International Journal of Pharmaceutics 621 (2022) 121798

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Solid-state and particle size control of pharmaceutical cocrystals using

atomization-based techniques
Aaron O’Sullivan , Barry Long , Vivek Verma , Kevin M. Ryan , Luis Padrela *
SSPC Research Centre, Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland

A R T I C L E I N F O A B S T R A C T

Keywords: Poor bioavailability and aqueous solubility represent a major constraint during the development of new API
Supercritical fluids molecules and can influence the impact of new medicines or halt their approval to the market. Cocrystals offer a
Spray drying novel and competitive advantage over other conventional methods with respect towards the substantial
Nanoparticles
improvement in solubility profiles relative to the single-API crystals. Furthermore, the production of such coc­
Regulatory
rystals through atomization-based methods allow for greater control, with respect to particle size reduction, to
Antisolvent
Precipitation further increase the solubility of the API. Such atomization-based methods include supercritical fluid methods,
Multicomponent systems conventional spray drying and electrohydrodynamic atomization/electrospraying. The influence of process pa­
rameters such as solution flow rates, pressure and solution concentration, in controlling the solid-state and final
particle size are discussed in this review with respect to atomization-based methods. For the last decade, liter­
ature has been attempting to catch-up with new regulatory rulings regarding the classification of cocrystals, due
in part to data sparsity. In recent years, there has been an increase in cocrystal publications, specifically
employing atomization-based methods. This review considers the benefits to employing atomization-based
methods for the generation of pharmaceutical cocrystals, examines the most recent regulatory changes
regarding cocrystals and provides an outlook towards the future of this field.

1. Introduction utilized to improve API solubility (Desiraju, 2013). Crystal engineering

Some of the most significant obstacles facing the pharmaceutical
industry during the development of new APIs (Active Pharmaceutical
Ingredients) include low aqueous solubility and thus, low oral
bioavailability. It is reported that 40% of the top 200 marketed APIs
have low solubility and up to 90% of drugs in the pipeline are estimated
to have the same issue, which is heavily influenced by the relatively
recent increase in lipophilicity of new chemical entities (Sathisaran and
Dalvi, 2018; Rodriguez-Aller et al., 2015). The biopharmaceutical
classification system (BCS) divides APIs based on their solubility and
permeability into four classes, with class II (low solubility, high
permeability) and class IV (low solubility, low permeability) drugs ex­
pected to account for a significant majority of new API molecules in the
pipeline. Crystal engineering methods have been employed over the
years to overcome this issue. Crystal engineering utilizes a comprehen­
sive knowledge of intermolecular interactions to predict and control
crystal packing and the resulting physical and chemical properties of the
newly designed crystal structures, offering a set of methods which can be
utilizes various predictive models to determine and predict crystal lat­
tice structures. Cocrystal formation is one attractive crystal engineering
approach for the improvement of API properties and inclusion of su­
pramolecular synthon prediction and cocrystallization theory are useful
crystal engineering tools (Desiraju, 2013). Cocrystals are an example of
multicomponent crystalline materials which, unlike salts, do not require
ionizable groups, and unlike (co)amorphous solids, do not typically pose
issues with low thermodynamic instability (Bavishi and Borkhataria,
2016). However, thermodynamically unstable cocrystals have been
identified, such as the Exemestane-maleic acid cocrystal (Jasani et al.,
2019). Cocrystals are defined by the Food and Drug Administration
(FDA) as “solids that are crystalline materials composed of two or more
molecules in the same crystal lattice” (Aitipamula, 2012).
Conventional methods which have been employed for the production
of pharmaceutical cocrystals include spontaneous contact formation,
liquid-assisted/neat grinding, extrusion-based methods, and solution
evaporation (Karimi-Jafari et al., 2018). Although these methods have
been successful in the formation of various cocrystals (Friscic and Jones,

* Corresponding author.
E-mail address: Luis.Padrela@ul.ie (L. Padrela).

https://doi.org/10.1016/j.ijpharm.2022.121798
Received 25 January 2022; Received in revised form 28 April 2022; Accepted 29 April 2022
Available online 4 May 2022
0378-5173/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
A. O’Sullivan et al.
2009; Weyna et al., 2009; Maheshwari et al., 2009), they provide little
control regarding the particle size of the resulting dried cocrystals. The
inclusion of an atomization step within a cocrystallization procedure
allows for more control on the resulting particle size, which has been
shown to play a role in the solubility of drug molecules with a reduction
in particle size leading to an increase in solubility (Van Eerdenbrugh
et al., 2010). Atomization involves the conversion of a bulk liquid into a
spray comprised of micro/nano-droplets containing the drug molecules.
This resulting spray can be dried far quicker than bulk solutions due to
the larger surface area. Particles also require a relatively short residence
time in the drying chamber after atomization due to this large surface
area, making this a suitable process for thermolabile compounds. A
significant risk in atomization-based methods relates to nozzle clogging,
which can occur with viscous liquids and when API molecules crystallize
prior to atomization (Lefebvre and McDonell, 2017). Processes which
utilize atomization during a cocrystallization process include spray
drying, electrospraying, spray congealing, and supercritical fluid (SCF)
based methods such as supercritical enhanced atomization (SEA) and
rapid expansion of supercritical solutions (RESS).
Section 2 provides a comprehensive overview of pharmaceutical
cocrystals including the mechanisms by which they are created, as well
as their various advantages and disadvantages for pharmaceutical for­
mulations. Following from this, atomization-based cocrystallization
techniques are discussed in Section 3 based on their propensity to pro­
duce cocrystals, cocrystal solvates/hydrates and polymorphs. Section 4
discusses the regulatory aspects and outlooks for the commercial pro­
duction and market accessibility of micro and nano-sized cocrystal
formulations.
2. Cocrystals
Within the pharmaceutical industry, APIs are known to exist in many
different solid forms such as cocrystals, polymorphs, salts, and amor­
phous solid dispersions, with each possessing unique attributes to boost
the physicochemical profile of the API. At a broad level, these APIs can
be classified as amorphous or crystalline, and an overview of these solid
forms is provided in Fig. 1. Amorphous solids may display a short-term
molecular order but unlike crystalline solids, are incapable of devel­
oping any kind of long-term molecular order. Multicomponent amor­
phous materials include solvates/hydrates, salts and coamorphous
materials (very weak to none intermolecular interactions) (Yu et al.,
Fig. 1. Classification of the various solid state forms of APIs according to structure and composition of single/multicomponent forms (adapted from (Aitipa­
mula, 2012).
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International Journal of Pharmaceutics 621 (2022) 121798
2001; Narala, 2021). Single component crystals can be considered
anhydrous but may also exhibit polymorphism, where different molec­
ular arrangements of the API can occur, which may display variations in
stability, solubility and in other physicochemical properties (Higashi
et al., 2017). Multicomponent crystalline materials may be considered to
be in one of three major categories: hydrates/solvates, salts, and coc­
rystals (Narala, 2021; Qiao et al., 2011). This review focuses on the
various atomization methods reported to date in the literature, which
have demonstrated an ability to not only produce pharmaceutical coc­
rystals, but control their resulting particle size and solid form, such as
hydrated and non-hydrated forms, as well as cocrystal polymorphs.
There has been debate as to the full description and definition of
pharmaceutical cocrystals between researchers and regulatory bodies
such as the US Food and Drug Administration (FDA). This debate will be
covered in detail in section 4, but a recently adopted definition of coc­
rystals supplied by the FDA describes these as APIs themselves (rather
than intermediate products), allowing cocrystals to be considered as API
polymorphs or salts from a regulatory perspective. However, cocrystals
themselves are still described in this guidance document as crystalline
materials made up of two or more molecules within a single crystal
lattice. Unlike API polymorphs, cocrystals contain more than one type of
molecule and, unlike salts, the cocrystal components interact non-
ionically (FDA, 2018). Cocrystals themselves can be further sub-
divided into categories based on the nature of their components. The
most common type of cocrystals discussed in literature is molecular
cocrystals, which are regarded as crystalline structures composed of at
least two neutral molecules (generally an API and coformer). Molecular
cocrystals are typically observed to maintain their cocrystalline struc­
ture by halogen or hydrogen bonds (Duggirala et al., 2016). Ionic coc­
rystals are another subtype of cocrystals which have been defined as
multicomponent species composed of a salt and an ionic or molecular
compound. These cocrystals differs from salts as complete proton
transfer is not observed in these intermolecular bonds (Smith et al.,
2013). Although ionic cocrystals may occasionally be less thermody­
namically stable than the corresponding single API, they generally
display stronger intermolecular bonds coupled with a greater degree of
change in their properties compared to the API (Duggirala et al., 2016;
Long, 2021; Braga et al., 2013).
Molecular and ionic cocrystals can be considered anhydrous coc­
rystals, cocrystal hydrates/solvates or cocrystals of salts (Qiao et al.,
2011). Solvates are crystalline compounds, which include solvent
A. O’Sullivan et al.
molecules in their crystal lattice in either a stoichiometric or non-
stoichiometric ratio (referred to as pseudopolymorphs by the FDA)
(FDA, 2018). Solvates are referred to as hydrates when the solvent
involved is water (FDA, 2018). Aitipamula et al. stated that cocrystalline
materials have a higher tendency to form hydrates/solvates than single
component crystals. This is based on their study highlighting a greater
percentage of cocrystal solvates/hydrates reported in Cambridge struc­
tural database (CSD) in comparison to single component crystalline
hydrate/solvates (Aitipamula et al., 2010). However, Healy et al. stated
that cocrystallization can reduce the tendency of hydrate formation due
to competitive hydrogen bonding of the coformer with the API, rather
than with water molecules (Healy et al., 2017).
Similarly to API crystals, cocrystals can also exhibit polymorphism
which may result in cocrystal polymorphs with altered physiochemical
properties (Qiao et al., 2011). It is estimated that up to 50% of APIs
exhibit at least one polymorphic form and cocrystals can also fall under
this category (Aitipamula et al., 2010). Polymorphs form due to struc­
tural changes of cocrystal components/reactants, but changes leading to
polymorphs are also seen within the intermolecular interactions be­
tween these components (Qiao et al., 2011). As such, there are several
major distinctions of cocrystal polymorphs such as conformational
polymorphs, synthon polymorphs and tautomeric polymorphs. Synthon
polymorphs, generally refer to alterations within the hydrogen bonding
motif, or synthons. These supramolecular synthons are structural crystal
units formed by intermolecular interaction and can be considered homo-
or hetero-synthons (Reddy et al., 1996). Homosynthons are formed as
dimers by two similar reacting functional groups, whereas hetero­
synthons are formed by different reacting functional groups. In many
cases, this form of polymorphism causes a change from a cocrystal
containing both a homosynthon and a heterosynthon, to a polymorph
containing two heterosynthons (Mukherjee and Desiraju, 2011; Aitipa­
mula et al., 2014). One example of this are the polymorphs observed
within the 4-hydroxybenzoic acid and 4,4-bipyridine cocrystal. Form I
contains a hydroxyl-pyridine synthon and an acid dimer, whereas the
form II polymorph contains two heterosynthons, an acid-pyridine syn­
thon and a carbonyl-hydroxyl synthon. It must also be noted that this
form of polymorphism is more prevalent in cocrystal species with a high
number of hydrogen bonds or the capacity for a high number of
hydrogen bonds (Mukherjee and Desiraju, 2011; Aitipamula et al.,
2014). Another classification of cocrystal polymorphs are conforma­
tional polymorphs. This refers to the ability of ‘flexible’ molecules to
exhibit different molecular conformations within the molecules itself (or
within the coformer), but such changes may also be seen within inter­
molecular bonds, as seen in cocrystals. It is this flexible nature seen in
many API molecules which allow for the high occurrence of API poly­
morphism. This polymorphism is primarily seen in cocrystal structures
which contain a molecule with degrees of torsional freedom allowing for
molecular structure alterations (Aitipamula et al., 2014). Packing
polymorphs are another form of cocrystal polymorphism and refers to
changes in the overall three-dimensional packing of cocrystals. There is
no clear indication as to when this form of polymorphism will occur, but
unlike conformational polymorphs, packing polymorphs generally occur
in cocrystal systems with limited conformational freedom. The final type
of cocrystal polymorphism is tautomeric polymorphs (Aitipamula et al.,
2014). These polymorphic forms arise due to changes in the position of
protons and/or electrons and occurs due to a proton moving from one
polar atom to another allowing the transformation of hydrogen donor
atom to a hydrogen acceptor, and the inverse happens to another atom
(Martin, 2009). The formation of these various multicomponent crys­
talline materials happens by means of several mechanisms, giving rise to
a defined and repeating crystal lattice structure.
2.1. Mechanisms of cocrystallization
When discussing the mechanism behind the formation of multi­
component solids such as cocrystals, it is necessary to look at the solids
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International Journal of Pharmaceutics 621 (2022) 121798
at a macroscopic and microscopic view. Macroscopic level mechanisms
tend to be determined based on the method of cocrystallization, and
relate to bulk phase transformation events such as molecular diffusion,
eutectic formation and amorphous phase-mediated cocrystallization
(Friscic and Jones, 2009). Mechanisms of cocrystal formation at the
microscopic level are generally determined by the nature of the re­
actants and the solvent. Such determinants include available functional
groups, component solubilities and molecular ratio of API to the
coformer(s). It has been observed that certain cocrystals are only pro­
duced in the presence of a specific solvent, for example the production of
the 1:1 pimelic acid – 1,1-diferrocene cocrystal in the presence of
methanol (Karimi-Jafari et al., 2018; Friscic and Jones, 2009). Micro­
scopic cocrystal formation involve molecular recognition events such as
the formation of supramolecular synthons and hydrogen and /or
halogen bonds (Friscic and Jones, 2009).
The various design-based approaches to determine the possibility of
producing a particular cocrystal or for the screening of cocrystals
include the use of: CSD, structural analysis for hydrogen bond pro­
pensity, supramolecular synthon prediction, Hansen solubility parame­
ters, and pKa values (Buddhadev and Garala, 2021; Salem et al., 2019).
Bonding between API molecules and coformers (or other APIs) is pri­
marily by non-covalent interactions such as hydrogen and halogen
bonding as mentioned earlier, and Van Der Waals attractions. Although
cocrystal prediction is still in its early years, methods such as empirical
observation and an analysis of the available hydrogen bond donor and
acceptors provide an alternative route for cocrystal prediction and for­
mation, limiting the amount of ‘trial and error’ experiments required.
However, the most successful method for simple design based cocrystal
prediction is the consideration of supramolecular synthons (Buddhadev
and Garala, 2021). Intermolecular interactions allow for the formation
of structurally significant crystal units which are known as supramo­
lecular synthons (Reddy et al., 1996). In recent years, this synthon-based
design coupled with the propensity for both hydrogen and halogen
bonding has allowed for a much more reliable medium to predict coc­
rystal formation. Common reacting functional groups involved in su­
pramolecular synthons during cocrystal formation include carboxylic
acids, alcohols, and amides (Buddhadev and Garala, 2021). It has also
been observed that there is a far higher propensity for the formation of
heterosynthons in comparison to homosynthons. A CSD analysis illus­
trated that 34% of molecular carboxylic acid entries form homosynthons
whereas the remaining 66% from heterosynthons. Similarly, only 26%
of the molecular alcohol entries have been observed forming homo­
synthons whereas the remaining 74% form heterosynthons (Shattock,
2008). An analysis using the CSD specifically highlighted that alcohol-
alcohol and COOH-COOH supramolecular homosynthons are less fav­
oured than supramolecular heterosynthons alcohol-aromatic nitrogen
and acid-aromatic nitrogen. However, when both supramolecular het­
erosynthons may be formed, the acid-aromatic nitrogen is more strongly
favoured (Shattock, 2008).
The propensity of whether two reactants form a cocrystal or a salt
may be determined based on pKa values. If the difference of pKa values
(base – acid) (ΔpKa) is greater than three, it is likely that a salt will form
under appropriate conditions. Contrary to this, a ΔpKa value less than
zero is a good indication that a cocrystal will form rather than a salt.
Some issues may reside in ΔpKa values between zero and three, which
has been described as a cocrystal to salt continuum, where the pro­
pensity for either a cocrystal or salt to form is unclear and difficult to
determine (Buddhadev and Garala, 2021). As mentioned earlier, sol­
vates and hydrates are another form of multicomponent crystalline
materials that can be composed of a single molecule with incorporated
solvent molecules, or a cocrystal system may incorporate a solvent
molecule within its crystal lattice also. This may be formed using
solvent-assisted cocrystallization methods such as wet grinding, solvent
evaporation, and spray drying, where the solvent utilized for cocrys­
tallization is entrapped within the cocrystal structure, or by dry/neat
methods such as neat grinding in which one or more of the reactants is a
A. O’Sullivan et al. International Journal of Pharmaceutics 621 (2022) 121798

