Assessment of Co-sublimation for the Formation of Multicomponent Crystals

Article abstract of DOI:10.1021/acs.cgd.0c01148

The merits of co-sublimation and mechanochemistry as screening techniques for multicomponent crystal formation are compared. Several multicomponent crystals that can be formed both mechanochemically and by sublimation are investigated, allowing for a comparison between the relatively unknown technique of co-sublimation and a well-known, robust solid-state screening methodology. This work aims to determine the general utility and versatility of co-sublimation in the preparation of multicomponent crystals. Co-crystals and salts, as well as their polymorphs, have been investigated, and problems that can arise due to sublimation temperature differences, isomerization, and degradation are discussed. Co-sublimation is shown to be a valuable co-crystallization technique for the discovery and identification of new multicomponent materials.

Full text of DOI:10.1021/acs.cgd.0c01148

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Article
Assessment of Co-sublimation for the Formation of Multicomponent
Crystals
Jean Lombard,* Delia A. Haynes, and Tanya le Roex
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ABSTRACT: The merits of co-sublimation and mechanochemis-
try as screening techniques for multicomponent crystal formation
are compared. Several multicomponent crystals that can be formed
both mechanochemically and by sublimation are investigated,
allowing for a comparison between the relatively unknown
technique of co-sublimation and a well-known, robust solid-state
screening methodology. This work aims to determine the general
utility and versatility of co-sublimation in the preparation of
multicomponent crystals. Co-crystals and salts, as well as their
polymorphs, have been investigated, and problems that can arise
due to sublimation temperature differences, isomerization, and degradation are discussed. Co-sublimation is shown to be a valuable
co-crystallization technique for the discovery and identification of new multicomponent materials.
A number of other crystallization11−13 and computa-
INTRODUCTION
■
tional14,15 techniques have been employed for the screening
A multicomponent crystal forms when two or more different
of potential multicomponent crystals; however, due to the
molecules or ions solidify together as a crystalline single-phase
large number of variables, one can never be sure whether all
material. When such a material contains only neutral
solid forms have been identified. It is possible that multi-
components in a stoichiometric ratio, it is called a co-crystal.1
component crystal forms exist that are not detected due to
When the components are charged, such as when a hydrogen
biases imposed by the techniques themselves. For instance,
atom shifts from an acid to a base, a salt is formed. Such an ion
two coformers may not be soluble in the same solvents, which
pair may also crystallize alongside the neutral conjugate form
would inhibit their interaction and co-crystallization when
of either the acid or the base, in which case, the material can be
solution-based techniques are used. It has also been shown that
called a co-crystal salt.2 Multicomponent crystals are of
the solvent used can favor, or disfavor, specific types of
significant interest due to the potential improvement of
intermolecular interactions.16,17 Therefore, if all multicompo-
physical properties they may offer over the single-component
nent forms are to be discovered, it is important that a variety of
material.3 A multicomponent material can have different
crystallization techniques are used.10 This led us to study
mechanical properties,4 optical properties,5 thermal stability,6
crystallization by sublimation as an alternative to the standard
or reactivity7 when compared to its constituent species. The
solution-based crystallization techniques.
discovery of new multicomponent forms is therefore an
important step in the development of new materials.
Co-sublimation of neutral components to yield multi-
component crystals has not been studied in great depth, and
In order to identify new multicomponent forms, a molecule
when used, it is often simply reported as an inconsequential
of interest will often be co-crystallized with a large number of
other organic molecules, called coformers. Such systematic
detailthe general versatility and practicality of this technique
has not been discussed. During co-sublimation, neutral
multicomponent screening tests need to be simple, fast, and
components are simultaneously sublimed so that they may
efficient. Solution crystallization is perhaps the most widely
interact in the gas phase and crystallize as the multicomponent
used co-crystallization methodology; however, mechanochem-
form. A limited number of co-crystals have been formed by co-
ical grinding has been shown to require less time and effort8
and be more effective when it comes to screening for
multicomponent crystals.9,10 To carry out mechanochemical
Received: August 16, 2020
Revised: October 15, 2020
screening, the two components are either ground together by
hand in a mortar and pestle, or milled mechanically. A small
amount of solvent can be added to speed up the reaction
(liquid-assisted grinding; LAG) and the transformation usually
does not take longer than 30 min.
