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Preparation of pharmaceutical co-crystals through

sustainable processes using supercritical carbon
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Cite this: RSC Adv., 2016, 6, 71134

dioxide: a review
Concepción Pando,* Albertina Cabañas and Isaac A. Cuadra

Received 27th April 2016
Accepted 14th July 2016
DOI: 10.1039/c6ra10917a
www.rsc.org/advances
The preparation of pharmaceutical co-crystals using supercritical CO2 (scCO2) is reviewed. Co-crystallization is
an emerging and powerful technique to improve the physicochemical properties of an active pharmaceutical
ingredient (API). The solid-state and solution co-crystallization methods usually employed present several
disadvantages that may be overcome using the supercritical methods. All the methods employing scCO2
have low environmental impact and operate at relatively low temperature avoiding API degradation and
producing solvent-free pharmaceuticals. The role of the fluid varies from one method to another. In the
rapid expansion of supercritical solutions (RESS) the API and the coformer are dissolved in scCO2. In the co-
crystallization with supercritical solvents (CSS), the fluid also acts as a solvent that facilitates molecular
interactions in a suspension of the API and coformer powders. However, in the supercritical antisolvent (SAS)
and the gas antisolvent (GAS) crystallizations scCO2 acts as an antisolvent that induces precipitation of the
API and the coformer previously dissolved in an organic solvent. In the atomization and antisolvent (AAS)
technique and supercritical fluid enhanced atomization (SEA) the fluid may act either as a spray enhancer or
an antisolvent depending on the process conditions. Each method is described and its application,
advantages and disadvantages are discussed. Future perspectives and areas to be investigated are outlined.

Dpto. de Quı́mica Fı́sica I, Facultad C. Quı́micas, Universidad Complutense, E-28040
Madrid, Spain. E-mail: pando@quim.ucm.es; Fax: +34 91394 4135; Tel: +34 91394
4304
1. Introduction
Co-crystallization is an emerging and powerful technique aimed
at improving the physicochemical properties of an active
pharmaceutical ingredient (API). Properties such as the

Concepción Pando is Professor Albertina Cabañas is Associate

of Physical Chemistry at Uni-
versidad Complutense de
Madrid (UCM), Spain. She
received her PhD degree at UCM
in 1979 and was a Fulbright
scholar at Brigham Young
University, USA (1981–82), per-
forming calorimetric studies of
mixtures involving supercritical
uids. She has studied phase
equilibria and thermodynamic
properties of uid and liquid
mixtures formed by CO2. She has experience in supercritical uid
extraction and is currently involved in the fabrication and
micronization of materials in supercritical CO2 aimed to applica-
tions in catalysis and pharmacology.
Professor in the Physical Chem-
istry Department at Universidad
Complutense de Madrid (UCM)
Spain since 2007. She received
her PhD degree at UCM in 1998
performing thermodynamic
studies of mixtures involving
supercritical uids. Aerwards,
she investigated the synthesis of
metal oxide nanoparticles in
supercritical water using
continuous reactors (1999–
2000, University of Nottingham, U.K.) and the deposition of high-
quality metal lms from supercritical CO2 solutions (2001–2003,
University of Massachusets, USA). She was “Ramón y Cajal” Fellow
(2003–2007, UCM, Spain). Her current research focuses on the
synthesis of nanomaterials using supercritical uids as green
solvents.

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solubility and chemical stability are modied by establishing

a new solid form through the interaction of the API with
a coformer at a supramolecular level.1–3 Coformers are usually
molecules included on the generally recognized as safe (GRAS)
list4 that can interact with the API. Nutraceuticals are another
class of compounds with an established safety record that may
be used as coformers.5 Pharmaceutical co-crystals resulting
from the interaction of two different APIs have been also
prepared.6 A co-crystal may be dened as a multiple component
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crystal that consists of two or more solid components in a de-

nite stoichiometric ratio held together via noncovalent and
nonionic interactions. Usually, two components are involved.
The co-crystal structure is the result of weak but directional
molecular recognition events very oen based on hydrogen
bonding.7 These intermolecular interactions or synthons are
classied either as heterosynthons (e.g. carboxylic acid–amide,
pyridine–carboxilic acid synthons) or homosynthons (e.g.
carboxylic acid–carboxilic acid, amide–amide synthons). Fig. 1
shows the molecular structures of the anti-inammatory drug
diunisal and nicotinamide, a member of the vitamin B family
widely used as a coformer, together with the supramolecular
structure of the 2 : 1 diunisal–nicotinamide co-crystal showing
the heterosynthons involved. This co-crystal has been recently
prepared by liquid assisted ball mill grinding and by solution Fig. 1 Molecular structures of diflunisal, nicotinamide, and the 2 : 1
crystallization from ethanol,8,9 and by a method based on using diflunisal–nicotinamide co-crystal showing the supramolecular het-
supercritical CO2 (scCO2) as antisolvent.10 The 2 : 1 diunisal– erosynthons involved.
nicotinamide co-crystal exhibits an enhanced dissolution rate
with respect to that of pure diunisal.
Pharmaceutical co-crystals can be prepared by solution
methods, evaporative or cooling crystallization or solid-state by solution and solid state methods, several authors proposed
grinding and mixing.11 Solution co-crystallization is the to use co-crystallization methods based on the utilization of
method preferred if single crystals are desired for crystal supercritical CO2. These supercritical methods are also aimed
structure elucidation although sometimes this method fails in to the development of production processes with very low
the preparation of a co-crystal already obtained by a mechano- environmental impact, fewer steps and a reduced used of
chemical method. These preparation methods bear the risk of organic solvents, therefore fullling the requirements for
producing the homocrystals (single component crystalline sustainable processes in the pharmaceutical industry. In this
phases) together with the co-crystal. Either the experimental paper, the supercritical co-crystallization methods are reviewed,
conditions are established empirically by trial and error or each method is presented in a separate section, and the oper-
a considerable effort is devoted to obtain ternary phase ating conditions, the properties of the co-crystals obtained so
diagrams of the two components and the solvent that allow far and the advantages and disadvantages of the methods are
understanding the mechanism of a solution co-crystalliza- examined. Usually, the co-crystals obtained by a supercritical
tion.11–13 In addition, remaining residues of the solvents may method are compared to those previously prepared by a solid-
pose a problem. To overcome some of the difficulties presented state grinding or solution method. Another section is devoted
to modeling efforts. The state-of art, the future perspectives and
the problems related to the application of these methods in the
B.Sc. Degree in Chemical Engi- pharmaceutical industries are also discussed. Finally, the
neering at the University Com- possibilities for application of the co-crystallization methods
plutense of Madrid (UCM), M.Sc. based on supercritical CO2 in other elds different from that of
in Industrial Processes Engi- pharmaceutics are summarized.
neering at UCM, Ph.D. student
working on the micronization of
particles using supercritical
2. Supercritical carbon dioxide and its
carbon dioxide as an antisolvent. use in the field of pharmaceuticals
Research on enhanced oil
Supercritical uids are pure substances or mixtures at a pres-
extraction at the Research and
sure and temperature higher than their critical coordinates, Pc
Development Centre of the
and Tc. Fig. 2 shows the pressure–temperature phase diagram of
Spanish oil company CEPSA.
carbon dioxide and the area where CO2 exists as a supercritical

