research papers
The competition between cocrystallization and
ISSN 1600-5767
Received 1 March 2019
Accepted 5 June 2019
Edited by G. Kostorz, ETH Zurich, Switzerland
Keywords: competition; solvent evaporation
rate; metastable zone width; nucleation order;
formation mechanisms.
# 2019 International Union of Crystallography
J. Appl. Cryst. (2019). 52, 769–776
separated crystallization based on crystallization
from solution
Shanhu Sun,a Haobin Zhang,a* Jinjiang Xu,a Shumin Wang,b Hongfan Wang,b
Zhihui Yu,b Lang Zhao,b Chunhua Zhua and Jie Suna*
a
Institute of Chemical Materials, China Academy of Engineering Physics, Mianyang 621900, Sichuan, People’s Republic
of China, and bSchool of Materials Science and Engineering, Southwest University of Science and Technology, Mianyang
621010, Sichuan, People’s Republic of China. *Correspondence e-mail: zhhb0115@163.com, sunjie@caep.cn
The competition between cocrystallization and separated crystallization in a
solvent was explored via X-ray diffraction and high-performance liquid
chromatography methods in different solvents and by considering the solvent
evaporation rate. The results revealed that the solvent system and solvent
evaporation rate can affect the nucleation order of the cocrystal and coformers
in the solution. In fact, solubility tests in different solvents confirmed that the
solubility plays a key role in the cocrystal formation process. Furthermore, the
width of the metastable zone influenced the solute nucleation order and was a
decisive factor in the cocrystal formation process when the solvent evaporation
rate was varied. Cocrystals could therefore be obtained by adjusting the solvents
and solvent evaporation rate. The preparation of kinetic 2,4,6,8,10,12-hexa-
nitrohexaazaisowurtzitane–2,4,6-trinitrophenol cocrystals via rapid solvent
evaporation proves the practicability of this theory.
1. Introduction
Cocrystallization is considered a powerful tool for modifying
and optimizing the properties of certain materials including
pharmaceuticals (Ueto et al., 2012), energetic materials
(Bolton & Matzger, 2011), nonlinear optical materials (Pan et
al., 1996), ferroelectrics (Horiuchi & Tokura, 2008) and
organic electronics (Zhu et al., 2012). During this process, two
or more types of these materials are combined, via hydrogen
bonding, – stacking, p– stacking, halogen bonding, van der
Waals forces and other non-covalent interactions, to form a
novel cocrystal material. This combination changes the
performance of the coformers significantly without changing
the chemical structure (Basavoju et al., 2006). Cocrystalliza-
tion is a more convenient and effective material-modification
method than traditional strategies, where novel molecular
materials with unpredictable performance are synthesized
(Fischer et al., 2012).
Explosive cocrystal synthesis, a smart-material functionality
improvement method (Bolton & Matzger, 2011), provides a
means for achieving a combination of high energy and low
sensitivity on the molecular level (Liu et al., 2016). To date,
well behaved explosive cocrystals based on 2,4,6-trinitro-
toluene (TNT) (Landenberger & Matzger, 2010),
2,4,6,8,10,12-hexanitrohexaazaisowurtzitane (CL-20) (Bolton
et al., 2012; Yang et al., 2012), 1,3,5,7-tetranitro-1,3,5,7-
tetrazacyclooctane (HMX) (Landenberger & Matzger, 2012)
https://doi.org/10.1107/S1600576719008094 769
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Table 1
The specific methods and results of cocrystallization under different conditions.
Materials Solvent
CL-20, HMX Acetone
CL-20, HMX Acetone
CL-20, TNT Acetone
CL-20, TNT Acetone
CL-20, TNT Acetone/methanol (1:6, v/v)
CL-20, TNT Acetone/methanol (1:6, v/v)
CL-20, TNT Benzene/ethyl acetate (4:1, v/v)
CL-20, TNT Benzene/ethyl acetate (4:1, v/v)
CL-20, TNP Ethyl acetate
CL-20, TNP Ethyl acetate
and benzotrifuroxan (Zhang et al., 2013) have been obtained.