solvate/hydrate. This allows the solvent molecules within the solvated ionizable groups/sites. The generation of amorphous compounds rather
reactant(s) to be included within the resulting cocrystal solvate structure than crystalline has also shown a positive influence on compound sol­
(Friscic and Jones, 2009). ubility, however thermodynamic instability issues may arise which can
cause conversion to a more stable crystalline form during manufacture,
storage or transportation. Consequently, significant testing by regula­
2.2. Impact of cocrystallization on API physicochemical properties
tory bodies is needed to ensure that no conversion occurs before being
administered to patients (Bavishi and Borkhataria, 2016). Amorphous
Multicomponent crystalline materials as discussed above, provide an
solid dispersions (ASD) have proven quite effective in enhancing the
avenue by which pharmaceutical companies can improve API properties
solubility and bioavailability of pharmaceutical formulations, however,
such as solubility, bioavailability, and permeability. However, these
there is a lack of data explaining the underlying mechanisms behind
improved properties, relative to the single component API cannot be
drug liberation and permeation from ASDs (Schittny et al., 2020).
estimated or predicted easily and must be experimentally characterized
Cocrystals however can be produced regardless of whether the reactants
during the generation of a new multicomponent system. Prediction of
contain ionizable groups, and cocrystals have exhibited higher ther­
cocrystal properties has only been successful by a small number of
modynamic stability. Cocrystals utilize supersaturation to improve their
methods, such as the construction of artificial neural networks (Gamidi
aqueous solubility through the creation of metastable and supersatu­
and Rasmuson, 2020). These altered properties can have significantly
rated states. This overall mechanism has been described as the spring
beneficial effects such as improved solubility, dissolution rate and
and parachute phenomenon (Bavishi and Borkhataria, 2016). As coc­
bioavailability but can also have adverse effects such as increased
rystals are usually held together by relatively weak hydrogen bond(s),
toxicity which may require significant testing to be performed prior to
dissociation within an aqueous biological system is relatively rapid. The
filing to patent a new cocrystal system.
more soluble coformer solubilizes within the aqueous medium leaving
the hydrophobic API molecules behind which are supersaturated. This
2.2.1. Solubility, dissolution rate and bioavailability
high energy drug form immediately precipitates and is known as the
Perhaps the most valuable property of a cocrystal is an increase in its
spring (within the spring and parachute phenomenon). This creates
aqueous solubility. A major method for solubility enhancement in the
mildly aggregated API clusters. But to maintain this newly supersatu­
past and at present in certain cases, is salt formation (Bavishi and Bor­
rated solution to allow for adsorption, precipitation inhibitors
khataria, 2016). However, salt formation is limited to APIs with suitable

Table 1
Summary of reported/produced pharmaceutical cocrystals during the year 2021, and the associated increase in apparent solubility compared to the raw API.
API Coformer Ratio Method Increase in Solubility Relative to Reference
Raw API

Artemisinin Orcinol 1:1 Solvent evaporation 26-fold (Kaur et al., 2021)

Resorcinol 2:1 Seeded solvent evaporation 21-fold
Carvedilol Tartaric acid – Antisolvent precipitation 2000-fold (Mohammady et al., 2021)
ultrasonication
Rosuvastatin L-Asparagine 1:1 Solvent evaporation 2.17-fold (Vemuri and Lankalapalli,
L-Glutamine 1:1 1.60-fold 2021)
Metaxalone Nicotinamide 1:1 Solvent evaporation 8.6-fold (Gohel et al., 2021)
4-hydroxybenzoic acid 1:1 3.4-fold
Diltiazem Fumaric acid 1:1 Solvent Evaporation − 16.5-fold (Diniz, 2021)
Aceclofenac Salicylic acid 1:1 Neat grinding 7-fold (Pekamwar and Kulkarni,
2021)
Azithromycin Neotame 1:1 Solvent Evaporation < 2-fold (Upadhye, xxxx)
loratadine Succinic acid 1:1 Solution method 2-fold (Setyawan et al., 20212021)
5-Flurouracil phenolic acid nutraceutical ferulic acid 1:1:1 Liquid assisted grinding 1.64-fold (Yu et al., 2021)
+ water
Ceritinib Nicotinamide 1:1 Neat grinding 119-fold (Awasthi et al., 2021)
1:2 155.3-fold
2:1 83.1-fold
Diacerein β-Resorcylic Acid 1:3 Antisolvent crystallization 2.3 – 2.8-fold (Patel and Raval, 2020)
Apixaban Caffeine 1:1 – 3-fold* (Madan et al., 2021)
Paliperidone P-hydroxybenzoic acid 1:1 Solvent evaporation 141.6-fold (Thimmasetty et al., 2021)
Aceclofenac Dimethyl urea 1:2 Liquid/neat grinding 3.43-fold* (Afzal et al., 2021)
Curcumin Ascorbic acid – Solvent evaporation 576-fold (Pantwalawalkar et al.,
2021)
Naproxen L-alanine 1:1 Liquid assisted grinding 1.4-fold* (Latif, 2021)
Rebamipide Oxalic acid 1:1 Liquid assisted grinding 7.29-fold (Jindal et al., 2021)
Citric acid 12.58-fold
3,4-dihydroxybenzoic acid 11.36-fold
Nevirapine Salicylamide – Solvent drop grinding 4.5-fold (Panzade et al., 2021)
3-hydroxybenzoic acid
Ethionamide Baicalein 1:1 Seeded solvent evaporation 8.71-fold (Wang, 2021)
Axitinib Fumaric acid 1:1.5 Liquid assisted grinding + slurrying 11.7-fold (Ren et al., 2021)
Suberic acid 1:1 5.5-fold
Trans-cinnamic acid 1:1 1.9-fold
Bergenin Isonicotinamide 1:1 Liquid assisted grinding + rapid 1.57 – 2.87-fold (Liu, 2021)
solvent removal
Telmisartan 3,5-dihydroxy benzoic acid 1:1 Liquid assisted grinding + slurrying 3-fold (Yu, 2021)
Nicorandil Suberic acid 1:0.5 Liquid assisted grinding 1.9-fold (Mannava et al., 2021)
Lornoxicam 1,3-dimethyl urea 1:3 Liquid assisted grinding, solvent 2.52-fold (Fatima et al., 2021)
evaporation
Telmisartan Oxalic acid – – 7-fold (Dhibar et al., 2021)

* fold increase related to the area under the curve (AUC) rather than solubility.