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Scheme 1. Summary of the Coformers Used for the Multicomponent Crystallizations, as Well as Their Predicted Vaporization
Enthalpies at 101.325 kPa23
Table 1. Summary of the Multicomponent Crystals Investigated, Which Includes the Sample Code Used in This Report, the
Coformers, Stoichiometry, Classification in Terms of Ionization, and the Temperature Used for Crystallization by Co-
sublimation (Tsubl
)
code
coformers
classification
Tsubl (°C)
code
coformers
PIP
classification
2:1 salt
1:1 salt
Tsubl (°C)
1
2
3
4
5
CAF
CAF
THE
THE
THE
FA
SAL
OA
SAL
OA
1:1 co-crystal
2:1 co-crystal
1:1 co-crystal
2:1 co-crystal
1:1 co-crystal
1:2 co-crystal
2:1 co-crystal salt
2:1 co-crystal salt
1:1 co-crystal
1:1 co-crystal
2:1 salt
140
120
140
160
120
140
140
140
100
100
100
9a
9b
10
SA
SA
MA
FA
FA
NA
140
120
120
170
NA
130
120
110
NA
190
PIP
a
PYR
PYR
PYR
3PIC
3PIC
OA
HMT
4PP
4PP
1:1 salt
11a
11b
1:2 co-crystal
1:1 co-crystal salt
1:2 co-crystal
1:1 co-crystal salt
1:1 salt
1:1 co-crystal
1:1 salt
1:1 co-crystal
a
INAM
23LUT
23LUT
23LUT
BA
6a
12a
12b
FA
FA
a
6b I
FA
FA
a
6b II
13
14
15
NA
PYG
GA
PYG
7 I
7 II
8
NAM
NAM
MA
BA
BPY
a
16
a
These crystal structures are presented here for the first time.
sublimation,18−22 and we have recently shown that molecular
salts and co-crystal salts can easily be formed by sublimation as
well.19 We generally employ a very simple sublimation
strategy: an evacuated Schlenk tube containing a mixture of
starting materials is heated using an oil bath. The use of more
sophisticated apparatus may improve the outcome of co-
sublimation experiments and produce higher yields. However,
our goal in this work was not to perfect the formation of a
particular co-crystal, but rather to study a wide variety of
systems so that some general observations can be made
regarding the technique of co-sublimation itself.
In this study, we report on the co-crystallization of 16
combinations of common organic molecules (Scheme 1, Table
1) by mechanochemistry (neat- and liquid-assisted grinding)
and co-sublimation in order to determine how these
techniques compare. Can sublimation compete with a robust
screening technique such as mechanochemistry? Does
crystallization by sublimation offer any advantage over other
methods? Common problems that can be encountered during
co-sublimation will be discussed, as well as how they can
potentially be overcome.
B
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Products were analyzed by PXRD and, where possible,
SCXRD. The majority of the crystal structures have been
reported previously; however, five new multicomponent
materials were identified (Table 1), and their crystal structures
determined. Full experimental details and information
regarding these crystal structures are given in the Supporting
Information.
Simple Co-crystals. A series of known co-crystals
containing the xanthines caffeine (CAF) and theophylline
(THE) were investigated (Figure 1). These co-crystals were
EXPERIMENTAL SECTION
■
Compounds were purchased from Sigma-Aldrich and used without
further purification (Scheme 1).
Mechanochemistry. A FTS1000 Shaker Mill from Form-tech
Scientific was used for mechanochemical experiments, which were
performed using two 15 mL stainless steel grinding jars each with two
6 mm steel balls as the milling medium. Milling was carried out either
without any solvent (neat) or with the addition of a small amount of
solvent (η = 0.25 μL mg−1), added with a micropipette. Unless
otherwise stated, samples were milled at room temperature for 20 min
at 20 Hz.