After cocrystallization, the energy and safety requirements of
the explosives were effectively balanced, and the thermal
properties were significantly improved by adjusting the
oxygen balance (Xu et al., 2019). Cocrystals have, in general,
been prepared via grinding (Friščić & Jones, 2009), melt
recrystallization (Berry et al., 2008) or crystallization from
solution (Chiarella et al., 2007), as the high sensitivity and
instability of explosives have limited the use of some common
cocrystal preparation methods. Various solvent-dependent
preparation methods, including bead milling with solvents
(Qiu et al., 2015) and slurry preparation (Sun et al., 2018), have
been employed for the synthesis of explosive cocrystals.
However, oriented design and complete synthesis of cocrystals
via these conventional methods is impossible. The experi-
mental results usually revealed the formation of separated
coformer crystallization products and the cocrystallization
products. Owing to the lack of knowledge regarding the
formation mechanism of cocrystals in a solvent, the basis for
the competition between cocrystallization and separated
crystallization remains unclear. This competition, which can
be exploited for the efficient preparation of explosive
cocrystals, has received little attention.
We have investigated the competition between cocrystalli-
zation and separated crystallization in a solvent via X-ray
diffraction (XRD) of the CL-20/TNT and CL-20/HMX
cocrystal formation processes in different solvents and by
varying the solvent evaporation rate. The results revealed that
the solvent system and solvent evaporation rate can affect the
nucleation order of the cocrystal and coformers. Additionally,
the solubility of the cocrystal and coformers was investigated
via high-performance liquid chromatography (HPLC)
methods. The results indicated that the solubility and width of
the metastable zone associated with these components influ-
ence the formation process of solute under different solvent
evaporation rate conditions. Subsequently, the kinetic CL-20/
TNP (2,4,6-trinitrophenol) cocrystal was obtained, through a
rotary evaporation method, by changing the nucleation order
of the cocrystal and coformers. These findings improve our
knowledge of the competition between cocrystallization and
separated crystallization and provide important guidance for
the synthesis of cocrystals.
770 Shanhu Sun et al.  Competition between cocrystallization and separated crystallization
Method Results
Slow CL-20 and HMX convert to CL-20/HMX cocrystals
Fast CL-20, HMX and a small fraction of CL-20/HMX cocrystals
Slow CL-20/TNT cocrystals
Fast CL-20/TNT cocrystals
Slow CL-20/TNT cocrystals
Fast CL-20 and TNT
Slow Precipitation CL-20, CL-20/TNT cocrystals in order
Fast CL-20 and TNT
Slow CL-20 and TNP
Fast CL-20/TNP cocrystals
2. Experimental
2.1. Materials
Raw CL-20, HMX and TNT were provided by the Institute
of Chemical Materials, China Academy of Engineering
Physics. Anhydrous acetone and ethyl acetate were provided
by Sinopharm Chemical Reagent Factory. Anhydrous
methanol, toluene and TNP were purchased from Chengdu
Kelong Chemical Reagent Factory.
2.2. Cocrystallization
The slow solvent evaporation products were obtained by
slowly evaporating a solution of CL-20 and other coformers in
a fixed stoichiometric ratio at room temperature. The fast
solvent evaporation products were obtained from rotary
evaporation of a solution of CL-20 and other coformers in a
fixed stoichiometric ratio under a pressure of 0.08 Mpa at
313 K. The experimental results under different solvents and
experimental methods are shown in Table 1.
2.3. Solubility determinations
HPLC is a commonly used quantitative analysis method,
which is characterized by high resolution, speed, repeatability
and precision (Elias & Bauer, 2006; Li et al., 2010). We used an
SB-C18 column, the mobile phase was 45/55, and the injection
volume was 10 ml. These conditions yielded retention times of
3.80, 8.48, 2.70 and 11.46 min for HMX, CL-20, TNP and TNT,
respectively. In the quantitative analysis experiment, the
standard curve method was used to determine the concen-
tration of substances in the solution. Typically, we dosed
standard solutions of CL-20, HMX and TNT at 1, 0.5, 0.1, 0.02
and 0.004 mg ml1. The measured concentration and peak
area of a standard substance are related via the following
linear equation:
y ¼ ax þ b; ð1Þ
where y is the measured peak area of the substance, x is the
concentration of the substance to be measured, a is the slope
of the standard curve and b is the intercept of the standard
curve with the y axis.
