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2.4. Penapisan
termal Beberapa metode termal untuk penapisan cocrystal telah diadaptasi dari penapisan
polimorf. Dua metode yang paling umum untuk penyaringan termal dari potensi kristal adalah
melalui pengamatan selama pencairan biner oleh HSM dan dengan mempelajari perilaku fase
dua komponen menggunakan DSC. Dengan metode ini, campuran fisik dari dua komponen
pembentuk kokristal potensial ditempatkan di dalam DSC, di mana mereka dipanaskan di luar
titik eutektik mereka. If cocrystallization is possible then an endothermic peak associated with
the eutectic melting will be observed. This will be immediately followed by an exothermic peak
indicating that full or partial cocrystallization has taken place, between the two components.
Another endothermic point will then be observed which should correspond with the cocrystals
melting point. In contrast, if the cocrystallization is not possible between the two components,
then an endothermic peak indicating the eutectic melting is observed which may be
accompanied by further peaks indicating the melt or degradation points of the individual
compounds [54,55]. This technique was first demonstrated by Lu et al. where DSC was used
to screen twenty possible cocrystal forming systems. Sixteen cocrystals were formed, including
nine previously undiscovered, demonstrating the DSCs potential for cocrystal screening [56].
This method of experimental screening is popular as it does not require the time-consuming
work of solubility determination and is considered green technology due to the absent of
organic solvents [15].
More recently, Shayanfar and Jouyban expanded upon Lu et al. work, assessing the feasibility
of the thermal screening via the DSC approach to screen for cocrystals of ketoconazole. Here,
binary mixtures of ketoconazole and either nicotinamide or 4-amino benzoic acid coformers
were prepared and heated in the DSC to confirm cocrystal formation [57]. Using the rules
outlined by Lu et al., (ie the presence of two endothermic events for the eutectic and melting
point and one exothermic event immediately following the eutectic melt) it was evident that
cocrystallization between ketoconazole and 4-amino benzoic acid was possible. A 2:1 mixture
of ketoconazole and 4-amino benzoic acid was then scaled-up via solvent evaporation,
producing the cocrystal in larger quantities. The DSC approach was further explored by Surov
et al. in a study comparing four different cocrystal screening techniques in the development of
bicalutamide cocrystals [58]. Here 1:1 mixtures of bicalutamide and one of eight
pharmaceutically acceptable coformers were prepared and screened using DSC, LAG, slurry
sonication and solution crystallization. Though the study noted the DSC method to be the most
“simple and rapid” method of cocrystal screening, using this approach it was only possible to
identify one potential cocrystal of bicalutamide (1:1 bicalutamide-salicylamide cocrystal). The
resulting thermograms for the bicalutamide-salicylamide cocrystal contained the characteristic
exothermic event indicative of cocrystal formation, confirming that cocrystallization was
possible. For the other systems tested, on such exothermic event was present, however the
presence of only one peak does not imply that no cocrystal is formed as it is possible for the
peaks to overlap, thus the other systems cannot be discounted on the basis of a DSC screen
alone [53, 54]. This was confirmed after all three alternative screening techniques revealed the
successful cocrystallization of a second cocrystal system of bicalutamide and benzamide (1:1),
as well as the bicalutamide-salicylamide cocrystal. It was summarized that DSC screening,
while quick and efficient, cannot be used to screen for cocrystals in isolation.
However, in a comparative study by Manin et al., DSC was found to be the most effective
thermal screening method when combined with HSM [59]. The utilization of HSM is desirable
as it allows the interpretation of any ambiguous results, such as in cases where melting points
may overlap [60]. It is also possible to combine DSC with Fourier-transform infrared
spectroscopy to establish the correlation between the thermal response and the structural
changes of the sample [61]. Mohammad et al. have proposed a combined Hansen solubility
parameter (HSP) and DSC as a useful and effective cocrystal screening approach to short list
potential coformers prior to complex laboratory screening experiments [62]. With the HSP
process, the miscibility of cocrystal constituents are predicted using their respective solubility
parameters to assess the likelihood of cocrystal formation. If the solubility difference of an API
and coformer are less than seven, then they are considered miscible and likely to form a
cocrystal. In this study, the miscibility of indomethacin and 33 different coformers were
calculated using HSP. In this instance, all but one of the API-coformer pairs predicted to be
miscible were confirmed to be so, with all miscible API-coformer pairs forming indomethacin
A technique known as the Kofler contact method utilizes HSM to give a clearer indication of
whether or not cocrystallization has occurred. Here, the cocrystal components which displays
the higher melting point is heated up to that point and melted, before being allowed to solidify.
Meanwhile the cocrystal component with the lower melting point is heated to melting and then
placed in contact with the other solidified component. At this point the component with the
higher melting point is dissolved in the liquid component, creating a mixing zone where the
sample is quenched and recrystallized. This sample is then placed under glass slides alongside
two pure samples of the two cocrystal constituents and heated once again to its melting point
with the two pure samples, under a HSM equipped with a polarizer. Using the HSM equipment,
one can view the newly formed cocrystal alongside the two constituents. The cocrystal will
retain birefringence, allowing it to be distinguishable from the eutectic phase and from the pure
samples, giving a clear indicator of whether cocrystallization was successful [53]. This
technique was successfully demonstrated by Berry et al. who employed the Kofler contact
method to probe the binary phase behaviour of nicotinamide with seven different APIs. Though
three of the systems were failures (owing to incompatible hydrogen bonding and steric
hindrance) three new cocrystal systems were identified (with flurbiprofen, ketoprofen and
salicylic acid) and their structures determined [60].
An alternative approach to thermal screening involves measuring the saturation temperatures
of the cocrystal constituents to predict whether crystallization is possible. This technique was
first demonstrated by Ter Horst et al. who used this method to screen for new cocrystal forms
of carbamazepine and cinnamic acid with a variety of coformers, successfully identifying 4
new cocrystals of carbamazepine (with isonicotinamide, nicotinamide, benzamide and
3nitrobenzamide) and two cocrystals of cinnamic acid with (isonicotinamide and
3nitrobenzamide) [63]. The cocrystal is more stable than the two individual components
meaning, that in an appropriate solvent, the cocrystals solubility will be lower than either
component. Therefore, cocrystallization should be achieved once the product of the component
concentrations exceeds a set value at a constant temperature. Using Ter Horst's approach, by
measuring saturation temperature at a composition which correlates to saturation with respect
to both components at a reference temperature, it is possible to asses if cocrystallization has
occurred if the measured saturation temperature is more than 10˚C higher than the reference.