Co-sublimation. Co-sublimation was carried out by simulta-
neously subliming the starting materials in a Schlenk tube, with a
physical mixture of the starting materials placed together at the
bottom of the tube. The sublimation tube was evacuated (0.6 mbar
line pressure) and the end containing the coformers heated in an oil
bath. In most cases, a thin Schlenk tube (14 mm diameter, 220 mm
length) was used so that a temperature gradient formed along the
sides of the tube, along which crystals could deposit depending on
their vapor pressure (usually within a few hours). This temperature
gradient resulted in products crystallizing in separate bands, allowing
for easy removal of pure materials. In some cases, sublimation was
carried out using a larger Schlenk tube equipped with a water-cooled
cold finger on which crystals could grow.
Re-sublimation. The term re-sublimation is used to describe the
recrystallization by sublimation of pre-formed multicomponent
material. This is distinct from co-sublimation, where unreacted
coformers are sublimed. Experimentally, re-sublimation was carried
out in a similar manner to co-sublimation. Instead of unreacted
neutral starting materials, the pre-formed multicomponent materials
(formed by grinding) were added to the tube and sublimed to form
crystals of the multicomponent materials.
Powder X-ray Diffraction. Powder X-ray diffraction (PXRD) was
carried out at room temperature using a Bruker D2 Phaser benchtop
diffractometer equipped with a copper radiation source (λ = 1.54183
Å) and operating at 30 kV and 10 mA. Powdered samples were loaded
onto a zero-background holder and data collected in the range of 2θ =
4−40° at a speed of 0.5 s per scan (0.016° step size). Data analysis
was carried out using X’Pert HighScore Plus.24
Single-Crystal X-ray Diffraction. Single-crystal X-ray diffraction
(SCXRD) was carried out using a Bruker Duo diffractometer
equipped with a CCD area detector and an Incoatec IμS microsource
coupled with a multilayer mirror optics monochromator. Data were
collected at room temperature or 100 K, with the temperature being
controlled by an Oxford Cryosystems Cryostat (700 Series Cryo-
stream Plus). Single crystals were irradiated (MoKα, λ = 0.71073 Å)
and data collected and reduced using the Bruker software package
SAINT,25 operated through the Apex3 software. Data were
subsequently corrected for absorption and other systematic errors
using SADABS.26,27 Crystal structures were solved using direct
methods (SHELXT-18)28 within the graphical user interface
XSeed,29,30 and then refined using SHELXL-18.31 All atoms (except
hydrogen atoms) were refined anisotropically. Hydrogen atoms
bonded to carbon atoms were placed in calculated positions using
riding models, while O-H and N-H hydrogen atoms were located
using electron density maps and their positions allowed to refine.
Images were created using POV-ray,32 as visualized within XSeed.29,30
IR Spectroscopy. Fourier Transform Infrared spectroscopy
(FTIR) was carried out using a Bruker Alpha P spectrometer with
a Platinum ATR attachment.
Figure 1. Hydrogen bonding between coformers in the crystal
structures of co-crystals 1−5 formed by caffeine and theophylline.
Images were generated from crystal structures deposited in the
Cambridge Structural Database; refcodes are indicated with references
to the literature.33−37
straightforward to synthesize by both mechanochemistry and
co-sublimation. The starting materials do not degrade, and
their sublimation temperatures are comparable, such that there
exists a temperature at which both sublime at a similar rate,
ensuring the coformers are in the gas phase simultaneously.
The co-crystallization of caffeine and salicylic acid is described
here as a representative example. Co-crystals 2−5 can be
formed in a similar manner; details are reported in the
Supporting Information.
CAF and SAL. The combination of CAF and SAL produced
a 1:1 co-crystal (1) in all experiments. Grinding a 1:1 molar
ratio of caffeine and salicylic acid without the addition of
solvent led to the formation of 1 in quantitative yield. Co-
sublimation of the two starting materials (1:1 molar ratio) in
vacuo in a Schlenk tube at 140 °C (a temperature at which
both compounds sublime rapidly) yielded a powder of the co-
crystal in between bands of CAF and SAL crystals (Figure 2).
While the amount of 1 that formed was relatively small, the
three crystallization zones did not overlap, and pure co-crystal
powder could be collected for identification via PXRD (Figure
3).
