do not
have the appropriate solid state properties or cannot be formed due
to the absence of ionizable sites in the API. Salt formation is an
acidbase reaction between the API and an acidic or basic
substance. The widespread use of salt formation is evidenced by
the large number of marketed crystalline salts of APIs (Stahl, 2002;
Serajuddin, 2007). Salt formation is a three component system
having an acid (A), a base (B) and one or more solvents. A salt is
formed by transfer of a proton (H+) from an acid (A) to base (B).
A-H + B (A-) (B+- H)
Proton transfer is thought to mainly depend on the pKa
values of the components. The general rules for the packing of
hydrogen bonded molecules in crystals were developed (Etter,
1982, 1990 and 1991). When there is no such transfer and the
.

Journal of Applied Pharmaceutical Science 01 (08); 2011: 01-05

components are instead present in the crystal as neutral entities, the

product is generally defined as a co-crystal. In other words, a cocrystal is an A-B composite in which no proton transfer occurred.
A thermodynamic picture (see Figure 3) of the nucleation
phenomenon reveals interplay between the volume and surface
terms in nucleation initiation. Volume term-favouring aggregation
is an exothermic process that leads to a reduction in Gibbs free
energy throughout the system. On the other hand, surface term
allows the dissolution of molecular aggregates, which would
otherwise be nucleating, by utilising energy. r* is the critical radius
of molecular aggregate at which nuclei spontaneously grow.
Formation of nuclei is a compromise between volume and surface
term. Volume term favours aggregation whereas surface term
allows dissolution. Nuclei result when there is high volume
surface ratio. Below r*, aggregates dissolve whereas above r*
nuclei form macroscopic crystals Figure 2.
The diffusion-controlled formation of a liquid-like cluster
of solute molecules; and/or the organisation of clusters into an
ordered crystalline structure Figure 3.

Fig 2. Thermodynamic Relationship between Activation Energy for Nucleation and

Mean Radius of Molecular Aggregate.

Fig 4. Concentration of Solute during Crystallization.

Supersaturation is the basic driving force for

crystallisation and is defined as the concentration of the solute in
excess of saturated concentration under given conditions of
temperature. It is composed of two zones, the metastable and
unstable zones Figure 4. The two zones are defined so that the
metastable region shows crystals growing without nucleating,
whereas in the unstable region crystals appear after nucleation.
The formation of a salt or co-crystal can be predicted from
pKa value of acid (A) and a base (B). Salt formation generally
requires a difference of about 2.7 pKa units between the conjugate
base and the conjugate acid (A) i.e. [ pKa (base) - pKa (acid )
2.7]. For example, succinic acid having pKa 4.2 form co-crystal
with urea base (pKa 0.1) while succinic acid form salt with Llysine base having pKa 9.5. Generally base pKa values are not
sufficiently high to allow proton transfer when co-crystal is formed
(Whitesides, 2006).
Cocrystal Solubility
Cocrystal solubility is dependent on cocrystal component
concentration, solution complexation, and ionization when one or
more components are ionizable. Mathematical models have been
developed that describe the solubility of binary cocrystals with
nonionizable components based on the equilibria between cocrystal
and cocrystal components in solution (Nehm, Rodrguez-Spong et
al., 2006).
Bioavailability
If cocrystals are going to be a viable alternative for solid
state forms of a drug, bioavailability studies need to be performed.
Two manuscripts have been recently published that report the first
bioavailability studies using cocrystals.

Fig 3. Course of Crystallization and its Rate-limiting Steps.

CHARACTERIZATION OF CO-CRYSTALS
Characterization of co-crystals involves both structure
(infrared spectroscopy, single crystal x-ray crystallography and
powder x-ray diffraction) (Callear, 2008; Wenger, 2008; Basavoju
S, 2008) and physical properties (e.g. melting point apparatus,

Journal of Applied Pharmaceutical Science 01 (08); 2011: 01-05

differential scanning calorimetry, thermogravimetric analysis)

(Basavoju S, 2008; Lu J, 2009). The analytical potential of NIR
spectroscopy for co-crystal screening using Raman spectroscopy as
a comparative method has been reported (Alles M, 2008). A
compound-sparing, automated and green differential scanning
calorimetric method was developed for rapid co-crystal screening
which demonstrated the formation of carbamazepine nicotinamide co-crystals (Lu E, 2008). Co-crystals of a
phosphodiesterase-IV inhibitor with L-tartaric acid were
characterized (Variankaval et al., 2006). Co-crystals of ()gossypol with a C1-8 carboxylic acid or C1-8 sulfonic acid which
are useful as inhibitors of Bcl-2 family proteins and use of cocrystals of ()-gossypol with a C1-8 carboxylic acid or C1-8
sulfonic acid for inducing apoptosis in cells and for sensitizing
cells to the induction of apoptotic cell death were characterized
((e.g. (-)-Gossypol- acetic acid co-crystals ) (Wang S, United
States Patent 7432300).
Plots of pH versus solubility were employed to compare
the solubility of molecular salts and co-crystals (Cooke C., 2008).
Mathematical model was developed that describes the solubility of
co-crystals by taking into consideration the equilibria between cocrystal, co-crystal components, and solution complexes and was
applied to the phase diagrams of carbamazepine/nicotinamide cocrystal in organic solvents. The dependence of co-crystal solubility
on solubility product and complexation constants provided a
powerful approach to design co-crystal screening methods and to
formulate solutions with co-crystal components where
crystallization does not occurred (Nehm S., 2006). A method was
developed to estimate the co-crystal solubility in pure solvent and
co-crystal solubility was found to be directly proportional to the
solubility of constituent reactants for carbamazepine, caffeine, and
theophylline co-crystals (Good D., 2009). The phase
transformation of API to co-crystal has been shown to depend on
solution and co-crystal chemistry where non-stoichiometric
concentrations of co-crystal reactants lead to thermodynamically
favorable conditions for co-crystallization.A new approach to
model co-crystal phase diagrams was recently reported and its
application to an active pharmaceutical ingredient and glutaric acid
co-crystal demonstrated good agreement between calculated and
experimental data (Ainouz A., 2009). The scientists provided the
foundation to experimentally assess the thermodynamic stability of
a co-crystal with respect to its component forms using data for the
carbamazepinenicotinamide system (Schartman R., 2009). Cocrystal formation should generally be predictable by comparing the
relative stability of the most stable co-crystal and its pure
components found on the computed crystal energy landscapes. The
thermodynamically favored structure prediction of the co-crystals
of p-aminobenzoic acid with 2,2'-bipyridine, based only on the
atomic connectivity of the component molecules and assumed
stiochiometry was reported (Karamertzanis P., 2008).
The most stable solid form of tiotropium fumarate i.e. a
new salt-co-crystal of tiotropium fumarate with fumaric acid
structure consisted of matched cations and anions (a salt) together
with a nonionized free acid moiety as the co-former (co-crystal),

