PERSPECTIVE

pubs.acs.org/crystal

Solubility Advantage of Amorphous Drugs and

Pharmaceutical Cocrystals
Published as part of the Crystal Growth & Design 10th Anniversary Perspective
N. Jagadeesh Babu and Ashwini Nangia*,

Laboratory of Biophysics and Surface Analysis, School of Pharmacy, Boots Science Building, Room D09, University of Nottingham,
University Park, Nottingham, NG7 2RD, U.K.

School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India
ABSTRACT: The current phase of drug development is witnessing
an oncoming crisis due to the combined eects of increasing R&D
costs, decreasing number of new drug molecules being launched,
several blockbuster drugs falling o the patent cli, and a high
proportion of advanced drug candidates exhibiting poor aqueous
solubility. The traditional approach of salt formulation to improve
drug solubility is unsuccessful with molecules that lack ionizable
functional groups, have sensitive moieties that are prone to
decomposition/racemization, and/or are not suciently acidic/
basic to enable salt formation. Several novel examples of pharmaceutical cocrystals from the past decade are reviewed, and the
enhanced solubility proles of cocrystals are analyzed. The peak
dissolution for pharmaceutical cocrystals occurs in a short time
(<30 min), and high solubility is maintained over a suciently long
period (4
6 h) for the best cases. The enhanced solubility of drug
cocrystals is similar to the supersaturation phenomenon characteristic of amorphous drugs. However, in contrast to the metastable nature of amorphous phases, cocrystals are stable owing to their
crystalline nature. Yet, cocrystals can exhibit dramatic solubility advantage over the stable crystalline drug form, often comparable to
amorphous pharmaceuticals. The spring and parachute concept for amorphous drug dissolution is adapted to explain the solubility
advantage of pharmaceutical cocrystals. Thus (1) the cocrystal dissociates to amorphous or nanocrystalline drug clusters (the spring),
which (2) transform via fast dissolving metastable polymorphs to the insoluble crystalline modication following the Ostwalds Law of
Stages, to give (3) high apparent solubility for cocrystals and optimal drug concentration (the parachute) in the aqueous medium.

INTRODUCTION
According to the Biopharmaceutics Classication System
(BCS),1 drugs are classied into four categories depending on
their solubility and permeability parameters (Figure 1). The
seminal work of Amidon2 showed that drug absorption in the
gastrointestinal (GI) tract is controlled by membrane permeability and solubility/dissolution rate. Permeability is measured
as the partitioning of the drug molecule in its uncharged or
neutral state between n-octanol and water, represented by log P
and C log P parameters. The reference standard for dening high
or low permeability boundary is the n-octanol/water partition
coecient for metoprolol (log P 1.72). Drugs having log P > 1.72
are categorized as high-permeability because metoprolol is
known to be 95% absorbed from the GI tract. Since experimental
human jejunal membrane permeability data are available for 29
reference drugs only, the correlation is based on estimated or
calculated log P (or C log P) values. The agreement between the
literature and calculated values was excellent. In silico permeability calculations demonstrated 75% accuracy in classifying
r 2011 American Chemical Society

these 29 drugs with human permeability data and 90% accuracy

for the 14/29 FDA reference drugs for permeability. High/low
solubility is dened with reference to the Dose number, Do,
which is the ratio of the highest drug dose strength in the
administered volume (taken as 250 mL = a glass of water) to
the saturation solubility of that drug in water (measured in mg/L).
A Do value of <1 means a highly soluble drug whereas Do is >1 for
low solubility compounds. In simple terms, Do is the number of
glasses of water required to dissolve the tablet at its highest dose.
Do values of 25
100 are considered low solubility drugs and this
number can even exceed 1000 (Figure 1). Apart from the
dimensionless Do parameter, solubility classication for drugs in
low, moderate, and high category3 is given in Table 1.
The serious problem posed by low solubility drugs was
highlighted in recent Chemical & Engineering News articles.4
Received: April 18, 2011
Revised:
May 16, 2011
Published: May 18, 2011
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Figure 1. The Biopharmaceutics Classication System of drugs (ref 1)

according to intestinal absorption and oral administration parameters.
The Do solubility scale is shown on top.

Table 1. Solubility Classication of Drugs with Dose of about

1 mg/kg (mg of drug/kg of body weight)a
solubility (mg/L)

classication

comments

<20

low

will have solubility problems

20
65

moderate

may have solubility problems

>65

high

no solubility problem

Data are taken from ref 3.

Table 2. Low Solubility Drugs in the Market and in the

Development Pipeline According to the Biopharmaceutics
Classication Systema
BCS
class

% drugs

% drugs

solubility

permeability

on market

in R&D pipeline
5
10

high

high

35

II

low

high

30

60
70

III

high

low

25

5
10

IV

low

low

10

10
20

Data are taken from ref 4b.

Over 80% drugs are sold as tablets. About 40% of marketed drugs
have low solubility. More alarming is double the percentage of
drug candidates in the R&D pipeline (80
90%) which could fail
due to solubility problems (Table 2). A major cause for the
current crisis in drug solubility may be traced to the High
Throughput Combinatorial Medicinal Chemistry research programs popular in the 1990s.5 Thousands of new drug molecules
were discovered and screened for biological activity using
dimethyl sulfoxide (DMSO) and polyethyleneglycol (PEG) as
solvents in robotic set ups. Whereas this rapid screening technology produced hundreds of molecules which bind strongly to drug
targets, the use of DMSO and PEG as solvents resulted in those
molecules having extremely low aqueous solubilities (g/L
range), often referred to as brick dust or chalk powder
compounds. That a drugs behavior depends on much more
than the molecular structure4 has led to the emphasis shifting
often in pharmaceutical R&Ds from MedChem to PharmDev
(medicinal chemistry discovery to pharmaceutical form development). There is a heightened awareness that the solid
drug form dictates properties such as stability, solubility, hygroscopicity, dissolution rate, and bioavailability in the past
decade. Incidentally, this period coincides with the launch of

Figure 2. A cocrystal is a stoichiometric molecular complex of a

molecule (blue) with a coformer (red) assembled via noncovalent
interactions, predominantly hydrogen bonds. In a pharmaceutical
cocrystal, the molecule is an API and the coformer is a GRAS compound.
Crystallization of the API gives the reference drug form, whereas
cocrystallization leads to multicomponent crystal structures (cocrystal).

Crystal Growth & Design journal in the year 2000. The 10th
Anniversary of CG&D6 roughly coincides with an increasing
focus on the development of novel solid drug forms as an
important and innovative step in pharmaceutical R&D.7 Slowly
but perceptibly New Form Discovery is the frontrunner solution
to thicken the pipeline of new drugs compared to New Molecular
Entities until about a decade ago. Topical reviews in CG&D,8
journals, and books9 highlight this paradigm shift toward pharmaceutical form discovery, selection, and optimization. The looming
patent clis for several blockbuster drugs in the coming decade10
mean that new R&D strategies must be devised for the continued
growth of the global pharmaceutical industry. The search for new
pharmaceutical solids such as polymorphs, hydrates, solvates, cocrystals, salts, etc. by manual experimentation has become a highthroughput crystallization technology11 in the 21st Century.
We present in this Perspective some recent examples of
cocrystals that exhibit enhanced solubility compared to the
reference drugs and compare their dissolution proles with those
of amorphous drugs. We are aware that even the denition of
what is a cocrystal (or co-crystal)12 is not agreeable on a common
platform,13 although there is some consensus on the meaning
and usage of the word pharmaceutical cocrystal.14 We will use the
word cocrystal to describe hydrogen-bonded molecular complexes schematized in Figure 2. When the molecule (blue) is an
active pharmaceutical ingredient (API) and the coformer (red) is
a molecule selected from the list of benign chemicals for human
consumption (generally regarded as safe by the FDA or
GRAS),15 the resulting crystalline adduct is a pharmaceutical
cocrystal. Such molecular complexes or cocrystals (other names
are molecular compounds, heteromolecular complexes, addition
compounds) of drugs with partner molecules having complementary functional groups were reported by the Caira group16 in
the mid 1990s, but they lay dormant for a few years. The
popularity of cocrystals (a nomenclature that now supersedes
earlier terminologies such as molecular compounds, molecular
complexes, etc.) in the crystal engineering17 and pharmaceutical
chemistry communities may be traced to the feature article by
Almarsson and Zaworotko in 2004.14 Blagden et al.9a recently
highlighted the use of hydrogen bonding (Etter)18 and crystal
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Table 3. BCS Classication of a Few Drugs in the Market (Listed Alphabetically in Each Category)a
Class I
high solubility, high permeability