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uid. Carbon dioxide is the most commonly used supercritical
uid because it is nontoxic, non-ammable, inexpensive, has
moderate critical temperature and pressure (31.0  C and 7.39
MPa) and is a byproduct in ethanol and ammonia plants.
Therefore, scCO2 is considered a green solvent.14 Supercritical
CO2 densities and solvation power are intermediate between
those of gases and liquids and can be easily modied with small
changes in temperature and pressure, the uid behavior may be
tuned from that of a liquid at a high pressure to that of a gas at
low pressure; meanwhile the uid maintains good transport
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properties. Values for the scCO2 viscosity coefficient are low and
similar to those of gases while values for the diffusivity coeffi-
cient are high in comparison to those of liquids. A pressure
reduction aer scCO2 treatment allows the preparation of
solvent-free pharmaceuticals. Other advantages are operation at
moderate temperatures in an inert atmosphere thus avoiding
the product degradation and the substitution or limited use of
organic solvents.
Different supercritical techniques have been widely used to
improve an API physicochemical properties.15 The solubility
and bioavailability of pharmaceuticals may be increased via size
reduction. Several supercritical methods for drug micronization
are available.16 The possibility of tuning the uid properties
through changes in temperature and pressure allows the
control of particle size and morphology. Moreover, the solvent-
free particles exhibit narrow size distributions very appropriate
for pharmaceutical applications. In comparison with traditional
methods, the production of drug microparticles using scCO2
requires fewer steps thus allowing a simplication and better
control of the process.
Changes of the crystal habit or polymorphic form through
scCO2 treatment are also possible.17–22 APIs can exist as different
solid phases classied as polymorphs that differ in crystal
structure and exhibit different thermodynamic, spectroscopic
and surface properties. Consequently, the various polymorphs
of a given API can have different bioavailability, activity and
even toxicity. Moreover, the presence of different crystal phases
Fig. 2 Pressure–temperature phase diagram of carbon dioxide.
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can accelerate undesirable polymorphic transformations. Poly-
morphic purity is an important parameter in a pharmaceutical
product. Conventional crystallization techniques usually lead to
a mixture of different polymorphs. However, supercritical uid
techniques may allow the crystallization of a single polymorph
because there are additional variables to play with such as the
pressure and density of the uid and furthermore they can be
one-step processes.
Very oen API formulations consist in a core material (the
API) surrounded by a coating or carrier material. In other
formulations the API particles are embedded in a carrier
material. Usually, a natural or synthetic polymer is used to
prepare both types of formulations, although fats or sugars may
be also used.23 Composite microparticles present several
advantages, in the rst place, they are easier to handle and dose
than the pure particles of an API. The material selected as shell/
carrier depends on the intended use of the composite micro-
particles and improves its properties. A biodegradable carrier is
used to achieve a controlled delivery of the active ingredient into
the targeted media.24,25 If the API is susceptible of degradation,
the carrier acts as a protection against aggressive agents. If the
API is poorly soluble in the targeted media, the carrier facilitates
its solubilization. This is the case of a number of poorly water-
soluble drugs. For drugs with low solubility in the crystalline
state, the possibility of improving their solubility, dissolution
rate and bioavailability due to the formation of an amorphous
form in a solid dispersion presents additional advantages. On
the other hand, in some cases composite particles exhibit
smaller sizes than that of the pure drug processed under the
same conditions.26 These formulations can be prepared by
coprecipitation, encapsulation or impregnation in scCO2 or
extraction of an emulsion using scCO2.15,23–31
The adaptation of the already existing supercritical tech-
niques and the proposal of new ones aimed to the preparation
of pharmaceutical co-crystals started in 2002;32 its fast devel-
opment in the last ve years10,32–51 prompted us to undertake
this review. The supercritical co-crystallization methods are
listed in Table 1; all of them share the advantages associated to
the use of CO2 already mentioned and have specic advantages
of their own that will be discussed and compared. The order of
presentation of the methods follows the chronological order of
the application of each method in the literature. The role of
scCO2 differs from one method to another. In the rapid
expansion of supercritical solutions (RESS) the API and the
coformer are dissolved in scCO2. In the co-crystallization with
supercritical solvent (CSS), the uid also acts as a solvent that
facilitates molecular interactions and thereby nucleation and
growth of co-crystals in a suspension of the API and coformer
powders. However, scCO2 acts as an antisolvent that induces
precipitation of the API and the coformer previously dissolved
in an organic solvent in the supercritical antisolvent (SAS) and
gas antisolvent (GAS) crystallizations. In the atomization and
antisolvent (AAS) and in the supercritical uid enhanced
atomization (SEA) techniques the uid has the dual role of
antisolvent and spray enhancer. Prior to the description of the
supercritical methods and in order to present the results of
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Table 1 Methods used to obtain pharmaceutical co-crystals using scCO2a
Method Acronym Role of CO2
Rapid expansion of RESS Solvent
supercritical solutions
Co-crystallization with CSS Solvent and molecular
supercritical solvent mobility enhancer
Supercritical antisolvent SAS Antisolvent
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crystallization
Atomization and antisolvent AAS Spray enhancer or antisolvent
crystallization
Supercritical uid enhanced SEA Spray enhancer or antisolvent
atomization
Gas antisolvent crystallization GAS Antisolvent
a
Two co-crystallization patents should be added to this table: Mazen and Townend50 led a general process including GAS, SAS and SEDS (solution
enhanced dispersion by supercritical uids); Hoand and Van Rosmalen51 patented a method similar to CSS.
their application, it is necessary to briey review the techniques
involved in the evaluation of pharmaceutical co-crystals.
3. Evaluation of pharmaceuticals co-
crystals
The methods used to evaluate pharmaceuticals co-crystals
prepared using scCO2 do not differ from those used for co-
crystals prepared by conventional methods. Most co-crystals
obtained using scCO2 have been previously obtained by these
methods and the co-crystal characterization available in the
literature serves as a guide to evaluate the co-crystal obtained by
the supercritical method. The characterization methods are
aimed to study the crystal size and morphology, its purity,
structure and interactions and the physical properties such as
the dissolution rate involved in the co-crystal pharmacological
use.1 Crystal size and morphology are usually investigated by
scanning electron microscopy (SEM). Optical microscopy has
been also used. Particle size distribution may be obtained from
SEM images or in a separate laser diffraction experiment. The
co-crystal size is an important characteristic although micron-
ization is not the principal objective in the scCO2 co-
crystallization techniques. The pharmacological benets are
expected to derive from the new formulation. Nevertheless,
a small particle size would also help in the case of poorly-
soluble APIs.
The composition of the powders produced is a key issue. The
coformers homocrystals may precipitate together with the
desired co-crystal. High performance liquid chromatography
(HPLC) may be used to establish the co-crystal purity. Using the
adequate mass balance equations, the amount of co-crystals in
the produced power can be determined. On the other hand,
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Reference
Vemavarapu et al. 2002,32 Vemavarapu et al. 2009,33
Müllers et al. 2015 (ref. 46)
Padrela et al. 2009,34 Padrela et al. 2015 (ref. 44)
Padrela et al. 2009,34 Chen et al. 2015,47
Cuadra et al. 2016,10 Hiendrawan et al. 2016,48
Neurohr et al. 2016 (ref. 49)
Padrela et al. 2009 (ref. 34)
Padrela et al. 2010,35 Tiago et al. 2013,40
Padrela et al. 2014 (ref. 41)
Shikhar et al. 2011,36 Ober and Gupta 2012,37
Ober et al. 2013,38 Neurohr et al. 2013,39
Harscoat-Schiavo et al. 2015,42 Neurohr et al. 2015,43
Erriguible et al. 2015 (ref. 45)
when organic solvents are required the absence of solvent
residues should be conrmed. Differential scanning calorim-
etry (DSC), infrared spectroscopy (FTIR) and X-ray diffraction
(XRD) are used to establish the co-crystal structure and inter-
actions. X-ray diffraction (XRD) of single crystals obtained from
solution co-crystallization is the preferred tool to determine the
solid state structure of a given co-crystal. Powder or microcrys-
talline samples are usually the result of supercritical methods.
Therefore, if a new co-crystal is obtained by a supercritical
method a parallel solution preparation is recommended.
Aerwards, XRD is used to identify the co-crystal and to study
the commercial coformers and establish their polymorphic
form. Padrela et al. also proposed a method for the quantica-
tion of co-crystals in the precipitate based on power XRD data.52
DSC is used to obtain melting point data and thermal data such
as the enthalpy of melting. Usually, the co-crystal melting point
is either comprised between those of the API and the coformer
or lower than both of them.1 DSC is also used to assess the co-
crystal purity. The appearance of one or two peaks corre-
sponding to the homocrystals together with the co-crystal peak
indicates that conditions of the co-crystallization method need