2.5. Slurry screening
Slurry based techniques have been adapted from polymorph screening, and proved an effective
method when screening for cocrystals. In this method, the API will be added to the mixture,
with cocrystallization taking place at the point where the concentration of the constituents is
above the critical activity of the coformer. In the slurry method, the cocrystals constituents are
suspended in a solvent where partial dissolution occurs, resulting in activity values of one for
both components. This means the slurry activity is greater than the critical coformer activity
required for cocrystallization. When allowed sufficient time and mobility, nucleation will
occur, causing the API and coformers to convert to the cocrystal via solution-mediated phase
transformation, until either of the component activities decrease to the critical value [64,65].
In the first instance of large scale screening using a slurry based method, Zhang et al. slurried
known stoichiometry of 16 known API-coformer systems for periods varying between twelve
hours to eight days [66]. The stoichiometry tested were either 2:1 or 1:1 of 10 different API
including caffeine, cis-itraconazole, trimethoprim, sulfamethazine, carbamazepine, aspirin,
piroxicam and flurbiprofen were mixed with twelve different coformers including
nicotinamide, saccharin and other common acid based coformers. Different solvents utilized in
the slurry include, acetonitrile, cyclohexane, methylene chloride and n-heptane. In addition to
producing known cocrystals for thirteen of the systems tested, two new solvated structures were
reported for 1:1 trimethoprim-sulfamethoxypyridazine cocrystals, using acetonitrile and
methylene chloride. Furthermore, new unsolvated structures for 2:1 ibuprofen-nicotinamide
and 1:1 aspirin- 4,4′-dipyridyl were reported.
In a more recent study, Bučar et al. screened for new cocrystals of theophylline using
solutionmediated phase transformation using nine different (di)-hydroxybenzoic acids as
coformers as part of an extended study to establish synthon hierarchies in cocrystals with
multiple hydrogenbonding functional groups [67]. The screening revealed eight new cocrystals
of theophylline as well as the formation of a salt. In another instance, new cocrystal structures
were reported for stanolone and mestanolone after extensive screening via slurry crystallization
with eleven different pharmaceutically acceptable coformers. Two new cocrystal forms were
reported; stanolone-L-tartaric acid (1:1) and mestanolone-salicylic acid (1:1) [68]. The method
has also been used to identify nine new cocrystals of caffeine with different carboxylic acid
based coformers [69].
A slightly different approach, first reported by Rodríguez-Hornedo et al. involves using
nonstoichiometric solution compositions to achieve supersaturation of cocrystals in solvents
where the cocrystal components have non-equivalent solubilities. This is known as the reaction
crystallisation approach [65]. If the cocrystal constituents do not have similar solubilities there
is a chance that the evaporation of the equimolar solution will result in a single component
crystal as opposed to the cocrystal, due to supersaturation being generated with respect to less
soluble reactant. Using this approach one of the cocrystal formers is added to a saturated
solution of the other component, allowing the solution to become super saturated with respect
to the cocrystal form. Childs et al. expanded upon this work, successfully employing reaction
crystallization by adding carbamazepine to saturated solutions of 18 different coformers in one
of four separate solvents (water, ethanol, acetonitrile or ethyl acetate), leading to the
identification of 27 unique solid forms [70].
2.6. Mechanochemical grinding based screening
The mechanochemical grinding approach to screening for cocrystals is essentially the same as
described for salts. This approach uses kinetic energy to incite cocrystallization by
mechanically grinding the cocrystal components at various speeds usually by either manual
grinding or through a ball milling process. The ball milling technique induces cocrystallization
through particle size reduction via impact with numerus steel balls, when the components are
loaded alongside the steel balls into a rotating chamber. As with salt screening, the process can
be either neat grinding or LAG. This technique provides innate advantages over more
traditional solution based methods of having lower costs and lesser waste than solution based
methods; dissolution of the cocrystal constituents is not required, removing any issues relating
to solubility differences between API and coformer; and there is a reduced chance of the solvent
interacting with the API, disturbing solute-solute interaction (this drawback is removed
completely using neat grinding methods) [71].
In an early example, Friščić et al. [72] demonstrated the effectiveness of mechanochemical
grinding compared to solution methods in screening for ternary cocrystals of caffeine and
succinic acid (1:1). Screening was done by adding a diverse range of 25 potential 'guest'
compounds alongside the caffeine: succinic acid cocrystal and ball milling for 20 minutes and
liquid assisted experiments, acetonitrile was also added. This was performed alongside
traditional solution based methods. Out of 25 potential hits, only four cocrystals were found
using the solution based methods compared to the 16 cocrystals found in the neat grinding
studies and 18 in the LAG studies, demonstrating the potential of mechanochemical grinding.
In a more recent study, Heiden et al [73] used both neat grinding and LAG via ball milling to
successfully screen for cocrystals of theophylline-benzoic acid (1:1).
Recently, LAG has proven the more popular method, due to the higher success rate of the
method compare to neat grinding. This was demonstrated by Friščić et al. in a comparative
study of the neat and LAG [74]. Out of four known cocrystal structures tested only one,
theophylline-L-malic cocrystal, was successfully obtained using neat grinding methods while
LAG was able to produce all four targeted structures. Furthermore, the theophylline-L-malic
cocrystals produced via LAG were found to have a greater degree of crystallinity compared to
their neat grinding produced counterparts after x-ray powder diffraction (XRPD) analysis. LAG
has also been shown to be the preferable method when screening for cocrystal hydrates. In one
study, neat grinding was performed with the hydrated and anhydrous forms of theophylline and
caffeine API with citric acid coformers. The same was carried out using a LAG with a water
solvent. Ultimately, hydrated cocrystals were possible between the theophylline and citric acid,
but the same cannot be said of the caffeine, which only provides an anhydrous cocrystals with
citric acid, even when both reactants are crystalline hydrates. Cocrystal hydrates of both API
were achievable via LAG suggesting it is the more efficient method of screening for cocrystal
hydrates [75]. Nevertheless, for extensive screening purposes, both methods of screening
should be employed as some cocrystals forms may be exclusively obtainable through neat
methods. One such case was presented by Imai et al. who reported the synthesis of a bis-βnapthol- benzoquinone (1:1.5), which is not obtainable through solution methods [76].
One drawback of this method is that it is time-consuming due to the need to grind coformers
with the drug individually. Yamamoto el al. overcame this issue through development of a
“cocrystal cocktail method” where up to four coformers of similar moieties could be co-ground
with the drug via ball milling [77]. This is a synthon-oriented screening method where multiple
forms of different API-coformer pairs can be identified at once and have their bonding
hierarchy's easily classified. The cocrystal cocktail method was found to reduce the workload
by half. A slightly different approach was employed by Li et al. who combined neat grinding
with conventional solution screening methods for greater screening diversity [78]. In the first
stage of screening, up to 25 coformers were ground alongside glutaric acid API in a ball mill
for 20 minutes. The resulting solids were analysed through DSC and XRPD and any trace
amount of a new peak or diffraction pattern respectively was treated as a 'lead'. These leads
were then followed up in a solvent based screen to assess the developability of the cocrystals.