4
A. O’Sullivan et al.
(parachute) are incorporated. Over time, this saturated amorphous
phase solution (which has been given sufficient time to reach a highly
soluble dose) will convert to a metastable form with a superior solubility
before converting to the final, stable polymorph (Bavishi and Borkha­
taria, 2016). There have been several reported cases in which solubility
has been improved for poorly soluble drugs cocrystallization such as
Ritonavir cocrystallized with adipic acid (6-fold increase), and dip­
fluzine cocrystallized with benzoic acid (500-fold increase) (Bavishi and
Borkhataria, 2016; Lin et al., 2014). Table 1 summarizes several recently
reported pharmaceutical cocrystals and the increase in API solubility
seen in comparison to the pure API. Kuminek et al. cocrystallized the
BCS class II drug Posaconazole with p-aminobenzoic acid with a stoi­
chiometric ratio of 2:3. The solubilities and dissolution rates for this
cocrystal far exceeded those of the pure Posaconazole drug substance
during studies carried out in a medium which mimicked physiological
conditions within intestinal fluids (Kuminek et al., 2019).
Conversely, solubility has also been observed to decrease upon coc­
rystallization. For many pharmaceutical compounds (BCS Class II and
IV), this may be considered to be a major disadvantage to the majority of
poorly soluble compounds but can serve to benefit when a prolonged
residence time within the body is required. One such example of this was
achieved with a broad-spectrum antibiotic used to treat tuberculosis,
moxifloxacin. Eedara et al. produced a new unreported cocrystal of
moxifloxacin with cinnamic acid and demonstrated that an API to
coformer ratio of 1:2 produced a cocrystal with a decreased solubility
and slower dissolution rate, which is hypothesised to increase the resi­
dence time within the lung of tuberculosis patients (Eedara et al., 2018).
This is one of the few studies which reported a decrease in solubility of a
cocrystal in comparison to the stable API molecule. However, despite the
limited reports of reduced solubility, this system highlights that coc­
rystals may also be used when time-delayed release of an API is neces­
sary, although increases in solubility are usually the aim with cocrystals.
Oral bioavailability of a drug refers to the amount of the API that is
available to enter the systemic circulatory system and low oral
bioavailability is a major constraint within the pharmaceutical industry
(Kumar et al., 2018). The use of polymers and excipients to maintain
supersaturation and delay precipitation (parachutes within the spring
and parachute phenomenon], have been shown to positively influence
the bioavailability of cocrystalline APIs (Karimi-Jafari et al., 2018).
Dipfluzine-benzoic acid cocrystals showed a significant improvement
over the pure drug substance in all previously mentioned areas of sol­
ubility, dissolution rate and bioavailability and is an excellent example
of the extent of which cocrystallization with an appropriate coformer
can have on resulting drug properties (Lin et al., 2014). Martin et al.
produced a ketoconazole – p-aminobenzoic acid cocrystal for the
enhancement of drug properties, of this BCS class II drug. The resulting
cocrystal demonstrated an aqueous solubility ten times greater than the
pure drug substance along with almost a 7-fold increase in bioavail­
ability. Additionally, the antifungal effect of this drug was significantly
increased after cocrystallization with p-aminobenzoic acid (Martin
et al., 2020).
2.2.2. Stability
Determining the stability of pharmaceutical cocrystals relative to
other crystalline components such as solvates, and polymorphic forms of
the APIs is a critical requirement during the filing of a new chemical
entity. Such studies include thermal stability, chemical stability, solu­
tion stability and relative humidity stability during the manufacture,
transportation and storage stages (Kumar et al., 2018). Thermal stability
analysis can be carried out by hot stage microscopy to determine the
phase transition conditions, as well as differential scanning calorimetry
(DSC) which is primarily utilized to determine a substances melting
point. The melting point of a substance provides a strong indication of
thermal stability, with an increase in melting point of the cocrystal
relative to the API suggesting an increase in thermal stability (Kumar
et al., 2018; Shaikh et al., 2018). Although there may be a minor link
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International Journal of Pharmaceutics 621 (2022) 121798
between the types of supramolecular synthons and the resulting coc­
rystals melting point, it has been observed that packing efficiency plays
a larger role in determining the melting point and thus, the thermal
stability of the resulting cocrysnotal. A study by Wang et al. looked at the
melting points of three cocrystals of the same API, apremilast, a BCS
class IV drug used to treat psoriasis, with three different coformers:
nicotinamide, caffeine, and acetylsalicylic acid. It was determined that
the packing efficiency for the nicotinamide and caffeine cocrystals were
71.3 % and 75.6 % which is believed to be the reason behind the higher
melting point of the apremilast-caffeine cocrystal in comparison to the
apremilast-nicotinamide cocrystal. The higher melting point of caffeine
over nicotinamide is also believed to influence this. An increase in
packing efficiency is indicative of strong structural interactions. These
cocrystals exhibited lower melting temperatures than the API but higher
than each of the coformers. The apremilast-acetylsalicylic acid cocrystal
displayed a greater packing efficiency and in turn, also displayed greater
thermal stability seen by the cocrystals melting point of 183.5 ◦ C and
decomposition temperature of 180.4 ◦ C (Wang et al., 2018). This is an
excellent example of the relationship between packing efficiency and
resulting thermal stability.
Chemical stability may also become altered due to cocrystallization
of an API with an appropriate coformer. Chemical stability is regarded as
any structural alterations of the API cocrystal by chemical reaction. Such
reactions include oxidation and reduction reactions, as well as hydro­
lysis and dehydration reactions, but few studies exist in which chemical
stability is directly accessed upon cocrystallization. Guo et al. investi­
gated improving the stability of the drug nicorandil, which is generally
regarded as chemically unstable, as well as being unstable at higher
temperatures and higher humidity. Cocrystallization of this drug by
reaction cocrystallization was carried out with various coformers,
namely salicylic acid, 2,5-dihydroxybenzoic acid, 3-hydroxybenzoic
acid, and 1-hydroxy-2-naphthoic acid. The lack of stability of the pure
drug nicorandil can be attributed to self-catalysed decomposition due to
crystal packing. However, the addition of such organic acid coformers
within the crystal lattice allowed for the realignment of the nicorandil
crystals preventing this form of decomposition. Hydrothermal stability
was also increased due to cocrystallization as long-term storage at 40 ◦ C
and a relative humidity of 75 % caused a large reduction of stable pure
nicorandil with a final content of only 2 % after 20 days of storage. The
cocrystals, however, retained a nicorandil content greater than 90 %
under the same storage conditions demonstrating their superior stability
over the pure drug. Among these improvements, other improvements
seen within the cocrystal include an increase in thermal stability and
dissolution rates in comparison to the pure drug substance (Guo et al.,
2020). This is an excellent example as to the many benefits a cocrystal
can induce on a drug system when appropriate coformers and produc­
tion methods are utilized.
Other forms of stability such as photostability have been seen to vary
after cocrystallization, although it has not been reported extensively in
the literature. Photostability refers to a substance propensity to react
during prolonged exposure to light. Cocrystallization has been reported
to influence the photostability of APIs. Shinozaki et al. produced a 1:1
cocrystal from the API Levofloxacin with another API, Metacetamol. The
resulting cocrystal proved to have a reduced photodegradation than the
corresponding Levofloxacin hydrate indicating the ability of cocrystal­
lization to alter the photostability of an API molecule (Shinozaki et al.,
2019). This may lengthen the drugs storage light or allow it to be stored
in an area with light exposure, without concerns regarding losses in drug
stability. A similar instance occurred during the cocrystallization of
furosemide with various coformers. Upon cocrystallization, it was
observed that the absorption range of the furosemide-nicotinamide
cocrystal shifted to a shorter wavelength in comparison to pure furose­
mide and the other cocrystals. This allowed for an increase in photo­
stability for the resulting furosemide cocrystal.
A. O’Sullivan et al.
2.2.3. Permeability
Poor permeability is observed in BSC class III and IV drugs. Perme­
ability refers to a drugs ability to cross biological membranes to enter
areas of the body, most notably the circulatory system through the in­
testinal wall (Lennernaäs, 1998). A link between solubility and perme­
ability has been observed when permeability is driven by passive
diffusion, which is directly related to the concentration gradient (Rao
et al., 2011; Zhang et al., 2019). An increase in solubility leads to a
greater concentration gradient, leading to increased permeability. Other
factors play a role in this also such as particle size and polarity (Rao
et al., 2011; Zhang et al., 2019). Hydrochlorothiazide (HCZ) has been
extensively studied as a cocrystallization candidate (Sanphui et al.,
2015; Ranjan et al., 2017; El-Gizawy et al., 2015; Gopi et al., 2017; Al-
Otaibi et al., 2019; Al-Otaibi et al., 2020), as it is a BCS class IV drug
exhibiting low solubilities and permeabilities. Sanphui et al. cocrystal­
lized HCZ with the coformers nicotinic acid, nicotinamide, p-amino­
benzoic acid, succinimide and resorcinol via the wet grinding method
(Sanphui et al., 2015). Solubilities were increased for all cocrystals in
comparison to the pure drug substance except for cocrystals incorpo­
rating nicotinic acid and succinimide, which displayed reduced aqueous
solubilities. Permeability of the API and the cocrystals were investigated
using Franz diffusion cells with the help of a MW 14000 Da dialysis
membrane. The cocrystal which utilized succinimide as coformer had a
reduced permeability which may be attributed to its reduced solubility.
Cocrystals of nicotinamide and nicotinic acid displayed the highest
solubilities. These cocrystals not only displayed a higher initial perme­
ability, but also displayed a superior permeability once a steady state
was reached, as determined by the concentration gradient (Sanphui
et al., 2015). Another BSC class IV drug, acetazolamide, was investigated
to determine if its low solubility and permeability could be improved by
forming multicomponent crystalline materials. A cocrystal of acetazol­
amide with theophylline was formed by liquid assisted grinding fol­
lowed by solvent evaporation. In addition, a salt of acetazolamide with
piperazine was formed by reaction crystallization. Salt formation was
predicted as ΔpKa was found to be 2.35. Although this lies within the
cocrystal to salt continuum, the authors understood that this was a good
indication of salt formation as ΔpKa was close to 3.0 (Buddhadev and
Garala, 2021; Zhang et al., 2019). The generation of infrared spectra
confirmed the presence of the cocrystal and salt. Solubility studies
showed an increase in solubility at higher pH values for the cocrystal,
due to its slight acidity. The opposite was seen for the salt as it is slightly
alkaline, and its solubility decreased with increasing pH solutions. At pH
6.8, the concentrations of the API acetazolamide solution, the cocrystal
solution and the salt solution were 0.72, 2.18 and 10.59 mg/ml,
respectively. The difference between the solubilities of the salt and
cocrystal can be attributed to the higher solubility of the coformer
piperazine (for the salt) compared to theophylline (for the cocrystal),
and to the lower melting point of the salt relatively to the cocrystal
(confirmed by TG-DSC). Permeation diffusion of the salt and cocrystal
were also investigated, using a Franz diffusion cell at pH 6.8. Both the
salt and the cocrystal showed a larger degree of permeability during the
initial lag phase and once a steady state was reached in comparison with
the pure drug substance. The cocrystal performed better than the salt
despite the higher solubility of the salt. This is believed to be due to the
increased polarity of the salt negatively effecting its diffusion across the
membrane (Zhang et al., 2019). Production of cocrystals and even salts
of poorly soluble and/or poorly permeable API molecules has been
shown to be an effective and flexible method to improve various prop­
erties of pharmaceutical drugs.
2.3. Particle size control
The topic of particle size control within the pharmaceutical industry,
in particular small molecule APIs, generally aims at reducing particle
size and reducing particle size distribution in an effort to improve and
control drug physicochemical properties such as solubility and dissolu­
6
International Journal of Pharmaceutics 621 (2022) 121798
tion rate (Sun et al., 2012; Hanada et al., 2014). The Noyes Whitney (1)
equation states that the dissolution rate increases with a reduction in
particle size. In this equation, dC/dT refers to the dissolution rate, D is
the drugs diffusion coefficient, A is the drug particles effective surface
area, h is the thickness of the diffusion membrane, Cs refers to the drugs
saturation solubility at the diffusion layer and Cb refers to the drug
concentration (Mathur et al., 2011; Dizaj et al., 2015). Wang et al.
investigated the particle size reduction of coenzyme Q10 in an attempt
to improve dissolution rate, without the use of stabilizers, additives and/
or surfactants and showed an increase in apparent solubility, dissolution
rate and bioavailability as particle size decreased (Sun et al., 2012).
There has been an increase in recent years in the number of papers
published in the literature on nano-sized cocrystals, and a variety of
methods have been utilized for this (Mohammady et al., 2021; Tan et al.,
2021; Karashima et al., 2016; Pi et al., 2019; Bhandari et al., 2020;
Salem et al., 2021; Witika et al., 2021; Cocrystals, 2021).
dC DA(CS − Cb )
= (1)
dt h
Sander et al. produced a caffeine and dihydroxybenzoic acid nano-
cocrystal using the sonochemistry method (Sander et al., 2010).
Initially, the API and coformer were separately dissolved in acetone and
injected into an antisolvent (hexane) while simultaneously being soni­
cated to allow for nanocrystallization, with cocrystal particles collected
by filtration. Scanning Electron Microscopy (SEM) confirmed the pres­
ence of plate-shaped particles of the cocrystal with a large particle size
distribution, ranging from 200 nm to 5 μm. To produce cocrystal par­
ticles with a reduced particle size, a two solvent system was then carried
out by choosing two solvents (chloroform and acetone) with which the
respective solutes have a higher solubility, promoting rapid nucleation
(Sander et al., 2010). When a surfactant was included, the resulting
cocrystals displayed a particle size 136.4 nm with reduced agglomera­
tion (Sander et al., 2010). Hickey et. al. (Hickey et al., 2007) investi­
gated the control of particle size of a carbamazepine cocrystal, with
saccharin as conformer, and compared the resulting cocrystal with the
marketed drug substance. The cocrystal was prepared by conventional
cooling precipitation from an alcohol. Metal mesh sieves were used for
the separation of cocrystal particles based on crystal size. As expected, a
reduction in particle size generally led to an increase in solubility, with
the largest mean dissolution and largest total percentage dissolved after
60 min seen in the sample with the smallest size particles (<53 μm)
(Hickey et al., 2007). These studies have demonstrated an increase in
cocrystal solubility through particle size reduction. Mechanochemistry
methods such as neat and liquid assisted grinding (LAG) have been used
for the production of various types of cocrystals (also in the nano-size
range) but are incapable of direct control over resulting particle size,
and undesirable solvates may also occur. Polymer assisted grinding
(POLAG) overcomes the solvate issues by employing a solid or liquid
polymer which is incapable of forming a solvate (Hasa et al., 2015).
There are a substantial number of top-down and bottom-up methods
which appear to provide varying levels of control over the final particle
size of pharmaceutical materials. One of the most popular top-down
methods is milling which allows for the reduction in size of previously
produced particles through particle attrition. Fully stable particles are
usually dry milled while particles with a tendency to agglomerate can be
milled in liquid suspension with stabilizing surfactants. Wet milling
usually produces smaller particles with a narrower size distribution.
Unfortunately, sieving is required to achieve a desired particle size
distribution, and due to the low flowability and cohesive nature of the
resulting particles, the addition of excipients is generally required. Other
issues with this process include a high energy consumption and the in­
clusion of undesirable mill surface materials (Kumar et al., 2021). High
pressure homogenisation (HPH) is another method for particle size
reduction which involves the passing of a drug suspension through a
small aperture<20 µm. This high shear method causes the disruption of
particles suspended in a non-solvent leading to the production of smaller
A. O’Sullivan et al. International Journal of Pharmaceutics 621 (2022) 121798

particles. The movement of particles from a high pressure zone to a low
pressure zone also leads to particle size reduction through cavitation
(Kumar et al., 2021; Preiss et al., 2022). Although this method prevents
drug amorphization and polymorphic conversion and has a lower me­
chanical energy requirement than milling. However, clogging can occur
without a preliminary particle size reduction step prior to this method
(Kumar et al., 2021). Atomization based processes are attractive method
to control and reduce particle sizes. These methods offer significant
flexibility since the resulting particle size is influenced by the chosen
atomization/drying method and through altering process parameters
and set-up configurations (Kumar et al., 2021).
2.4. Current trends in the field of pharmaceutical cocrystals
The field of pharmaceutical cocrystals has experienced a steady
growth over the past number of years with nine cocrystals being
approved by the FDA for commercial use, all of which are summarized in
Table 2. The first commercially available cocrystal, Beta-Chlor or chloral
betaine, achieved a US patent for commercial use in 1962. This was
originally produced to mask the unpleasant taste of the API chloral
hydrate, which is a sedative, but the increased thermal stability asso­
ciated with this cocrystal was not realized until 2016, when it was first
described as a pharmaceutical cocrystal. This compound is formed by an
exothermic reaction in water when heated to 60 ◦ C (Kavanagh et al.,
2019; O’Nolan et al., 2016; Petrow et al., 1962). Following the approval
of beta-chlor, Depakote was FDA approved in 1983 as a means of
improving the solid form of the API and coformer by reducing their
hygroscopicity. Depakote is a 3:1 cocrystal of sodium valproate and
valproic acid, and is used for the prevention of seizures in patients
suffering with epilepsy (Petruševski et al., 2008). Another cocrystal
whose structure was not uncovered until years later is the caffeine-citric
acid cocrystal. Approved as a complex in 1999 to treat infantile apnoea,
it was determined to be cocrystalline in 2007 (Kavanagh et al., 2019;
Karki et al., 2007). Lexapro (Escitalopram) is an antidepressant, formed
by escitalopram oxalate salt and oxalic acid. This cocrystal was found to
be a more effective antidepressant than its enantiomer citalopram
(Harrison et al., 2007). Suglat was approved for use as a sodium glucose
transport 2 inhibitor in Japan in 2014 and is a 1:1 cocrystal of Ipragli­
flozin and L-proline. It is used for the treatment of diabetes and similarly
to the raw Ipragliflozin, the cocrystal with L-proline does not convert to
a hydrate form under high stress conditions, and therefore has increased
long term stability (Roy and Ghosh, 2020). Entresto, approved for use in
2015, is the first and only commercially available multidrug cocrystal in
that both reactants, Sacubitril and Valsartan, are API molecules. Sacu­
bitril improves the neurohormonal system within the heart whilst val­
sartan reduces the damage caused by angiotensin II to allow for effective
treatment of heart failure (Feng et al., 2012; Fala, 2015). Odomzo is a
diphosphate molecule formed through the bonding of a monophosphate
salt (sonidegib monophosphate) with phosphoric acid and acts as a cell
surface kinase inhibitor. This cocrystal was approved in 2015 for the
treatment of basal cell carcinomas (Roy and Ghosh, 2020). Steglato is a
cocrystal of etugliflozin and L-pyroglutamic acid and was produced
through a collaborative effort by Pfizer and MSD. Similarly to Suglat, it
is a sodium glucose transport 2 inhibitor and approved for the treatment
of diabetes in 2017 (Roy and Ghosh, 2020; Bowles et al., 2014). More
recently, Mayzent, a cocrystal produced by Novartis, became the first
available treatment for secondary progressive multiple sclerosis, a form
of multiple sclerosis found in patients experiencing relapse (T-Cells). It is
a 2:1 cocrystal of Siponimod, the API which is a sphingosine 1-phos­
phate receptor modulator, and fumaric acid (Roy and Ghosh, 2020). It
also exhibits polymorphism, but only the thermodynamically stable
form I is sold commercially (EMA, Assessment report: Mayzent - Euro­
pean Medicines Agency. Procedure No. EMEA/H/C/004712/0000,
2019).
Table 2 illustrates the number of pharmaceutical cocrystals that have
been approved by the FDA, while Fig. 2 illustrates the number of pub­
lications and patents per year in the field of pharmaceutical cocrystals. A
steady increase can be seen in the increase in publications and patents
per year since 2004, with publications and patents displaying a 165 %
and 378 % increase respectively, between 2010 and 2020.
3. Solid-state and particle engineering of cocrystals using
atomization-based methods
Atomization is the process in which a solution (in the case of coc­
rystals, one that contains an API and coformer) is broken into small
droplets by high-speed fluids (e.g. CO2, N2, hot air) and then dried to
produce a final powder. The selection on the nozzle type, orifice size and
atomizing gas has a significant effect on the resulting particle sizes. One
category of nozzles are pressure nozzles which allow for atomization by
pressurized solution flow through a small orifice which commonly
ranges from 10 − 1000 μm in diameter (Lefebvre and McDonell, 2017).
The change from a high-pressure environment to a low pressure one,
allows for the dispersion of a liquid stream into micro/nano-droplets and

Table 2
List of commercially available pharmaceutical cocrystals (Kavanagh et al., 2019; Roy and Ghosh, 2020).
Drug API Coformer Manufacturer Medical Dosage Year of Approval
Indication Administration

Beta- Chloral Hydrate Betaine Mead Johnson Sedation Oral (tablet) 1962 (O’Nolan et al., 2016)
Chlor®
Depakote® Sodium Valproate Valproic acid AbbVie Epilepsy Oral (tablet) 1983 (Petruševski et al., 2008)
Cafcit® Caffeine Citric acid Hikma Infantile Intravenous or Oral 1999 (Karki et al., 2007; Administration, F.a.D.,
Apnoea Caffeine citrate - New drug application (NDA 20-
793/S-001., 2000)
Lexapro® Escitalopram oxalic acid Forest Depression Oral (tablet) 2002 (Harrison et al., 2007; Masilamani and
oxalate salt Laboratories Ruppelt, 2003)
Abilify® Aripiprazole Fumaric Acid Otsuka Depression, Oral (tablet) 2006 (Devarakonda, 2009/0054455A1, 2007.)
Pharmaceutical Autism
Suglat® Ipragliflozin L-proline Astellas/ Diabetes Several solid and liquid 2014 (Imamura, et al., 2012)
Kotobuki formulations
Entresto® Sacubitril Valsartan Novartis Heart Failure Oral 2015 (Feng et al., 2012)
Odomzo® Sonidegib Phosphoric acid Novartis Basal Cell Oral 2015 (EMA, Odomzo, , 2015)
Monophosphate Carcinoma
Steglatro® Ertugliflozin L-pyroglutamic Pfizer/MSD Diabetes Oral 2017 (Bowles et al., 2014)
acid
Mayzent® Siponimod Fumaric acid Novartis Multiple Oral 2019 (FDA., 2019)
Sclerosis
Seglentis® Celecoxib Tramadol Kowa Acute Pain Oral 2021 (Elliott and Chan, 2021)
Pharmaceuticals