RESULTS AND DISCUSSION
■
A number of multicomponent materials formed from small
organic molecules were investigated (Table 1). Results are
discussed below grouped according to either the type of
multicomponent material or the type of molecules used. In all
cases, co-crystallization was attempted by mechanochemical
grinding using a ball mill, and by vacuum sublimation.
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particularly by using additives42 and controlling the temper-
ature of the area where de-sublimation occurs.43,44 To our
knowledge, the use of sublimation to selectively prepare a
specific multicomponent crystal polymorph has not been
reported. Two sets of multicomponent polymorphs will be
presented here to compare their formation using solid-state
and gas-phase techniques.
FA and 23LUT. The combination of fumaric acid and 2,3-
lutidine is known to form a 1:2 co-crystal (6a) and a 2:1 co-
crystal salt (6b I) (CSD refcodes: RESFOL and RESFIF).45
Using co-sublimation, we discovered that a second polymorph
of the co-crystal salt, 6b II, could also be produced. Due to the
similarities between these materials, the crystal structures of 6a
and 6b I were re-determined along with that of 6b II.
The crystal structure of 6a comprises hydrogen-bonded
base-acid-base trimers, while the co-crystal salts (6b I and 6b
II) are made up of infinite hydrogen-bonded nets of FA and
FA− with pendant cations (Figure 4). In both 6b I and 6b II,
Figure 2. Schematic representation of the co-sublimation of CAF and
SAL in a Schlenk tube, which yielded a powder of the co-crystal in
between bands of CAF and SAL crystals.
Figure 3. Experimental powder patterns of 1 obtained from (a) co-
sublimation and (b) neat grinding, compared to (c) the pattern
simulated from single-crystal data obtained from the CSD (refcode:
XOBCAT).33
Co-crystals 2−5 could be prepared by co-sublimation in a
similar fashion. From these simple co-crystallizations, we
observe a general trend. When two starting materials are
combined using co-sublimation the more volatile component
crystallizes high up in the sublimation tube, in the coolest
region. The least volatile component crystallizes lower down in
the tube where it is warmer, and the co-crystal crystallizes
between these two limits. The three crystallization zones do
not usually overlap, allowing the collection of pure co-crystal
from these experiments.
In the case of 1−5, the co-crystals obtained by co-
sublimation are equivalent to those formed mechanochemi-
cally. They were quick to form, and in each case, co-
sublimation was successful on the first attempt, provided a
suitable sublimation temperature, at which both components
can sublime, was chosen.
Polymorphic Systems. Molecules can often arrange in
more than one way when they solidify, and thereby form
polymorphs. Even though such polymorphs contain the same
components, they can differ with regard to their physical
properties.38 Unfortunately, regulating which form is obtained
is not always easy. It is possible to selectively isolate a
particular polymorph of a pure- or multicomponent material
when carrying out crystallizations in solution or mechano-
chemically, by altering variables such as the temperature and
the solvent used.39−41 It is also possible to selectively obtain
polymorphs of molecular materials when using sublimation,
Figure 4. Packing diagram for 6b I (top) and 6b II (bottom), both
viewed along [100]. Each polymorph is made up of identical layers
that differ in how they stack.
each hydrogen fumarate ion forms an additional charge-
assisted hydrogen bond with a lutidinium cation which is
positioned inside each of the apertures in the nets (Figure 4).
Two of these nets pair up to form a bilayer such that the
apertures align. Each of these holes in the bilayers is then filled
with two cations, one bonded to each net. The layers exist in
both polymorphs, and they are identical in this regard.
However, the way in which the layers stack is slightly shifted
in each form (Figure 4).
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All three crystal forms were produced mechanochemically,
but not as pure materials. Co-crystal 6a was obtained by
milling a 1:2 ratio of FA and 23LUT; however, using a 2:1
ratio led to formation of both polymorphs 6b I and 6b II
simultaneously (with the peaks for 6b II in the powder pattern
being much less prominent) (Figure S7). Additionally, when
ground, 6b II partially converted to 6b Ieven during
preparation of a powdered material for PXRD. This makes
sense considering the polymorphs only differ by a slight shift of
the layers within their structures. However, the transformation
did not proceed to completion; some 6b II remained even
after 3 h of milling.