Class II
low solubility, high permeability

diltiazem, metformin hydrochloride, metoprolol,

atovaquone, carbamazepine, danazol, felodipine,

paracetamol, propranolol, pseudoephedrine sulfate,

glibenclamide, griseofulvin, ketoconazole, mefenamic acid,

theophyline, verapamil

nicardipine, nifedipine, nisoldipine, troglitrazone

Class III
high solubility, low permeability

Class IV
low solubility, low permeability

acyclovir, alendronate, atenolol, captopril, cimetidine,

cefuroxime, chlorothiazine, cyclosporin, furosemide,

enalprilate, neomycin, ranitidine

itraconazole, tobramycin

Data taken from ref 25.

engineering (Desiraju)19 strategies to improve the solubility and

dissolution prole of drugs. The literature discussed in this article
is taken from papers published largely in the past decade.

SOLUBILITY OF PHARMACEUTICALS
When a solute is placed in a solvent, mixing of solute and
solvent molecules occurs due to randomization, that is, entropy
of mixing is the driving factor. The second factor is enthalpy:
intermolecular interactions and hydrogen bonds between
the solute and solvent molecules are stronger compared to
solute 3 3 3 solute and solvent 3 3 3 solvent interactions. The stronger solute 3 3 3 solvent hydrogen bonds favor dissolution of the
solid for enthalpic reasons. The free energy of mixing (eq 1) will
determine the possibility and extent of the solute and solvent
mixing in solution. As is true for any thermodynamic process,
mixing will occur spontaneously when Gmix is negative.
Gmix H mix
TSmix

where T is the temperature in Kelvin. The same equation is

applicable to single and multicomponent drug forms such as [A],
[B], [A: B], [A B
], etc. where A represents drug and B is the
coformer or salt former as molecule, ion, etc. The gain in the
enthalpy of hydration arising from hydrogen bonds made
between water and the dissolving compound(s) more than
compensates for the energy required to break the solid-state
species. Because of charge-assisted hydrogen bonds and electrostatic interactions, the enthalpy of hydration for ionic salts is
greater than that for neutral cocrystals. Hence, salts are more
water-soluble and the preferred formulation for improving drug
dissolution and solubility.
The mixing of molecules begins at the surface and continues
until saturation of the solution is reached. The number of
molecules leaving the bulk solid into the solution and those
reattaching becomes equal in a state of dynamic equilibrium. The
amount of solute which dissolves in the solvent at the equilibrium
state is the solubility of the substance. The rate at which this state
is reached is the dissolution rate.20 Thus solubility is a thermodynamic parameter, while dissolution is a kinetic phenomenon.
Both these factors are important for pharmaceutical solids
because a drug will deliver its therapeutic eect only if a sucient
amount of the eective dose is absorbed fast enough in the
stomach and gastrointestinal tract. The equilibrium method of
solubility measurement is suited for those drugs that do not
undergo transformation in the biological medium (which is
aqueous and in the pH range 1
7) for a long enough time
(between 24 and 48 h). The intrinsic dissolution rate (IDR)
measurement overcomes the eects of crystal habit and particle
size. The apparent solubility (Cm) refers to the concentration of

the drug at the apparent equilibrium or supersaturation. Apparent solubility is distinct from equilibrium solubility (Cs) which is
reached at innite time. For stable, crystalline drug forms, Cm has
about the same value as Cs. The apparent solubility of a
metastable drug form (Cm), be it anhydrate, polymorph, or
cocrystal, is a calculated parameter and not measured directly
like the equilibrium solubility (Cs). The dissolution rate is
proportional to drug solubility provided that there are no phase
transitions. For drugs that undergo phase change during the
solubility experiment, the IDR of the drug must be measured
(designated Jm and Js for metastable and stable polymorphs), and
these values in turn are used to estimate the apparent solubility of
the metastable species (eq 2).21 Equation 2 can be derived from
the Noyes
Whitney
Nernst equation. The use of apparent
solubility measurements are exemplied elsewhere.22 The disk
intrinsic dissolution rate (DIDR)23 is yet another approach to
determine the solubility class membership, suited to those drugs
which undergo a phase transformation. DIDR is a rate phenomenon instead of an equilibrium quantity and hence likely to
correlate more closely with in vivo drug dissolution dynamics
than solubility.
Cm Cs  J m =J s

In general, crystalline forms of drugs are the most stable

(highest density and melting point) and consequently have the
lowest free energy and solubility. Solvated forms (termed
pseudopolymorphs) are the least soluble form in that solvent;
that is, hydrates will generally be less soluble than anhydrate
drugs in water. Because the hydrate form already has drug 3 3 3
water hydrogen bonds, the free energy released on further
bonding with solvent water molecules is less than that for the
anhydrate form. Consequently, drug hydrates are less soluble
than their anhydrate.24 Amorphous drugs are the least stable.
Such high entropy phases are prepared by arresting or freezing
the molecules faster than they can organize in the crystalline
lattice. Amorphous phases can exist as solids or even as supercooled glassy states. They lack the long-range order and periodicity characteristic of the crystalline state. The high free energy
and low density of the amorphous phase mean that amorphous
drugs dissolve faster than their crystalline forms. However, their
metastable nature and transformation to the crystalline form
during storage are serious concerns for drug developers.
Apart from good oral absorption, the drug must be permeable
through the GI membrane. BCS class I drugs have good solubility
and good permeability. Some common examples of BCS class
I
IV drugs in the market25 are listed in Table 3.
There are two well-practiced approaches in the prior art to
improve drug solubility. (1) The formation of salts is the oldest
and most popular method for improving the stability and
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PERSPECTIVE

solubility of drug substances.26 (2) By amorphization, that is, the

preparation of high energy metastable amorphous drug formulations of faster dissolution rates.27 A major driving force for the
higher solubility of salts is the ionic and electrostatic interactions.
Basic or acidic drug molecules are converted into salts by reaction
with inorganic acids and bases. Charged counterions, such as
Cl
, PO4
3, Na, Ca2, etc. dramatically increase the ionic,
polar, and hydrogen bonding interactions with solvent water
molecules and in this way rapidly transport the ionized drug to
the aqueous medium. The higher free energy of the amorphous
phase, the random orientation of molecules, and the larger
surface area due to smaller particle size increase the exposure
of hydrophobic and hydrophilic functional groups leading to
improved wettability for amorphous drugs. However, transformation of the metastable amorphous form to the stable crystalline phase during dissolution is a serious complication.28 A high
glass transition temperature (Tg > 75 C) minimizes accidental
phase transition even though there are examples of drugs that
undergo crystallization below Tg, promoted by water molecules
and surface crystallization. Polymer additives such as polyvinylpyridone (PVP), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyethyleneglycol (PEG), etc. are
used as stabilizers29 to increase the glass transition temperature
of amorphous drugs. Apart for the above methods, there are
several other drug delivery strategies such as micronization,

inclusion complexes with cyclodextrins and surfactants, nanoparticle vehicles, dispersion in dierent carriers, polymorphs,
polyamorphs, supersaturating drug-delivery systems (SDDS),
etc. described elsewhere.7,30