7
A. O’Sullivan et al.
Fig. 2. Number of publications (red bars) and patents (green bars) per year
regarding pharmaceutical cocrystals since 2004, as determined by Scopus
(adapted from().
Kavanagh et al., 2019
are primarily associated with conventional spray drying. Rotary atom­
izers on the other hand involve the injection of solution to the centre of a
nozzle chamber. As this chamber rotates at high speeds, the solution
flows to the periphery of this nozzle where it leaves through apertures
allowing for atomization. Air-assisted atomizers utilize high pressure gas
streams (usually air or nitrogen) to aid in solution dispersion resulting in
a fine spray of droplets. In these types of atomizers, the compressed gas
can come into contact with the solution after it has passed through the
orifice (external gas–liquid mixing) or within the nozzle such that the
gas and the solution leave the nozzle together as a mixed phase (internal
gas–liquid mixing) (Lefebvre and McDonell, 2017). One such example
includes coaxial nozzles which are often used in supercritical fluid
drying. This type of nozzle is composed of a nozzle pipe with a small
diameter, within a pipe with a larger diameter. The solution flows
through the small diameter pipe while the supercritical medium flows
through the larger pipe. In the absence of a mixer, this leads to external
mixing but the inclusion of a mixer allows for internal mixing and the
atomization of the mixture of supercritical fluid and solution (Padrela
et al., 2018). Other variations of atomizers have included the use of an
electric charge as seen in electrospraying, ultrasonication or vibration to
improve aspects of the atomization step which will be later discussed in
this review (Lefebvre and McDonell, 2017). Atomization provides a
large variety of options to tailor the drying process for the substances
being dried, such as droplets containing API molecules, by manipulating
the residence time and interaction between solvent, solutes, and atom­
izing fluid, such that processes such as cocrystallization is favoured.
There are multiple different methods which utilize the atomization
mechanism to produce pharmaceutical cocrystals and cocrystal solvates,
hydrates, polymorphs and cocrystals (and cocrystal polymorphs and
solvates), which will be discussed below with respect to their unique
advantages and challenges.
3.1. Supercritical fluid-based methods
In this review, most of the supercritical fluid-based methods dis­
cussed use carbon dioxide (CO2) as the supercritical fluid, based on its
mild critical parameters (Tc = 31.1 ◦ C and Pc = 7.38 MPa) (Padrela et al.,
2018). Table 3 lists the critical temperature (Tc) and pressure (Pc) of the
most commonly used compounds for supercritical processing (Ruhan
8
International Journal of Pharmaceutics 621 (2022) 121798
Table 3
List of commonly used supercritical fluids and their respective critical temper­
ature and pressure (Ruhan and Motonobu, 2009; Negoescu, 2017; Reid et al.,
1987).
Compound Critical Temperature (◦ C) Critical Pressure (MPa)
Carbon Dioxide (CO2) 31 7.4
Water (H2O) 374 22.1
Nitrogen (N2) − 147 3.4
Methanol (CH3OH) 239 8.1
Methane (CH4) − 83 4.6
and Motonobu, 2009; Negoescu, 2017). The low critical temperature of
CO2 is of particular interest as it allows for the processing of thermally
sensitive compounds, including (bio)pharmaceuticals. The solubility
behaviour of many substances in supercritical CO2 (scCO2) increases
with increasing pressure, which means that separation and purification
processes can be designed employing scCO2 as an extraction solvent.
Despite this tuneable solubility based on the pressure, the solubility of
most pharmaceutical drug molecules is low in scCO2, representing a
major challenge for methods that employ this scCO2 as a solvent. Su­
percritical CO2 is commonly used for extraction purposes, most
commonly for the decaffeination of coffee in industry (Kim, 2008;
Sökmen et al., 2018) and for the extraction of essential oils and food
products in academia (Sökmen et al., 2018; Khaw, 2017; Gallego et al.,
2019). However, scCO2 can also be used for the production of phar­
maceutical drug particles. Supercritical CO2 has three unique roles
which makes it widely versatile for the generation of pharmaceutical
drug powders: as a solvent, antisolvent or co-antisolvent, and as an
additive or spray enhancer. The selection on the scCO2 role to use is
primarily influenced by the solubility of the organic solvent and/or the
solutes in scCO2. Each of these roles and the various processes associated
with them will be discussed in greater detail in this review paper.
3.1.1. Supercritical CO2 as a solvent
The first role of scCO2 that will be considered is when the SCF acts as
a solvent to dissolve all, or part of the solutes involved in the final
formulation. This role can eliminate or greatly reduce the requirement
for organic solvents and thus reduce the number of steps required for
drug processing. However, as a solvent, scCO2 faces some limitations as
the solubility of APIs vary in scCO2, many of which possess a low sol­
ubility in scCO2. The solubility of APIs in scCO2 is influenced by its
polarity with non-polar compounds exhibiting an increased solubility in
scCO2 compared to polar compounds. Due to the control over API/
coformer solubility through the use of co-solvents, precipitation times
can be controlled to a degree, and as such, it is possible to obtain various
solid-state forms including pharmaceutical cocrystals. Additionally, due
to the reduced solubility of APIs and coformers at lower pressures, it is
less likely that conversion will take place once precipitation has
occurred (Padrela et al., 2018; Wang and Su, 2020).
Rapid expansion of supercritical solutions (RESS)
The first method which employed scCO2 as a solvent was named as
rapid expansion of supercritical solutions (RESS), which was first re­
ported in the 1980 s by Smith et al. (Matson et al., 1987; Matson et al.,
1986; Matson et al., 1987; Petersen et al., 1986; Smith, 1986). This
method involves the dissolution of a solute(s) in scCO2 in a solubiliza­
tion vessel. The pressure and temperature of scCO2 can be adjusted to
achieve a saturated (or near-saturated) fluid solution. This solution
containing the dissolved API and coformer flows through a pre-
expansion zone and is then rapidly expanded through a capillary
nozzle into a collection chamber (expansion vessel), where CO2 is
removed via a vent. The rapid depressurization causes a high degree of
supersaturation which results in homogenous nucleation and causes fine
solute particles (<1 μm) to precipitate with a narrow particle size dis­
tribution (Kumar et al., 2021). The time taken for precipitation to occur
was first estimated by Smith et al. to be in the range of microseconds and
A. O’Sullivan et al.
this short time can favour the production of metastable forms, accord­
ingly to the Ostwald’s rule of stages that states that the first form ob­
tained is usually the least stable one (Matson et al., 1987; Petersen et al.,
1986; Smith, 1986; Schmelzer and Abyzov, 2017; Matson et al., 1987).
In order to accommodate APIs with poor solubility in scCO2, several
adaptations of this method were created, which include a liquid solvent
being present in the expansion vessel (RESOLV/RESSAS) which aimed to
reduce the amount of particle coagulation that was observed after
passing through the nozzle, the use of a solid co-solvent (RESS-SC)
which aided the solvation of APIs in the solubilization vessel, and the use
of a non-solvent (RESS-N) (Kumar et al., 2021; Xiang et al., 2019;
Sodeifian et al., 2018). However, these variations have yet to be utilized
for cocrystal production.
Vemavarapu et al. investigated the coprecipitation of 12 different
API-additive/coformer/dopant mixtures using the RESS process. Su­
percritical CO2 was employed to demonstrate the ability of this process
to produce various solid-state forms of APIs such as hydrates, cocrystals
and amorphous forms. The RESS process utilized here tested both an
80:20 and 20:80 mixtures of the drug and additive/coformer/dopant in
the extraction vessel. Pressure and temperatures were varied for each of
the mixtures to determine their impact on the produced products solid-
state (Vemavarapu et al., 2009). A reduction in crystallinity was
observed in all cases. Vemavarapu et al. successfully cocrystallized sal­
icylic acid with acetylsalicylic acid and benzoic acid. Cocrystallization of
salicylic acid with the additive aspirin lead to a morphological change
from long needles to what was described as “dense networks”. The in­
clusion of aspirin in the extraction vessel also allowed for a five-fold
improvement in salicylic acid yields in the final product due to co-
solute mediated solubility improvement, allowing for a more efficient
solubilization of salicylic acid in scCO2. It was also reported that a
powder with a low melting point was obtained for both the salicylic
acid-acetylsalicylic acid cocrystal, and the salicylic acid-benzoic acid
cocrystal, possibly due to the formation of a eutectic melt (Vemavarapu
et al., 2009). The salicylic acid-acetylsalicylic acid cocrystal PXRD
pattern demonstrated a sharp reduction in crystallinity, which the au­
thors proposed to be attributed to eutectic formation (Vemavarapu
et al., 2009). This process also demonstrated the ability to control the
formation of a hydrated or anhydrous cocrystal of theophylline and
caffeine. The formation of a cocrystal hydrate was observed at lower
temperature set conditions in the process which utilized a theophylline
and caffeine mixture. However, an increase in temperature or an in­
crease in the caffeine composition (as high caffeine levels can compete
with water molecules during crystallization) in the starting material
mixture prevented the formation of a hydrated crystalline form
(Vemavarapu et al., 2009). The RESS process has demonstrated relative
control over hydrate formation where applicable, as well as the ability to
improve the resulting cocrystalline material solubility and yields
through the use of co-solutes (additives). However, a major drawback of
this method and other supercritical solvent-based methods for cocrystal
production is the selective solubilization/extraction of the reactants.
One example of this phenomenon is with theophylline-theobromine
cocrystals. It was found that an increase in temperature and/or pres­
sure led to an increase in the general amount of theophylline in the
cocrystals (Vemavarapu et al., 2009). The general selectivity of super­
critical solvents is an unfavourable feature for their use in pharmaceu­
tical crystallization, but Vemavarapu et al. demonstrated the ability to
manipulate this downfall to a certain degree to promote desired crys­
tallization, whilst improving yields and demonstrating a general control
over the solid-state of the resulting cocrystalline materials.
The RESS method has also shown promise in its ability to simulta­
neously (co)crystallize and micronize APIs due to the rapid depressur­
ization (Sodeifian et al., 2018; Martello et al., 2019; Türk and Bolten,
2016; Ghoreishi et al., 2016; Paisana et al., 2016). Müllers et. al.
attempted to produce cocrystals of ibuprofen and nicotinamide in a
single RESS process for cocrystallization and micronization. The re­
actants were dissolved in supercritical CO2 over 24 h, which then the
9
International Journal of Pharmaceutics 621 (2022) 121798
solution was atomized at a constant flow rate for 1 h through a 150 µm
orifice nozzle, and the cocrystal particles were collected within a filter
medium. A slow solvent evaporation method was also used to produce
these same cocrystals, where the resulting powder was ground and
passed through a 250 μm sieve to produce a cocrystal with a similar
surface area for comparative dissolution studies with the unprocessed
ibuprofen (Mullers et al., 2015). The cocrystals produced by RESS and
solvent evaporation were equally pure with an identical molecular
constitution. Bother the physical mixture and cocrystallization of
Ibuprofen and nicotinamide proved to improve the solubility of
Ibuprofen. However, dissolution rate of ibuprofen was only increased
after cocrystallization. The surface area of the cocrystals produced by
RESS were ten times larger than the unprocessed API, indicating a
smaller particle size. Pure ibuprofen was also processed by RESS and
displayed a surface area four times greater than the unprocessed
ibuprofen, again highlighting the ability of this method to greatly reduce
particle size. This size reduction led to an increase in dissolution rate
compared to cocrystals prepared by solvent evaporation (Mullers et al.,
2015).
Overall, there are not a significant number of methods which employ
scCO2 as a solvent coupled with atomization for the production of coc­
rystals. This is primarily as a result of a significant majority of APIs and
coformers exhibiting poor solubility in scCO2. This type of scCO2 pro­
cessing (employing scCO2 as a solvent) can experience significant uptake
in the coming years as a large proportion of APIs are exhibiting greater
hydrophobicity. As discussed in an earlier section, currently scCO2
methods are extensively used to extract oils and lipid-like substances
based on their favourable solubility and this introduces a new solvent-
free method to produce APIs. A variation of the RESS method is the
controlled expansion of supercritical solutions (CESS) method employed
and patented by Nanoform, which have claimed to produce API particles
as small as 10 nm. Nanoform state that, unlike RESS, the CESS method
might provide significant control over the crystallization process
through controlled flow, mass transfer, pressure and particle collection
in dry ice (Nanoform, What our technology can achieve., 2021; Pessi
et al., 2016). Although the CESS method has not been reported for the
production of cocrystals, it may be an attractive alternative to RESS for
simultaneous cocrystallization and micronization.
3.1.2. Supercritical CO2 as an anti-solvent
Using scCO2 as an anti-solvent is, by far, the most popular approach
with respect to drug processing using SCFs. This is primarily due to the
improved solubility and miscibility of organic solvents in scCO2
compared to APIs (Wu and Su, 2018; Said-Galiyev et al., 2004). Due to
the popularity of this role, there are multiple methods, many of which
include atomization, that have been developed for the production and
processing of pharmaceuticals, including the production of cocrystals.
The scCO2 antisolvent effect provides a unique mechanism to induce
precipitation of APIs and coformers through extremely high supersatu­
ration levels. Using scCO2 as an antisolvent can provide greater control
over the solid state (crystalline forms or amorphous) of the APIs, in
addition to other physical properties such as particle size and shape
(Padrela et al., 2018; Franco and De Marco, 2021; Franco and De Marco,
2020). Fig. 3 depicts a schematic of a typical supercritical antisolvent
method resulting in the production of cocrystals. The SCF solubilizes
within the liquid solvent, reducing its solvation power and inducing
supersaturation and thus, antisolvent nucleation. An atomization step
then allows the removal of the liquid solvent from the atomized feed
solution into the supercritical medium (Padrela et al., 2009). This sec­
tion will investigate various scCO2 antisolvent methods which employ
atomization as part of their mechanisms, and those that have demon­
strated control over the solid-state and particle size of pharmaceutical
cocrystals. Gas antisolvent (GAS) crystallization is a popular method
which has been utilized for the production of pharmaceutical cocrystals,
but it does not involve an atomization-based micronization step and thus
will not be discussed in detail in this section (Long, 2021; Pessoa, 2019).
A. O’Sullivan et al.
Fig. 3. Schematic representation of a typical scCO2-antisolvent method that
results in the generation of cocrystal particles. 1: Supercritical CO2 interacts and
mixes with the liquid solvent that contains dissolved cocrystal reactants; 2:
scCO2 is flushed out which contains the liquid solvent in which the reactants
were initially dissolved in; 3: cocrystal particles precipitate out of the solution.
The use of scCO2 as an additive or spray enhancer has also been used in
combination with antisolvent methods. However, methods which only
utilize the supercritical fluid as a spray enhancer will be discussed
further in section 3.1.3.
Supercritical antisolvent (SAS)
One method that utilizes supercritical fluids as an antisolvent is the
supercritical antisolvent (SAS) method. The SAS method involves the
atomization of an organic feed solution, that the API and coformer has
been dissolved in, into a pressurized precipitation chamber. The pre­
cipitation chamber contains the supercritical CO2 at pre-determined
operating conditions and is introduced to the chamber through a sepa­
rate inlet to the solution (although a coaxial nozzle has been used in
combination with this in some cases (Padrela et al., 2009)) (Park, 2007;
Neurohr et al., 2016). The interaction of the atomized feed solution with
the scCO2 leads to volumetric expansion and subsequent precipitation of
the solid cocrystalline particles (Park, 2007; Neurohr et al., 2016).
As scCO2 is easily atomized and possesses density similar to liquids, it
is a very effective medium in an atomization process, aiding in the
breakup of a liquid stream into small droplets thus creating small par­
ticles. For this reason, supercritical based methods such as the SAS
method have been effective in reducing particle sizes of pharmaceutical
substances (Montes et al., 2016; Yoon et al., 2016; Montes et al., 2016;
Pan, 2020; Xu, 2020). The SAS method, in particular, involves the
mixing of the supercritical fluid and the feed solution prior to atomi­
zation, allowing for antisolvent nucleation, thereby increasing mass
transfer which has a positive impact on particle size reduction (Vorobei
and Parenago, 2021; Ha, 2020; Reverchon and De Marco, 2011). Table 4
provides a list of all cocrystals produced using the SAS method to date,
along with corresponding particle sizes.
Hiendrawan et al. employed the SAS method in the production of a
cocrystal of paracetamol and dipicolinic acid from a methanolic solution
(Hiendrawan et al., 2016). Equally pure cocrystal products were pro­
duced from the SAS process, compared to conventional methods such as
10
International Journal of Pharmaceutics 621 (2022) 121798
rapid solvent evaporation. Similar to that which has been reported by
other studies (Zhao et al., 2018; Cuadra, 2020), the particle size of the
paracetamol-dipicolinic acid cocrystals produced by SAS (4.18 ± 0.054
µm) was smaller than that of the as-received paracetamol and the coc­
rystals produced by rapid solvent evaporation (45.33 ± 0.43 µm and
64.93 ± 0.095 µm, respectively). Reduced particle size generally leads
to an increase in cohesion leading to poor flowability, however the
opposite was observed in this study due to polyhedral particle
morphology of the cocrystal (compared to as-received paracetamol)
resulting in reduced particle contact points. Thus, these smaller coc­
rystals produced by SAS displayed improved flowability. However, the
flowability of the cocrystals produced by solvent evaporation was
slightly better than that of the SAS produced cocrystals due to their
larger particle size. The SAS process also produced cocrystalline pow­
ders with narrower size distribution than that of the solvent evaporation
process (Hiendrawan et al., 2016). Cocrystallization increased both
solubility and dissolution rate of paracetamol, but this increase was
higher in the SAS produced cocrystals due to their reduced particle sizes.
Due to the polyhedral morphology, the cocrystals displayed improved
compressibility and therefore tabletability, which was the primary aim
of that study (Hiendrawan et al., 2016).
Alternatively, Zhao et al produced a different cocrystal of paraceta­
mol with trimethylglycine by SAS, but unlike Hiendrawan et al. (Hien­
drawan et al., 2016), investigated the effect of changing SAS process
parameters and compared the resulting formulations with those of ball
milling. In preliminary experiments, it was found that the tensile
strength of the cocrystals was above the minimum value required for
effective tabletting (2 MPa) and as such, the authors focused on
improving the drug content in the final cocrystalline formulation. The
optimized SAS process conditions increased tensile strength of the coc­
rystal up to 11.13 MPa and displayed increased drug contents of
61.17%. Raw paracetamol and trimethylglycine showed the largest
particle sizes of approximately 400 μm and 90 μm, respectively, and the
largest particle size distributions. The smallest particle size was obtained
from the optimized SAS sample of approximately 8 µm, whilst other
particle sizes were not reported (Zhao et al., 2018). Samples produced
by the SAS method displayed the optimum tabletability.
Neurohr et al. investigated the ability of the SAS process to produce a
pure cocrystalline powder of the naproxen-nicotinamide cocrystal. So­
lution and scCO2 flow rates were varied, and in all cases the percentage
of cocrystal produced ranged from 94 − 100%, demonstrating the ability
of the SAS method to produce highly pure formulations. The particle
sizes of the initial runs ranged from 300 to 400 μm and remained
consistent through the variation of flow rates. An increase in solution
concentration produced cocrystals with a similar particle size. The au­
thors of that study proposed that these similar particle sizes could be
attributed to low supersaturation levels. As such, to promote higher
levels of supersaturation, the weight-based flow ratio of CO2-to-solution
was increased from 11 to 36 g/g. This increase of supersaturation levels
resulted in reduced particle sizes to as low as 15 μm, but heterogeneity
was observed in the form of naproxen homocrystals. To combat this, the
ratio of API to coformer was changed from 2:1 to 2:2 which produced a
more pure formulation of cocrystal of approximately 99% (Neurohr
et al., 2016). This paper demonstrated an ability of the SAS process to
control and manipulate the solid state of the resulting dried formulation
through altering supersaturation levels and even the proportion of API
and coformer, allowing for the simultaneous reduction in particle size
and prevention of homocrystal production.
It is not often that a cocrystalline system can be produced by both a
supercritical solvent method as well as an antisolvent method due to
their distinct modes of operation. Supercritical solvent-based methods
require that both the API and coformer are approximately equally sol­
uble in the supercritical fluid, whereas antisolvent methods require that
the API and coformer are relatively insoluble in the supercritical fluid, a
far more common instance. Cuadra et al. compared the production of
cocrystals of 5-flourouracil with various coformers (urea and thiourea)
A. O’Sullivan et al. International Journal of Pharmaceutics 621 (2022) 121798