Using this method five new cocrystals were identified as potential cocrystal candidates for
pharmaceutical development within a significantly smaller timeframe. Another approach,
which combines both neat and liquid assisted grinding, saw carbamazepine co-ground with a
diverse number of coformers via mortar and pestle in the initial stage [79]. If a partial
conversion was observed, then a liquid-assisted method through ball milling was employed.
Here, carbamazepine was co-processed with eight different coformers using eight different
solvents and results were compared to cocrystals produced through solution growth. Results
demonstrated that all cocrystals prepared via solution growth were reproducible through the
more cost-effective, environmentally friendly grinding method. Different stoichiometries,
grinding times and rates are variables that can result in different crystals forms in neat grinding
experiments. With LAG, the variety in solvents can provide great diversity in the crystal forms
produced. In the previously mentioned study it was found that dimethylformamide (DMF) and
dimethylsulfoxide (DMSO) provided greater crystallization space which led to a greater
number of cocrystals [79]. Friščić et al. have concluded that the cocrystal formation in liquid
assisted methods is dictated by saturation levels of reactants rather than the type of the process
2.7 Translational development of pharmaceutical cocrystals
The last two decades research and development on pharmaceutical cocrystals has gained
momentum both in industry and academia leading to enhanced scientific understanding,
expansion in intellectual property landscape and evolution of regulatory guidelines [81,82].
According to Kale et al. selecting appropriate formulation and process design together with
understanding material properties during preformulation stage can mitigate the challenges in
the translational development of pharmaceutical cocrystals [81]. Currently, there are two
cocrystal-based products on the market and more in development (Table 1).
Table 1. Cocrystals in clinical development and market.
oxalateoxalic acid
(Lexapro®, Lundbeck)
Cocrystal of a salt which is a
selective serotonin reuptake
inhibitor for the treatment of
Marketed (2009)
Multidrug cocrystal for the
treatment of symptomatic chronic
heart failure and reduced ejection
fraction in adult patients
Marketed (2015)
ErtuglifozinLpyroglutamic acid (1:1) Cocrystal for the prevention of
hyperglycaemia in type-2 diabetes
trials [81,82]
(Phase III)
(Phase II)
Multidrug cocrystal for acute
postoperative pain
Cocrystal developed for the
potential treatment of rheumatoid
arthritis containing a tyrosine
kinase inhibitor
(Phase I)
3. Phase diagrams and cocrystallization
Phase diagrams are often considered the method of choice for depicting the thermodynamic
relationships between cocrystals and their individual components (API and coformer). They
can be used as tools towards the more efficient cocrystal search (ie selection of coformer or
solvent) and the prediction of the most suitable preparation method [85]. The phase diagrams
that have been used to depict the phase behaviour of crystallizing systems can be classified in
three types: i) binary phase diagrams, ii) phase solubility diagrams and iii) ternary phase
i) Binary phase diagrams (BPDs)
BPDs of an API and a coformer provide information on the thermal stability of the cocrystal
system and on whether the interaction of the two components is strong enough to generate a
thermodynamically stable cocrystal [85]. BPDs are temperature-composition maps which
indicate the equilibrium phases present at a given temperature and composition of API and
coformer (Fig. 2, [86]). Yamashita et al. reported the use of a small-scale and high-throughput
screening method for cocrystals and salts based on BPDs using thermal analysis (ie DSC) alone
or in tandem with X-ray analysis [55]. Despite their usefulness in thermal screening methods,
BPDs do not take into account the presence of the solvent and thus provide little information
regarding solution based crystallization methods.
With solution based methods for the preparation of cocrystals the solvent acts as a catalyst
reducing the activation energy barrier of the cocrystallization influencing the kinetics, but not
the thermodynamics, of the transformation [87]. An exception to this is when the solvent
becomes a part of the crystal structure, as seen in the case of solvates. Thus, in solution based
crystallization methods the solvent can be considered as the third component of a ternary
system. Phase solubility diagrams and ternary phase diagrams are the most commonly used
types of graphical representation for a ternary system depicting the solubility and stability of
cocrystals in solution [88–90].
ii) Phase solubility diagrams (PSDs)
PSDs display the solution concentration at equilibrium with the solid phase. Particularly for
cocrystals a PSD shows the solubility curve of the API, coformer and cocrystal phases as a
function of solution concentration of the drug or the coformer expressed as molarity [70].
Therefore, a PSD provides information regarding the stability of different solid phases. A
representative phase solubility diagram for indomethacin-saccharin (1:1) cocrystal in ethyl
acetate is given in Fig. 3.
Fig. 3 shows that the cocrystal solubility decreases non-linearly with increasing coformer
concentration, an analogous effect of the common ions on the solubility of sparingly soluble
salts [88,91]. Moreover, as it is depicted in Fig. 3, the cocrystal exhibits lower solubility
compared to the drug in region IV, indicating that only cocrystals are supersaturated in this
region. Such a knowledge is of paramount importance regarding the scaling-up of the process,
as conditions should be carefully selected to ensure that the crystallisation is conducted in
region IV in order to isolate the pure cocrystal [91].
Nehm et al. derived a mathematical model to describe the solubility behaviour of the cocrystals
as a function of cocrystal component concentration in solution by considering the solubility
product (Ksp) and solution complexation constants (K11 and K12) for 1:1 and 1:2 complexes of
cocrystal components formed in solution [88]. After successful application of the model to the
PSD of carbamazepine-nicotinamide (1:1) cocrystals in various solvents, it was concluded that
solubility product and solution complexation constants explain the PSDs of the cocrystals.
Currently, adaptation of the mathematical models has been applied in a few studies and together
with determination of other parameters such as the eutectic constants (Keu) can be useful
diagnostic tools for the screening and scaling-up of pharmaceutical cocrystals [88,91]. In cases
where the solubilities of components (ie drug, coformer) in the solvent/antisolvent mixtures
show strong deviation from ideal-solution, calculations using the perturbed-chain statistical
associating fluid theory (PC-SAFT) show to be in good agreement with experimental data and
thus are useful tools for increasing the efficiency of cocrystal formation by predicting the
solubility of pharmaceutical cocrystals in solvent/antisolvent mixtures [92].
iii) Ternary phase diagrams (TPDs)
Ternary diagrams are commonly used in physical chemistry to represent the phase behaviour
of three-component systems. In most cases, they are equilateral triangles with each side corner
of the triangle corresponding to a pure component. The area of such triangles covers all the
possible combinations of the three components and the sum of the perpendicular distances from
any point to each side of the diagram is a constant equal to the length of any of the sides. In the
field of cocrystals, ternary phase diagrams (TPDs) are mole-based equilateral triangles which
represent the total composition of solid phases and liquid phases at equilibrium [70,89]. TPDs
can be generated by determining the solubility curves of each solid phase (ie drug, coformer
and cocrystal) in the solvent at a specific temperature (Fig. 4).