SOLUBILITY OF AMORPHOUS DRUGS

The dissolution prole and solubility of amorphous forms of a
few drugs compared to their crystalline phases are discussed below.
Atorvastatin Calcium. The equilibrium solubility of crystalline atorvastatin calcium is only 140 g/mL, whereas amorphous
particles prepared by supercritical antisolvent process (SAS)
have high apparent solubility of 460 g/mL. However, the amorphous phase solubility decreases after 24 h to about 200 g/mL.31
Their powder dissolution curves are displayed in Figure 3. The lack
of long-range order in the amorphous phase and its higher Gibbs
free energy resulted in rapid dissolution evidenced in the maximum supersaturated concentration after 10 min, which then
decreased due to solvent-mediated transformation of amorphous
to crystalline atorvastatin (Table 4). Even so, a higher concentration of atorvastatin for the amorphous form (300 g/mL), more
than twice than that for the crystalline phase, was maintained for
up to 3 h. The intrinsic dissolution rates of amorphous atorvastatin
showed peak plasma concentration at 10
15 min, which then
decreased over the next 5
6 h due to increase in the crystalline
content (Figure 4). The amorphous form dissolution curves have
slopes and peak values higher than those of the crystalline form,
reaching the asymptotic equilibrium value at 8 h. The transient
increase in IDR and apparent solubility of the amorphous drug
were sufficient to deliver a 2
4 times higher oral dose in rats.

Figure 3. Powder dissolution proles of unprocessed atorvastatin

calcium particles (9), SAS processed amorphous atorvastatin calcium
precipitated from acetone solution (b), SAS processed amorphous
atorvastatin calcium precipitated from THF solution (2), spray-dried
amorphous atorvastatin calcium from acetone solution (O), and spraydried amorphous atorvastatin calcium from THF solution () (n = 3,
mean ( S.D.). Published with permission from ref 31. Copyright 2008
Elsevier.

Figure 4. Plasma concentration
time curves of atorvastatin calcium.

Symbols are the same as in Figure 3 (n = 5, mean ( S.D.). Published with
permission from ref 31. Copyright 2008 Elsevier.

Table 4. Intrinsic Dissolution Rate and Solubility of Crystalline and Amorphous Atorvastatin Calcium in Water at 37 Ca
intrinsic dissolution rate g/(min/cm2)

form

solubility g/mL

mean particle size

142.2

3.83 ( 0.08 m

crystalline

84.9

amorphous

early phase (10 min)

late phase

SASAb

288.5 ( 3.4)

179.5 ( 2.1)

483.2 ( 3.4)

68.7 ( 15.8 nm

SDAc

280.1 ( 3.3)

175.5 ( 2.1)

469.1 ( 3.3)

3.62 ( 0.15 m

Increase in IDR and solubility compared to the crystalline form is given as ( times). Data are taken from ref 31. b SASA: supercritical antisolvent
amorphous from acetone. c SDA: spray-dried amorphous from acetone.
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Table 5. Interaction Radius of Intact and Ground Cefditoren

Pivoxil with Watera

grinding time (min)

interaction radius with water (cal/cm3)1/2

11.4

1
3

12.0
8.2

6.4

10

5.3

20

4.2

30

5.9

Data are taken from ref 32.

Figure 5. Dissolution patterns of intact and ground cefditoren pivoxil in

water at 37 C. Grinding time: 0 min (9), 1 min (0), 3 min (2), 5 min
(), 10 min (b), 20 min (O), and 30 min ((). Published with
permission from ref 32. Copyright 1999 Elsevier.

Figure 6. Relationship between crystallinity and concentration of

cefditoren pivoxil at 20 min. Published with permission from ref 32.
Copyright 1999 Elsevier.

Cefditoren Pivoxil. The decrease in crystalline content of

cefditoren pivoxil due to grinding and its reduced particle size
were correlated with the apparent solubility of the drug.32 Crystalline cefditoren pivoxil was ground in a mechanical ball mill and the
change in amorphous content was monitored with time by X-ray
powder diffraction. The characteristic amorphous hump, a
broad and shallow peak centered at 20
25 2, was clear after
30 min of grinding. There was a decrease in particle size and
interaction radius after a longer grinding time (Table 5). The
dissolution curves in water showed a maximum concentration at
about 20 min, and the curves are higher after longer grinding.
Thus, the peak concentration correlates nicely with the extent of
amorphous
crystalline drug content (Figures 5 and 6).

Figure 7. Dissolution proles for HGAP nanosized CFA (9) and

spray-dried CFA (b). Published with permission from ref 33. Copyright
2006 American Chemical Society.

Figure 8. Plasma concentration vs time prole after oral administration

of unprocessed CFA (b), spray dried CFA (9), PPT-CFA (O), and
sono-CFA (2) in rats. Published with permission from ref 34a. Copyright 2008 Elsevier.

Cefuroxime Axetil (CFA). CFA is a cephalosporin antibiotic

(BCS class IV drug) possessing high activity against a wide
spectrum of Gram-positive and Gram-negative microorganisms. The amorphous form of CFA has higher solubility and
good stability. Amorphous CFA nanoparticles were prepared
by the novel high-gravity antisolvent precipitation (HGAP)
method to further improve the dissolution rate.33 CFA particles prepared by HGAP were spherical with a mean particle size
of 305 nm, while commercial spray-dried CFA particles were
hollow spheres with a mean particle size of 15 m. The small
particle size and large specific surface area of amorphous CFA
nanoparticles resulted in a faster dissolution rate (Figure 7). At
37 C, the dissolution rate of the nanosized CFA was increased
to 78% after 30 min, while only 51% of the commercial spraydried CFA dissolved at that time. After 80 min, all of the
nanosized CFA particles had completely dissolved, but there
was still 40% of spray-dried CFA undissolved. In another
article,34 it was reported that the plasma concentration for
SONO
CFA (prepared by sonoprecipitation) exhibited significant improvement in drug absorption than the spray-dried
PPT-CFA (precipitation without sonication) or unprocessed
CFA (crystalline) (Figure 8). Both the Cmax and AUC0
24h
values of SONO
CFA were approximately 1.5 fold better than
those of the spray-dried CFA and 2-fold greater than crystalline
CFA, indicating a remarkable improvement in the oral absorption of CFA when administered in the form of amorphous
nanoparticles. PPT-CFA also showed improvement in
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Figure 9. Experimental aqueous solubility of amorphous and crystalline

indomethacin at 25 C (b amorphous, 9 -crystal). Published with the
permission from ref 35a. Copyright 2000 Plenum Publishing.

PERSPECTIVE

Figure 11. Dissolution prole of wet milled itraconazole (ITZ) colloidal dispersion and URF-ITZ colloidal dispersion (ultra rapid freeze) in
simulated lung uid (pH 7.4) at supersaturation conditions (100 times
the equilibrium solubility of micronized crystalline ITZ was added) in a
USP Dissolution Tester at 100 rpm and 37 C. Published with
permission from ref 37. Copyright 2010 Elsevier.