Table 4
List of pharmaceutical cocrystals produced by various supercritical CO2-based atomization methods, along with the corresponding solvents and processing conditions.
Role of Method API Coformer Solvent Nozzle FSOL P (MPa) T (◦ C) Particle Reference
SCF Diameter (ml/ size
min) range

Solvent RESS Mefenamic acid Nicotinamide N/A 100 μm N/A 9.1 – 40 – 90 Not (Vaksler, 2021)
19.3 reported
Ibuprofen Nicotinamide N/A 150 μm N/A 30 50 Not (Mullers et al.,
reported 2015)
Salicylic acid Acetylsalicylic acid, N/A Not N/A 7.6 – 62 35–100 Not (Vemavarapu
Benzoic acid reported reported et al., 2009)
Acetylsalicylic acid Benzoic acid Not
reported
Tolbutamide Chlorpropamide Not
reported
Theophylline Theobromine, Caffeine Not
reported
Antisolvent SAS Paracetamol Nitroisophthalic acid Methanol 254 μm 1 10.0 40 4.66 μm (Tjandrawinata
et al., 2019)
Paracetamol Dipicolinic acid Methanol 254 μm 1 10.0 40 4.18 μm (Hiendrawan,
2016)
5-Flourouracil Urea Methanol 100 μm 1 8.0 40 10–60 (Cuadra, 2020)
μm
5-Flourouracil Thiourea Methanol 100 μm 1 10.0 40 5–65 μm (Cuadra, 2020)
Carbamazepine Saccharin Methanol, 100 μm 1 10.0 – 40.0 – 5 – 10 μm (Cuadra, 2018)
ethanol, 15.0 60.0
DCM, DMSO
Naproxen Nicotinamide Acetone 180 μm 2 – 13 10 37 300 – (Neurohr,
400 μm 2016)
Indomethacin Saccharin Ethanol, 80 and – 9.6 – 50 - (Padrela, 2009)
acetone, 200 μm 10.5
methanol,
THF, ethyl
acetate
Paracetamol Trimethylglycine DCM + 500 μm 1.2 10.0 45 - (Zhao, 2018)
methanol
Diflunisal Nicotinamide Acetone, 100 μm 1 10.0 – 35 – 40 Not (Cuadra, 2016)
ethanol 12.0 reported
AAS Indomethacin Saccharin Ethanol, 80 and – 6.0 – 50 – 70 0.5 – 0.7 (Padrela, 2009)
acetone, 200 μm 12.0 μm
methanol,
THF, ethyl
acetate
Theophylline, Saccharin Ethanol 100 μm – 8.0 – 8.2 50 Not (Padrela, xxxx)
Caffeine, reported
Sulfamethazine
Spray SEA Theophylline Urea, Saccharin, gentisic THF 100 μm – 4.0 – 40 – 70 0.5–0.7 (Padrela, 2014)
Enhancer acid, Salicylic acid, 10.0 μm
glutaric acid, sorbic
acid, 1-hydroxy-2-naph­
thoic acid, oxalic acid,
maleic acid,
nicotinamide
Theophylline Saccharin THF 100 μm – 8.0 50 Not (Tiago, 2013)
reported
Indomethacin, Saccharin Ethanol 100 μm – 7.8 – 8.3 50 0.3–10 (Padrela, 2010)
theophylline, µm
caffeine,
sulfamethazine,
aspirin
carbamazepine
Carbamazepine Saccharin Ethanol, Not Not Not Not Not (Padrela, 2019)
methanol reported reported reported reported reported

SCF (supercritical fluid), RESS (rapid expansion of supercritical solutions), SAS (supercritical antisolvent), AAS (atomization and antisolvent), SEA (supercritical
enhanced atomization), API (active pharmaceutical ingredient), DCM (dichloromethane), DMSO (dimethyl sulfoxide), THF (tetrahydrofuron), FSOL (solution flow
rate), P (pressure), T (temperature).

by the SAS and the CSS (cocrystallization with supercritical solvent)
methods (Cuadra, 2020). The CSS method involves the solubilization of
the solid components (API and coformer) in scCO2 in a high-pressure
vessel, or the formation of a slurry my partially insoluble materials.
This is followed by depressurization and subsequent induction of su­
persaturation which drives the precipitation of the cocrystals. Co-
solvents have been used in the past to aid in the solubilization of re­
actants in scCO2 (Padrela et al., 2009; Cuadra, 2020; Ribas, 2019).
Methanol was employed as the solvent in the SAS method due to the
high solubility of the API and coformers in it. In the CSS method, as the
API and coformers have reduced solubility in scCO2, methanol was also
used as a co-solvent due to its ability to increase the solubility of polar
compounds in scCO2 (Cuadra, 2020; Li, 2011; Bitencourt, 2019). The
CSS method only produced cocrystals when methanol was included as a
co-solvent (to improve the amount of API and coformer that would be
dissolved), which highlighted the importance of the solubility of the