J. Appl. Cryst. (2019). 52, 769–776

During the sample preparation experiment, an excess of
solutes (cocrystals or coformers) was added to 3 ml of solvent.
The suspensions were agitated at 288 K for 1 h and then left to
stand for 2 h. The solid was filtered off twice before diluting
the solution. The saturated solutions of solutes were then
diluted 100, 500 or 1000 times, depending on the tests to be
performed. The concentration of each substance was deter-
mined by substituting the respective peak area into
equation (1).
After testing by HPLC, the solubility of each substance was
determined from the respective concentration, using the
following linear equation:
SA=B ¼ ðAa Bb Þ1=ðaþbÞ ; ð2Þ
where A and B represent the two coformers in an A/B
cocrystal, a and b represent the stoichiometric numbers of the
substances A and B, respectively, and S is the solubility of the
cocrystals.
2.4. X-ray diffraction
In this experiment, XRD patterns were recorded on a
Bruker D8 Advance with Cu K radiation ( = 1.5419 Å),
equipped with a VÅNTEC-1 detector and operated under the
conditions 40 kV/40 mA. The 2 range was from 5 to 45 with
a scanning step of 0.02 /0.5 s.
3. Results and discussion
XRD is a direct and effective method for detecting the poly-
morphic transformation of materials. The differences in
characteristic peaks can be used to identify and distinguish
between different crystal forms as well as to monitor the
transformation process occurring during formation of the
cocrystal. Table 2 shows the characteristic peaks composing
Figure 1
A comparison of experimental results under different solvent evaporation rates. CL-20-HMX (left) and CL-20-TNT (right).
J. Appl. Cryst. (2019). 52, 769–776 Shanhu Sun et al.
research papers
Table 2
The characteristic peaks in standard XRD spectra of cocrystals and
coformers.
Single crystal CCDC Characteristic peaks ( )
CL-20/HMX 875458 10.89, 11.49, 13.25
CL-20/TNT – 8.82, 12.37, 14.57, 22.60, 25.10
-HMX 673524 14.74, 16.09, 20.57, 29.72, 31.95
TNT – 12.69, 15.85, 23.01, 29.18, 29.22
-CL-20 117776 12.01, 13.66, 13.89, 27.50, 27.93
-CL-20 117777 13.75, 24.08, 28.23
"-CL-20 117779 12.62, 13.85, 15.75, 30.36
the standard XRD spectra of the CL-20/TNT and CL-20/HMX
cocrystals (Bolton et al., 2012). Peaks corresponding to the
respective polymorphic coformers, i.e. -CL-20, -CL-20,
"-CL-20 (Nielsen et al., 1998), -HMX (Zhurova et al., 2007)
and TNT (Golovina et al., 1994), are also shown. XRD can be
considered a simple characterization method for qualitative
analysis of the components in cocrystal samples.
Detection of the cocrystal formation process is essential for
investigating the competition between cocrystallization and
separated crystallization in the solvent. In the present work,
the high solubility of CL-20 and TNT in acetone leads to
instantaneous crystal nucleation and growth in the solvent
and, hence, detection of the CL-20/TNT cocrystal formation
process is difficult. In contrast, the formation of the CL-20/
HMX cocrystal is a long process where separated crystal-
lization of HMX and CL-20 precedes the thermodynamic
equilibrium transformation from CL-20 and HMX to the CL-
20/HMX cocrystal, as previously reported (Sun et al., 2018).