Figure 12. Plasma concentration of ITZ in rats after a single-dose

inhalation of nebulized ITZ which was wet-milled or URF colloidal
dispersion. Published with permission from ref 37. Copyright 2010
Elsevier.

Figure 10. Dissolution of indomethacin and amorphous indomethacin prepared by melt quenching and cryogrinding at 7 mL/min ow rate
in the dissolution cell: melt quenched (9), melt quenched cryoground
(b), 1 h cryoground ((), 3 h cryoground (), and crystalline (2). (a)
Cumulative amount vs time, and (b) dissolution rate vs time. Published
with permission from ref 36. Copyright 2010 American Chemical
Society.

Cmax and Tmax over unprocessed and spray-dried CFA owing to

the amorphous and porous nature of particles.
Indomethacin. The solubility of amorphous indomethacin is
greater than that of the crystalline form over a wide temperature range of 5
45 C. The peak solubility always occurred in the
first 10
15 min of the experiment, and this value is at least two
times higher than the steady-state solubility35 (Figure 9) at the
end of experiment (2 h). There was partial conversion of the
metastable amorphous phase to the crystalline form(s) by supersaturation of the dissolution medium during the solubility run.
Although in vitro to in vivo kinetic measurements and transformation rates are not known, it is expected that the solubility

advantage of the amorphous form will be realized in animal and

human trials. In a related paper,36 amorphous indomethacin was
prepared by melt quenching and cryogrinding and the improved
dissolution rates were compared with indomethacin
(Figure 10) in a flow cell. The phase transformation from
amorphous to the phase in water was monitored by in situ
Raman microscopy.
Itraconazole. It is known that drug particles in the 100 nm size
dissolve much faster than micronized particles (about micrometer -sized particles). The potential for increased surface area
and electrostatic interactions between ultrafine particles and the
aqueous medium can dramatically improve bioavailability. Itraconazole (ITZ) is a highly insoluble drug (ng/mL solubility in
water). The effect of crystalline vs amorphous nanoparticles on
drug bioavailability was compared. The nanocrystalline drug was
prepared by wet milling and the amorphous nanostructured
aggregates by ultrarapid freeze process (URF).37 There was 3
6
fold improvement in the Cmax concentration which peaks quite
early in the concentration vs time profile (Figures 11 and 12).
Interestingly, the dissolution profiles match very nicely with
the concentration of ITZ in plasma (good in vitro in vivo
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correlation). Some salient pharmacokinetic parameters are compared in Table 6.

Solubility Trends. The ratio of solubility between amorphous
to crystalline polymorphs of the same drug (4
14) is much
higher than those between crystalline polymorphs (2
3
times).38 The calculated solubility ratio is even higher
(10
1600, see Table 7), but such predictions are not reliable
because of amorphous-to-crystalline transformation during the
dissolution/bioavailability experiments. Some well-known examples of amorphous: crystalline solubility advantage are nifedipine
(6),39 ritonavir, a class IV drug (10),40 and tolbutamide
(4
6).41

DISSOLUTION PROFILE OF PHARMACEUTICAL

COCRYSTALS
After discussing the solubility advantage of a few amorphous
drugs (in native state or stabilized in a polymer matrix) over the
crystalline modication, a few examples from the cocrystal
category are illustrated. Even though sporadic examples of drug
cocrystals were reported in the 1990s16 and perhaps even
earlier,13d a systematic eort to rationally modify the physicochemical properties of drugs via cocrystal engineering is of recent
times, notably in the past decade. Cocrystals oer several benets
over traditional salts. (1) Drug molecules which lack easily
ionizable functional groups (such as those containing carboxamide, phenol, weakly basic N-heterocycles, etc.) can be intermolecularly manipulated via cocrystals to tune their physicochemical properties. (2) A practical advantage is that the number
of neutral GRAS coformers15 far exceeds the number of available
counterions for making pharmaceutical salts.26 (3) Since drug
molecules advancing past MedChem discovery laboratories are
becoming more complex and highly functionalized, there is a
need to develop novel methods for solubility improvement under
mild and neutral crystallization conditions rather than the
extreme pH regimes of salt titration. The last reason is equally
applicable to chiral drugs which may undergo racemization
during salt formation. The following examples demonstrate that
pharmaceutical cocrystals oer a viable platform to improve the
solubility of BCS class II and IV drugs.

Digoxin
Hydroquinone. One of the earliest examples of

solubility/dissolution advantage in a drug complex is the digoxin

hydroquinone molecular complex reported by Higuchi and Ikeda
in 1974.42 The authors estimated a 1:1.5 stoichiometry for the
complex based on the concentration of hydroquinone in solution.
Even though the word cocrystal is not strictly applicable here
because the exact stoichiometry of drug to coformer was not
established, the increase in bioavailability of the cocrystal compared to the drug (Figure 13) is notable. The concluding line of
this historical paper,43 The principle of complexing a drug with
substances such as hydroquinone to enhance dissolution might be
applied to other medications whose adsorption is erratic following
poor in vivo dissolution, was a very early forecast of the now
mature field of pharmaceutical cocrystals over 30 years later.
AMG517 Cocrystals. AMG517 is a development lead candidate of Amgen for the treatment of chronic pain. The ether
linkage flanked by pyrimidine and benzathiazole moieties makes
the structure sensitive to degradation in the strongly acidic pH
conditions of salt formation. The structures of about a dozen
cocrystals of AMG517 with carboxylic acids and carboxamides
were determined by single crystal X-ray diffraction, the cocrystals
were characterized using differential scanning calorimetry, thermal gravimetry analysis, powder X-ray diffraction (DSC, TGA,
PXRD), and their solubility/stability were determined. Solubilities were measured in a slurry (3.33 mg/mL) under fasted
simulated intestinal fluid conditions (FaSIF, pH 6.8, small
intestine conditions).44 Solubilities could not be measured at
0.01 N HCl (pH 2, stomach conditions)44,45 because they were

Table 6. Plasma ITZ Concentration in Rats after a Single

Dose Inhalation of Nebulized Aerosol Itraconazolea
pharmacokinetic parameters

wet-milled ITZ

URF-ITZ

Cmax (ng/mL)
Tmax (h)

50
2.7

180
4.0

AUC0
24 (ng h/mL)

662

2543

Data taken from ref 37.

Figure 13. Dissolution rate proles obtained for the digoxin

hydroquinone complex and free digoxin under comparable dissolution
conditions. Published with permission from ref 42. Copyright
1974 Wiley.

Table 7. Predicted and Experimental Solubility Ratio for Amorphous to Crystalline Drug Forms.a
drug

forms

calculated solubility ratio

experimental solubility ratio

temperature (C)

4.5

medium

indomethacin

amorphous/ -crystal

15
40

25

water

glibenclamide

amorphous/crystal

100
1600

14

23

buer

glucose

amorphous/crystal

15
50

21

20

ethanol

griseofulvin

amorphous/crystal

40
440

1.4

21

water

hydrochlorothiazide
iopanoic acid

amorphous/crystal
amorphous/I-crystal

20
110
12
20

1.1
3.7

37
37

HCl and PVP

buer

polythiazide

amorphous/crystal

50
450

9.8

37

HCl and PVP

Data taken from ref 35a.

