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pubs.acs.org/crystal
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 (46 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
PERSPECTIVE
classication
comments
<20
low
2065
moderate
>65
high
no solubility problem
% drugs
% drugs
solubility
permeability
on market
in R&D pipeline
510
high
high
35
II
low
high
30
6070
III
high
low
25
510
IV
low
low
10
1020
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 (8090%) 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
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
theophyline, verapamil
itraconazole, tobramycin
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
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 NoyesWhitneyNernst 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
PERSPECTIVE
inclusion complexes with cyclodextrins and surfactants, nanoparticle vehicles, dispersion in dierent carriers, polymorphs,
polyamorphs, supersaturating drug-delivery systems (SDDS),
etc. described elsewhere.7,30
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
142.2
3.83 ( 0.08 m
crystalline
84.9
amorphous
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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11.4
1
3
12.0
8.2
6.4
10
5.3
20
4.2
30
5.9
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 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.
PERSPECTIVE
wet-milled ITZ
URF-ITZ
Cmax (ng/mL)
Tmax (h)
50
2.7
180
4.0
662
2543
Table 7. Predicted and Experimental Solubility Ratio for Amorphous to Crystalline Drug Forms.a
drug
forms
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
polythiazide
amorphous/crystal
50 450
9.8
37
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.
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.
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
Figure 16. Phase diagram of CBZNCT system. Solid lines are CBZ
(horizontal) and NCT (vertical) solubility curves, dashed lines are
CBZNCT cocrystal solubility curves, solid square symbols are measurement points, solid red circle is the point A corresponding to the
intersection of CBZ and CBZNCT 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
CBZNCT saturated curves at 25 C, and location of the experiments.
Published with permission from ref 46. Copyright 2009 Elsevier.
Table 8. Cocrystallization Experiments Started at Dierent Points of the Phase Diagram and the Resulting Solid Phasea
run
diagram
nucleation, C
crystallization
suspension
IVb
25
CBZNCT
CBZNCT
IVa
25
CBZNCT
IVb
32
CBZNCT
CBZNCT
4
5
IVa
III
26
36 (25)
CBZNCT
CBZ and CBZNCT
CBZNCT
CBZ and CBZNCT
IIIb
41 (41)
CBZ
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
carbamazepinesaccharin cocrystal. Published with permission from
ref 47. Copyright 2007 Elsevier.
PERSPECTIVE
Figure 19. Dissolution prole of lamotrigine and crystal forms in (a) water and (b) pH 1 HCl solution. Lamotrigine, 2 = lamotriginemethyl paraben
(form II), 3 = lamotriginenicotinamide (anhydrate), 4 = lamotriginenicotinamide (monohydrate), and 5 = lamotriginesaccharinate salt. Published
with permission from ref 46. Copyright 2009 American Chemical Society.
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.
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.
PERSPECTIVE
Figure 24. Celecoxibnicotinamide 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, CelNic 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.
PERSPECTIVE
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REFERENCES
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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