At the eutectic or invariant points (E1 and E2), the solution is saturated with two solid phases
that is the drug and cocrystal, at E1, and coformer and cocrystal, at E2. Based on the Gibbs rule
of phases, there are six zones in a typical TPD, for a system where a drug and coformer are
linked by one stoichiometric relationship (drug + coformer � cocrystal). Straight lines drawn
from the eutectic points to the corresponding pure solid phases (drug, coformer, and the drug
coformer stoichiometric ratio which is 0.50 in the case of a 1:1 cocrystal) together with the
cocrystal solubility curve (E1 to E2) determine the six zones. Zone 1 comprises of
undersaturated solutions of both drug and coformer and is bounded by the solubility curves of
the drug (a to E1), the cocrystal (E1 to E2) and the coformer (E2 to b). The drug is the stable
solid phase in zone 2, the cocrystal in zone 3 and the coformer in zone 4. In zones 5 and 6
(invariant regions), a mixture of cocrystal and drug or cocrystal and coformer exist,
respectively. In each of these zones, the stable solid phases are in equilibrium with a liquid
Cocrystal systems can be distinguished in congruently and incongruently saturated solutions
[89,90]. Congruently saturating cocrystals are thermodynamically stable when slurried in a
solvent whilst incongruently saturating systems undergo transformation leading to the
formation of less soluble solid form. The congruency or incongruency of a cocrystal system in
a solvent is linked to the relative solubility of the pure cocrystal-components in solvent. More
specifically, when the solubility of the drug and coformer is similar in the solvent, it is likely
that the cocrystal system will be congruently saturating while when the solubilities differ
largely, the cocrystal will be incongruently saturating in the solvent [70]. The TPDs for a
congruently and an incongruently saturating 1:1 cocrystal are shown in Fig. 5.
A congruently saturating cocrystal exhibits a more symmetrical TPD (Fig. 5a) compared to an
incongruently saturating system (Fig. 4b), as in the latter case the zone in which the cocrystal
is the stable phase (zone D-C+L) has moved towards the axis of the component with the highest
solubility in the solvent (in this case the coformer, Fig. 5b). For a 1:1 congruently saturating
cocrystal, the solubility curve (E1 to E2) crosses the cocrystal component stoichiometric ratio
line (dashed line), while for an incongruently saturating cocrystal the maximum solubility lies
outside the cocrystal component stoichiometric ratio line.
Construction of TPDs based on experimental solid-liquid equilibrium data in various solvents
and temperatures has been applied in a series of studies to rationally select the method and
conditions of cocrystallization [70,89,93].
Solution crystallization is the most commonly used method for the production of single crystals
and the subsequent crystallographic characterization of cocrystals, but also for scaling-up
purposes. However, the outcomes of solution crystallization are sometimes unpredictable as
there is the risk of crystallizing the single component phases due to the complicated parameters
involved. In contrast to preparation methods in small scale, in which usually binary systems
are used (eg melt crystallization and mechanochemistry), in the solution crystallization the
solubilities of the components in the solvent at different temperatures should be considered
ahead of stoichiometries as different fractions of the cocrystal components can dissolve in the
liquid phase [85]. Therefore, in solution cocrystallization, PSDs and TPDs are important tools
for mapping out the critical region (ie the region where the cocrystal is the only stable solid
phase) thus guiding the selection of crystallization parameters and the starting point for solution
cocrystallization, avoiding the formation of undesired phases. Specifically, data regarding both
the solvent and temperature are important as they have an effect on the phase diagram of a
cocrystal system [89].
Tong et al. generated TPDs of the ethenzamide-saccharin (1:1) cocrystal system in different
solvents (ethanol, methanol and ethyl acetate) where its components were dissolving differently
based on the selected solvent. The ehtenzamide-saccharin system dissolved congruently in
ethyl acetate due to similar solubility of ethenzamide and saccharin, but incongruently in
ethanol and methanol due to different solubility, where an excess of ethenzamide is required to
isolate the cocrystal and in turn would increase the cost for the cocrystal production [94]. Based
on the constructed TPDs, ethyl acetate was identified as the solvent of choice for the production
of the ethenzamide-saccharin cocrystals, as the larger and more symmetric region for the
cocrystal was found to be beneficial in cooling and suspension crystallization.
In many cases, a cocrystal hydrate or solvate can be formed during solution crystallization apart
from the cocrystal. Phase diagrams have been used not only to understand the transformation
pathways, but also how to suppress the formation of hydrates or solvates. For example, TPDs
of the theophylline–citric acid anhydrous/hydrated cocrystals have been used for a qualitative
depiction of the stability domains with coformers that modulate the water activity. Water
activities at eutectic points were measured and related to the stability of the anhydrous/hydrated
cocrystal phases in solutions and in vapour phase in a range of relative humidities. It was found
that the presence of coformers that modulate the water activity as trace level impurities with
cocrystal can alter hygroscopic behaviour and stability [95] . For avoiding the problem of
solvation of indomethacin-nicotinamide (1:1) cocrystal in methanol, TPDs in methanol and
methanol/ethyl acetate, at 25 oC and 40 oC, were compared by Sun et al. [96]. The comparison
showed that when increased temperature and/or solvent mixtures were used, the stability region
of indomethacin methanolate was narrowed or even disappeared. By fine-tuning these two
parameters solvate formation could be suppressed, indicating that solubility results and
corresponding phase diagrams can provide the basis as a guide for the manufacturing of
indomethacin-nicotinamide (1:1) cocrystals.