to be modied. Raman spectroscopy is sometimes used to
complement the DSC and XRD ndings. Interactions between
the API and the coformer in the co-crystal are investigated using
FTIR. The functional groups in the co-crystal spectrum show
differences in the wavenumbers and intensity of the vibrational
modes in comparison to those of the two coformers individual
spectra. Furthermore, bands characteristic of the synthons
established are observed. For instance, for the diunisal–nico-
tinamide co-crystals whose structure is shown in Fig. 1 bands
characteristic of the acid–pyridine nitrogen synthon and the
carboxylic acid–amide hydrogen bonds were observed in the co-
crystal spectrum.10
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The determination of the solubility of APIs and coformers in
scCO2 may be necessary in order to optimize the experiments
when solubility data are not available in the literature. Also,
phase diagrams for the quaternary systems formed by the API,
the coformer, a solvent and CO2 are required in order to
understand the co-crystallization mechanism. This type of data
is not directly related to the crystal evaluation although it is
essential to understand the co-crystallization mechanisms.
Co-crystal dissolution proles need to be obtained and
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compared to those of the API. For poorly soluble APIs an
improvement in the dissolution rate is considered a benet of
the new formulation. Physical and chemical stability studies are
also conducted; relative humidity stability experiments need to
be carried out if hygroscopicity leads to form changes or
degradation. Finally, the yield should be also studied because it
gives an idea whether the process can be applied in the
industry.
4. Rapid expansion of supercritical
solutions, RESS
In the RESS process solutes are dissolved in supercritical CO2
forming a homogeneous supercritical solution. Solute nucle-
ation is induced by rapidly reducing the solution density
through expansion to atmospheric conditions. This expansion
causes a high supersaturation that leads to a very homogeneous
nucleation rate. Fig. 3 shows a scheme of a RESS setup.32 Liquid
CO2 is pressurized using a pump and is fed to a preheater where
the temperature of the pressurized liquid is raised to that of
a supercritical uid. scCO2 is then fed to the saturation vessel
that contains the solutes to be co-crystallized and glass beads
aimed at improving the extraction efficiency and buffering the
turbulent ow of the uid through the vessel. The saturated
uid solution ows from the temperature-controlled reaction
vessel into a pre-expansion chamber maintained at 50 degrees
above the extraction temperature. Temperature is also
controlled in the lines and connectors to avoid premature
precipitation of the solutes. The saturated solution passes
through a micrometering valve maintained at 100 to 150  C
prior to the rapid expansion. The expansion device is a stainless
steel capillary inserted through the cap of the collection vial.
Fig. 3 Schematic representation of a RESS process:32 (V) valve, (P) pressure measurement, (TC) temperature controller, (MV) micrometering
valve.
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Aer solid precipitation CO2 is exhausted through a lter and
passes through a 5 m tubing before entering a ow meter that
allows to obtain a reliable estimate of the average ow rates
through the system.
Although many APIs are scarcely soluble in scCO2 the RESS
method has been used to produce micro and nanoparticles of
several pharmaceuticals.16 As to co-crystals, the rapid expansion
of chlorpropamide–urea–CO2 solutions was used by Vemavar-
apu et al. in 2002 (ref. 32) to disrupt the crystalline structure of
chlorpropamide with urea. Chlorpropamide is an API poorly
soluble in water that belongs to the sulfonylurea hypoglycemic
agents. Although the aim of Vemavarapu et al. was crystal
doping, this study can be considered the rst attempt to obtain
a co-crystal using scCO2. RESS recrystallization of commercial
chlorpropamide (polymorph A) resulted in polymorph conver-
sion to forms C and V depending on the temperature and
pressure. Temperature was varied from 46 to 103  C and two
levels of pressure (27.6 and 55.2 MPa) were tried at each
temperature. The evidence of crystal disruption through RESS
was conrmed by changes in the XRD patterns and the lowering
of the melting point in comparison to those of the pure crystal
polymorphs. SEM images revealed a particle size reduction of
up to one order of magnitude as a consequence of RESS pro-
cessing. The doped crystals thus formed are expected to show
a dissolution rate enhancement. In contrast, chlorpropamide
recrystallizations from liquid organic solvents lacked the ability
to produce polymorphic changes. Also, the incorporation of
urea into the drug lattice was found to be insufficient. Although
minor reductions in the melting temperatures and the heat of
fusion values were observed with respect to those of pure
chlorpropamide, powder XRD patterns revealed no signicant
disruption in the crystallinity. A few years later, Vemavarapu
et al.33 used this technique for the coprecipitation of twelve
drug-additive mixtures and observed several phenomena
including co-crystal and hydrate formation and polymorphic
transitions. Temperature was varied from 35 to 100  C and
pressure was varied from 7.6 and 62.1 MPa. According to
Vemavarapu et al., different crystallization mechanisms
competed depending on factors such as the interactions
between the drug and the coformer and their relative solubility
in the supercritical uid. In this study, the composition of
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several co-crystals of theophylline and caffeine was determined
by HPLC and found to be dependent on that of the starting
mixture. Depending on the relative amount of API and additive
in the co-crystal varying levels of crystallinity ranging from pure
crystals to amorphous mixtures could be found. These results
led these authors to conclude that RESS could not be used to
consistently dope crystals.
Recently, Müllers et al.46 have used RESS to obtain co-crystals
with coformers that have sufficient solubility in scCO2.
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Ibuprofen and nicotinamide were dissolved in scCO2 at 30 MPa
and 50  C with molar ratios of 0.5 : 1, 1 : 1 and 2 : 1. The
difference in solubility was taken into account in order to obtain
a supercritical solution with the correct stoichiometry. The co-
crystals obtained were thoroughly characterized. A 1 : 1
ibuprofen–nicotinamide co-crystal of high purity was produced
with a yield of 20%. The RESS co-crystal was shown to be
equivalent to the co-crystal prepared by slow solvent evapora-
tion. The crystalline micronized co-crystal product was
produced by RESS in a one-step process without the need of
organic solvents or further processing such as drying or size
reduction. The disadvantages of the RESS method are the low
solubility of many APIs in scCO2 that oen requires the use of
high pressures and the low yield and throughput rates. A mole
fraction solubility of at least 10 4 is required for RESS crystal-
lization of a pure API.16 As to the low throughput rates, Müllers
et al. suggested that they could be improved by implementing
a continuously running process.
5. Supercritical antisolvent
crystallization, SAS
The SAS method is based on the relatively low solvent power of
scCO2 for solutes such pharmaceuticals and its good miscibility
with many organic solvents. The API and the coformer are
Fig. 4 Schematic representation of a SAS setup:10 (BPR) back pressure regulator, (P) pressure measurement, (V) valve, (TC) temperature
controller, (T) temperature measurement.
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simultaneously dissolved in a polar organic solvent such as
ethanol or acetone and scCO2 is used as antisolvent to induce
the co-crystal precipitation. SAS has been widely applied to
obtain pharmaceutical particles.16 As to co-crystals, the group of
Prof. Gomes de Azevedo was the rst to apply this method in the
preparation of indomethacin–saccharin co-crystals.34 Recently,
Cuadra et al.,10 Chen et al.,47 Hiendrawan et al.,48 and Neurohr
et al.49 prepared by this method piracetam–salicylic acid,
diunisal–nicotinamide, paracetamol–dipicolinic acid, and
naproxen–nicotinamide co-crystals, respectively.
A scheme of the SAS setup is shown in Fig. 4.10 Supercritical
carbon dioxide is introduced in a precipitation chamber using
a high-pressure pump at constant ow rate. Then the organic
solution containing the drugs is fed through a second pump
also at a constant ow rate reaching steady state operating
conditions and an adequate supercritical uid/solvent ratio. A
given amount is sprayed in the precipitation chamber through
a nozzle. The chamber is heated and both temperature and
pressure are controlled. When the uid dissolves in the solu-
tion, the mixture becomes supersaturated and precipitation
starts. The co-crystals are collected at the bottom and walls of
the precipitation chamber. At the end of the precipitation
process, the chamber is washed with excess CO2 to remove the
residual content of the liquid solvent. The CO2 + organic solvent
mixture is introduced into a separation chamber where the
solvent is recovered. The solvent-free particles exhibit narrow
size distributions. The pharmaceutical co-crystals obtained
using SAS are listed in Table 2 together with the solvent,
temperature, pressure, concentration, and the mass ow ratio
of the solution to the supercritical uid used.
Cuadra et al.10 used the SAS setup shown in Fig. 4 to obtain
co-crystals of the anti-inammatory drug diunisal and nico-
tinamide. The drug and coformer molar ratio in solutions fol-
lowed the 2 : 1 stoichiometric co-crystal composition. The
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Table 2 Pharmaceutical co-crystals prepared via the SAS process and experimental conditions: T and P are the temperature and pressure in the
precipitation vessel, and R is the mass flow ratio of the solution to the supercritical fluid. The API and coformer molar ratio in the solution follows
the co-crystal stoichiometrya