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PERSPECTIVE

Figure 14. (a) Structure of AMG517. (b) Solubility of AMG517 and its ve cocrystals with carboxylic acids. The cocrystals show spring and parachute
(benzoic, hexanoic) or spring only (lactic) prole. The pure drug has peak solubility of 5 g/mL. The proles are similar for the other carboxylic acid and
carboxamide cocrystals studied (c and d). All measurements were carried out on 3.33 mg/mL concentration slurry in fasted simulated intestinal uid
(pH 6.8). Published with permission from ref 44. Copyright 2008 and 2009 American Chemical Society.

generally lower under acidic conditions and due to instability of

the drug at low pH. The crystal structures confirmed that the
product is a neutral cocrystal and not an ionic salt; that is, the
COOH is hydrogen bonded to the thiazole N and the NH donor
is bonded to the CdO in a neutral motif. The Smax of benzoic
acid cocrystal (21 g/mL) is about 10 times higher than that of
the pure drug (2 g/mL) in FaSIF conditions (Figure 14).
Although there was conversion of the cocrystal to the drug
hydrate at the end of the solubility experiment (24 h), the transient
advantage in improved solubility (during 1
3 h) is high enough to
give increased drug exposure in pharmacokinetic studies. Most of
the drug cocrystals were found to be stable after 1 month at 40 C/
75% RH conditions; they were not hygroscopic and there was no
perceptible change in their PXRD line pattern. A control experiment on the AMG517
sorbic acid cocrystal45 showed that the
solubility advantage is lost as the cocrystal disintegrates to the drug
and the coformer. The Smax of 29 g/mL at 1.1 h for the cocrystal
declined rapidly to reach the drug solubility value of 4 g/mL at
2.5 h (Figure 15), and after that point the free base solubility operated.
These dissolution rate curves suggest that the enhanced apparent
solubility will apply in the upper GI tract for drug absorption.
Carbamazepine Cocrystals. Carbamazepine, an important
antiepileptic agent, exists in four polymorphic forms. This waterinsoluble drug with a high dose (>100 mg/day) is the archetype for
evaluating solubility improvement in cocrystals. The carbamazepine

nicotinamide (CBZ
NCT) crystal structure is sustained by the
carboxamide homosynthon between drug molecules which are

Figure 15. Solubility of AMG517 free base, sorbic acid cocrystal, and
coformer. Smax occurs at 1.1 h and the equilibrium value is reached at
2.5 h. Published with permission from ref 45. Copyright 2008 WileyInterscience.

flanked on both sides by NCT coformers via mutual N
H 3 3 3 O

hydrogen bonds. The solubilities of CBZ, NCT, and CBZ
NCT
were determined in absolute ethanol at set temperatures between 25
and 60 C.46 The equilibrium was taken to have been reached when a
few crystals remained in suspension. The final form was confirmed
by X-ray powder diffraction or visual microscopy of the solid residue.
The solubility curves are shown in Figure 16. The concentration of
CBZ and NCT in equilibrium with the cocrystal is related by eq 3.
K sp CBZNCT

The solubility product was calculated by dissolving the cocrystal in EtOH at 25 C (Ksp = 0.0125 (mol/L)2). The inverse
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PERSPECTIVE

relationship of CBZ
NCT cocrystal solubility with increasing

NCT concentration is clear in Figure 16a. The solubility of pure
CBZ is invariant to the NCT amount in solution. In the expanded
view diagram (Figure 16b), the concentration of both CBZ and
NCT decrease as the cocrystal grows with consumption of
both components. The phase diagram is divided into four regions:
(I) undersaturated clear solution; (II) solution in equilibrium with
CBZ crystals; (III) point A in equilibrium with both CBZ and

Figure 16. Phase diagram of CBZ
NCT system. Solid lines are CBZ
(horizontal) and NCT (vertical) solubility curves, dashed lines are
CBZ
NCT cocrystal solubility curves, solid square symbols are measurement points, solid red circle is the point A corresponding to the
intersection of CBZ and CBZ
NCT solubility curves at 25 C, and solid
diamond symbols are the initial operating conditions. (a) Broad view of
the phase diagram at dierent temperatures including NCT solubility
curve, and (b) restricted view of the phase diagram with only CBZ and
CBZ
NCT saturated curves at 25 C, and location of the experiments.
Published with permission from ref 46. Copyright 2009 Elsevier.

CBZ
NCT; and (IV) solution in equilibrium with cocrystals. No

crystalline phase can develop in domain I. In domain IIa only CBZ
can nucleate whereas in IIb both CBZ and CBZ
NCT can
nucleate (supersaturated for both species), but the cocrystal is
the metastable phase whereas the drug is stable. Both drug and
cocrystal can nucleate in this zone. In IVa region, both drug and
cocrystal can nucleate, but the relative stabilities are reversed with
respect to zone IIa
cocrystal is stable whereas the drug is
metastable. In zone IVb, the solution is undersaturated in CBZ but
supersaturated in CBZ
NCT cocrystal; here only cocrystal will
nucleate. Since the solubility of NCT is high, the coformer is
undersaturated in this region of the phase diagram and it will never
nucleate at the concentrations considered. The results of slurry
crystallization experiments monitored by a video camera, SEM
images, and powder XRD are summarized in Table 8. The
combined data suggest that CBZ
NCT cocrystals grow on the
crystal faces of CBZ. The lower induction time for the cocrystal to
appear when the solution is supersaturated in CBZ (run 2 vs run 1)
indicates a heteronucleation mechanism for CBZ
NCT crystal
nucleation. The phase diagram for CBZ and NCT constructed in
EtOH show the importance of initial conditions of crystallization
on the nal outcome. Although the thermodynamic product is
reached in the end, kinetic aspects are important in the experiment
design.
A 1:1 cocrystal of carbamazepine
saccharin (CBZ
SAC)
was crystallized from alcoholic solvents. The cocrystal showed
a dependence of dissolution rate on particle size: particles
<150 m diameter were >80% dissolved after 60 min, whereas
larger crystals >500 m (up to 1 mm diameter) were <50%
dissolved (Figure 17). Conversion to the less soluble dihydrate
form of carbamazepine on the larger crystals surface during the
dissolution experiment is a reason for the reduced solubility of
larger crystals. The conclusions of this study47 were that (i) the
chemical stability in the solid-state is good and similar to the
marketed form of carbamazepine, (ii) the physical stability of the
cocrystal is comparable to the anhydrous polymorph form 3, and
(iii) the cocrystal dissolution rate depends on particle size above
150 m and the smaller crystals convert slowly to the dihydrate
compared to the drug absorption time scale. The bioavailability
of the cocrystal was compared with the marketed drug Tegretol
in dogs (Figure 18) using crystals of 50 m size at a dose
equivalent to 200 mg of the drug. The absorption of CBZ
SAC
cocrystal occurred rapidly in 1 h at the peak concentration. The
cocrystal showed higher plasma levels, AUC and Cmax compared
to Tegetrol, the marketed carbamazepine drug. The level of
saccharin delivered along with the drug cocrystal at the highest
approved dose level is close to the currently accepted limits.
Lamotrigine Cocrystals/Salts. Lamotrigine is amply amenable to cocrystal engineering48,49 because of its amino-pyridine

Table 8. Cocrystallization Experiments Started at Dierent Points of the Phase Diagram and the Resulting Solid Phasea

run

starting point location in phase

temperature of CBZ
NCT (CBZ)

solid phases observed in suspension during

nal solid phases in

diagram

nucleation, C

crystallization

suspension

IVb

25

CBZ
NCT

CBZ
NCT

IVa

25

CBZ and CBZ
NCT

CBZ
NCT

IVb

32

CBZ
NCT

CBZ
NCT

4
5

IVa
III

26
36 (25)

CBZ
NCT
CBZ and CBZ
NCT

CBZ
NCT
CBZ and CBZ
NCT

IIIb

41 (41)

CBZ and CBZ
NCT

CBZ

Data are taken from ref 46.