TPDs can also guide the selection of a suitable method for the preparation of a cocrystal by
providing insight on how to access the area of the diagram where the cocrystal is the only
thermodynamically stable phase. Chiarella et al. constructed TPDs of trans-cinnamic
acidnicotinamide (1:1) cocrystal at different solvents and temperatures as a basis for
understanding current crystallisation methodologies [89]. In general, for congruently saturating
cocrystal systems in a solvent or solvent mixtures, the cocrystal can be prepared by evaporation
of stoichiometric solutions of the cocrystal components. Instead, for incongruently saturating
system, non-stoichiometric solution concentrations can be used as in the case of reaction
crystallization where the solution becomes supersaturated with respect to the cocrystal as the
drug is dissolved in a saturated solution of the coformer [70]. Interestingly, spray drying and
supercritical fluids drying of stoichiometric incongruently saturating cocrystal systems
generated pure cocrystals suggesting that the formation of cocrystals by this method may be
kinetically controlled or mediated by the glassy state of the materials [97,98]. In Table 1, the
use of PSDs and TPDs for the screening, small-scale preparation and scaling-up of cocrystals
in several studies is reported.
Table 2. Some studies based on PSDs and TPDs for the screening, small-scale preparation and
scaling-up of pharmaceutical cocrystals.
Cocrystal system
Carbamazepine ith
reaction and slurry acids
PSDs and TPDs illustrate how [70]
saturation of reactants leads to
supersaturation of the
(1:1) and (2:1)
acid Importance of solvent in the
stoichiometrically diverse
Myricetin cocryst als
A novel strategy for the [61]
preparation of pharmaceutical
cocrystals without knowledge
of the stoichiometric ratio
based on PSDs and TPDs
and solution
lproline and imidazole
throughput screening was
milling/grinding or solution
crystallization methods.
TPD and PSD in ethanol as
tools for mapping out the
regions of thermodynamic
stability of the cocrystal and
its components
Smallscale preparation
of cocrystals
Salicylic acid-4,4'cocrystallization
dipyridyl (2:1)
Carbamazepinecocrystallization Shift
saccharin (1:1)
carbamazepinesaccharin PSD
depicts the dramatic change in
solubility which is the
primary driving force
towards crystallization by antisolvent
Two solution
A crystallization method [103]
based on TPDs by mixing
two kinds of different
eutectic solutions
Spray drying
CarbamazepinenicotinamideBased on PSD and TPD,
the under-saturated
region with respect to
cocrystal was identified
and selected as target
region to initiate the
CarbamazepinenicotinamideUse of PSD for solvent
selection and optimization
of solution crystallization
conditions, including the
initial concentration of the
acidnicotinamideUse of TPD in developing a [106]
controlled approach to
crystallization using a
baffled crystallizer
4. Solution based scale-up methods of cocrystals
Various methods have been reported for the production of cocrystals that can be broadly
divided into liquid-based (eg evaporative, cooling, slurry, antisolvent and reaction
cocrystallization) and solid-based methods (eg mechanochemistry and twin-screw extrusion).
While mechanochemistry (neat grinding and LAG) is one of the most widely used screening
methods for the formation of cocrystals, its scalability is limited and the intensive energy input
may induce some degree of amorphization and crystal defects, compromising the purity of the
cocrystals formed [107]. Twin-screw extrusion (TSE) employing a combination of controlled
heat and shear deformation, has been successfully used for cocrystal formation [108]. Despite
being an environmentally-friendly method that can be used for the continuous manufacturing
of pharmaceutical cocrystals with high quality, yield and throughput [109], the elevated
temperature required during the TSE process may limit its suitability for thermally unstable
Friščić et al. introduced the empirical parameter η (μl mg-1) for the characterization of the liquid
methods, defined as the ratio of the volume of the liquid V (μl) and the sum of the masses of
the API and the coformer (mg) [80]. Based on the value of η, liquid-based methods can be
further subdivided into slurry crystallization (η=2-12 μl mg-1) and solution-based
crystallization (η>12μl mg-1). The main advantage of solution based crystallization methods is
the fact that they enable removal of impurities from the recrystallized product. Also, solution
based crystallization is a prevailing approach for producing cocrystals on a commercial scale
due to the availability of solution-crystallization equipment (eg large stirred tank reactors) in
the pharmaceutical manufacturing plants [110]. In addition, by changing process parameters
(eg solvent, polymer-induced heteronucleation) numerous pathways can be accessed in the
phase solubility diagram indicating that solution based crystallization methods require strict
control but they also offer unique opportunities as each of these pathways may give rise to
unique materials (eg cocrystal polymorphs) [111].
Solution based crystallization methods can be employed in various stages of cocrystal
production, from the initial stage of screening using high-throughput methods (in μg) to the
small laboratory scale (in mg) for characterization, the lab-bench pilot scale (in g) and the
scaling-up for commercial production (in kg). During screening, evaporative crystallization is
the most commonly used technique for the production of cocrystals due to its simplicity.
However, techniques such as cooling crystallization and antisolvent crystallization are
preferred for industrial crystallization as they provide more control over crystallization
conditions. In particular, cooling crystallization is considered as the “workhorse” of industrial
crystallization for the past 100 years providing effective purification and control of solid form
and other particle attributes [112]. Thus, a common first step towards the scaling-up of a
crystallization process is to convert from a small-scale evaporation processes into cooling
crystallization [113].
In this section, studies on the scale-up of cocrystals using solution based crystallization methods
will be reviewed with emphasis on the role of phase diagrams as tools towards scalingup.
Special focus will be placed on studies where process analytical technology (PAT) and quality
by design (QbD) principles were implemented for the design, optimization and control of the
crystallization process.
Hickey et al. reported the production of carbamazepine-saccharin (1:1) cocrystals applied on a
30-g batch size using a conventional cooling crystallization process from ethanol/methanol
mixture [114]. The temperature was reduced from 70 oC, at 10 oC increments, to induce
precipitation. Cocrystals started to appear at 50 oC and the temperature was further lowered
down to drive additional precipitation. No seeding was required as the 1:1 cocrystal was found
to be the phase that nucleates from the solution in the supersaturated state. Crystal growth was
found to be a function of cooling rate and incubation time. Cocrystals of plate-like morphology
were collected from all the crystallization trials. Regarding crystal size, near-saturated
crystallization resulted in very large crystals while rapid cooling in smaller crystals. A 76%
solid recovery of cocrystals was reported by this method, indicating the potential of cooling
crystallization as a scale-up method.
Sheikh et al. incorporated well-established techniques and procedures used in singlecomponent
crystallization to a complicated cocrystal system of carbamazepine and nicotinamide, which
have significantly different solubilities, and proposed a scalable solution crystallization
methodology enabling manipulation and control of the process leading to desired performance
and product characteristics [105]. The essential elements of the methodology were: i)
development of a solvent selection rationale, ii) identification of domains of thermodynamic
stability in the multi-component solid-liquid phase equilibrium diagram and iii) identification
of the mechanism for inducing nucleation and subsequent control of desaturation kinetics.