11
A. O’Sullivan et al.
starting materials in scCO2. The produced 5-flurouracil-urea cocrystal
particles exhibited plate-like shape, with a length of 10–60 µm, width of
2–6 µm, and thickness of 10–20 nm (Cuadra, 2020). The lack of an at­
omization step resulted in the production of much larger particles in the
CSS method, comparatively to SAS, but the low solubility of reactants in
scCO2 (even with the addition of an appropriate co-solvent) may have
led to the formation of a mixed crystalline phase of cocrystals and
homocrystals. The use of thiourea as the coformer in the SAS process led
to the formation of a mixed phase of cocrystal and API homocrystals.
These particles also displayed a plate-like shape with a particle length of
5–65 µm, width of 4–8 µm, and thickness of 0.5–3 µm in SAS. The CSS
method also produced a mixture of cocrystal and API homocrystals for
both urea and thiourea. Particle sizes for the CSS produced cocrystal
were not reported, but from the SEM images it is clear that the particle
lengths well-exceed 100 µm, which is in agreement with typical particle
sizes reported when using the CSS method and surpassing those of the
reported SAS particle sizes (Padrela et al., 2018). Similar to the study
discussed above by Cuadra et al., the presence of homocrystals in the
precipitate is likely due to an incongruent saturating system, as urea and
thiourea have higher solubilities in methanol than 5-flourouracil.
Despite the addition of methanol, the production of homocrystals in
the CSS method is due to low solubilities of the solutes in scCO2. The co-
solvent improved this as no cocrystals could be produced without it, but
it is likely that higher levels of solubility in the supercritical medium
would be required for the CSS method (Cuadra, 2020).
A few cocrystals are known for exhibiting various polymorphic
forms. One example is the carbamazepine-saccharin (CBZ-SAC) cocrys­
tal, which exhibits two polymorphic forms, the stable form I and the
metastable form II. Cuadra et al. investigated the influence of operating
conditions such as pressure (10–15 MPa), temperature (40–60 ◦ C), sol­
vent choice (methanol, ethanol, dichloromethane (DCM) and dime­
thylsulfoxide (DMSO)), and API concentration (15–30 mg/ml) within an
SAS process on the polymorphic form of the 1:1 CBZ-SAC cocrystal. The
use of DMSO as a solvent produced no precipitate, as coformer solubility
may have been enhanced in DMSO-CO2 system. PXRD confirmed the
presence of cocrystal form I when methanol was used, but a mixture of
forms I and II was observed when either ethanol or DCM was used.
Operational conditions were then varied whilst using methanol as the
solvent to improve yields. When a temperature of 40 ◦ C and pressure of
10 MPa was used, a pure phase of form I was produced with yields of 65
%, compared to 50 % under pressure conditions of 15 MPa. However, at
60 ◦ C a mixture of form I and II was produced, most probably due to
changes in the ternary phase diagram causing an incongruent saturating
system. The higher temperature may have also allowed for a more rapid
drying process which may have favoured the formation of metastable
forms, according to Ostwald’s rule of stages (Schmelzer and Abyzov,
2017; Grossjohann, 2015; Walsh, 2018; Walsh, 2018; Tawfeek et al.,
2020). The authors pointed out that the reason methanol was the only
solvent to yield a pure sample of one of the cocrystal polymorphs is
because carbamazepine and saccharin have similar solubilities in
methanol, creating a congruently saturating system (Cuadra, 2018). This
has previously been noted to lead to the formation of homocrystals, but
in the case of carbamazepine and saccharin, it lead to the formation of a
mixed phase of cocrystal forms I and II (Neurohr et al., 2016; Cuadra,
2018).
Atomization and antisolvent (AAS)
The atomization and antisolvent (AAS) method has been considered
a derivative of the SAS method discussed above, but with the major
difference being the precipitation chamber is held at atmospheric
pressure rather than high pressure. This method primarily utilizes a
coaxial nozzle with a small mixing chamber for the atomization of the
mixed scCO2/solution phase. This mixing allows for the induction of
supersaturation and antisolvent nucleation. After the two feed streams
mix for a small period of time, the homogenously mixed phase passes
through the nozzle, producing the atomized feed stream which, unlike
SAS, is further dried by thermal means similar to conventional spray
12
International Journal of Pharmaceutics 621 (2022) 121798
drying, as discussed further in section 4.2 (MacEachern et al., 2020).
This method has been successful in the production of nano-sized lyso­
zyme particles, as well as several API cocrystals (see Table 4) which
utilized saccharin as the coformer (Padrela et al., 2009; Rodrigues,
2009; Padrela). Padrela et al. produced indomethacin-saccharin coc­
rystals using both the SAS and AAS method. Both methods utilized a
coaxial nozzle with a 30 µl mixing volume for the induction of super­
saturation and antisolvent nucleation. Within the AAS configuration, the
SCF used can be altered between CO2 and N2, and other variations can be
made to the pressure, solvent used, and mass flow ratio of the SCF and
organic solution. Where nitrogen was utilized as the SCF, cocrystals
formed in the liquid feed solution and were further dried by the nitrogen
gas. DSC and PXRD analysis confirmed the production of pure cocrystal
formulations, however enthalpy of fusion values showed minor varia­
tions inferring the formation of polycrystals. The SAS-produced coc­
rystals displayed no significant changes in morphology when operating
conditions such as pressure or solvent were varied. These consistently
formed mixtures of block and needle-like particles with an approximate
size of 5 μm. The AAS-produced cocrystals displayed a more spherical/
granular morphology with a mean diameter of 500–700 nm, which was
also unaffected by changes in process conditions, solvent choice, or the
SCF used. The larger size of SAS produced cocrystals may be attributed
to the enhanced time in contact with the liquid organic solvent, which
allowed for crystal growth, prior to solvent extraction by the super­
critical medium. The mixed particle morphology obtained in SAS was
due to the crystallization mechanisms. These include the reduction of
the organic liquids solvent power by the dissolution of the SCF in the
solvent, and the removal of the solvent from the atomized droplets into
the SCF. Whether these mechanisms occur simultaneously or not plays a
large role in the final particle size and shape (Padrela et al., 2009).
Padrela et al. also successfully produced cocrystals using saccharin as a
coformer with several APIs, including theophylline, caffeine, and sul­
famethazine using the AAS method and demonstrated the method’s
ability to produce less agglomerated particles than conventional
methods (Padrela).
3.1.3. Supercritical CO2 as a spray enhancer/additive
Supercritical CO2 can also act as a spray enhancer or additive, such
that it may be a solute or a co-solvent. The unique properties of scCO2
make it an attractive candidate to feature as an additive or an atomizing
fluid (spray enhancer). This SCF possesses the density similar to that of a
liquid at mild pressures and temperatures compared to other SCFs (see
Table 3). Secondly, it is capable of dissolving in many substances such as
polymers, leading to a reduction in their melting temperature, such that
they can be used with thermally labile materials. The third and final
feature, also observed in antisolvent-based atomization methods, is its
ability to be easily atomized allowing the disruption of solution streams
into fine droplets, resulting in a greater level of control over the physi­
cochemical properties of pharmaceutical powders. This role of scCO2 is
commonly observed in combination with other previously mentioned
methods and can be regarded as complimentary to such methods. Ex­
amples of supercritical spray enhancing methods include supercritical
enhanced atomization (SEA), supercritical assisted atomization (SAA),
and particle formation from gas saturated solutions (PGSS) (Campardelli
et al., 2016; Peng, 2019; Ndayishimiye and Chun, 2018).
Supercritical enhanced atomization (SEA)
The only method which utilizes the spray enhancing ability of SCFs
for cocrystal production, is the supercritical enhanced atomization
(SEA) method. This method is occasionally labelled as the supercritical-
assisted spray drying method (SASD), but both SEA and SASD methods
appear to be somewhat identical in mechanism and design. The SEA
method is also the only method which has been used for cocrystal pro­
duction which only utilizes the spray enhancer/additive role of SCFs.
Unlike the AAS method, the mixing volume and time are low which does
not allow for any antisolvent crystallization, only antisolvent nucleation
in some cases (Jung and Perrut, 2001; Long, 2019). The SCF low
A. O’Sullivan et al.
viscosity and high density allows them to be effective in breaking up
liquid streams to allow for effective micronization and simultaneous
drying. This method has shown promise in vaccine production, cocrys­
tallization, and lipid dispersion of cocrystals (Padrela et al., 2010; Tiago,
2013; Rodrigues, 2012).
The SEA method was first introduced in a 2010 publication for the
screening of pharmaceutical cocrystals (Padrela et al., 2010). Saccharin
was utilized as the coformer in the screening of cocrystal systems which
included the APIs indomethacin, theophylline, caffeine, sulfamethazine,
aspirin, and carbamazepine in methanol solutions. With regards to the
theophylline-saccharin screening tests, two molar ratios were investi­
gated, 1:1 and 1:2. Analysis by PXRD and DSC highlighted the presence
of the 1:1 cocrystal, as well as a new cocrystal with reactant ratios of 1:2.
All other APIs tested produced pure cocrystalline formulations. Particle
sizes of cocrystals produced by SEA were compared to conventional
methods such as grinding. Cocrystal system produced by SEA were
found to have smaller median particle sizes compared to those produced
by grinding. Specifically, theophylline-saccharin cocrystals produced by
SEA had a mean particle size of 500 nm, whereas grinding produced
cocrystals with a mean particle size of approximately 700 nm, demon­
strating the impact of atomization as well as scCO2 on reducing cocrystal
particle sizes (Padrela et al., 2010).
A publication which further built upon the above mentioned article
(Padrela et al., 2010) sought to produce theophylline cocrystals with
various coformers (see Table 4) to achieve a cocrystal with appropriate
dissolution kinetics for medical use (Padrela et al., 2014). This paper
determined that the theophylline cocrystals solubilities were dependent
on the coformer solubility, as the coformers with aqueous solubilities
lower than that of the API (gentisic acid, hydroxy-2-naphthoic acid,
saccharin, salicylic acid), generated cocrystals with aqueous solubilities
lower than that of the API (Padrela et al., 2014). In line with this,
coformers with high aqueous solubilities (urea, glutaric acid, maleic
acid, nicotinamide, oxalic acid, sorbic acid) generated cocrystals with
higher solubilities than that of the API, theophylline. Particle sizes and
morphology were measured for the cocrystal systems to determine the
effect of process variables such as solution concentration, temperature,
and pressure. All cocrystals produced by the SEA method presented an
average size between 500 and 700 nm indicating that coformer choice
had little impact on particle size. Coformer choice did show an effect on
cocrystal morphology. Cocrystals with gentisic acid and saccharin pro­
duced granular/plate-like particles, whilst nicotinamide and sorbic acid
coformers produced cocrystals with a needle-like shape. Variation in
solution concentration or pressure had little impact on the resulting
particle sizes. However, temperature did show an effect on particle size,
as temperatures below the solvent boiling point yielded particles of
500–600 nm, whilst 800–900 nm particles were generated at tempera­
tures above the solvent boiling point (Padrela et al., 2014).
Subsequently, Padrela et al. investigated the simultaneous cocrys­
tallization and lipid dispersion of the theophylline-saccharin cocrystal
using the SEA process, to improve the stability of the API. To produce the
lipid loaded cocrystals, solutions of the cocrystal reactants and hydro­
genated palm oil were atomized with scCO2 into the heated precipita­
tion chamber with a filter for particle collection. The PXRD
diffractograms confirmed the cocrystals purity. Cocrystallization
significantly improved the stability of the API under 92% humidity
conditions from several days to over 6 months. This was observed with
and without lipid dispersion. Lipid dispersion also slowed the release of
the API, preventing the formation of its hydrated form (Tiago, 2013).
Although the SEA method has not yet demonstrated a great ability to
control the solid-state of cocrystalline systems apart from an ability to
produce a pure cocrystalline formulation, it has shown an ability to
produce polymorphs of cocrystals which have not been produced by
other methods. This method has also been effective in reducing cocrystal
particle sizes and particle size distributions in comparison to conven­
tional methods, such as grinding.
13
International Journal of Pharmaceutics 621 (2022) 121798
3.2. Conventional spray drying
Spray drying refers to the atomization of a feed solution followed by
thermal drying by a heated stream of gas. Nitrogen is the most
commonly used atomizing gas, particularly when using organic solvents,
but heated air can be used when the proportion of organic solvent in the
atomized solution is lower than 20 % v/v. After atomization, the feed
solution meets the hot gas in either a co-current configuration (same
flow direction) which allows for less particle agglomeration, or a
counter-current (feed and gas flow in opposite directions) configuration
which allows for a reduction in energy input for evaporation (Patel et al.,
2009; Piatkowski and Zbicinski, 2006). The geometry of the drying
chamber, where the solvent is removed from the precipitated API, can
have significant effect on the final solid-state form, particle size and
morphology. Vertical drying chambers are more commonly used than
horizontal chambers, but atomizers such as the rotary atomizer are more
effective in horizontal drying chambers due to the wide spray formed
(Patel et al., 2009; Mujumdar et al., 2010). A drying chamber may also
be considered a single stage or two-stage drying chamber. Two-stage
drying chambers allow the gas and feed solution to mix prior to atom­
ization into the drying chambers, while a second feed of hot gas further
dries the atomized feed. This drying process allows for lower tempera­
ture and is more suited for thermolabile products. Single stage drying
does not include this mixing step (Patel et al., 2009; Mujumdar et al.,
2010). Smaller droplets can produce smaller particles but if the drying
process has not been altered accordingly, the particles can become
damaged by prolonged exposure to the hot gas. Similarly, large droplets
may produce larger dried particles but steps must be made to ensure that
those particles are fully dried before collection (Patel et al., 2009;
Cotabarren, 2018). Bertin et al. noted that air flow rate and feed solution
concentration had large impact on the droplet size and thus, the size of
the resulting ciprofloxacin hydrochloride particles (Cotabarren, 2018).
Conventional spray drying has been employed for cocrystal pro­
duction in recent years. Weng et al. investigated the effects of various
parameters within a spray drying configuration on resulting particle size
of cocrystals of itraconazole and suberic acid. The operating conditions
that were examined in that study included gas flow and solution con­
centration (Weng, 2019). Gas flow has been reported to impact the at­
omization rate which may generate smaller particles, while solution
concentration may affect the quantity of solute (cocrystal) inside each
droplet. (Karashima, 2017). Lower solution concentrations may result in
smaller particle sizes due to less solute being present in each droplet,
while a larger atomizing gas flow rate would allow for an increased rate
of atomization leading to smaller droplets (Karashima, 2017; Littringer,
2013; Arzi and Sosnik, 2018; Baumann et al., 2021; Lu, 2022). Addi­
tionally, the solution concentration may influence the supersaturation at
the point of atomization and can play a role in controlling the solid-state
of the API atomized, in that low supersaturation levels might lead to
more stable forms while high supersaturation levels might lead to
metastable or amorphous forms (Grossjohann, 2015; Walsh, 2018;
Walsh, 2018; Tawfeek et al., 2020). In this study, Weng et al., gas flow
rate were set to either 601 or 742 Nl/h, while solution concentration was
varied between 1.14, 3.41 and 5.68 mmol/L. In general, reduced solute
concentration and increased gas flow rate led to a decrease in particle
size, but the smallest particle size of 2.56 μm was observed using solu­
tion concentrations of 3.41 mmol/L and a gas flow rate of 742 Nl/h.
Whilst larger gas flows produced smaller particles, larger particle sizes
of approximately 4 μm were produced in runs which utilized solution
concentrations of 1.14 mmol/L (Weng, 2019). This was attributed to
particle agglomeration, which is often seen in smaller sized crystals due
to their electrostatic nature (Weng, 2019; Karashima, 2017).
Several publications have demonstrated the ability of a spray drying
configuration to produce a(n) (co)amorphous pharmaceutical product
(Walsh, 2018; Lenz, 2017; Wicaksono, 2021; Fung and Suryanarayanan,
2019; Matsuda, 1984; Lyu et al., 2017; Jog and Burgess, 2018). Tawfeek
et al. demonstrated the ability to control the solid state of the
A. O’Sullivan et al. International Journal of Pharmaceutics 621 (2022) 121798

indomethacin-nicotinamide system to produce wither the cocrystal or a
fully coamorphous product (Tawfeek et al., 2020). That study aimed to
produce fully coamorphous products by spray drying homogenous sus­
pensions of the indomethacin-nicotinamide cocrystal, whilst varying
solution concentration, pump rate, inlet temperature and aspirator flow
rate to influence the crystallinity of the produced product. Inlet tem­
perature has been shown to influence the crystallinity of a final phar­
maceutical product. Higher temperatures lead to an increase in droplet
solvent evaporation which, as mentioned earlier, leads to higher su­
persaturation levels which would typically promote the formation of
metastable and coamorphous/amorphous products (Lyu et al., 2017;
Jog and Burgess, 2018; Jensen, 2016). Assumingly, an increase in so­
lution concentration leads to further high supersaturation levels result­
ing in a coamorphous product, whilst a reduced solution flow rate would
also indicate less solute in the chamber causing a more rapid evapora­
tion of solvent droplets. Tawfeek et al. reported the lowest degree of
crystallinity of 0.77 % in the final product occurred using the highest
solution concentration values of 10 mg/ml along with the lowest solu­
tion flow rate and highest inlet temperatures of 15 % and 150 ◦ C,
respectively, again due to rapid solvent evaporation. All runs had a large
reduction in crystallinity (<8 % crystallinity remaining) except one run
which displayed 43.54 % crystallinity. This is believed to have been
caused by a relatively high moisture content, coupled with the high
aspirator rate. As the feed solution employed in this study was a
cocrystal suspension, the moisture content coupled with a high aspirator
rate could attribute the high level of crystallinity to retained cocrystal.
Apart from this run, the next highest level of crystallinity achieved was
7.86 % (Tawfeek et al., 2020). This run utilized low concentration and
low temperature allowing for a slower drying process, which is in
agreement with the theory above in that these conditions induce lower
levels of supersaturation, keeping the product more crystalline (Tawfeek
et al., 2020). The manipulation of processing conditions to influence
supersaturation levels is an effective method to control product crys­
tallinity, particularly during spray drying due to the already rapid
evaporation process.
Excipients have also shown an effect on cocrystal solid state, as
demonstrated by Walsh et al. The difference in Hansen Solubility Pa­
rameters (HSP) has been employed as a general indication as to the solid
state of the spray dried formulation (Walsh, 2018). Low ΔHSP values
between API and coformer is a strong indication of cocrystal production,
as the two components are easily miscible, which is favourable for
cocrystal formation (Salem et al., 2019; Walsh, 2018; Mohammad et al.,
2011). However, it has been reported that a difference in HSP values
between cocrystal and the excipient greater than 9.6 MPa0.5 (ΔHSP >
9.6 MPa0.5), is a strong indication of cocrystal formation, whilst values
below 9.6 MPa0.5 indicate an unlikelihood towards cocrystal production.
These low ΔHSP values indicate a high miscibility between cocrystal
and excipient which, in turn, blocks interactions between the API and

Table 5
List of pharmaceutical cocrystals and coamorphous pharmaceutical formulations produced by conventional spray drying, along with the corresponding solvents and
processing conditions (years 2015–2021).
API Coformer Solvent Nozzle FSOL FGAS Aspiration Outlet Particle size Reference
Diameter (ml/ (unit/ rate (m3/h) (◦ C) range (μm)
(mm) min) h)

Itraconazole Suberic acid Ethanol + – 1.5 601 – 35 50 2.56 ± 2.27 (Weng, 2019)
chloroform 742 NL
Sulfadimidine 4-aminosalicylic Ethanol – 9 – 10 667 NL 35 50 – 57 1 – 10 (Walsh, 2018)
acid
Indomethacin Nicotinamide Ethanol + water – – – – – - (Tawfeek et al., 2020)
Indomethacin Arginine Acetone, Water 0.7 6 40 m3 – 50 0.169 (Lenz, 2017)
Ketoconazole Oxalic acid Methanol – 3.5 – – 35 - (Fung and
Tartaric acid Suryanarayanan,
Citric acid 2019)
Succinic acid
Atorvastatin Isonicotinamide Methanol – 5 600 L – 55 - (Wicaksono, 2021)
calcium Maleic acid
Indomethacin Arginine Acetone + water – 6 667 L/h – 50 - (Jensen, 2016)
Histidine
Lysine
Sulfadimidine 4-aminosalicylic Ethanol – 9 – 10 473 NL 35 50 – 57 - (Grossjohann, 2015)
acid
Niclosamide Urea IPA 0.7 3–6 246 L 30 40 – 88 2 – 3.4 (MacEachern, 2021)
Niclosamide Nicotinamide Ethanol 0.7 1 – – 40 – 45 1–5 (Ray, 2020)
Cilostazol 4 HBA Acetone + – – 1 kg – – 53 – 91 (Urano, 2020)
2,4-di-HBA methanol 63 – 85
2,5-di-HBA -
Carbamazepine Saccharin Ethanol + 0.7 – – – – - (Padrela, 2019)
methanol
Caffeine Dapsone Acetone, – 10 ml/ 670 L – – ~5.1 – 5.4 (do Amaral, L.H., ,
ethanol, ethyl min 2018)
acetate
Ketoconazole Oxalic acid Methanol – 3.5 – – 35 - (Fung, 2018)
Tartaric acid
Citric acid
Succinic acid
Sulfadimidine 4-aminosalicylic Ethanol – 9 – 10 473 NL 35 50 – 57 5.7 ± 0.7 (Serrano, 2016)
acid
Sulfadimidine 4-aminosalicylic Ethanol 0.7 9–10 473 NL – 50 – 57 5.7 ± 0.7 (Serrano, 2016)
acid
Sodium Lactose Water – 3 40 m3 – 63 – 65 (Sovago, 2016)
naproxen
Theophylline Saccharin Methanol – 5 357 L – 50 – 55 <5 (Alhalaweh, 2013)
Urea Methanol – 5 357 L – 50 – 55 <5
Nicotinamide Water – 5 357 L – 50 – 55 <5

API (active pharmaceutical ingredient), HBA (hydroxybenzoic acid), FSOL (solution flow rate), FGAS (atomizing gas flow rate).