Heating FA and 23LUT together under vacuum produced
all three forms by sublimation. Different ratios of starting
materials were used, but this did not appear to have an effect
on the product obtained, and co-sublimation of these
molecules most often produced a mixture of 6b I and 6b II,
as single crystals, irrespective of the ratios used. On occasion,
these crystals were accompanied by a powder of 6a (Figure 5).
Figure 6. Hydrogen bonding in (a) 7 I and (b) 7 II. Images generated
from published crystal structures.46
Co-subliming NAM and BA in a 1:1 molar ratio at 100 °C
led to formation of polycrystalline 7 I and 7 II, as a mixture.
BA and NAM crystallized above and below the multi-
component crystals, respectively. Conversely, depending on
the solvent used, grinding a 1:1 molar ratio of these starting
materials produced either 7 II or a material with a PXRD
pattern corresponding to a previously reported material for
which the crystal structure has not been determined.46 In the
published study, more variables were explored (such as
different solvent additives and milling duration) and the
authors found that it was possible to form both 7 I and 7 II
mechanochemically, and determined the crystal structures
from powder diffraction data.
In general, we have observed that co-sublimation can be
used for the formation of polymorphic multicomponent
crystals, but not in a selective mannermixtures of
polymorphs are obtained. Sublimation apparatus which allows
for more precise control over temperature may be useful in this
regard. However, polymorphs that are not easily identified in
an initial series of LAG screening experiments can be identified
using co-sublimation. These may form as powders, but, as we
see in the case of 6b I and 6b II, can also sublime as single
crystals. Co-sublimation could therefore be useful both for the
identification of polymorphs and for the determination of their
crystal structures.
Figure 5. Simulated powder diffraction patterns for (a) 6a, (b) 6b I,
and (c) 6b II. A mixture of these three forms can be obtained by co-
sublimation (d).
Co-crystallization When Molecules Have Different
Sublimation Temperatures. For multicomponent crystals
to form by co-sublimation, the coformers need to encounter
one another in the gas phase. However, the components to be
co-sublimed need not have the same sublimation temperature
for there to be enough of each present in the gas phase. Often,
as in the previous examples, each coformer crystallizes
separately from sublimation, with the multicomponent material
crystallizing in between them. However, if one coformer has a
much lower sublimation temperature than the other, it may
sublime and crystallize as the molecular material completely
separately from the other component.
Fortunately, it is possible to modify the amount of each
component present in the gas phase to some extent. The
simplest way to go about this is by changing the relative
amounts of the starting materials used as this will influence the
relative amounts of each coformer in the gas phase during the
initial stages of co-sublimation. Technically, the amount of
each component in the gas phase at equilibrium is only
It should be noted that single crystals of all three forms were
also obtained from solution, also as mixtures that mostly
contained only 6b I and 6b II (crystals of 6a were obtained
only once). The same was observed during re-sublimation of
pre-formed 6a, 6b I, and 6b II, i.e., crystals of the two
polymorphs formed, occasionally accompanied by the co-
crystal.
NAM and BA. The combination of nicotinamide and
benzoic acid is known to form two 1:1 co-crystal polymorphs
(7 I and 7 II) (CSD refcodes: GAZCES and GAZCES01).46
Lukin et al. reported two further polymorphs that could be
obtained mechanochemically; however, their structures have
not been determined.46 In both polymorphs, 7 I and 7 II, the
carboxylic acid functional group of BA forms a hydrogen bond
to the pyridine nitrogen atom of NAM. However, in 7 I, the
amide groups also hydrogen bond to form NAM dimers, while
in 7 II, the N−H and O of each amide interact with two
different NAM molecules (Figure 6).