Following this methodology, ethanol was the solvent of choice since the solubility of
carbamazepine (API) is approximately half that of the nicotinamide (coformer). This allows a
large driving force for the formation of cocrystal and the widest window for phase-pure
crystallisation of cocrystals. Seeding was used to induce controlled secondary nucleation and
significant de-saturation via crystal growth. A solution of an appropriate concentration was
used for the post-filtration washing of the cocrystals, allowing efficient removal of residual
solution from the wet cake without risking cocrystal stability (ie conversion to the pure
components). Following a rational process design, a robust process at a 1L-scale with yields in
excess of 90% and throughput of 14 L kg-1 was established.
Cocrystals apart from their ability to modify the physicochemical and mechanical properties of
APIs have been used as intermediates in the purification or racemic resolution of APIs [115].
Billot et al. investigated the use of crystallization to purify SAR1, a kinase inhibitor for the
treatment of acute myeloid leukaemia that was found to be resistant to conventional purification
techniques (eg chromatorgraphy and impurity adsorption) [116]. Moreover, even though SAR1
exhibits a rich population of solvates, purification via formation of solvates and subsequent
desolvation was found to be inadequate for the crude API feedstock where the presence of
impurities inhibited nucleation and formation of solvates. A two-step crystallization approach
was employed comprising the formation of a cocrystal between the API and a coformer in the
chlorobenzene feedstock followed by the cleavage of the solvate to isolate the API. An initial
five carboxylic acids were selected as potential coformers, based on the synthon approach.
Then, phase diagrams were constructed as indispensable tools facilitating: i) the selection of
the best coformer and ii) the recovery of a purified API within specification for residual solvent.
Specifically, benzoic acid was selected as the best coformer due to the congruent solubility of
the API and this coformer in chlorobenzene. On the contrary, the incongruent solubility of
benzoic acid and the API in isopropanol makes it the most suitable solvent for the cleavage of
the cocrystal, allowing reformation of the pure API by using low solvent volumes. The
crystallization process was initially developed at a laboratory scale and was successfully
transferred to the pilot plant using a filter-drier at a 10-kg scale. At pilot-plant scale, purification
was found to be effective, with the product assay increasing from 65% before crystallization
with benzoic acid to 99% while the purity was retained during the cleavage step. An overall
yield of 54% was reported for the two steps and the final product was found to comply with the
International Conference for Harmonisation (ICH) specification for residual solvents and for
polymorphic form.
5. Process analytical technology for monitoring of solution based cocrystallization
Process analytical technology (PAT) is defined by the US Food and Drug Administration
(FDA) as “a system for the design, analysis and control of manufacturing processes through
timely measurements of critical quality and performance attributes of raw and in-process
materials and processes, with the goal of ensuring final product quality” [117]. Implementation
of PAT involves a combination of i) scientifically-based process design and optimization to
identify critical material attributes and critical process parameters, ii) suitable sensor
technologies, iii) chemometrics for the interpretation of multivariate data provided by the
sensor technologies and iv) feedback process control strategies to ensure production of final
products with the desired quality [118]. Application of PAT is the key enabler for the
implementation of QbD concepts in pharmaceutical manufacturing processes such as
crystallization [118].
Regarding monitoring of crystallization processes, sensor technologies should be capable of
measuring key process variables (eg supersaturation) and desired quality attributes (eg size,
shape and polymorphic form) which impact on properties such as solubility, dissolution and
bioavailability but also on downstream operations such as filtration [118]. Sensor technologies
can be differentiated based on whether they provide information related to the liquid or the
solid phase [119]. Monitoring the liquid phase provides information regarding the
supersaturation that can be inferred from the measured solute concentration and the equilibrium
saturation concentration at the same temperature. Real-time sensing techniques that have been
used for the measurement of the solute concentration are attenuated total reflection Fourier
refractometry and conductivity [120]. Monitoring of the solid phase provides information
regarding crystal size distribution (CSD), shape and polymorphic form. Real-time sensing
techniques that have been used for the determination of these crystal attributes include total
(back) scattering of suspension for particle concentration, forward light scattering for CSD,
focused beam reflectance measurement (FBRM) for chord length distribution and detection of
nucleation events, ultrasound attenuation for CSD, imaging techniques for CSD and shape
determination and Raman scattering for quantification of polymorphic forms in suspension
[121]. Below, studies on the use of PAT sensors for the monitoring and control of
crystallization processes are reviewed in detail.
Gagniere et al. selected the cocrystal of carbamazepine-nicotinamide to study its crystallization
kinetics using PAT sensors [122]. Using an in-situ video probe, they investigated the evolution
of solid phases during the cooling crystallization process operated in batch mode. As
carbamazepine-nicotinamide cocrystals (needles) and carbamazepine single crystals (platelets)
exhibited different habits, the video probe was an efficient analysis tool capable to detect and
monitor the evolution of these two solid phases in the slurry. Through this monitoring, it was
demonstrated that the initial conditions were important for the pathway of the crystallization
and relationships between carbamazepine-nicotinamide cocrystals and carbamazepine crystals
were observed, indicating that the nucleation of the cocrystal may be favoured by the presence
of drug crystals. Limitations in the use of the video probe was the qualitative rather than
quantitative nature of information provided and its limited visualization ability when the
cocrystal concentration exceeded 10% weight. In order to complete the study, a quantitative
monitoring was carried out in concentrated slurry (solid content up to 30% weight) using an insitu ATR-FTIR spectroscopy probe which provided estimates of the solute concentrations of
both carbamazepine and nicotinamide at various temperatures [123]. The concentration profiles
allowed the construction of phase diagrams showing the kinetic pathways of the crystallization
process, the determination of the solid form nucleation and the change in the proportion of each
solid phase present in suspension (Fig. 6). Knowledge of the phase diagram at the initial and
final temperatures of the crystallization process allowed the definition of the “safe” operation
region in which crystallization should be conducted to avoid the appearance of solid phases
other than the cocrystal. Moreover, in-situ monitoring of solute concentrations of
carbamazepine and nicotinamide by the ATR-FTIR probe showed that it is possible to induce
solution-mediated phase transitions (SMPT) by manipulating the amount of the coformer.
Specifically, addition of nicotinamide in dry form allowed a shift in the phase diagram, leading
to an SMPT from carbamazepine crystals towards cocrystals [124]. In this way, shifting the
overall slurry composition to the desired zone of the phase diagram by adding a certain amount
of one of the components of the cocrystal system can be used as a retreatment process in cases
where the cocrystal phase is polluted by another crystalline phase [125].