14
A. O’Sullivan et al.
coformer (Walsh, 2018). This was shown to be the case regarding spray
drying to produce the sulfadimidine – 4-aminosalycilic acid cocrystals.
Any excipient used, regardless of whether they were amorphous or
crystalline by nature, produced cocrystals when ΔHSP values were
greater than 9.6 MPa0.5. A mixture of cocrystal and reactants was found
when using glycine and polyvinyl alcohol (PVA) as excipients which
displayed ΔHSP values of 6.6 and 4.9 MPa0.5, respectively. Hydrox­
ypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP) and sol­
uplus (which produced ΔHSP values of 1.9, 4.4 and 3.9 MPa0.5
respectively) resulted in fully amorphous products. However, this is not
a golden rule. Chitosan was one tested excipient which proved to be an
exception, as it led to the production of cocrystal mixed with reactants
while exhibiting a ΔHSP value 11.2 MPa0.5. This occurred due to in­
teractions between this alkaline polymer and the acidic coformer 4-ami­
nosalycilic acid (Walsh, 2018).
Spray drying has also demonstrated an ability to produce different
polymorphic forms of pharmaceutical cocrystals. A summary of pro­
duced cocrystals is listed in Table 5. The rapid drying process observed
during spray drying can allow for the production of less stable or
metastable polymorphs (Grossjohann, 2015; Walsh, 2018; Lu, 2022).
Grossjohann et al. demonstrated the ability of spray drying to produce a
new polymorphic form of the sulfadimidine – 4-aminosalycilic acid
cocrystal (form II) compared to the previously reported form I produced
by LAG (liquid-assisted grinding) (Grossjohann, 2015). Over the
extended period of time assessed, both polymorphs displayed similar
stability retention, but it would be hypothesized that the rapidly spray
dried polymorph may be less stable over a longer period of time.
3.3. Electrospraying/electrohydrodynamic atomization
Electrospraying (also call electrohydrodynamic atomization) is a
relatively new method which has been employed for the production of
cocrystals of pharmaceutical compounds including energetic cocrystals
for use as explosives (Patil et al., 2016; Huang, 2018; Patil et al., 2017;
Patil, 2018; Patil et al., 2018; Emami, 2018; Emami, 2018; Solaimalai,
2019). A summary of all pharmaceutical cocrystals produced by this
method is presented in Table 6. The mechanistic details of the electro­
spraying method involves electric forces coupled with the atomization of
a feed solution of API and coformer into charged droplets. This form of
atomization forms a Taylor cone with high vibrational energy at the tip
of the atomizer needle. This then transforms into a cone jet which
further propagates into a very fine mist of charged droplets. Optimiza­
tion of process parameters such as potential difference, solution flow
rate and working distance (distance between needle and grounded
collection plate) is required to ensure this mist of charged droplets forms
(Emami, 2018). Atomization methods afford for a high nucleation rate
Table 6
List of pharmaceutical cocrystals reported to date produced by the electrospraying/ electrohydrodynamic atomization method, with the corresponding solvents and
operating conditions.
API Coformer Solvent
Caffeine Maleic acid Methanol, acetone, ethyl
acetate, water
Carbamazepine, Nicotinamide Methanol, ethanol
Itraconazole
Forskolin Ascorbic acid, Ethanol
nicotinamide, caffeine
Quercetin Caffeine, Nicotinamide Methanol
Indomethacin, Saccharin, Nicotinamide, Methanol, Ethanol,
Naproxen Isonicotinamide Acetone, Ethyl Acetate
Plumbagin Nicotinamide Methanol
Carbamazepine Saccharin Ethanol + methanol
API (active pharmaceutical ingredient), FSOL (solution flow rate), T (temperature).
International Journal of Pharmaceutics 621 (2022) 121798
due to their rapid solvent evaporation ability. However, the added
combined vibrational energy of the formed Taylor cone during the
electrospraying method increases this nucleation rate further (Patil
et al., 2017). Another primary advantage of this method over other
atomization-based methods discussed here is the higher yields achieved,
as particles are attracted to and collected on an inversely charged plate
(Patil et al., 2016; Patil et al., 2017; Rodrigues, 2018).
This method has shown an ability to produce various polymorphic
crystal forms (Padrela et al., 2019; Patil et al., 2016; Patil et al., 2017;
Patil et al., 2017; Al-Ani, 2020). Sharvil Patil (Patil et al., 2016; Patil
et al., 2017; Patil, 2018; Patil et al., 2018) first produced cocrystals by
this method in 2016, and demonstrated the ability of the method to
produce various polymorphic cocrystal forms (Patil et al., 2016). Patil
et al. aimed at the production of caffeine and maleic acid cocrystals.
Three polymorphic forms of this cocrystal exist, forms I and II of the 1:1
cocrystal, and form I of the 2:1 cocrystal. Solvents chosen for this system
were acetone, methanol, ethyl acetate and distilled water. It is less en­
ergy efficient to use water for such a process, as it has a relatively large
surface tension, requiring a high voltage of 20 kV for effective atomi­
zation. This high voltage was used for all other solvent systems. Despite
the reactant ratio in the feed solution (1:1 or 2:1), both forms I and II of
the 1:1 cocrystal formed when using solvents ethyl acetate and acetone.
Unlike methanol and water, ethyl acetate and acetone are aprotic sol­
vents lacking acidic hydrogen groups and thus, produced 1:1 cocrystals
as they could not act as hydrogen bond donors. When using water as the
solvent, the 2:1 cocrystal was produced. This may be attributed to the
stronger attractive forces of maleic acid with water, allowing for a more
predominant caffeine precipitation, resulting in the formation of 2:1
caffeine-maleic acid cocrystals. However, the volatility of the other
solvents compared with water may also play a role in this. The highly
volatile nature of methanol, acetone and ethyl acetate compared to
water may have influenced the generation of the 1:1 cocrystals as crystal
growth occurs much more rapidly in these volatile solvents (Patil et al.,
2016). Solvent choice with this cocrystal has been noted in the past
(Leyssens, 2012). Padrela et al. also highlighted the innate ability of the
electrospraying method to generate metastable cocrystal forms, unlike
other methods. Carbamazepine-saccharin cocrystals were produced by
various methods from either ethanol or methanol solutions. Solvent
evaporation from methanol produced the metastable form II of
carbamazepine-saccharin cocrystal, whilst the stable form I was pro­
duced from ethanol. This may be attributed to the lower boiling point of
methanol, allowing for a more rapid evaporation. Spray drying pro­
duced a mix of forms I and II from both solvents but the percentage of
form II present increased with the use of methanol, again attributed to a
lower boiling point and therefore accelerated evaporation (Padrela
et al., 2019). This was also aided by the larger droplets generally
Voltage Working FSOL T Particle size Reference
(kV) distance (cm) (ml/h) (◦ C) (μm)
20 25 2 – - (Patil et al.,
2016)
20 25 2 40 - (Patil et al.,
2017)
15 20 2 40 1–2.5 (Patil, 2018)
15 25 2 40 - (Patil et al.,
2018)
20 20 2.4 – 0.219–1.000 (Emami, 2018)
15 25 1.5 25 - (Solaimalai,
2019)
– 14 – – - (Padrela,
2019)
15
A. O’Sullivan et al.
observed in conventional spray drying allowing for polymorphic trans­
formation (Padrela et al., 2019; Halliwell, 2017). Supercritical nano
spray drying produced form I cocrystals only, whilst electrospraying
produced from II only (Padrela et al., 2019). This again shows the ability
of electrospraying over other established methods, to consistently pro­
duce pure metastable polymorphic forms of pharmaceutical cocrystals.
Emami et al. first investigated the production of nano-sized cocrys­
tals via the electrospraying method. The specific cocrystal systems
looked at include indomethacin with saccharin or nicotinamide, and
naproxen with nicotinamide or isonicotinamide. The electrospraying
method was successful in producing all of these cocrystals, except
indomethacin-nicotinamide which was found to be coamorphous
(Emami, 2018). This may be attributed to the rapid evaporation
observed in this method, coupled with the propensity for indomethacin
to form amorphous/metastable forms after electrospraying and other
rapid evaporation methods such as spray drying (Padrela et al., 2019;
Nyström et al., 2011; Karmwar, 2011). For all successfully produced
cocrystals by electrospraying, pure cocrystal powders were formed
regardless of whether the saturation conditions were congruent or
incongruent (Emami, 2018). Whether a solution is congruent or incon­
gruent is determined by the solubility of the cocrystal components at a
set temperature in a particular solvent, and the concentration of the
reactants at the eutectic point. A congruently formed cocrystal is ther­
modynamically stable and can be formed readily, whereas an incon­
gruently saturating system produces a less stable solid form due to solid-
state transformations (Alhalaweh and Velaga, 2010). Particle size was
also analysed in this study and the smallest cocrystal particles were that
of indomethacin-saccharin when processed with acetone. This may be in
part due to acetone possessing the lowest boiling point of all solvents
used in this study, allowing for rapid evaporation (Emami, 2018). Unlike
the needle-like micron-sized particles obtained from solvent evapora­
tion, the indomethacin-saccharin cocrystal produced by electrospraying
displayed a morphology dependent on the concentration of the initial
feed solution. At low concentrations (7.5 mg/ml), porous block-like
particles with a mean diameter of 219 nm were produced. Conversely
at higher concentrations (15 mg/ml), µm-sized needle-like particles
were produced along with 400 nm block-like particles. Two naproxen
cocrystals were also produced with nicotinamide and isonicotinamide
coformers, both of which displayed a plate/flake-like shape (Emami,
Fig. 4. SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis of the four primary atomization-based techniques utilized for cocrystal production (Karimi-
Jafari et al., 2018; Padrela, 2018; Emami, 2018; Emami, 2018).
16
International Journal of Pharmaceutics 621 (2022) 121798
2018).
The main advantage that the electrospraying and other atomization-
based methods display over other cocrystallization methods, which do
not include an atomization step, is their ability to atomize the feed so­
lution to control the particle size of cocrystals of both congruent and
incongruent systems, highlighting the power of this method, negating
the need to construct ternary phase diagrams (Emami, 2018). Fig. 4
below summarizes the strengths, weaknesses, opportunities and threats
of the four main atomization-based methods for cocrystal production.
3.4. Other methods
3.4.1. Spray flash evaporation
Spray flash evaporation is another drying/crystallization method
which has been sparsely investigated within the pharmaceutical sector
regarding cocrystal production but has been looked at extensively with
its use in the production of other substances such as explosive materials
(Huang, 2018; Li, 2015; Spitzer, 2014). In recent years, spray flash
evaporation has garnered attention for its potential for water desalina­
tion (Coty, 2020; Chen, 2018). Spray flash evaporation begins with the
heating and pressurization (using nitrogen) of the solution containing
the desired material. The solution is then sprayed through a heated
atomizer into the drying chamber, which is held at a pressure lower than
that saturation pressure of the solution. Flash evaporation occurs,
allowing the removal of the solvent as a vapor, as observed in Fig. 5
(Coty, 2020; Chen, 2018). This method has shown potential for the
production of nano-sized APIs such as crystals, cocrystals, and nano-
sized core shell structures (Coty, 2020). Spitzer et al. produced nano-
sized cocrystals for the first time using the spray flash evaporation
method. 2:1 cocrystals of caffeine and oxalic acid, were produced along
with 1:1 cocrystals of caffeine and glutaric acid. Acetone solutions of
cocrystal components were prepared in a low boiling solvent as
required. The solution was atomized at a pressure of 4.0 – 6.0 MPa
through a heated hollow-cone atomizer into a 0.5 MPa atomization
chamber. The sharp and sudden pressure drop produced a thermody­
namically unstable solution which regained its stability through the
conversion of excess energy into latent energy, causing accelerated
evaporation. A coupled temperature drop prevented the growth of the
produced cocrystals. PXRD confirmed cocrystal production and all mean
A. O’Sullivan et al.
Fig. 5. Illustration describing the mechanisms of solvent removal in spray-freeze drying, spray congealing and spray flash evaporation.
particle sizes were found to be in the nano-size range, with caffeine-
glutaric acid cocrystals displaying a mean particle size of 111 nm
(Spitzer, 2014). Unfortunately, no particle size measurements were re­
ported for the caffeine-oxalic acid cocrystal (Ghosh, 2020).
3.4.2. Spray congealing
Spray congealing, also described as spray cooling or spray chilling, is
a technique which combines aspects of spray drying technology with hot
melt extrusion and can be tailored to be both a scalable and ‘green’
method for pharmaceutical particle engineering (Albertini, 2008). With
the purpose of cocrystallization, this process begins by homogenously
mixing the API and coformer in a heated vessel to produce a molten feed
solution. This solution enters a jacketed feed line and is atomized
through a heated nozzle (Duarte, 2016). Typically rotary atomizers are
utilized in spray congealing but these generate a wide spray and, as a
result, a wide drying/evaporation chamber is required (Albertini, 2008).
A cooled gas, typically nitrogen, is used to solidify the atomized molten
feed and, similarly to spray drying, can be carried out in a co-current or
counter-current configuration. A cyclone, filter or other capture mech­
anisms can be utilized for the separation of the solid particles from the
off gas (Duarte, 2016). The first and only reported paper on the pro­
duction of cocrystals by spray congealing was carried out by Duarte et al.
as a solvent free approach. These authors investigated the production of
two caffeine cocrystals, with glutaric acid and salicylic acid as coform­
ers, as well as the carbamazepine-nicotinamide cocrystal. Melting
occurred within a mixed, heated vessel until the total 30 g of API and
coformer melted. A jacketed two-fluid nozzle was utilized for the at­
omization of the molten feed mixture and nitrogen was utilized for
droplet solidification in a co-current mode. Inlet and outlet temperatures
varied depending on the nature of the reactants within the feed melt.
The caffeine-salicylic acid and carbamazepine-nicotinamide cocrystals
were utilized to determine the feasibility of the process to produce
pharmaceutical cocrystals, and their presence was confirmed by PXRD
and DSC. Mean particle sizes of the caffeine and carbamazepine coc­
rystals were 13.59 μm and 31.56 μm, respectively, and were composed
of agglomerates of needle-like cocrystal particles. Inlet temperature
influenced the drying capacity of the method to produce fully dried
caffeine-glutaric acid cocrystals, whilst atmospheric pressure influenced
the final particle size. It was noted that larger molten droplets (and thus
larger final particles) led to the production of higher amounts of reactant
impurities in the final formulations, most likely due to an inefficient
cooling stage (Duarte, 2016). It can be hypothesized that with further
variation of process variables, an increase in purity levels might be
achieved by a decrease in particle size. Nevertheless, this study
demonstrated the ability to produce pure cocrystal formulations with a
reduced particle size by the solvent -free spray congealing method.
17
International Journal of Pharmaceutics 621 (2022) 121798
3.4.3. Spray-freeze drying
Spray-freeze drying is a combination of the atomization ability of
spray drying coupled with the sublimination drying process seen in
lyophilization. This is a method which is capable of producing porous
particles at a reduced temperature, as compared to spray drying and
spray congealing, making it suitable for thermolabile molecules and
biomolecules (Tanaka, 2020; Eddleston, 2013). A general process flow
for spray-freeze drying begins with the atomization of a feed solution
directly into a source held at a reduced temperature. Liquid nitrogen is
commonly utilized for this. In the case of cocrystal production, this
produces frozen droplets of API, coformer and solvent. A freeze dryer is
then utilized to sublime the solvent by reducing the pressure below the
solvents’ triple points and by applying a gentle heat. This typically
generates a dried, porous and partially amorphous product (Tanaka,
2020; Eddleston, 2013). To the best of our knowledge, Tanaka et al. is
the only researcher who has published work on cocrystallization by
spray-freeze drying. The aim of that study was to produce 2:1 cocrystals
of theophylline and oxalic acid for use as inhalable therapeutics, with an