This indicates that the formation process of the CL-20/TNT
cocrystal may have occurred via direct precipitation, where
the thermodynamic equilibrium stage was avoided. The
occurrence of direct precipitation was confirmed through
experiments employing rapid crystallization with a rotary
evaporator under decompressed conditions. These experiments
 Competition between cocrystallization and separated crystallization 771
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were aimed at obtaining rapid crystallization products from Table 3
the CL-20–HMX and CL-20–TNT solutions (see Fig. 1 for the The solubilities of cocrystal and coformers in different solvents.
experimental results corresponding to different solvent Solubility
evaporation rates). The pure CL-20/HMX cocrystal could be Solvent Solute Components Peak area (mol l1)
obtained after a prolonged separated crystallization and Methanol/acetone CL-20 + TNT CL-20 144.15 0.58
thermodynamic equilibrium transformation process under TNT 244.94 1.046
slow solvent evaporation conditions. However, under fast CL-20/TNT CL-20/TNT 226.53 0.463
solvent evaporation conditions, this cocrystal constituted only Benzene/ethyl acetate CL-20 + TNT CL-20 12.80 0.039
a small fraction of the resulting mixtures, which consisted TNT 636.84 1.44
mainly of -CL-20 and -HMX (as shown on the left-hand CL-20/TNT CL-20/TNT 90.86 0.19
side of Fig. 1). These results showed that the thermodynamic Acetone CL-20 + TNT CL-20 288.56 1.13
equilibrium transformation from separated crystallization to TNT 379.75 1.34
cocrystallization was a slow process, which was unachievable CL-20/TNT CL-20/TNT 251.82 1.03
under fast solvent evaporation conditions. Therefore, rapid Acetone CL-20 + HMX CL-20 6.08 0.02
formation of the pure CL-20/TNT cocrystal phase was unat- HMX 788.01 1.52
tainable via thermodynamic equilibrium transformation from CL-20/HMX† – – –
CL-20 and TNT, i.e. the cocrystal was directly nucleated as † The solubility of the CL-20/HMX cocrystal cannot be accurately measured owing to
CL-20/TNT (see right-hand side of Fig. 1). conversion of the CL-20/HMX cocrystal to CL-20 and HMX in acetone.
To determine the formation process of the CL-20/TNT
cocrystal, two solvent mixtures of benzene/ethyl acetate (4:1,
v/v) and methanol/acetone (6:1, v/v) were used to reduce the precipitated in order. The precipitated CL-20 then completely
precipitation rate of the crystals. When a benzene/ethyl transformed into the CL-20/TNT cocrystal.
acetate mixture was used as the solvent, the "-CL-20 phase It is well known that nucleation and growth of solutes are
and CL-20/TNT cocrystal phase precipitated in order. The related to their solubility under slow solvent evaporation
TNT phase was, however, not detected during the formation conditions. Therefore, the effect of solubility on the nucleation
process, as shown in Fig. 2. Two different results were obtained order of solutes was assumed to be important. To accurately
when the evaporation rate of the methanol/acetone mixture determine the solubility of each component in the solution,
was varied. At 288 K, the solvent evaporated slowly in still air the HPLC standard curve method was employed for quanti-
and only the CL-20/TNT cocrystal formed during the crys- tative analysis of the component concentration characterizing
tallization process. If the reactor was placed in a moving air the solution (see Table 3). The different lattice energies of the
environment at 313 K, the solvent evaporation rate increased cocrystal and coformers lead to different solubilities in the
and the "-CL-20 phase and the CL-20/TNT cocrystal phase solvent. The solubility of the CL-20/TNT cocrystal in acetone
(i.e. the solvent) was lower than those of CL-20 and TNT, and
the solutes precipitated as CL-20/TNT cocrystals. Further-
more, owing to the low solubility of CL-20 in benzene, the
solubility of CL-20 in benzene/ethyl acetate (i.e. the solvent)
was lower than that of the CL-20/TNT cocrystal. Therefore,
the CL-20 phase and the CL-20/TNT cocrystal were nucleated
in order. The addition of methanol, a non-solvent for CL-20
and TNT, to acetone (i.e. the methanol/acetone solvent)
resulted in reduced solubility of the solutes. The solubility test
results revealed that, in this solvent, the solubility of the CL-
20/TNT cocrystal was slightly lower than those of the cofor-
mers and, hence, the cocrystal precipitated first under slow
solvent evaporation conditions. In other words, the nucleation
order of the cocrystal and coformers changed, owing to
differing solubilities of the solutes in different solvents.