In a follow-up study, the cooling crystallization of carbamazepine and nicotinamide was
monitored using two in-situ calibration-free PAT sensors: a FBRM probe sensor for CSD
determination and an in-house-built video probe for shape and CSD determination [126]. The
different habits of the drug and the cocrystal allowed the discrimination between them with
these two sensors. The video probe provided qualitative understanding of the phenomena inside
the crystalliser but it could only be used in low solid concentrations as it becomes blind in high
solid concentrations. On the other hand, the FBRM probe can operate in a wide range of solid
concentrations but its measurements should be analysed with caution since they can lead to
misinterpretation of the phenomena. Thus, it was highlighted that a combination of probes
providing complementary data is essential for the correct interpretation of the data when the
industrial development of a crystallization process is carried out.
In a series of studies, Yu and co-workers studied the cooling crystallization of the polymorphic
caffeine-glutaric acid system in acetonitrile, implementing PAT and QbD methodology. The
phase diagram of caffeine-glutaric acid-acetonitrile was constructed in the temperature range
of 10-35 oC using ATR-FTIR spectroscopy for in-situ measurement of solute concentrations
and by exploiting SMPT for location of eutectic points. Knowledge of the phase diagram
changes with temperature and evaluation of possible kinetic pathways allowed the
establishment of the operating region for the crystallization process [127]. In a second study,
the crystallization process was monitored using ATR-FTIR spectroscopy combined with
particle vision measurement (PVM) and supersaturation was calculated as the difference
between the transient concentration of the cocrystal and its solubility [128]. Seeding with the
stable form II was found to avoid nucleation of the metastable form I. In addition, feedback
control of supersaturation was implemented and enabled: i) the maintenance of supersaturation
close to its set point, ii) the elimination of the often problematic polymorphic transformation
process to the metastable form I of cocrystal, and iii) the production of largest particles and
lowest proportion of fines.
In a follow-up study, the design space of the caffeine-glutaric acid crystallization for process
development and scale-up was determined [129]. Polymorphic purity was chosen as a critical
quality attribute and its relationship with five process parameters, namely cooling profile, seed
loading, seeding temperature, seed particle size distribution and starting concentration, was
described by a first-principles process model and an empirical supersaturation threshold. After
the estimation of the model parameters on a bench scale, the supersaturation threshold was
obtained from a few experiments in a 1-L crystalliser. Monte Carlo modelling was employed
to quantify the risks associated with model parameter uncertainty and operational variability.
These risks, while assessed to be significant, could be effectively mitigated by sufficient aging
after seeding. The operating ranges of starting concentration, seeding temperature and seed
loading were modelled and verified experimentally by scaling-up to a 10-L crystalliser.
Caffeine-glutaric acid was also selected as a model system by Sheng et al., who developed a
calibration-free method based on Raman spectroscopy for the on-line identification of
impurities during crystallization [130]. Employing multivariate analysis methods (ie principal
component analysis and discriminant analysis) on the Raman spectra, offered a simple and
industrially amenable approach for identification of impurity in the form of pure component
during crystallization without the need for elaborate calibration.
5.1. Current state of scaling up solution based cocrystallization processes
Conventionally, crystallisation processes are operated via batch production. Whilst batch
process may appear simple and allow flexibility to respond to varying customised design
requirements, the underlying science and its control are highly complex resulting in increased
manufacturing costs and batch-to-batch variations in product quality (eg purity, size, shape)
[131]. Continuous crystallisation is gaining momentum in the pharmaceutical industry as the
regulatory authorities support the implementation of continuous manufacturing [132].
Development of continuous production over batch crystallization offers many potential
advantages including better process control, consistent product quality, shorter development
time, reduced costs, more robust scale-up and more efficient use of reagents, solvents and
energy which in turn minimise the production of waste material and reactor downtime for
maintenance and cleaning [131,133].
Zhao et al. discovered a α-lipoic acid-nicotinamide (1:1) cocrystal with enhanced thermal
stability compared with α-lipoic acid, offering significant advantages regarding the production
and storage of this nutritional supplement [106]. In this study, the rapid translation of the
cocrystal from gram to kilogram scale was also reported using a continuous cooling
crystallization process supported by a systematic approach to process design. Specifically, from
the discovery to scaling-up the following consecutive steps were employed: screening of
αlipoic acid with different coformers using liquid-assisted grinding (LAG) and small-scale
solution cocrystallization, generation of single crystal of α-lipoic acid-nicotinamide (1:1)
cocrystal for structure elucidation and characterization, crystallization of this system using
oscillatory baffled cooling crystallizer in batch mode which was further linearly scaled-up to
continuous cocrystallization. The TPD of α-lipoic acid and nicotinamide in the mixed solvent
of isopropanol/hexane was constructed to identify the critical region in which crystallization of
pure cocrystal occurs while the influence of the temperature in the critical region was also
investigated. Based on the TPD, the starting concentration of α-lipoic acid, nicotinamide and
the cooling profiles were selected to ensure that crystallization would take place within the
critical region increasing the purity of the final product and the yield of the process. During
continuous cocrystallization, solid content and particle size distributions were monitored using
a FBRM probe. The continuous crystallization process used resulted in over 1 kg of high purity
solid cocrystals at a throughput of 350 gh-1. This study demonstrated that combining continuous
processing with a systematic approach to design holds a great potential as an effective and rapid
route towards scaling-up of novel cocrystals.
Polymorphic cocrystal systems are particularly challenging systems as different polymorphs
often crystallize together as a mixture, making the isolation of the desired polymorphic form
difficult. Powell et al., selected the polymorphic urea-barbituric acid cocrystal system and
investigated polymorph control in cooling crystallization applying the concept of periodic flow
crystallization by using a novel crystallizer based on periodic mixed suspension mixed product
removal (PMSMPR) [134]. The PMSMPR operation involves controlled disruptions applied to
the inlet and outlet flow of an otherwise continuous mixed suspension mixed product removal
(MSMPR) crystalliser and it was found to be a promising strategy for the isolation of pure
polymorphic form of a cocrystal in the pharmaceutical industry. Moreover, in this study the
crystallization process was monitored using a composite sensor array (CSA) consisting of
FBRM, ATR-UV/Vis, particle vision and measurement (PVM) and Raman probe. Use of CSA
is an emerging area in crystallization monitoring as it allows information from different PAT
sensors to be combined and applied for automated decision support and feedback control of the
crystallization process (Fig. 7) [135].