increased stability within humid environments during storage or in the
lungs themselves. Water was utilized as the solvent and a 2-fluid nozzle
carried out atomization. Spray dried cocrystals were utilized as a means
of comparison and the median particle size determined by SEM images
was not statistically different between the two processes (7.00–7.20
µm). However, due to the more porous structure of the spray freeze dried
samples, mass median aerodynamic diameter (MMAD) was smaller in
spray-freeze dried samples than in spray dried samples, 3.03 μm and
3.46 μm respectively. However, all powders produced by spray-freeze
drying had a lower level of crystallinity than that of spray dried pow­
ders due to hygroscopicity, but cocrystallization itself overcomes this
negative effect by reducing moisture absorption. This allows for greater
control of surface hygroscopicity and good pulmonary delivery. The
cocrystals displayed increased stability under high humidity conditions
in comparison to the API. The freeze-drying stage of the process allowed
for the formation of hydrogen bonds between theophylline and oxalic
acid which prevented the formation of a theophylline monohydrate
form. Oxalic acid is preferred to water molecules as the molecular dis­
tance as well as the energies for reaction are lower during cocrystal
formation rather than hydration, thus the cocrystal is hydroscopically
more stable (Tanaka, 2020). Although spray drying is a more robust
process with the ability to utilize various solvents and produce particles
with higher levels of crystallinity, spray-freeze drying allows for the
production of porous particles with improved aerodynamic properties
and a reduced MMAD.
3.5. Comparison of production methods
Carbamazepine-saccharin cocrystal
A. O’Sullivan et al.
The polymorphic carbamazepine-saccharin cocrystal has been pro­
duced using various techniques, including atomization-based methods
mentioned in this review. Padrela et al. reported polymorphic control of
this cocrystal through the use of several techniques, namely electro­
spraying, supercritical CO2 nano spray drying, and conventional spray
drying, as well as different solvents (Padrela et al., 2019). Prior to this,
Cuadra et al. also produced forms I and II of this cocrystal using the
supercritical antisolvent (SAS) method (Cuadra, 2018). Cuadra found it
possible to utilize the SAS method to produce pure cocrystal form I using
methanol as the solvent at 40 ◦ C, whilst a mixture of forms I and II was
obtained at 60 ◦ C, or while employing ethanol or DMSO as the solvent.
The author speculated that changes in temperature and solvent system
affected the ternary phase diagram leading to variations in polymorphic
outcome (Cuadra, 2018). Padrela et al. found solvent selection to have a
negligible effect on polymorphic outcome. Conventional spray drying
was incapable of producing a pure polymorphic product, but the use of
methanol favoured the production of the metastable form II. Due to the
relatively large droplets produced during this method, solvent mediated
polymorphic transformation may occur leading to mixtures of poly­
morphs. Supercritical CO2 nano spray drying produced form I only,
regardless of the solvent employed. This may have been caused by
several mechanisms within this technique; the antisolvent/spray
enhancer role favouring form I, or form I nuclei segregation by nano­
confinement, or accelerated transformation of form II to I by the rapid
drying process. Opposing to this, electrospraying produced the meta­
stable form II of the cocrystal, regardless of solvent choice, possibly due
to an electrocaloric effect (Padrela et al., 2019).
Both studies found that the stable form I displayed a plate like
morphology whilst form II displayed a needle like morphology, but
neither study reported any particle sizes. However, from SEM images
seen in Fig. 6, it appears as though the cocrystals produced by Padrela
Fig. 6. SEM images of the carbamazepine-saccharin cocrystal produced by electrospraying (form II) (A), supercritical nano spray-drying (SASD/SEA) (form I) (B),
conventional spray drying (form I and II) (C) (reproduced with permissions (Padrela, 2019) and the supercritical antisolvent (SAS) method (form I) (D) (reproduced
with permission (Cuadra, 2018).
18
International Journal of Pharmaceutics 621 (2022) 121798
et al. are smaller than that produced by SAS. Supercritical CO2 nano
spray drying appears to have generated the smallest particles due to
drying aided by both antisolvent and thermal means (Cuadra, 2018;
Padrela et al., 2019).
Indomethacin-saccharin cocrystal
The indomethacin-saccharin cocrystal has been produced by several
methods, including several supercritical atomization-based methods,
namely SAS, AAS (Padrela et al., 2009) and SEA (Padrela et al., 2010).
All three methods were successful in producing the pure cocrystal,
regardless of the mechanism of nucleation/crystal growth/solvent
removal. The SAS and AAS processes reported no major differences in
product composition or particle size with variations in processing con­
ditions, while no variations were seen in the studying employing the SEA
method (Padrela et al., 2009; Padrela et al., 2010).
The resulting particle sizes for SEA produced cocrystal seen in
Fig. 7C, was between 0.3 and 10 μm and were seen as granular and
lightly agglomerated. AAS produced cocrystal particles displayed a
spherical to granular morphology with a particle size between 0.5 and
0.7 μm. The SAS particles however displayed a more elongated shape
with similar particle sizes to those seen in AAS. Overall, the AAS and SAS
methods produced slightly smaller particle sizes, with the AAS method
displaying a more uniform particle size. The CSS method was unsuc­
cessful in producing the cocrystal effectively as the reactants are poorly
soluble within the SCF. For this reason, most experimental conditions
produced little to no cocrystal using the CSS method. Cocrystal particles
that were produced by this method (seen in Fig. 7D) were large and
agglomerated, with some particles exceeding 100 μm in length. The
unsuccessfulness of this method can be attributed to the reactants lack of
solubility within the SCF, and the exclusion of an atomization step (or
any other mechanical micronization mechanism) (Padrela et al., 2009).
A. O’Sullivan et al.
Fig. 7. SEM images of the Indomethacin-Saccharin cocrystal produced by the SAS method (A), AAS method (B) (reproduced with permission (Padrela, 2009), the
SEA method (C) (reproduced with permission (Padrela, 2010) and CSS method (D) (reproduced with permission (Padrela, 2009).
4. Practical considerations
4.1. Regulatory guidelines
Due to the acceleration of scientific and medical research, it can be
challenging to effectively introduce regulatory guidelines and proced­
ures for the continuously expanding list of emerging pharmaceutical
technologies, and for new chemical entities as medicines. As a result,
novel technologies may impact and slow down the pace of the regulatory
approval process, intended to introduce new therapies and medicines for
patients in a safe manner. In the case of pharmaceutical cocrystals, these
delays and obstacles were almost magnified to the point that it may not
be a cost-effective opportunity to pursue this type of drug systems. As
the popularity of publications and patents began to rise (as described in
Fig. 2), the FDA published a draft guidance document on the regulatory
classification of cocrystals in 2011. This draft was followed by the
release of the full guidance document in 2013, describing cocrystals as
crystalline solids at room temperature composed of two or more mole­
cules within a crystal lattice. The document recognised the reported
similarities between cocrystals, polymorphs and salts, but from a regu­
latory perspective it described pharmaceutical cocrystals as drug prod­
uct intermediates which are to be made subject to additional
regulations. This unattractive guidance document led to a plateau in the
progress of cocrystals in the literature and made them undesirable to the
pharmaceutical industry (Brittain, 2013; FDA, Draft, 2011). In 2015, the
European Medicines Agency (EMA) published a reflective paper
regarding the guidelines towards the use and regulation of cocrystals.
The EMA described cocrystals as “single phase crystalline structures
made up of two or more components in a definite stoichiometric ratio
where the arrangement in the crystal lattice is not based on ionic bonds”
and highlighted that cocrystal components may be neutral or ionized
(which is discussed in section 2 by molecular and ionic cocrystals). The
EMA however, outlined a different definition/explanation for pharma­
ceutical cocrystals. They stated that an abridged application may be
utilized for cocrystals, which states that they are bioequivalents of an
already approved API. This was justified by the similarity between
19
International Journal of Pharmaceutics 621 (2022) 121798
cocrystals and salts when administered orally, in that both substances
dissociate, releasing the API. Therefore, cocrystals may follow an
approval route based on EU Directives 2001/82/EC Article 13(2)(b) and
2001/83/EC Article 10(2)(b) stating that bioequivalence may be
demonstrated by appropriate bioavailability studies. Cocrystals which
are not administered orally may also fall under this regulatory approval
route providing there are no differences in safety or efficacy and
appropriate API dissociation is observed. This document also states that
the use of a coformer never before used in a medicinal product, will
require additional documentation similar to that required for the use of a
new excipient which is considered to be minor, relative to the process for
a new chemical entity (NCE) (EMA., 2015).
The FDA published a new draft guidance document on the regulatory
classification of cocrystals in 2016, followed by the publication of the
final document in 2018. The newest version of this guidance document
(published in 2018) reported that the pharmaceutical cocrystal approval
route will be similar to that of a new API polymorph, and will not be
regarded as a new API or a drug product intermediate (FDA., 2018). For
pharmaceutical cocrystal approval pathways, two possibilities exist with
cocrystals; the new drug application (NDA) pathway (505(b)(2)), and
the abbreviated new drug application (ANDA) pathway (505(j)). The
NDA route is applicable towards cocrystals whose API molecules are not
already a reference listed drug (RLD), which has been the case with
many cocrystals in the market, and thus must contain full reports on the
safety and efficacy of the drug products. However, if the API molecule
within the cocrystal is a previously approved drug (RLD), it may gain
approval through the ANDA route, as API polymorphs do. This approval
route focuses on providing evidence that the drug product in question is
the same as the RLD regarding administration, dosage, strength and
conditions of use (FDA., 2018; Research, C.f.D.E.a.2017). For example,
Mayzent, the most recently approved pharmaceutical cocrystal, fol­
lowed the NDA approval route as its active ingredient was never
approved as a standalone drug product (Unger, 2019).
A. O’Sullivan et al.
4.2. Quality attributes
In order to determine without doubt that a substance is a cocrystal or
not, for example, a salt, several assumptions listed in the FDAs guidance
document on cocrystal classification must be proved (FDA., 2018):
• Evidence must be provided to ensure both API and coformer are
present within a single unit cell.
• It must be demonstrated that “substantial dissociation” (FDA., 2018)
of API and coformer must occur prior to API interaction and arrival at
the site of pharmacological activity.
• Either ΔpKa values or spectroscopic tool must be used to demonstrate
the production of a cocrystal rather than a salt. If a ΔpKa value < 1 is
achieved, this is sufficient evidence to demonstrate cocrystal
production.
Critical quality attributes of nanocrystals and nano-cocrystals may
differ. Nanocrystals may be designed to follow one of two paths in vivo:
solid particle uptake into cells, and fast dissolution allowing for drug
absorption. Due to the nature of cocrystals and their primary function­
ality generally aiming at improving solubilities, nano-cocrystals follow
the latter path and thus, a set quantity of quality attributes must be
assessed. These include particle size, particle size distribution, and
particle shape and morphology, as well as product compositions and
solid-state properties. Solid state analysis can be carried out by processes
such as powdered X-ray diffraction (PXRD), differential scanning calo­
rimetry (DSC) nuclear magnetic resonance (NMR). Particle size and
shape, which may influence drug solubility, can be examined by dy­
namic light scattering (DLS), and various imaging-based techniques,
whilst surface characteristics can be determined by particle zeta po­
tential. Many of these techniques and more will need to be included in
the production of pharmaceutical cocrystals to ensure reproducible
products with predictable characteristics such as solubility, perme­
ability, and others (Peltonen, 2018).
5. Conclusions
The production of cocrystals has time and time again proved to
effectively improve various physiochemical properties of API molecules
and the field has continued to expand every year over the last decade.
The introduction of a nano-sizing step such as atomization further en­
hances these physiochemical profiles, such as dissolution rates, solubi­
lity, tabletability and permeability. Different atomization-based
methods have proven effective in producing these nano-cocrystals with
each method displaying its own advantages and disadvantages. Super­
critical fluid-based methods offer a green alternative to more conven­
tional methods, such as conventional spray drying, for the production of
nano-sized cocrystals with more narrow particle size distributions than
its conventional counterpart. However, these methods are most effective
for the removal of miscible organic solvents such as methanol and
ethanol and encounter issues regarding aqueous solvents. Solvent-based
SCF methods heavily rely on the solubility of the cocrystal reactants in
the SCF, which is a constraint in these methods. Although conventional
spray drying typically produces larger micron-sized particles, it has been
employed in the pharmaceutical industry for several years and is a much
more established method, which implies that the industry possesses a
better understanding of the intricacies of this method and may favour it
over novel methodologies. Other methods such as spray freeze drying,
spray congealing and spray flash evaporation have been sparingly
employed for cocrystal production but have nevertheless demonstrated
advantages over other methods. Spray congealing offers a green alter­
native to other methods as it does not require an aqueous or organic
phase. This method, however, requires that the API and coformer be
stable at the high temperatures employed. Spray-freeze drying offers
lower temperatures suitable for thermolabile compounds, particularly
biological samples, but has been shown to produce larger particle sizes
20
International Journal of Pharmaceutics 621 (2022) 121798
and particle size distributions adversely affecting the solubility profile of
an API. However, this method adversely introduces various stresses such
as dehydration, shear stresses during atomization, and freezing and
thawing stresses. Spray flash evaporation is a rapid and continuous
technique suitable for thermolabile materials, however it requires that
the reactants are both soluble in a low boiling solvent. The field of
pharmaceutical cocrystals has been increasing every year through pat­
ents and publications, but the recent updated definition of a cocrystal by
the FDA in 2018 (see section 4.1) has incentivized pharmaceutical
companies to explore the possibility of generating new cocrystals and
introduce a more competitive environment with the ability for quasi-
generic versions of the API, in the form of cocrystals, to be created.
This new level of competition may be considered as a threat to inno­
vative pharmaceutical companies, as it may prove difficult to argue
infringement of a crystal form patent if a cocrystal is produced instead. It
may also serve as an opportunity for these companies to thoroughly
consider all possible forms prior to a new drug filing, increasing the
degree of scrutiny required by these companies.
CRediT authorship contribution statement
Aaron O’Sullivan: Conceptualization, Writing – original draft.
Barry Long: Conceptualization, writing - review & editing. Vivek
Verma: Conceptualization, writing - review & editing. Kevin M. Ryan:
Supervision, writing - review & editing. Luis Padrela: Conceptualiza­
tion, Supervision, writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The authors acknowledge Science Foundation Ireland (SFI) for sup­
porting the work undertaken as part of the SFI frontiers project (grant
19/FFP/6896), at the SSPC Research Centre (Grant 12/RC/2275_P2),
and the financial support provided by Enterprise Ireland (grant CF2017-
0754-P).
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