Conversely, when the solvent evaporated in a moving air
environment at 313 K, the nucleation order of the solutes
changed, owing to the accelerated solvent evaporation rate. To
investigate the effects of this phenomenon, the reactor was
placed in a moving air environment at 313 K; the solvent
Figure 2 evaporation rate decreased and only the CL-20/TNT cocrystal
The formation process of the CL-20/TNT cocrystal in a benzene/ethyl formed during the crystallization process. Therefore, the
acetate solvent mixture. The eight lines from the bottom to the top are the
solvent evaporation rate rather than temperature and pressure
standard patterns of -CL-20, -CL-20, "-CL-20, TNT and the CL-20/
TNT cocrystal and the measured patterns of (1) "-CL-20, (2) coexisting plays an important role in cocrystal formation. The width of
"-CL-20 and CL-20/TNT, and (3) CL-20/TNT. the metastable zone, which is associated with supersaturation,

772 Shanhu Sun et al.  Competition between cocrystallization and separated crystallization J. Appl. Cryst. (2019). 52, 769–776

is correlated with the stirring speed and rate of temperature
change (Yang, 2015; Yang & Florence, 2017; Jat et al., 2013;
Kulkarni et al., 2013). In the present work, the experimental
results revealed that this width also varies with the solvent
evaporation rate. The width of the metastable zone can also
affect the nucleation order of the cocrystal and coformers.
These findings could be explained on the basis of the phase
solubility diagrams of the cocrystal and its coformers (Chow et
al., 2014; Lange & Sadowski, 2015). Under slow solvent
evaporation conditions, the concentration of solutes in the
solution increased gradually up to the phase lines of the
coformers or cocrystal. Therefore, the nucleation order of the
solutes depends on their solubilities in the solvent. On the
other hand, the solvent evaporation rate could affect the width
of the metastable zone and the stable state of cocrystal and
coformers with different lattice energies. The ternary phase
diagram of the solute crystallization process and, hence, the
nucleation order of solutes could be changed by adjusting the
solvent evaporation rate.
The solubility of the CL-20/TNT cocrystal in acetone is
lower than those of CL-20 and TNT. Owing to the slow
Figure 3
The phase diagrams of the crystallization process of saturated acetone
solutions of CL-20 and TNT under different solvent evaporation rate
conditions. (a) Slow solvent evaporation rate. (b) Fast solvent evapora-
tion rate. L denotes the liquid state.
J. Appl. Cryst. (2019). 52, 769–776 Shanhu Sun et al.
research papers
evaporation rate of the acetone solvent, the crystallization
process of the solutes yielded the phase line of the CL-20/TNT
cocrystal and, hence, the solutes nucleated as CL-20/TNT
cocrystals [see Fig. 3(a)]. Although the ternary phase diagram
changed under fast solvent evaporation conditions, the
nucleation order of the solutes remained the same [see
Fig. 3(b)], and the CL-20/TNT cocrystal precipitated.
The solubility test results revealed that the cocrystal solu-
bility in the benzene/ethyl acetate solvent mixture was higher
than that of CL-20 but lower than that of TNT. Therefore,
under slow solvent evaporation conditions, the phase line of
CL-20 occurred first. The CL-20 and TNT molecules began to
precipitate as CL-20/TNT cocrystals subsequently, when the
concentration of CL-20 and TNT reached the CL-20/TNT
cocrystal solubility. Owing to the decrease in concentration of
CL-20 in the solution, the nucleated CL-20 could be dissolved
and finally precipitated as a CL-20/TNT cocrystal phase [see
Fig. 4(a)]. The nucleation order of solutes changed under fast
solvent evaporation conditions, as indicated by the changing
ternary phase diagram of the solute crystallization process [see
Fig. 4(b)]. The supersaturation of the CL-20/TNT cocrystal
Figure 4
The phase diagrams of the crystallization process of saturated benzene/
ethyl acetate solutions of CL-20 and TNT under different solvent
evaporation rate conditions. (a) Slow solvent evaporation rate. (b) Fast
solvent evaporation rate.