and is unique amongst the large number of tiotropium salts that

have been prepared and characterized. The stoichiometry
cation/anion/co-former of 2:1:1 corresponded to a simple
polymorph of the 1:1 salt, and its identity as a co-crystal has been
established by single-crystal X-ray diffraction with some
corroborating evidence from the Raman and infrared spectra. A
detailed investigation of the bonding and geometry of the three
crystalline forms of the fumarate indicated that the hydrogen
bonding motifs are very similar, and that conformational
differences arising from the packing of the two thiophene rings into
the crystal structure is probably important in determining their
relative stabilities. A comparison with the structures of other
tiotropium salts indicated a correlation of the dihedral angle
between the two tiotropium thiophene rings with the stability of the
crystal forms (Pop M., 2009). Curcumin, the main component of
the spice turmeric, has been successfully used as a therapy to treat
human multiple myeloma (Schultz D., 2008). Also has shown to
possess anti-inflammatory and anti-cancer activities . However,
curcumin has extremely poor water solubility and bioavailability.
A series of pharmaceutically acceptable co-crystal formers are
under investigation to screen for co-crystal formation of curcumin
(Handler., 2007) .
Pharmaceutical co-crystals as intellectual property
Compared to other classes of solid forms, co-crystals
possessed particular scientific and regulatory advantages, and
alongside these advantages were intellectual property issues which
give co-crystals with unique opportunities and challenges.
Researchers reported the importance regarding patents on
pharmaceutical co-crystals to the pharmaceutical industry (Trask,
2007). The value of co-crystals to the pharmaceutical industry
should become clearer, mainly with respect to several relevant
legal and regulatory issues, as products containing co-crystal
technology come out from pharmaceutical development pipelines
onto the market.
APPLICATIONS OF CO-CRYSTALS
Compared to other solid-state modification techniques
employed by pharmaceutical industry, co-crystal formation appears
to be an advantageous alternative for drug discovery (e.g. new
molecule synthesis, nutraceutical co-crystals), drug delivery
(solubility, bioavailability) and chiral resolution. Experts are of the
opinion that pharmaceutical intellectual property landscape may
benefit through co-crystallization (Trask, 2007).
CONCLUSIONS AND PERSPECTIVES
Pharmaceuticals having a prominent role in the healthcare
of the future and pre-formulation activities need to utilize
innovations to respond to the challenges of new discoveries. The
newer crystallization techniques provide effective means to
discover alternate solid-state forms in complex organic molecules
like drugs. These techniques are comprehensive, they are
accompanied by enhanced crystallisation rates and they potentially
bypass the limitations of additive addition. Ascertaining the

Journal of Applied Pharmaceutical Science 01 (08); 2011: 01-05

metastable forms can prove to be of immense help for those

molecules that fail to arrive at the market because of their insoluble
temperament. Represent an advantageous class in the context of
pharmaceuticals.co-crystal form represent a new type of material
for pharmaceutical development and are relatively new to
pharmaceutical industry and pharmaceutical co-crystals have given
a new direction to deal with problems of poorly soluble drugs and
much more useful in pharmaceutical products than solvates or
hydrates. Relevance in API formulation includes the ability to finetune physical properties, characterization of API, identify and
develop new, proprietary forms of prescribed drugs and the
opportunity to generate intellectual property. A further challenging
aspect is related to the development of efficient co-crystal
screening technologies. As a rule, the solid-based techniques, such
as neat grinding and liquid-assisted grinding, tend to demonstrate a
higher selectivity, as compared to solvent-based approaches, in
revealing the co-crystallization potential between multiple
molecular species. From physical properties perspective, a key
advantage of co-crystals as a solid form of an API is the possibility
of achieving the high dissolution rate comparable to that of the
amorphous form, while maintaining the long-term chemical and
physical stability that crystalline forms provide. Finally, an
important legal aspect associated with co-crystals is the
opportunity for the research based pharmaceutical companies to
significantly expand their intellectual property portfolios. Judicious
use of these innovative technologies therefore, can help preformulation scientists to unveil the hidden fortunes present as
alternate solid forms. The portfolio of solid forms of
pharmaceutical molecules is nowadays very wide and somehow
difficult to overlook. A further increase in number of new cocrystals, or multicomponent compounds generally, and their
application in solid drug formulations are expected in future.
Conflict of Interest: Veerendra K Nanjwade is a Research Scholar
in the Pharmaceutics Department of KLE University College of
Pharmacy, Belgaum. But he declares no conflict of interest
regarding the manuscript. The other authors declare no conflict of
interest.
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