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Crystal Growth & Design

Figure 17. Mean dissolution proles (n = 3 carried out on 355 mg of

carbamazepine
saccharin cocrystal corresponding to 200 mg of pure
drug used for all sieved fractions) of various sizes of cocrystal in SGF at
37 C (9 >1000 m,  500
1000 m, O 300
500 m, 2 150
300 m,
0 53
150 m, ( <53 m). Published with permission from ref 47.
Copyright 2007 Elsevier.

functional group. Over a dozen cocrystals/salts have been

prepared, and the solubility trends for four of these compounds
are discussed49
lamotrigine cocrystal with methyl paraben
(form II), nicotinamide (anhydrate form and monohydrate),
saccharinate (salt form). The saccharinate salt exhibited the
highest concentration in water and maintained its peak profile
for 4 h (Figure 19a). The decrease in pH from 5.5 to 5.1 was
attributed as a reason for the highest dissolution rate of the
saccharinate salt. The increase in the solubility of lamotrigine is
higher in acidic medium compared to pure water by about 10%, it
being a basic drug. The methyl paraben cocrystal had the highest
dissolution profile in acidic medium and maintained its level for
4 h (Figure 19b). Nicotinamide cocrystal had the second highest
concentration profile in neutral medium whereas its hydrate
form was higher in acidic solution. Both these cocrystals showed
conversion to lamotrigine hydrate at the end of the dissolution
experiment.
Rodrguez-Hornedo50 recently proposed that cocrystal solubility is directly proportional to the solubility of its components.
However, the available data on lamotrigine cocrystals49 discussed
above shows mixed results. Nicotinamide has the highest solubility (1 g/mL); it is used as a hydrotrope for solubility
improvement, but its cocrystals exhibited the second highest
solubility after saccharinate and methyl paraben in neutral and
acidic medium, respectively. It appears that the theoretically
expected linear relationship between the solubility ratio of the
components plotted against the solubility of the cocrystal former
divided by the solubility of the API50a will be realized only when
the crystal structures have similar hydrogen bonding and molecular packing. For example, the isostructural salts48 of lamotrigine
with succinic acid, fumaric acid and DL-tartaric acid showed
solubility trends matching with those of the components. Thus,
dierences in hydrogen bond motifs and neutral/charged species
appear to override the contribution from the native solubility of
the coformer/salt former for predicting cocrystal solubility.
Itraconazole
Succinic Acid. Any discussion on pharmaceutical cocrystals is incomplete without mention of the classic
itraconazole case study.51 Itraconazole is an extremely waterinsoluble antifungal drug marketed in an amorphous form (as
Sporanox capsule) to achieve good oral bioavailability. Given that
the pKa of the piperazine N of itraconazole is 3.7, carboxylic acids
having pKa <1.7 should lead to salt formation ( pKa > 2
3).
The absence of known salts for itraconazole when Remenar
et al.51 published their seminal paper (early 2000s) suggested
that there could be problems with the traditional salts approach.

PERSPECTIVE

Figure 18. Average plasma time curves of carbamazepine concentrations from a crossover experiment in fasted beagle dogs (n = 4) given
oral doses of 200 mg of the active drug as Tegretol tablets and
carbamazepine
saccharin cocrystal. Published with permission from
ref 47. Copyright 2007 Elsevier.

Crystal engineering principles predicted that cocrystals should

form via the COOH 3 3 3 Narom heterosynthon between carboxylic acid coformers and the drug molecule. Crystalline complexes (Figure 20) exhibiting a dimeric motif of two drug
molecules with the appropriate diacid (succinic acid, fumaric
acid, tartaric acid, etc.) were obtained from polar aprotic solvents.
Surprisingly, there is a paucity of crystal structure data on
cocrystals and salts of itraconazole, and in general for 1,2,4triazole drugs, in the Cambridge Structural Database52 even
today. Solubility improvement for the weakly basic triazole drugs
is now possible through the novel cocrystals stratagem.
The dissolution prole of pure itraconazole, Sporanox formulation, and cocrystals in 0.1 N HCl (crystalline particles
<10 m) are compared in Figure 21. Drugs cocrystals have
4
20 fold higher concentration than the crystalline drug form
and the peak values were maintained for up to 8 h. The dissolution
rate of itraconazole
L-malic acid cocrystal matches with that of
the amorphous drug. The former being a crystalline modication
has good form stability. The ability to achieve and sustain high
transient concentrations of the drug in aqueous medium has
immense potential for improving drug bioavailability.
We have generally excluded pharmaceutical salts and cocrystal
salts and ionic complexes from the above discussion because the
literature is too vast on such species. The solubility of ionized
drug forms is enhanced/suppressed by several factors such as
counterion, pH, hydration, stoichiometry, etc.53 For example, the
550 times greater solubility of olanzapine dimaleate vs 225 times
for the monomaleate salt54 compared to the free base (43 mg/L)
was attributed to (1) higher amount of more soluble maleate
anion in the salt for a xed drug amount, (2) greater hydrogen
bonding potential of water with the more number of available O
acceptors in dimaleate salt, and (3) hydrogen bonding dierences between olanzapinium cation and maleate anion in the two
crystal structures. Ionic salts were reported for uoxetine hydrochloride, piroxicam, olanzapine, ciprooxacin and noroxacin,
salbutamol, nitrofurantoin, etc.55

SPRING AND PARACHUTE MODEL

In order to take advantage of instantaneous supersaturation
for improving drug dissolution, two conditions must be met:
generation of a metastable form of the drug, and maintenance of
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PERSPECTIVE

Figure 19. Dissolution prole of lamotrigine and crystal forms in (a) water and (b) pH 1 HCl solution. Lamotrigine, 2 = lamotrigine
methyl paraben
(form II), 3 = lamotrigine
nicotinamide (anhydrate), 4 = lamotrigine
nicotinamide (monohydrate), and 5 = lamotrigine
saccharinate salt. Published
with permission from ref 46. Copyright 2009 American Chemical Society.

Figure 20. Single crystal X-ray structure of itraconazole
succinic acid

(2:1). Published with the permission from ref 51. Copyright 2003
American Chemical Society.