 Competition between cocrystallization and separated crystallization 773
research papers
became higher than those of CL-20 and TNT. During the
crystallization process, the phase lines of CL-20 and TNT
occurred in order, and the separated crystallization products
of these lines were obtained under fast solvent evaporation
conditions.
Figure 5
The phase diagrams of the crystallization process of saturated methanol/
acetone solutions of CL-20 and TNT under different solvent evaporation
rate conditions. (a) Slow solvent evaporation rate. (b) Solvent was
evaporated in moving air environment at 313 K. (c) Fast solvent
evaporation rate.
774 Shanhu Sun et al.  Competition between cocrystallization and separated crystallization
The solubility of the CL-20/TNT cocrystal in the methanol/
acetone solvent mixture was lower than those of CL-20 and
TNT. Therefore, under slow solvent evaporation conditions,
the solute nucleated in the form of the CL-20/TNT cocrystal,
as shown in Fig. 5(a). For the same solvent, the formation
Figure 6
The phase diagrams of the crystallization process of saturated acetone
solutions of CL-20 and HMX under different solvent evaporation rate
conditions. (a) Slow solvent evaporation rate. (b) Fast solvent evapora-
tion rate. (c) Much faster solvent evaporation rate.
J. Appl. Cryst. (2019). 52, 769–776
 research papers
Table 4 conditions. Our results suggest that the crystallization rate has
The solubilities of Cl-20, TNP and the CL-20/TNP cocrystal. a considerable effect on the size and quality of the crystals.
Solvent Solute Components Peak area Solubility (mol l1) The tiny CL-20/TNP cocrystal with a large number of defects
prepared under rapid solvent evaporation rate conditions was
Ethyl acetate CL-20+TNP CL-20 434.99 0.85
TNP 250.11 0.80 unsuitable for the analysis of single-crystal data. However, the
CL-20/TNP CL-20/TNP 379.19 0.95 change of lattice parameters can result in significantly
different characteristic peak positions on the powder XRD
spectra compared with its coformers. Additionally, the
process of this cocrystal changed when the solvent was rapidly formation of cocrystals can be also demonstrated by the
evaporated in a moving air environment at 313 K [Fig. 5(b)]. spectral peak offset in, for example, solid-state nuclear
The phase line of CL-20 and the cocrystal occurred in order. magnetic resonance (SSNMR) spectroscopy or Fourier
The pure CL-20/TNT cocrystal was obtained after simulta- transform infrared (FT-IR) spectroscopy, caused by the
neous occurrence of the CL-20 and CL-20+CL-20/TNT change of intermolecular interactions (Chow et al., 2014; Vogt
cocrystal phase zone. However, the ternary phase diagram of et al., 2009). The crystal structure of the CL-20/TNP cocrystal
the solute crystallization process changed further under much was confirmed via powder XRD, SSNMR and FT-IR methods
faster solvent evaporation conditions. Moreover, the phase in our previous paper (Sun et al., 2019). Herein, the formation
lines of CL-20 and TNT occurred first and second (i.e. CL-20 mechanism of the CL-20/TNP cocrystal was identified by
and TNT precipitated first and second), respectively [see measuring the solubilities of CL-20, TNP and CL-20/TNP
Fig. 5(c)]. The separated crystallization products of these cocrystals in the solvent (see Table 4). As the table shows, the
components were therefore obtained. solubility of the CL-20/TNP cocrystal (0.95 mol l1) in ethyl
Similarly, the solubility of the CL-20/HMX cocrystal was acetate is higher than that of CL-20 (0.85 mol l1) and TNP
considerably higher than those of CL-20 and HMX in acetone.
The separated crystallization of HMX and CL-20 occurred
first during CL-20/HMX cocrystal formation under slow
solvent evaporation conditions [see Fig. 6(a)], and the
nucleation order remained unchanged under fast solvent
evaporation conditions [Fig. 6(b)]. This separated crystal-
lization was also achieved via the rotary evaporation method.