Co-crystal Solvent T ( C) P (MPa) R (g g 1) Reference

1 : 1 indomethacin–saccharin Ethanol 50 9.0 0.05 34

Acetone 50 8.4 0.12 34
Tetrahydrofurane 50 8.5 0.04 34
Methanol 50 8.6 0.06 34
Ethyl acetate 50 8.6 0.19 34
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2 : 1 diunisal–nicotinamide Acetoneb 35 10.0 0.04 10

Acetoneb 35 12.0 0.04 10
Acetoneb 40 10.0 0.04 10
Acetoneb 40 12.0 0.04 10
Ethanol 35 10.0 0.04 10
1 : 1 piracetam–salicylic acid Acetone 45 10.0 — 47
1 : 1 paracetamol–dipicolinic acid Methanol 40 10.0 0.03 48
2 : 1 naproxen–nicotinamideb Acetone 37 10.0 0.09–0.50 49
a
In the case of the naproxen–nicotinamide co-crystal a 2 : 2 molar ratio was also used. b Two different concentration values were used.

inuence of solvent (acetone and ethanol), concentration (two
levels), temperature (35 and 40  C) and pressure (10.0 and 12.0
MPa) was shown to be weak. Fig. 5 shows the SEM image of the
co-crystal obtained at 35  C, 10.0 MPa, and concentrations in
the acetone solution of 30.00 and 7.28 mg mL 1 for diunisal
and nicotinamide, respectively. A similar crystalline material in
the form of needles of uniform width was obtained in all
experiments. A yield of 70% was obtained for the co-crystal
prepared with the lower values of concentration in acetone at
the lower values of temperature and pressure. This pure co-
crystal was shown to exhibit the same crystal structure,
melting point and FTIR spectrum as co-crystals previously ob-
tained by assisted ball mill grinding and solution crystalliza-
tion. The dissolution prole of the 2 : 1 diunisal–nicotinamide
co-crystal was better than that of pure diunisal. The
Fig. 5 SEM image of the 2 : 1 diflunisal–nicotinamide co-crystal ob-
tained by SAS at 35  C, 10.0 MPa, and concentrations in the acetone
solution of 30.00 and 7.28 mg mL 1 for diflunisal and nicotinamide,
respectively (2 : 1 molar ratio).
application of the SAS technique to pure diunisal led to
a change in the diunisal polymorphic form.
Chen et al.47 obtained the 1 : 1 piracetam–salycilic acid co-
crystal at the conditions shown in Table 2. The co-crystal was
characterized by SEM, XRD, FTIR, DSC and thermogravimetric
analysis (TGA). The formation of the co-crystal and its satis-
factory thermal stability were conrmed. Dissolution studies
indicated that at a given time the co-crystal concentration is
close to half of that for pure piracetam. Therefore, the side effect
caused by a high dissolution rate of pure piracetam can be
regulated.
Hiendrawan et al.48 obtained the 1 : 1 paracetamol–dipico-
linic acid co-crystal at the conditions shown in Table 2 and
compare it to that obtained by a traditional solvent evaporation
method. The formation of new crystalline phases was conrmed
by XRD, DSC, FTIR, SEM and polarized light microscopy. The
SAS co-crystal particles had a mean diameter of 4.18 mm
(considerably smaller than that of solvent-evaporation particles)
and showed an enhanced dissolution rate with respect to both
pure paracetamol and the co-crystal produced by solvent evap-
oration. Both co-crystals were found to be stable and exhibited
better tableting properties than pure paracetamol.
Using a SAS setup similar to that shown in Fig. 4, Neurohr
et al.49 have recently prepared the 2 : 1 naproxen–nicotinamide
co-crystals. An acetone solution and CO2 were introduced into
a cylindrical vessel through two separated inlet ports. The vessel
was equipped with 8 sapphire windows distributed at top,
medium and bottom levels to visualize the injection and the
precipitation. The conditions of temperature and pressure were
kept constant at 37  C and 10 MPa while the CO2 and solution
ow rates were varied. The co-crystal particles exhibited a thin
plate-like morphology, a size distribution ranging from 20 mm
to 1 mm. Also, the SAS co-crystals showed the same hydrogen
bond interactions and crystalline structure than co-crystals
previously obtained by conventional and GAS techniques.42,43,45
By processing a 2 : 2 naproxen–nicotinamide solution instead of
a 2 : 1, Neurohr et al. obtained a co-crystal-pure powder. The
yield of precipitation ranged from 60 to 70%. A simulation was

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developed to obtain supersaturation distribution proles that
helped to establish conditions favoring co-crystallization
instead of homo-crystallization. The solubility data previously
obtained by Revelli et al.53 for the quaternary system naproxen–
nicotinamide–acetone–CO2 were taken into account. More
details about this simulation are given in Section 10.
Fig. 6 shows a scheme of the SAS setup used in the experi-
ments carried out by Gomes de Azevedo and coworkers34 which
has the versatility to be used for three different micronization
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observed in the microparticles obtained at different processing
conditions.
The one-step SAS process has the advantage of being appli-
cable for APIs and coformers poorly soluble in scCO2. The use of
a polar solvent may be mentioned as a disadvantage. Never-
theless, this solvent is easily separated and solvent-free co-
crystals with a narrow size distribution are obtained. Yield
values similar to that of 70% reported by Cuadra et al.10 and
Neurohr et al.49 and to those found for other pharmaceutical

techniques using CO2: the SAS process and the AAS and SEA crystals obtained by SAS may be expected.
processes which will be described in the next sections. The
supercritical uid is introduced in the precipitation vessel until
the desired pressure is reached, being regulated by a metering
6. Co-crystallization with
valve located at the exit. Next, the solution containing indo- supercritical solvent, CSS
methacin and saccharin is pumped through a coaxial nozzle that
Padrela et al. observed in 2009 that indomethacin–saccharin co-
includes three sections: the inlet where the two lines for each
crystals could be obtained if powders of the two coformers in
phase are introduced, a small mixing chamber where solution
a 1 : 1 molar ratio were suspended in scCO2.34 Pure co-crystals
and uid mix prior to their full mixing inside the precipitation
could not be prepared and Padrela et al. attributed this fact to
vessel and the orice disk where droplets are formed. The pre-
the poor dissolution of the coformers in scCO2. Recently,
expansion pressure (before de nozzle) is approximately 1 MPa
Padrela et al.44 further explored this co-crystallization technique
higher than the post-expansion pressure (aer the nozzle) that is
and found conditions for preparing pure co-crystals. A scheme
listed in Table 2. Indomethacin–saccharin co-crystals were ob-
of the CSS setup is shown in Fig. 7. The pure co-crystals ob-
tained at 50  C using 1 : 1 molar ratio solutions in ve different
tained via the CSS process and the experimental conditions
solvents, at pressure values of approximately 9 MPa and mass
used are listed in Table 3. The desired amounts of the two
ow ratio of the solution to the supercritical uid ranging from
powders are placed in a stainless steel high-pressure vessel with
0.04 to 0.19 g g 1. DSC, XRD and Raman spectroscopy were used
monitored temperature and pressure. Since suspensions
to identify/characterize and estimate the purity of the co-
replace the polar solvent solutions used in GAS or SAS, the size
crystalline phase that was shown to be the same as that one
of this high-pressure vessel is relatively small. Prior to its
previously obtained by a solution method. SEM analysis revealed
introduction into it, the CO2 is loaded using a compressor into
a mixture of needle and block shaped microparticles. Padrela
a second vessel that acts as a CO2 reservoir. Both vessels are
et al. attributed these two morphologies to competing mecha-
placed inside a temperature-controlled air chamber. In a typical
nisms in SAS co-crystallization. No remarkable differences were
experiment the API and the coformer are mixed with CO2 at 20.0

Fig. 6 Schematic representation of a AAS, SAS and SEA apparatus:34 (MV) metering valve, (TC) temperature controller, (P) pressure measurement,
(T) temperature measurement.

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scCO2 and its application requires that the API and the
coformer have sufficient solubilities in scCO2.
Padrela et al.44 have studied the mechanism of the CSS
process using the theophylline–saccharin as a model system.
Convection was revealed as the key parameter for successful co-
crystallization with high yield. Different conditions of pressure
(8–20 MPa), temperature (30 to 50  C) and convection regimes
were selected to study the CSS kinetics in the gas, supercritical
and liquid phase. The effect of temperature and pressure on the
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co-crystallization yield aer 2 h in CO2 was investigated. High

Fig. 7 Schematic representation of a CSS setup:44 (BPR) back pressure
regulator, (P) pressure measurement, (V) valve, (TC) temperature
controller, (T) temperature measurement.
MPa and 50  C under magnetic stirring for two hours. Then the
high-pressure vessel is slowly depressurized and the resulting
material is collected. In the CSS method, the uid acts as
a solvent that facilitates molecular interactions and thereby
nucleation and growth of co-crystals in despite of the low
solubility of the coformers in scCO2. Nevertheless, similarly to
the RESS method, the CSS method relies on the solvent power of
values were obtained at 50  C and pressures higher than the
CO2 critical pressure. On the other hand, experiments carried
out at constant pressures of 8.0 and 20.0 MPa and temperatures
increasing from 30 to 50  C revealed a slight decrease in the
yield as temperatures rise which may attributed to the decrease
in the CO2 density. Co-crystallization rates improved as the CO2
density increased. When different APIs were studied with
saccharin as coformer (namely, indomethacin, carbamazepine,
caffeine, sulfamethazine and acetylsalicylic acid), the rate
improved for the API more soluble in CO2. Therefore, a disso-
lution step seems to be involved in the co-crystallization
process. The use of CO2 together with the cosolvent ethanol
allowed the preparation of co-crystals that could not be ob-
tained in pure CO2. Some co-crystals could be also obtained
using supercritical N2 instead of CO2. However, the latter was
shown to be a better media for the co-crystallization process.
Equimolar amounts of the API and the coformer saccharin, and
a 300 rpm stirring were used in all cases. Homogeneity in the co-
crystallization medium caused by stirring was determinant for
a successful co-crystallization due to the enhancement of