Figure 21. Dissolution curves in 0.1 N HCl at 25 C. Sporanox capsule

amorphous form (9), crystalline itraconazole ((), L-malic acid cocrystal
(1), tartaric acid cocrystal (b), and succinic acid cocrystal (2).
Published with permission from ref 51. Copyright 2003 American
Chemical Society.

high drug concentration for a long enough time. Guzm
an et al.56

described the spring and parachute concept illustrated in
Figure 22. A number of methods are known to achieve

supersaturation of poorly soluble drug forms, for example,

crystalline salts, amorphous dispersion in polymer matrix, inorganic matrix as a carrier, nanoparticles, coground mixtures,
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Crystal Growth & Design

Figure 22. The spring and parachute concept to achieve high apparent
solubility for insoluble drugs. (1) The crystalline (stable) form has low
solubility. (2) A short-lived metastable species (i.e., amorphous phase)
shows peak solubility but quickly drops (within minutes to an hour) to the
low solubility of the crystalline form. (3) Highly soluble drug forms are
maintained for a long enough time (usually hours) in the metastable zone.

prodrugs of higher solubility, and cocrystals.30 Some of these

topics were covered in recent theme issues of the ACS journal
Molecular Pharmaceutics.57 Among the above strategies, salts and
cocrystals oer the unique advantage that they exist in crystalline
form and are inherently stable compared to the amorphous state,
which must be stabilized by additives and polymers.
The reasons for the peak solubility exhibited by amorphous
drugs are reasonably well understood. The higher free energy,
randomization of molecules, smaller particle size, larger surface
area, higher wettability, usually a combination of the above
eects, give the solubility advantage to amorphous drugs. On
the basis of the similarity of several [drug concentration] vs
[dissolution time] plots presented in this article, we propose that
hydrogen bonded cocrystals transiently give highly soluble active
drug species. Dissociation of the hydrogen-bonded drug 3 3 3 coformer cocrystal should occur in a short period (minutes to an
hour) in the biological medium because of weaker hydrogen
bonds compared to ionic bonding in salts. As the cocrystal
dissociates, the more water-soluble component (the coformer)
is extracted out of the crystal lattice into the aqueous medium.
The hydrophobic drug molecules, now in their native state,
become supersaturated in the aqueous biological solution and
immediately precipitate to give loosely aggregated clusters. This
sudden crashing out of the drug results in supramolecular
aggregates or clusters composed of randomly oriented molecules
which lack long-range order. Such nanosized molecular clusters
resemble the amorphous drug phase; that is, they have shortrange order but lack long-range periodicity. This in situ generated
amorphous drug form by the dissociation of the cocrystal can
exhibit the same kind of spike in drug solubility like the
amorphous drug dispersed in a polymer matrix (e.g., PVP,
HPMC, PEG, etc.). Thus the spring eect is achieved by
dissociation of the cocrystal to an amorphous-like drug form.
The maintenance of peak solubility, or parachute phenomenon, happens for a long enough time (120
300 min) to give high
dose solubility because transformation of these amorphous

PERSPECTIVE

Figure 23. Proposed mechanism for the solubility advantage of pharmaceutical cocrystals. The dissociation of the hydrogen bonded cocrystal in the aqueous medium liberates the more soluble coformer into the
solution, whereas the less soluble drug molecules aggregate as an
amorphous phase because of the sudden crashing out from solution.
These aggregates lack the long-range order and periodicity characteristic
of the crystalline state. The amorphous phase gives peak drug solubility
for a short period (the spring), which will gradually transform to
metastable polymorph(s) and thereby extend the metastable zone width
(the parachute eect). Finally, the drug will transform to the stable,
insoluble polymorph, but by this time the bulk of the drug has been
absorbed through the fast dissolving metastable state(s). The Ostwalds
Law of Stages could stretch the metastable zone width to several hours. If
the amorphous state directly transforms to the stable, crystalline form
without the intermediacy of metastable polymorphs (dash arrow), the
drug will exhibit spring eect only.

clusters to stable crystalline phases and/or crystal growth will

be a slow process in the dissolution medium. The amorphous to
crystalline phase transformation will be inhibited by additives,
polymers, excipients, solubilizers, etc. present in the stomach
along with the drug. The high-energy amorphous-phase rich
solution will transform to a metastable polymorph of the drug
(which will have higher solubility), and then nally to the stable,
thermodynamic, crystalline polymorph following the Ostwalds
Law of Stages58 (OLS). Direct observations of OLS were
recently reported.59 The appearance of homochiral L-serine
domains was observed using second harmonic generation imaging for a few seconds, which then converted to the SHG inactive
59a
DL-serine as crystallization progressed.
Amorphous paracetamol rst crystallized as metastable form III, which transformed to
metastable form II, and then to the stable form I.59b Metastable
form III was not identied under routine crystallizations from
solution, but identied only by starting from the amorphous
state. In eect OLS extends the metastable zone width of
Figure 22 to sustain the parachute eect. The proposed scenario
is schematized in Figure 23. An alternative pathway could be that
instead of amorphous drug clusters, a metastable nanocrystalline
form of the drug is released upon cocrystal dissociation. Either
way, high entropy particles and larger contact surface will lead to
faster dissolution. The rest of the events will follow a similar
trajectory. Thus cocrystals may be viewed as evolving from salts/
hydrates in terms of their structural origins (they are all multicomponent crystals as shown in Figure 2) and akin to prodrugs
because they improve drug solubility by releasing the active,
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PERSPECTIVE

Figure 24. Celecoxib
nicotinamide form conversion in dierent pH media. Published with permission from ref 61. Copyright 2007 American
Chemical Society.

Figure 25. Dissolution into 1% SDS in pH 6.5 phosphate buer at 37 C. PXRD patterns were recorded at the time of SDS addition. For samples
subjected to a presuspension, Cel
Nic was suspended at 2 mg/mL in the listed medium for 15 min prior to 5-fold dilution with 1.25% SDS in 25 mM
phosphate buer at pH 6.8. Published with permission from ref 61. Copyright 2007 American Chemical Society.

soluble drug form in vivo. Cocrystals are a kind of supramolecular

prodrugs.60
The elegant experiments of Remenar et al.61 on solubility
improvement of celecoxib
nicotinamide cocrystal (1:1) lend
credence to the above model. Celecoxib, a COX-2 inhibitor and
anti-inammatory agent, exists in four polymorphs I
IV.62 The
stable crystalline phase (Cel-III) is the marketed form but it has
very low solubility (<1 mg/L). Cel-IV dissolves twice as fast, has
two times higher bioavailability, and is shelf-stable for over a year.
Attempts to improve the bioavailability of celecoxib (via Na salt
and in organic vehicles) gave low oral drug delivery because of
rapid conversion to insoluble Cel-III upon addition in water. The
physical stability of Cel
Nic cocrystal (Figure 24) showed
conversion to metastable Cel-I (in 5 min) and then to the stable
polymorph Cel-III (in 30 min) in 0.01 N HCl at 37 C. Cel-Nic

dissolved to the extent of 80% of the target amount in 5 min in 1%

SDS solution reaching a solubility of 400 mg/L for celecoxib
whereas Cel-III achieved only 50% of the peak value; the drug
was 80% dissolved in 30 min (Figure 25). Therefore Cel
Nic
cocrystal exhibited a noticeable dissolution rate improvement
over Cel-III polymorph.
The intermediacy of an amorphous phase between Cel
Nic
and Cel-III was veried by PXRD plots (Figure 26). The crystal
structure of Cel-Nic contains R22(8) nicotinamide dimers N

H 3 3 3 O bonded to R44(18) macrocycle of the drug molecules.
Cel-III crystal structure on the other hand has R22(18) motif and
C(4) chains (see the original paper61 for crystal structure
diagrams). Due to large dierences in the solubility of celecoxib
and nicotinamide, the dissolution of the two species in the
biological test medium occurs at dierent rates. The removal
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Crystal Growth & Design

Figure 26. PXRD patterns of Cel-Nic stabilized by PVP as suspensions

in 0.01 N HCl. The concentration of all slurries was 2.0 mg/mL at 37 C.
The fate of the cocrystal transformation is dierent under the three
conditions given above due to wettability dierences, or faster/slower
dissolution in the presence/absence of surfactant. See the original paper
for details. Published with permission from ref 61. Copyright 2007
American Chemical Society.