6. Concluding remarks
The knowledge of phase diagrams (PSD and TPDs) has provided fundamental understanding
of cocrystal stabilities in solutions. Recently, experimental screening methods which rely on
phase diagrams, such as liquid assisted grinding and slurring or reaction crystallization, have
evolved as efficient and widely used cocrystal screening methods. In combination with in-silico
and semi-empirical methods, the implementation of rational screening methods has enhanced
the cocrystal screening efficiency that brought to light previously unknown cocrystals. Initial
reports on cocrystals preparation had only considered “gram” quantities for the purpose of
pharmaceutical characterization and in vivo studies. In most of the studies, solvent evaporation
crystallization of equimolar mixture of the API and conformer was performed to obtain gram
quantities, without much consideration to cocrystal phase diagrams. However, the need for the
implementation of QbD paradigm in pharmaceutical manufacturing processes has compelled
the development of science-based tools like phase diagrams in the crystallization process
development. Few subsequent studies have successfully employed phase diagrams and PAT
tools in scaling-up cocrystals in “kilogram” scale using cooling or cooling/anti-solvent batch
crystallization methods. Currently, the development of continuous crystallization methods for
cocrystals is an emerging area. Recent studies have provided perspectives on the potential
advantages of continuous crystallization and challenges involved in the form control. It is
emphasized that proper understanding of cocrystal phase behaviour is crucial in developing
continuous crystallization processes and for the quality of final product. Thus, solution phase
diagrams provide profound scientific basis and rationality in designing cocrystal screening and
scale-up processes, that eventually lead to rational experimental screening methods and robust
scale-up crystallization processes.
Funding sources
This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
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Figure 1. A shows monotropic transitions via DSC: Aa: The arrow marks the polymorphic
transition, before the new form melts; Ab: Here, the polymorphic transition is so slow that
it crystallizes; Ac: The pure α'-form melts low; Ad: the pure α-form melts high. B shows
enantiotropic transitions, (note: at Tt α and β are at thermodynamic equilibrium): Ba:
shows transition to form α to β in fine powder; Bb: transition to form α to β in course
crystals; Bc: reversible transition in fine powder; Bd: reversible transition in fine powder.
Adapted from reference [25].
Figure 2. Schematized binary phase diagram for cocrystal 2:1 L-proline-fumaric acid (eutectic
composition are represented symmetrically here, but they are not necessarily symmetrical
around the cocrystal composition). Reprinted with permission from [86]. Copyright 2013
American Chemical Society.
Figure 3. Phase solubility diagram (PSD) of indomethacin-saccharin cocrystal in ethyl acetate
at 25 o C. The blue line depicts the solubility of the cocrystal as a function of the saccharin
concentration. E1 and E2 are the eutectic points while a and b represent the solubility of
the drug and the coformer, respectively, in neat ethyl acetate. The dashed line represents
the 1:1 stoichiometric ratio between the drug and the coformer. Reprinted with permission
from [91]. Copyright 2011 American Chemical Society.
Figure 4. Construction of a ternary phase diagram (TPD) for a drug and coformer which give
a 1:1 cocrystal in a solvent at a specific temperature. XD, XCF and XCC are the solubility
curves of the drug, coformer and cocrystal, respectively, in the solvent. E1 and E2 are the
eutectic points while a and b represent the solubility of the drug and the coformer,
respectively, in neat solvent. Adapted from reference [87].
Figure 5. Ternary phase diagrams (TPDs) for (a) congruently and (b) incongruently saturating
cocrystal systems. L, D, C, and DC indicate liquid phase, drug, coformer, and cocrystal
solid phases, respectively. Adapted with permission from [97]. Copyright 2010 American
Chemical Society.
Figure 6. Phase diagram of the carbamazepine-nicotinamide system in ethanol at 25 °C. Solute
concentration pathways depending on the initial starting point in the phase diagram (solid
solubility curve). Reprinted with permission from [123]. Copyright 2009 American
Chemical Society.
Gambar 7. Three-stage PMSMPR cascade crystalliser used for the periodic flow
crystallization experiments. Real-time monitoring of the crystallization process is
achieved using a composite sensor array (CryPRINS: crystallisation process informatics
system developed at Loughborough University (UK), TC: thermocouple). Reprinted with
permission from [134]. Copyright 2015 American Chemical Society.
Figure 1. A shows monotropic transitions via DSC: Aa: The arrow marks the polymorphic
transition, before the new form melts; Ab: Here, the polymorphic transition is so slow that it
crystallizes; Ac: The pure α'-form melts low; Ad: the pure α-form melts high. B shows
enantiotropic transitions, (note: at Tt α and β are at thermodynamic equilibrium): Ba: shows
transition to form α to β in fine powder; Bb: transition to form α to β in course crystals; Bc:
reversible transition in fine powder; Bd: reversible transition in fine powder. Adapted from
reference [25].
Figure 2. Schematised binary phase diagram for cocrystal 2:1 L-proline-fumaric acid (eutectic
composition are represented symmetrically here, but they are not necessarily symmetrical
around the cocrystal composition). Reprinted with permission from [86]. Copyright 2013
American Chemical Society.
Figure 3. Phase solubility diagram (PSD) of indomethacin-saccharin cocrystal in ethyl acetate
at 25 o C. The blue line depicts the solubility of the cocrystal as a function of the saccharin
concentration. E1 and E2 are the eutectic points while a and b represent the solubility of the
drug and the coformer, respectively, in neat ethyl acetate. The dashed line represents the 1:1
stoichiometric ratio between the drug and the coformer. Reprinted with permission from [91].
Copyright 2011 American Chemical Society.
Figure 4. Construction of a ternary phase diagram (TPD) for a drug and coformer which give a
1:1 cocrystal in a solvent at a specific temperature. XD, XCF and XCC are the solubility curves
of the drug, coformer and cocrystal, respectively, in the solvent. E1 and E2 are the eutectic
points while a and b represent the solubility of the drug and the coformer, respectively, in neat
solvent. Adapted from reference [87].
Figure 5. Ternary phase diagrams (TPDs) for (a) congruently and (b) incongruently saturating
cocrystal systems. L, D, C, and DC indicate liquid phase, drug, coformer, and cocrystal solid
phases, respectively. Adapted with permission from [97]. Copyright 2010 American Chemical
Figure 6. Phase diagram of the carbamazepine-nicotinamide system in ethanol at 25 °C. Solute
concentration pathways depending on the initial starting point in the phase diagram (solid
line—carbamazepine solubility curve; dotted line—carbamazepine-nicotinamide solubility
curve). Reprinted with permission from [123]. Copyright 2009 American Chemical Society.
Figure 7.. Three-stage PMSMPR cascade crystalliser used for the periodic flow crystallization
experiments. Real-time monitoring of the crystallization process is achieved using a composite
sensor array (CryPRINS: crystallisation process informatics system developed at
Loughborough University (UK), TC: thermocouple). Reprinted with permission from [134].
Copyright 2015 American Chemical Society.
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