Table 3 Pharmaceutical co-crystals prepared via the CSS process and experimental conditions: T and P are the temperature and pressure in the
precipitation vessel

Suspension Reaction time

Co-crystal molar ratio T ( C) P (MPa) Cosolventa (h) Reference

1 : 1 indomethacin–saccharin 1:1 50 14 — 3.5–90 34

1:1 50 22 — 22 34
0.9 : 1 50 14 — 20 34
1:1 50 20.0 — 0–2.0b 44
1:1 50 20.0 Ethanol 2.0 44
1 : 1 theophylline–saccharin 1:1 50 20.0 — 0–2.0b 44
1:1 30 20.0 — 2.0 44
1:1 40 20.0 — 2.0 44
1:1 50 8.0 — 0–2.0 44
1:1 30 8.0 — 2.0 44
1:1 40 8.0 — 2.0 44
1:1 30 8.0 — 0–2.0 44
1:1 50 20.0 Ethanol 2.0 44
1 : 1 carbamazepine–saccharin 1:1 50 20.0 — 2.0c 44
1:1 50 20.0 Ethanol 2.0 44
1 : 1 caffeine–saccharin 1:1 50 20.0 — 2.0c 44
1:1 50 20.0 Ethanol 2.0 44
1 : 1 sulfamethazine–saccharin 1:1 50 20.0 — 2.0c 44
1:1 50 20.0 Ethanol 2.0 44
1 : 1 acetylsalicylic acid–saccharin 1:1 50 20.0 — 2.0c 44
1:1 50 20.0 Ethanol 2.0 44
a
1 mL of ethanol per mg of powder was added. b Reaction time was varied from 0 to 2 h. The 2 h experiment was repeated without stirring. c The
experiment was repeated without stirring.

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Review
molecular interactions between the two coformers. When stir-
ring was omitted either a mixture of the API and saccharin or
a mixture of co-crystal, API and saccharin was obtained.
CSS is a novel, simple and solvent-free batch process that
presents the additional advantage of using a small reactor thus
minimizing the volume under pressure, which is a problematic
factor for scale up. In 2009 Hoand and Van Rosmalen51
patented a method similar to the CSS method in which the API
and the coformer are brought simultaneously into contact with
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a supercritical or liqueed gas.
7. Atomization and antisolvent
crystallization, AAS
The AAS technique proposed by Padrela et al.34 is closely related
to the SAS and SEA techniques and the same apparatus shown
in Fig. 6 is used to carry out the three processes. The solution
containing the solutes is pumped through a coaxial nozzle into
the mixing chamber where it mixes with scCO2 prior to its
depressurization in a precipitation vessel. In the SAS technique
the precipitator is lled with CO2 at high pressure while in the
AAS technique it is at ambient pressure. CO2 may be replaced by
N2. Also, a secondary stream of dry N2 is fed into the precipi-
tation vessel to enhance the solvent extraction from the parti-
cles. In order to prepare indomethacin–saccharin co-crystals,
a 1 : 1 molar ratio mixture of indomethacin and saccharin
was dissolved in different solvents: ethanol, acetone, tetrahy-
drofurane, methanol and ethyl acetate. The pre-expansion
pressure, before de nozzle, was varied from 6 to 12 MPa and
the post-expansion pressure was comprised between 0.1 and 0.9
MPa. The mixing chamber temperature was set between 50 and
70  C. The mass ow-rate ratio of the solution and the scCO2
was varied from 0.03 to 0.19 g g 1. DSC, XRD, and Raman
spectroscopy were used to identify/characterize and estimate
the purity of the co-crystalline phase that was shown to be the
same as that one previously obtained by a solution method.
Pure indomethacin–saccharin co-crystals were prepared by AAS.
No remarkable differences were observed in the microparticles
obtained at different processing conditions. SEM images
showed small spherical co-crystal particles with similar size
distributions obtained using a laser diffraction aerosizer.
Average diameter values ranged from 0.5 to 0.7 mm. Padrela
et al. attributed this uniform behavior to similarities in the
solvents used and a common co-crystallization mechanism. In
a previous study, Rodrigues et al.54 showed that, depending on
the pre-nozzle conditions in the AAS process with CO2, crystal-
lization may be governed by supercritical antisolvent or spray
drying. In the indomethacin–saccharin co-crystal experiments
the spray drying mechanism prevails.
8. Supercritical fluid enhanced
atomization, SEA
The supercritical uid enhanced atomization proposed by the
group of Prof. Gomes de Azevedo35,40,41 is based on the super-
critical uid ability to enhance the breakup of liquid jets into
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ne droplets when depressurized simultaneously with liquid
solutions. SEA is closely related to the solution enhanced
dispersion by supercritical uids (SEDS) or the supercritical
assisted atomization (SAA) that have been used previously to
produce pharmaceutical microparticles16 and the AAS tech-
nique described in the previous section. The SEA setup is
essentially that shown in Fig. 6 for SAS and AAS. CO2 is
compressed until the desired pressure using a gas compressor
and is kept in a temperature-controlled gas storage cylinder.
The coaxial nozzle is essential for SEA and its ow is measured
by a mass ow meter. Temperatures are controlled inside the air
chamber or in a water bath. A tetrahydrofuran or ethanol
solution containing the API and the coformer is pumped
through the nozzle where it mixes with scCO2 before depres-
surization in a precipitation vessel. A considerable volume
reduction (10 times) takes place causing a strong pre-nozzle
acceleration that impulses the liquid breakup. Therefore, the
purpose of the small mixing chamber is the atomization
enhancement due to the high density and velocity of the
supercritical uid phase. It is not necessary to saturate the
solution with the antisolvent; this process does not rely on the
miscibility of both phases. The temperature of the precipitation
vessel (usually 50  C although values of 40, 60 and 70  C were
also used) is controlled and droplets are dried at this temper-
ature near atmospheric pressure (0.1–0.5 MPa). The liquid/gas
mass ow ratio was chosen to be below 50% solvent satura-
tion at atmospheric CO2 at 50  C. Particles are collected in the
precipitator walls and from a lter at the precipitator exit.
Critical data for the CO2 + ethanol or tetrahydrofuran mixtures
are required to control the coprecipitation mechanism by
choosing a value for the pressure of the mixture before the
nozzle. Above the critical pressure particles may precipitate by
the CO2 antisolvent effect, while below the critical pressure
supersaturation is driven by spray drying.54 The co-crystals ob-
tained by SEA and the experimental conditions used are listed
in Table 4. In contrast to AAS, SEA does not require the use of an
additional stream of N2 to enhance the solvent extraction from
particles. In a rst study Padrela et al.35 obtained co-crystals of
six different APIs with saccharin using ethanol as solvent,
a temperature of 50  C and a pressure before the nozzle of
approximately 8 MPa. Co-crystals were characterized by DSC,
XRD, laser diffraction aerosizer and SEM. A new co-crystalline
form was found for theophylline–saccharin. No residual peaks
of homocrystals were observed in the DSC thermograms.
Particle size distributions were in the 0.3–10 mm range. The 1 : 1
theophylline–saccharin co-crystal was later obtained at 50  C
and 8.0 MPa using tetrahydrofurane as solvent.40 This co-crystal
was shown to extend the API stability at 92% relative humidity
by 6 months with respect to that of the pure API. Dispersions of
theophylline and the co-crystal in hydrogenated palm oil were
also prepared. Padrela et al.41 also prepared and characterized
the co-crystals of theophylline and different coformers using
tetrahydrofurane as solvent. Particle size distributions were in
the 0.3–5 mm range. The inuence on the size distributions of
the SEA process variables, the chosen coformer, the concen-
tration of API and coformer, the value of pressure before the
nozzle, and the temperature in the mixing chamber was studied
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Table 4 Pharmaceutical co-crystals prepared via the SEA process and experimental conditions: P is the pressure before de nozzle, T is the
temperature in the mixing chamber, and R is the mass flow ratio of the solution to the supercritical fluid