of nicotinamide from the crystal lattice would require large scale

molecular organizations. The sudden collapse of the Cel-Nic
cocrystal lattice to a structure that lacks the main hydrogen bonds
motifs of Cel-III will lead to an amorphous, metastable phase
with free energy in between that of the cocrystal and Cel-III
structures. Cel
Nic dissociates to either Cel-III or Cel amorphous (Figure 26) depending on nonionic (Triton-X100) or
anionic (SDS) surfactant, which in turn is related to wettability of
the cocrystal by the surfactant. Such an in situ cocrystal to drug
transformation probably gives rise to nanosized celecoxib particles of higher dissolution rate compared to the free drug
(Figure 27).63 Thus the dissolution rate could be enhanced by
a nanosuspension of celecoxib, whether in amorphous or nanocrystalline form, resulting from dissociation of the drug cocrystal.
Another example to support the spring and parachute proposal illustrated in Figures 22 and 23 is the indomethacin

saccharin cocrystal.64 The cocrystal dissolves instantaneously in
pH 7.4 phosphate buer compared to the insoluble crystalline
-form of indomethacin. PXRD of the ltered precipitate
showed the amorphous phase along with a trace of the crystalline
R material, but no thermodynamic -form was detected. A few
other examples corroborate our drug cocrystal solubility advantage model. CBZ
SAC cocrystal did not exhibit phase transformation to carbamazepine dihydrate in aqueous slurry even after
24 h, and given its good stability the concentration prole was
similar to that of CBZ drug;47 that is, no spring eect was
observed (see Figure 17). The glutaric acid cocrystal of a
nonionizable API in development65 showed the opposite trend
to the above case: the cocrystal reached peak apparent solubility
(spring eect only), but then its concentration dropped (no
parachute phase) because of direct conversion to the stable
crystalline drug polymorph. Thus, the transient appearance of
an amorphous metastable phase of the drug gives the early spike
in apparent solubility and transformation to the stable crystalline
form via Ostwalds Law of Stages gives the gradually decreasing
dissolution rate until the equilibrium solubility is reached. The
gratifying expectation is that pharmaceutical cocrystals will

PERSPECTIVE

Figure 27. The dissolution proles of nanosized celecoxib stabilized

with Tween 80 (0), suspension of micronized celecoxib with the same
amount of Tween 80 ()), and pure celecoxib (). The results were
obtained with paddle dissolution test (900 mL of phosphate buer, pH
6.8, 50 rpm, 37 C without surfactant in medium. Published with
permission from ref 63. Copyright 2009 Elsevier.

exhibit a dramatic solubility advantage and enhanced drug uptake

in the few hours following oral administration.
There are of course other explanations for the higher solubility of
cocrystals compared to the pure drug. Rodrguez-Hornedo50
showed that the cocrystal eutectic constants (Keu) are a function
of cocrystal solubility across a broad range of chemical species,
solvents, and ionization states.50c Highly soluble cocrystals have
large eutectic constants, and high Keu values correspond to cocrystals of high solubility coformer and relatively less soluble drug.
Cocrystal solubility was found to be directly proportional to the
solubility of the coformer for carbamazepine, caeine, and theophylline among several bioactive molecules studied. Our understanding
of the complexities of drug solubility will improve with a better
knowledge of both the solid-state and solution chemistry.

OTHER USES OF COCRYSTALS

Solubility improvement is undoubtedly the most signicant
application of pharmaceutical cocrystals. Filterability and compaction are equally big hurdles at the manufacturing and tableting
stage. The cocrystal of acetaminophen with theophylline66 has a
at layer crystal structure of high tensile strength and superior
compression compared to the pure drug crystals which are brittle
due to a corrugated layer packing in the stable polymorph.
Methyl paraben acts as a molecular hook in the separation of
quinidine from its stereoisomer quinine by making a cocrystal
with the former active molecule via O
H 3 3 3 N hydrogen
bond.67 Surprising cases of renal failure in cats and dogs were
suddenly reported in the spring of 2007. The cause was attributed
to the melamine added in pet foods to increase the amino acid
assay which is based on the nitrogen content.68 Melamine forms a
1:1 cocrystal with cyanuric acid in vivo via multiple N
H 3 3 3 O
and N
H 3 3 3 N hydrogen bonds. Precipitation of the insoluble
cocrystal was the cause for renal toxicity leading to death in
domestic animals. A similar alarm was sounded in the US for
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Crystal Growth & Design

PERSPECTIVE

infant formula too.69 The last case is an example of cocrystal

having lower solubility compared to the pure components. This
property of cocrystals too has an application, for example in slow
releasing tablets. Again, a very early example comes from Higuchi
and Pitman.70 The molecular complexes of caeine and gentisic
acid are slow dissolving compared to caeine, and thus present a
potentially useful way of formulating caeine in dosage forms
such as chewable tablets that are intended to linger in the mouth.

Grants Commission (New Delhi, India) for continued support of

his research in crystal engineering and pharmaceutical chemistry.
The students of his research group provided valuable references
and critical comments during the writing of this article. The DST
is thanked for a JC Bose Fellowship. N.J.B. thanks the EPSRC for
support under Grant EP/G038740/1. We thank the reviewers
for their critical comments and valuable suggestions.

CONCLUSIONS AND FUTURE THOUGHTS

The eld of pharmaceutical cocrystals is barely 10 years young.
The early structural and physicochemical studies are promising
and project many exciting avenues for crystal engineers and
pharmaceutical chemists. Even as amorphous drugs and pharmaceutical cocrystals exhibit very similar peak solubility and concentration proles with time, the latter derivatives score on several
points. Because of their crystalline nature, cocrystals tend to be
stable to humidity and storage, they are less prone to undergo
phase transformations, and they are generally stable to drug
processing, wet granulation, tableting, compaction, etc. Cocrystals
may be viewed as supramolecular prodrugs that release a highly
soluble drug form in vivo. Intellectual property and patenting of
cocrystals as a new composition of matter (COM)71 and their
approval as novel combination or addition complexes of the active
drug under Section 505(b)(2) of the US-FDA should open newer
product opportunities for pharmaceutical cocrystals. The past
decade has witnessed numerous patent applications lings and
several patents being granted for pharmaceutical cocrystals72
which exhibit improved solubility and stability. A pharmaceutical
cocrystal designed using crystal engineering principles is yet to be
approved by the FDA as a marketable drug to the best of our
knowledge. The fact remains that there are already two drugs on
the market which would qualify as pharmaceutical cocrystals73
according to the currently accepted denition, valproate semisodium (1:1 sodium valproate/valproic acid complex) and Escitalopram oxalate oxalic acid hydrate (2:1:1:1 S-citalopram/dioxalate/
oxalic acid/water), although these terminologies were not in vogue
when these drugs were approved. A list of new drug candidates was
unveiled by pharmaceutical companies74 at the time this article was
in revision stage. Even a cursory look at the structures of these
molecules will alert the reader about the potential problems of low
solubility in the next generation of drugs.
The focus in this article was on the solid drug forms. A radically
dierent approach that completely circumvents the complex and
challenging issues associated with tablet formulation and solubility improvement is to move away from the solid-state, that is,
liquids as cocrystal and salt forms of drugs.75
Whether active pharmaceutical ingredients as crystalline salts,
cocrystals, or ionic liquids will be the standard practice in the
pharmaceutical industry: We look forward to an article in the
20th year of Crystal Growth and Design.

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AUTHOR INFORMATION
Corresponding Author

*E-mail: ashwini.nangia@gmail.com.

ACKNOWLEDGMENT
A.N. thanks the Department of Science and Technology,
Council of Scientic and Industrial Research, and University

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