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dependent on the vapor pressures of the solids, and not on the
quantities used. However, because co-crystallization starts as
soon as a sublimation experiment begins (as soon as heat is
applied), the compound with the lower volatility may not reach
equilibrium before co-crystallization occurs. Adding excess of
the less volatile solid allows more of that coformer to enter the
gas phase initially. Another possibility is to heat the coformers
at two different temperatures, so that they sublime almost
simultaneously; i.e., the vapor pressures of the two components
are equalized. Such an example has been published recently
where this technique was shown to be very effective.22 It is also
possible to control relative amounts of coformers in the gas
phase by pre-forming the multicomponent material, with the
desired stoichiometry, as a powder before sublimation is
carried out. When this multicomponent material is re-sublimed
under vacuum conditions, both coformers can potentially enter
the gas phase simultaneously, in the correct ratio. In this case,
sublimation has to be coupled with another technique, such as
grinding, but it has the potential to form diffraction-quality
single crystals. Three cases are reported here to demonstrate
each of these approaches.
SA and PIP. The combination of succinic acid and
piperazine is known to form a 2:1 salt (9a) (CSD refcode:
IMEZIL48) and a 1:1 salt (9b) (CSD refcode: BURWEQ49).
Note that 9a is classified as a co-crystal in the literature, but
our structure determination indicates clearly that it is a salt:
C−O bond lengths and FTIR indicate the presence of
carboxylate groups. The crystal structures of 9a and 9b were
re-determined for confirmation (Figure 7; details are given in
the Supporting Information).
MA and BPY. The combination of maleic acid and 4,4′-
bipyridine is known to form a 2:1 salt (8) from solution, the
structure of which has been previously determined (CSD
refcode: GIPQAX01).47 This adduct was crystallized from
solution; however, we observed that isomerization frequently
occurred in solution so that a fumaric acid co-crystal formed
instead. In our hands, salt 8 could be made mechanochemically
by grinding a 2:1 ratio of MA and BPY, but when recrystallized
from solution, the FA co-crystal formed instead. The simplest
way of obtaining single crystals of 8 turned out to be co-
sublimation, even though the starting materials differ greatly
with regard to sublimation temperature (BPY sublimation
starts at 50 °C and MA at 100 °C). When a 2:1 ratio of starting
materials was used, the salt did not form, as BPY is too volatile
compared to MA, and the starting materials sublimed
separately. However, when a 4:1 molar ratio of MA:BPY was
used, co-sublimation at 100 °C was successful and single
crystals of the salt formed within 4 h. It is therefore possible for
the gas-phase coformer concentration during co-sublimation to
be altered by changing stoichiometry and using an excess of
the least volatile starting material.
FA and 23LUT. The formation of co-crystal 6a and the co-
crystal salt polymorphs 6b I and 6b II were described earlier in
this paper; however, it is pertinent to mention them again at
this stage as the two coformers have vastly different volatilities.
The vaporization enthalpy of FA is roughly 66.0 kJ mol−1,
compared to that of 23LUT, which is 39.1 kJ mol−1 (Scheme
1). Apparatus has been designed in our group that can be used
to heat two compounds at two different temperatures under
vacuum (Figure S13).18 The apparatus consists of a U-shaped
tube with a removable bulb at each end in which compounds
are placed. The tube can be placed under vacuum and the
bulbs suspended in adjacent oil baths or heating pockets so
that each compound may be sublimed at the desired
temperature. In this way, FA was sublimed at 200 °C, while
23LUT was vaporized at 40 °C, so that both compounds
entered the gas phase simultaneously. The crystals that formed
in the connecting tube could be identified by PXRD and unit
cell determinations as 6b I and 6b II (Figure S14). Heating
coformers at different temperatures is therefore another useful
method of obtaining multicomponent crystals when vapor
pressures differ.
Figure 7. Top: Hydrogen-bonded ribbons in salt 9a that run along
the a axis. Bottom: Hydrogen-bonded layer in salt 9b, viewed along
[101].