Solution molar
Co-crystal Solventa ratio P (MPa) T ( C) R (g g 1) Reference

1 : 1 indomethacin–saccharin Ethanol 1:1 8.0 50 0.07 35

1 : 2 theophylline–saccharin Ethanol 1:2 8.2 50 0.12 35
1 : 1 theophylline–saccharin Ethanol 1:1 8.3 50 0.15 35
THF 1:1 8.0 50 0.28 40
THF 1:1 8.0 50 0.15; 0.19; 0.28 41
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THF 1:1 8.0 40 0.22 41

THF 1:1 8.0 60 0.27 41
THF 1:1 8.0 70 0.22 41
THF 1:1 4.0 50 0.18 41
THF 1:1 10.0 50 0.22 41
1 : 1 caffeine–saccharin Ethanol 1:1 8.0 50 0.06 35
1 : 1 sulfamethazine–saccharin Ethanol 1:1 8.1 50 0.11 35
1 : 1 acetylsalicylic acid–saccharin Ethanol 1:1 7.8 50 0.13 35
1 : 1 carbamazepine–saccharin Ethanol 1:1 8.0 50 0.12 35
1 : 1 theophylline–urea THF 1:1 8.2 50 0.09 41
1 : 1 theophylline–gentisic acid THF 1:1 8.2 50 0.28 41
1 : 1 theophylline–salicylic acid THF 1:1 8.0 50 0.12 41
1 : 1 theophylline–glutaric acid THF 1:1 8.1 50 0.16 41
1 : 1 theophylline–sorbic acid THF 1:1 8.4 50 0.26 41
1 : 1 theophylline–HNAb THF 1:1 8.1 50 0.09 41
2 : 1 theophylline–oxalic acid THF 2:1 8.1 50 0.13 41
1 : 1 theophylline–maleic acid THF 1:1 8.0 50 0.13 41
1 : 1 theophylline–nicotinamide THF 1:1 8.0 50 0.12 41
a
THF, tetrahydrofurane. b HNA, 1-hydroxy-2-naphthoic acid.

and the temperature was shown to be the only variable with
a signicant inuence. Mean particle sizes increased as
temperature rises. The nature of the coformer did inuence the
particles morphology and dissolution rate. The solubility of
each coformer in a phosphate buffered medium is related to the
dissolving rate behavior of the co-crystal. Coformers with low
solubility generate co-crystals with dissolving rates lower than
those of the pure API while highly soluble coformers generate
co-crystals with dissolving rates higher than those of the pure
API.
SEA is a simple, efficient and one-step method to produce co-
crystals. As Padrela et al. have pointed out,41 the SEA scale-up
seems relatively easy because with the exception of the high-
pressure nozzle SEA consists essentially in a conventional-
drying equipment which is already well established in the
pharmaceutical industry.
9. Gas antisolvent crystallization, GAS
In the GAS technique compressed CO2 is added very oen under
stirring to a solute-containing solution in a high-pressure vessel
until a desired pressure is obtained. The CO2 dissolves into the
liquid solvent, causing the liquid solvent to expand, its solubi-
lizing power to decrease and the solute to crystallize. GAS has
been very oen applied to obtain pharmaceutical particles.16
The co-crystals obtained by GAS and the experimental condi-
tions used are summarized in Table 5. Shikhar et al. used for the
rst time the GAS method to prepare pharmaceutical co-crys-
tals.36 An ethanol solution containing carbamazepine and
nicotinamide in amounts corresponding to the co-crystal stoi-
chiometric molar ratios 1 : 1 or 1 : 2 was introduced in a reactor
and CO2 was pumped at 11.0 MPa and 40  C and a ow rate of
90–95 mL min 1. CO2 was exhausted at regular intervals and the
pressure was maintained above 7.5 MPa. 6–7 cycles of 200 mL
were performed. DSC diagrams indicated that a pure 1 : 1 car-
bamazepine–nicotinamide co-crystal was obtained for the
solution with a 1 : 1 molar ratio while the 1 : 1 co-crystal and the
crystals of the nicotinamide in excess were obtained for the
solution with a 1 : 2 molar ratio. SEM images showed needle
shaped co-crystals, a morphology and size more favourable to
dissolution than those of pure carbamazepine particles that
exhibited an irregular form and dimensions exceeding the
width of the co-crystal needles. Dissolution rates improved by
a factor of 2.5 with respect to those obtained for pure
carbamazepine.
Ober and Gupta used the GAS method to prepare itracona-
zole–succinic acid co-crystals.37 Fig. 8 shows a scheme of the
GAS setup used. The crystallization vessel is equipped with
multiple sapphire windows for observation. A 0.2 mm lter is
attached to the CO2 inlet line within the crystallization vessel
which allows CO2 to be sprayed through the liquid solution thus
enhancing mass transfer. A second vessel connected in series
prior to the crystallization vessel serves as a CO2 reservoir.
Temperature is controlled in both vessels. The outlet line to
valve V3 is equipped with a 0.5 mm frit to prevent loss of parti-
cles during ushing. A ltered tetrahydrofurane solution con-
taining itraconazole and succinic acid is injected in the
crystallization vessel. Then CO2 is introduced into this vessel

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Table 5 Pharmaceutical co-crystals prepared via the GAS process and experimental conditions: T and P are the temperature and pressure in the
precipitation vessel, and S is the stirring rate

Solution molar CO2 introduction

Co-crystal Solventa ratio T ( C) P (MPa) rate (g min 1) S (rpm) Reference

1 : 1 carbamazepine–nicotinamide Ethanol 1:1 40 11.0 59–63 — 36

Ethanol 1:2 40 11.0 59–63 — 36
2 : 1 itraconazole–succinic acid THF 1 : 2.40 40 10.3 — — 37
2 : 1 itraconazole-L-malic acid THF 1 : 5.25 40 10.3 — — 38
2 : 1 naproxen–nicotinamide Acetone 2:1 35 10.0 2–20 63–500 39
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Acetone 1:2 35 10.0 3 63; 200 39

Acetone 1:2 35 10.0 4 500 39
Acetone 1 : 1b 35 10.0 3 60 39
Acetone 3:1 35 10.0 2 60 39
Acetone 2 : 1b 37 10.0 20 500 43
Acetone 2:1 37 10.0 3 500 43
1 : 1 4-aminosalicylate–nicotinamide DMSO 1:1 36 11.0 20 500 42
a
THF, tetrahydrofurane; DMSO, dimethylsulfoxide. b Three different concentrations were used.

from the CO2 reservoir heated at 40  C at a controlled ow
through valve V2. Pressure is then increased at constant rate
until a nal pressure of 10.3 MPa is achieved. For solvent
removal and CO2 ushing, valve V3 is opened and a back
pressure regulator is used to maintain the desired pressure.
Aer ushing with additional CO2, the vessel is depressurized
and the co-crystals are collected.
The starting amounts of itraconazole and succinic acid in
the solution used by Ober and Gupta37 were in the molar ratio
1 : 2.4 despite the co-crystal stoichiometry of 2 : 1. By using
excess succinic acid the amount of unco-crystallized itracona-
zole, the more expensive compound, was minimized. However,
this molar ratio led to the presence of excess unco-crystallized
material in the nal co-crystal powder. A parallel co-
crystallization using heptane as a liquid antisolvent was
carried out and gave a product yield of 69.4% while a product
yield of 75.4% was obtained for GAS. Co-crystals of similar
crystallinity, size and morphology, and identical chemical
structure were produced by the two methods. However, the
liquid antisolvent co-crystals exhibited an agglomeration
tendency that seems to be responsible for a lower dissolution
rate in comparison to that shown for the GAS co-crystal. Ober
et al.38 also used GAS following a similar experimental proce-
dure to prepare itraconazole-L-malic acid co-crystals. The HPLC
analysis and the comparison of the powder XRD to that previ-
ously obtained for a single crystal indicated that the powders
produced likely contain excess amorphous pure coformers in
addition to the 2 : 1 itraconazole-L-malic acid co-crystal. The
GAS co-crystals were also compared to those obtained using
heptane as an antisolvent. SEM images reveal that both
methods produce a homogeneous co-crystal phase with
different morphology from those of the pure components. The
liquid antisolvent particles had an irregular shape and smaller
size than those produced by GAS. The brous GAS particles
formed spherical aggregates and exhibited better dissolution
rates than those obtained from heptane. Moreover, the GAS
particles showed much better dissolution rates than the phys-
ical mixture of itraconazole and L-malic acid or the commercial
itraconazole alone.
The group of Prof. Subra-Paternault obtained in 2013 (ref.
39) the 2 : 1 naproxen–nicotinamide co-crystal using GAS and
continued to use this co-crystallization technique to the
present.42,43,45 The rest of this section is devoted to the ndings
of this group. Their GAS apparatus presents some differences
with respect to that used by Shikhar et al.36 or Ober et al.37,38
Fig. 9 shows a scheme of the GAS setup used by Subra-
Paternault and coworkers.19 The acetone solution containing
the two coformers is introduced into the precipitation vessel

Fig. 8 Schematic representation of the GAS apparatus used by Ober and Gupta:37 (P) pressure measurement, (V) valve, (TC) temperature
controller, (BPR) back pressure regulator.