As Fig. 6(c) shows, the CL-20/HMX cocrystal could be
obtained via spray flash evaporation (Doblas et al., 2016) and
ultrasonic spray-assisted electrostatic adsorption methods
(Gao et al., 2014), where the solvent evaporation rates are
considerably more rapid than those employed in the present
report. These experimental results also confirmed that the
solvent evaporation rate is effective in changing the nucleation
order of cocrystals and coformers.
These findings indicate that the solubility and width of the
metastable zone play a key role in determining the precipi-
tated forms of the solutes. During the solvent evaporation, the
molecules in the solvent may form crystals in two ways: by
combining with (i) homologous molecules to form separately
precipitated phases or (ii) heterogeneous molecules to form a
precipitated cocrystal phase. If the nucleation concentration of
the cocrystal is lower than that of at least one of the separate
phases, the cocrystal will precipitate first, as indicated by the
formation process of the CL-20/TNT cocrystal in acetone. The
separate phases will precipitate first in the opposite scenario.
Therefore, cocrystals can be efficiently obtained by adjusting
the nucleation order of the cocrystal and coformers under
different conditions.
On the basis of this theory, the kinetic CL-20/TNP cocrystal
has been successfully obtained by adjusting the solvent
evaporation rate. During the preparation process, the sepa-
rated crystallization products of CL-20 and TNP were
obtained in ethyl acetate under slow solvent evaporation Figure 7
The phase diagram used to explain the formation process of the CL-20/
conditions. The CL-20/TNP cocrystal was successfully TNP cocrystal under different solvent evaporation rates. (a) Slow solvent
obtained using rotary evaporation under decompressed evaporation rate. (b) Fast solvent evaporation rate.

J. Appl. Cryst. (2019). 52, 769–776 Shanhu Sun et al.  Competition between cocrystallization and separated crystallization 775
research papers
(0.80 mol l1). Therefore, the separated crystallization of CL-
20 and TNP was obtained under slow solvent evaporation
conditions. However, the nucleation order of the solutes
changed under fast solvent evaporation conditions. The phase
line of the CL-20/TNP cocrystal occurred first and the solutes
precipitated as this cocrystal (see Fig. 7 for the phase diagram
used to explain the cocrystal formation process at different
solvent evaporation rates). This experimental result verified
our findings regarding the competition between cocrystalli-
zation and separated crystallization in a solvent.
4. Conclusions
In summary, the competition between cocrystallization and
separated crystallization in a solvent was systematically
investigated. The results revealed that the solvent system and
solvent evaporation rate can affect the nucleation order of the
coformers and cocrystal. The solubilities of solutes in different
solvents were investigated and experiments were performed at
different solvent evaporation rates. The corresponding results
indicated that the solubility and the width of the metastable
zone play a key role in the competition between cocrystalli-
zation and separated crystallization. In fact, a distinct solubi-
lity order of the solutes in different solvents, i.e. acetone,
methanol/acetone (6:1, v/v) and benzene/ethyl acetate (4:1,
v/v), was noted. This order determined the nucleation order of
the coformers and cocrystal under slow solvent evaporation
conditions. In addition, the width of the metastable zone,
which is associated with supersaturation, can be adjusted by
changing the solvent evaporation rate. On the basis of these
findings, the CL-20/TNP cocrystal was obtained under fast
solvent evaporation conditions. The results confirmed that
novel cocrystals can be obtained by adjusting the nucleation
order of the cocrystal and coformers. These findings explain
the mechanism of rapid crystallization methods [such as spray
flash evaporation, spray drying (Alhalaweh & Velaga, 2010)
and the ultrasonic spray-assisted electrostatic adsorption
methods]. Furthermore, the findings can be used as a guide for
the selection of cocrystal preparation methods.
Acknowledgements
We gratefully thank the reviewers for their helpful discussion
and constructive suggestions which lead to a substantial
improvement in the quality of the work.
Funding information
This work was financially supported by the National Natural
Science Foundation of China (No. 11402237 and No.
11402239).
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