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Fig. 9 Schematic representation of the GAS apparatus used by Subra-Paternault and coworkers:19 (V) valve, (MV) metering valve, (TC)
temperature controller, (P) pressure measurement, (T) temperature measurement. The stirrer consists in a magnetically driven impeller whose
end is fitted with an eight-bladed disc turbine.
and CO2 is added. The vessel is equipped with a magnetically
driven impeller whose end tted with a turbine is plunged into
the solution to allow the dispersion of the antisolvent CO2. The
temperature of the vessel is controlled and kept at 35  C. CO2 is
introduced using a pump and a pressure of 10.0 MPa is
attained. Aer precipitation, the CO2-solvent solution is drawn
down at the vessel bottom and fresh CO2 is introduced in the
vessel to maintain the pressure. A lter is used to hold the
produced particles while the CO2-solvent solution is evacuated.
Finally, the vessel is depressurized through the exit line and
particles are collected.
In the preparation of the 2 : 1 naproxen–nicotinamide co-
crystal,39 the effect of the CO2 and the initial mixture compo-
sition (naproxen : nicotinamide molar ratio) and of CO2 and
acetone mixing conditions (CO2 introduction rate, stirring
speed) was investigated. The purity of co-crystal powers was
evaluated by HPLC and homocrystal identication was carried
out by XRD analysis. Results indicated that the co-crystal purity
was closed to 98  2% for the initial molar ratios in solution of
3 : 1, 2 : 1 and 1 : 1 but levelled down to 67% when a 1 : 2
solution was used. The mixing conditions did not inuence the
co-crystal stoichiometry or purity but inuenced the precipita-
tion yield and size distribution. Agitation was found to improve
the size distribution with a pronounced effect at high CO2
introduction rate. At the best conditions, a solution of naproxen
and nicotinamide following the co-crystal stoichiometric ratio
was used to collect 62% of the initial processed amount in the
vessel as a powder of sizes below 180 mm of 2 : 1 naproxen–
nicotinamide co-crystals with a purity of 98%. The hypothetical
triangular phase diagrams of the naproxen–nicotinamide–
acetone system and the naproxen–nicotinamide–(CO2 +
acetone) system served Neurohr et al.39 to establish a relation-
ship between the presence of homocrystals and the solubility of
the component in the CO2–acetone mixture so that when the
excess of one of the co-crystal coformers is lower than the
solubility limit, it is ushed out during the continuous step
of the process, whereas when it is above the limit, the
compound precipitates independently. In order to check this
hypothesis, Revelli et al.53 measured the solubility of naproxen,
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nicotinamide and their 2 : 1 molar ratio mixtures in CO2 +
acetone mixtures at 25.0 and 37.5  C and 10 MPa over all range
of CO2 compositions. The addition of CO2 to saturated solu-
tions produces the solute precipitation over all the range of CO2
compositions. For the quaternary system of naproxen–nicotin-
amide–acetone–CO2 with an initial mixture of naproxen and
nicotinamide in the 2 : 1 molar ratio, the solid phase is
composed only of the 2 : 1 naproxen–nicotinamide co-crystal. In
these two studies,39,53 the S-enantiomer of naproxen was used
since it is the one providing the desired physiological activity.
Recently, Neurohr et al.43 investigated the GAS co-
crystallization of naproxen racemic mixture and nicotinamide
dissolved in acetone and obtained a novel racemic co-crystal
containing both enantiomers of naproxen linked to nicotin-
amide, the achiral coformer. The structure of the molecular
complex and its intermolecular interactions were thoroughly
investigated. The processed solutions had a 2 : 1 naproxen–nico-
tinamide molar ratio. The antisolvent feed rate during the pres-
surization step was found to have a direct inuence on the co-
crystallization outcome. The racemic co-crystal was obtained at
slow and moderate CO2 feed rates (2 and 11 g min 1), while very
fast introduction of CO2 (20 g min 1) resulted in the formation of
a mixture of chiral co-crystals (conglomerate). The racemic phase
was shown to be the stable form. This was the rst time that
a conglomerate of co-crystals with nicotinamide was obtained. All
powders produced were co-crystal pure, no signicant excess of
naproxen or nicotinamide homocrystals was detected.
Harscoat-Schiavo et al.42 also studied the inuence of isom-
erism on the GAS recrystallization of aminosalicylate (ASA) and
its co-crystallization with nicotinamide. The experimental
conditions are described in Table 5. The isomers 3-ASA, 4-ASA
and 5-ASA were recrystallized as single species and important
changes in the morphology were observed. In the case of 3-ASA
the crystal lattice was also modied and a new polymorph was
obtained. Co-crystallization of each isomer with nicotinamide
resulted in the production of an ASA–nicotinamide co-crystal
only in the case of 4-ASA. This co-crystal has the same stoichi-
ometry and hydrogen networking than that previously obtained
by conventional methods.
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The GAS technique shares with the SAS technique the
advantage of not requiring a good solubility of the API and the
coformer in scCO2 while reducing the use of organic solvents
with respect to traditional solution-based processes. Moreover,
solvent-free particles with narrow size distributions are ob-
tained and the organic solvent may be recovered by simple
depressurization. In the GAS co-crystallizations carried out by
Shikhar et al.36 and the group of Prof. Subra-Paternault,39,42,43 co-
crystals of high purity are obtained. Therefore, it seems that the
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presence of other components together with the GAS co-crystal
powders of itraconazole–succinic acid and itraconazole-L-malic
acid could be avoided by modifying either the concentrations of
the API and the coformer in the solution or other parameters
of the GAS process. In addition, the group of Prof. Subra-
Paternault has explored promising GAS applications in the co-
crystallization of the API racemic mixture and the coformer,
and the inuence of the API isomerism on the GAS co-crystal.
The group also developed a GAS mathematical model45 that
will be discussed in the next section.
10. Modeling of co-crystallization
using scCO2
Considerable effort has been devoted over the last years towards
the understanding of the different supercritical crystallization
techniques.16,55–58 However, the formation of a co-crystal using
scCO2 as a solvent, antisolvent or spray enhancer requires a new
approach. The co-crystal formation is based on directional
molecular recognition events leading to a supramolecular
structure. We need to understand how these events take place in
the different supercritical co-crystallization processes. Ther-
modynamics, kinetics, nucleation and particle growth need to
be studied.
As described in the preceding sections, Prof. Gomes de
Azevedo and coworkers have made efforts to understand
different aspects of the various co-crystallization techniques
used by this group.34,35,40,41,44 The CSS, SAS and AAS methods
were simultaneously applied to obtain indomethacin–saccharin
co-crystals and their differences and analogies were discussed.34
Based on a previous study for one-component crystals,54
a spraying drying mechanism was proposed for the AAS indo-
methacin–saccharin co-crystallization. The relation between the
SEA coprecipitation mechanism and the critical pressure of the
CO2 + solvent mixtures formed was established; furthermore,
the inuence of the SEA process variables (the nature of the
coformer, the concentration of API and coformer, the value of
pressure before the nozzle, the temperature in the mixing
chamber) on the size distribution was also studied.35,40,41 A
similar study was carried out for the CSS method.44
As to the GAS method, the modeling efforts and the ther-
modynamic data obtained by the group of Prof. Subra-Pater-
nault39,42,43,53 have been already described in Section 9. Special
attention should be given in this section to the GAS mathe-
matical model developed by this group,45 the rst of its kind in
the case of co-crystallization. Although less frequent, the
complete simulation of SAS and GAS processes including
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RSC Advances
hydrodynamics of mixing, solubility and kinetics of nucleation
and particle growth has been developed.59–64 Even though none
of these studies is devoted specically to the case of pharma-
ceutical crystals, their ndings can be applied for the homo-
crystal production. The model proposed by Erriguible et al.45
describes the GAS co-crystallization with the aim of estimating
the key parameters related to nucleation and growth and is
based on the solubility data of naproxen, nicotinamide and
their 2 : 1 molar ratio mixtures in CO2 + acetone mixtures
previously obtained by Revelli et al.53 The liquid–vapour equi-
librium of CO2 + acetone was modelled using the Peng–Rob-
inson equation of state with quadratic mixing rules and its
effect on the equilibrium concentration of naproxen and nico-
tinamide in the liquid phase was taken into account. On the
other hand, the particle formation via primary and secondary
nucleations and the co-crystal growth driven by diffusion were
modelled on the basis of previous results for the GAS formation
of the 2 : 1 naproxen–nicotinamide co-crystal.39 Four additional
GAS experiments for the same co-crystal at a temperature of 37

C, a pressure of 10.0 MPa, and stirring rate of 500 rpm were
carried out at varying values of concentration and CO2 intro-
duction rate in order to obtain particle size distributions. The
2 : 1 molar ratio in solution was used in all cases. The yield
varied from 60 to 72%. A minimization algorithm allowed the
estimation of the nucleation and growth parameters. The
supersaturation ratio was expressed as a function of the solu-
bility product. A good agreement was found between predicted
and experimental size distributions. Nuclei formation was
shown to occur mostly through secondary nucleation. The effect
of concentration and CO2 introduction rate on both the crystal
size and the kinetic parameters was analyzed. The initial solu-
tion concentration was shown to have little inuence on crystal
size. However, a relatively low introduction rate of 3 g min 1 led
to bigger particles exhibiting mean sizes of ca. 50 mm while
mean sizes in the 25–30 mm interval were obtained for intro-
duction rates of 20 g min 1. Erriguible et al. attributed this
behavior to a lower supersaturation and longer growth time.
This successful co-crystallization model represents a very
important contribution to our understanding of the application
of the GAS process in the case of co-crystals.
Very recently49 the group of Prof. Subra-Paternault has also
developed a model for SAS co-crystallization that is based on
their earlier study dealing with single species SAS precipita-
tion62 and the GAS co-crystallization model discussed in the
preceding paragraph.45 The experimental investigations
described in Section 5 were focused on the effect of CO2 and
solution ow rates; their mass ratio was varied from 5 to 36. The
jet disintegration and the efficiency of the mixing were not
modied in this range of mass ow ratios. Consequently, the
appearance of homocrystals in the SAS preparation of the 2 : 1
naproxen–nicotinamide co-crystals seems to be driven by ther-
modynamics. An innovative representation of supersaturation
mapping through histograms of uid volumes/saturation
model was developed for the three species that may precipi-
tate: the API, the coformer and the co-crystal. Experimental
results seem to indicate that conditions that create discrep-
ancies of supersaturation levels and volumes between the three
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RSC Advances
species favor homo-crystallization while conditions leading to
more similarities tend to favor co-crystallization. Therefore,
a richer environment in solvent provides better conditions for
the co-crystal production.
11. Conclusions and future
perspectives
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A variety of pure co-crystals have been prepared using different
supercritical techniques. The use of scCO2 in the co-
crystallization of pharmaceuticals reduces the thermal and
mechanical stress on the API compared to grinding processes
and also either eliminates or reduces the used of organic
solvents compared to traditional solution methods. If a solvent
is required, depressurization allows its recovery and easy recy-
cling. Operation at moderate temperatures in an inert atmo-
sphere avoids the product degradation. Moreover, most
supercritical co-crystallization methods are one-step processes
that eliminate the need of further purication steps. The
solvent-free co-crystals are also micronized. This can be an
inconvenient with respect to structure elucidation but presents
advantages with respect to the drug dissolution proles. These
proles are improved with respect to those of the API alone or
co-crystals prepared by other methods. Nevertheless, the
structure and interactions of co-crystals obtained using scCO2
are the same as those of co-crystals previously prepared by
a solution or mechanochemical method. With rare exceptions
co-crystals are rst prepared using a conventional method and
the application of a supercritical method comes later. It is
a challenge to reverse this order and use supercritical methods
as a mean to investigate new co-crystals. DSC and FTIR may help
to identify the new structure. Next, a solution method will serve
to obtain the single crystals required for structure elucidation.
The possibility of tuning the uid properties through
changes in temperature and pressure that enable control of
particle size and/or morphology has been demonstrated in
some cases such as SEA: mean particle sizes increased as
temperatures rise from 40 to 70  C.41 These trends should be
further explored.
Co-crystal purity is an important issue. It is important to
make sure that traces of homocrystals are not present. This
seems to be the case of most co-crystals obtained through the
supercritical techniques described in this paper. In addition,
the product yield is an important parameter for scale up
purposes. Unfortunately, very oen the yield is not reported.
The values mentioned in this review indicate that good recovery
ratios are obtained.
Knowledge of the solubility of the API and the coformer in
scCO2 allows a better design of the co-crystallization process.
Fortunately, solubility data are usually available for the binary
systems CO2 + API and CO2 + coformer. These data may be used
to estimate the ternary data for CO2 + API + coformer. The study
of the quaternary system formed by the API, the coformer, the
solvent and CO2 is more complex and requires a considerable
experimental effort. Phase diagrams such as those measured by
Revelli et al.53 are essential to better understand the
71148 | RSC Adv., 2016, 6, 71134–71150
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Review
thermodynamics of co-crystallization. However, this type of
data is extremely scarce. Co-crystallization modeling efforts
embracing both thermodynamic and kinetic aspects may be
classied as phenomenological (those based on studying the
inuence of the process parameters on the characteristics of co-
crystal particles produced) and mathematical. Several studies of
the rst kind are available. The GAS mathematical model
described in the previous section45 should be recognized as
a pioneering study of the second kind.
The generation of co-crystals from a racemic mixture using
GAS opens a promising line. Neurohr et al.43 have shown the
versatility of this technology by switching from the production
of a racemic co-crystal to the formation of a mixture of chiral co-
crystals (conglomerate) simply by varying the CO2 ow rate.
Another area to explore is the possible manipulation of the
molecular recognition events that occur during co-crystal
formation by analogy with the many examples of crystal poly-
morphic control reported in the literature for APIs crystalliza-
tions using scCO2. A few well documented examples of co-
crystal polymorphism are found in the literature1 for conven-
tional co-crystallization methods and it would be interesting to
explore the possibilities of the supercritical methods in this
context.
The energy consumption required in scCO2 experiments, the
product yield that can be lower than that of a conventional co-
crystallization and the initial cost associated to the applica-
tion of supercritical methods in pharmaceutical industries may
be mentioned as disadvantages. However, pharmaceutical
companies are urged to develop production processes with very
low environmental impact, fewer steps and a reduced used of
organic solvents and the number of supercritical processes used
in the industry is steadily increasing in the last years. In
conclusion, this review shows the potential of several super-
critical methods for the design and preparation of pharma-
ceutical co-crystals, the fast development of this line of work is
anticipated.
12. The application of co-
crystallization methods based on
supercritical CO2 in other fields
The co-crystallization methods based on supercritical CO2 may
be also applied to obtain organic co-crystals. Compared with the
one-component organic single crystal, organic co-crystals
present advantages similar to those of pharmaceutical co-
crystals: novel and unique properties derived from the new
solid structure. Organic co-crystals provide a strategy for the
synthesis of novel multifunctional materials with a wide range
of applications.65–67 The interactions involved in these co-
crystals are classied into four categories: charge transfer, p–
p interaction, halogen bond and hydrogen bond. Co-
crystallization based upon halogen bonding usually involves
iodines and sometimes bromines and has attracted much
attention due to the resulting co-crystal potential applications
ranging from molecular conductivity to phosphorescence.68
Moreover, a diarylethene co-crystal based on the aryl–
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peruoroaryl interaction has been shown to convert light into
mechanical work.69
In the area of energetic materials, co-crystallization is
considered a tool to achieve an acceptable compromise between
a high energy output and a low sensitivity.70 To this end, a highly
energetic but highly sensitive compound is co-crystallized with
one that is less energetic and presents much less sensitivity. The
result may signicantly diminish sensitivity without impairing
energetic performance. The problem is that while most APIs have
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polar groups able to interact thus leading to co-crystal formation
most molecules involved in energetics exhibit nitro groups that
are less versatile to establish interactions sufficiently strong.
Nevertheless, this is an area of growing interest.70–73
On the other hand, polymeric co-crystalline forms consisting
in structures were a polymeric host and a low-molecular mass
guest are co-crystallized have been proposed for optical,
magnetic and electric applications.74 In some cases an ordered
polymer host structure is maintained aer guest removal and
a nanoporous crystalline form is obtained; in other cases an
accurate control of the orientation of the polymer and guest
molecules is achieved. Although a review of organic, energetic
and polymeric co-crystals is beyond the scope of this study, it
should be pointed out that all these applications may benet
from the use of the co-crystallization methods based on
supercritical CO2 described in this paper.
Acknowledgements
We gratefully acknowledge the nancial support of the Spanish
Ministry of Economy and Competitiveness (MINECO) through
the research project CTQ2013-41781-P. I. A. C. thanks MINECO
for its support through a FPI grant.
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