Grinding SA and PIP in a 2:1 molar ratio (neat- or liquid-
assisted), led to complete conversion to the salt 9a, while the
use of a 1:1 ratio led to the formation of 9b. However,
subliming a number of different molar ratios of SA and PIP at
120 and 140 °C (1:1, 2:1, and 4:1) led to the formation of
single crystals of 9b only. This may be a result of the
differences in vapor pressure of the two coformers. PIP is very
volatile and will even slowly sublime at room temperature. On
the other hand, SA only sublimes at 110−120 °C, which is why
co-sublimation was carried out at a higher temperature. At 120
and 140 °C, both compounds can sublime; however, PIP will
always start to sublime faster than SA, with co-crystallization
initiated before SA sublimation reaches equilibrium. This
means that, as soon as SA sublimes, it immediately crystallizes
with the PIP already present in the gas phase to form the 1:1
product (9b) instead of staying in the gas phase until SA is
concentrated enough to form the 2:1 product. In other words,
it is easier for the 1:1 salt to form than for the 2:1 salt that
requires two SA molecules in the gas phase for every one
molecule of PIP. Unfortunately, using an excess of succinic
acid did not rectify the problem.
Fortunately, both 9a and 9b were able to re-sublime if pre-
formed by grinding (9a at 160 °C and 9b at 140 °C). When re-
sublimed, 9a recrystallized as 9a, and 9b recrystallized as 9b,
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with some starting materials crystallizing separately. During re-
sublimation of a multicomponent crystal, the components can
vaporize individually. However, it is also possible that both
coformers sublime simultaneously in either a 1:1 or a 2:1 ratio
(in the case of 9a and 9b), so that either salt could in theory
deposit again from the gas phase. In this case, the gas-phase
stoichiometry is defined by the starting salts, and the volatility
differences experienced during co-sublimation are no longer a
limiting factor. Our previous work has indicated that some
molecules or ions remain hydrogen bonded when they enter
the gas phase.19 If pairs or clusters of molecules specific to a
particular material are retained in the gas phase, it would
further drive crystallization of that material. This is possibly
what is happening here too: we are not seeing interconversion
between 9a and 9b in the gas phase; 9b only re-sublimes as 9b.
Re-sublimation is therefore a viable alternative to co-
sublimation if single crystals are desired.
Clearly, compound volatility and the compatibility of
sublimation temperatures are important factors when growing
multicomponent crystals by sublimation. Coformers need to be
present in the gas phase in the correct stoichiometry for
multicomponent crystals to form. Gas-phase concentrations
can be manipulated to some extent by changing the ratio of
starting material used, heating coformers at different temper-
atures, or by pre-forming multicomponent materials before
sublimation so that the stoichiometry is pre-determined.
Co-crystallization When Coformers Can Isomerize.
The formation of certain multicomponent crystals can be
hindered by unwanted isomerization of the coformers.50 For
example, in solution, maleic acid isomerizes to fumaric acid in
the presence of a base. It has been reported that a co-crystal
between maleic acid and pyridine could not be obtained, as
pyridine catalyzes the transformation of maleic acid to fumaric
acid.50 Mohamed et al. reported that they could not form a co-
crystal or a salt with MA and PYR as this isomerization
happened within a few hours, while crystals took a week to
form. Isomerization in the gas phase may proceed differently
than in solution, and sublimation may thus present a new
synthetic pathway for multicomponent materials containing
these types of coformers. Additionally, crystal growth and
nucleation generally occur much faster during co-sublimation.
Crystals usually form within a few hours, and so it may be
possible to form a co-crystal with maleic acid before
isomerization can occur. We have already discussed a salt
containing MA and BPY (8)this salt was easily formed by
co-sublimation, while solution crystallization was often
accompanied by a fumaric acid co-crystal due to isomerization.
Here, we report three new co-crystals that were discovered by
co-sublimation involving maleic acid.
from grinding led to the same three multicomponent products
crystallizing.
When MA and PYR were combined in solution (using a
variety of common organic solvents and mild heating to aid
dissolution), they reacted covalently to form a zwitterionic
molecule (CSD refcode: SUCPYR).51 However, it was
eventually also possible to crystallize 10 from solution when
vials were placed in the refrigerator at 4 °C. Carrying out
crystallizations at low temperature allowed crystals to form
quickly (within 24 h), potentially trapping maleic acid before
isomerization could occur.
FA and PYR. Grinding a 1:2 molar ratio of fumaric acid and
pyridine led to crystallization of the new co-crystal salt that was
mentioned above, 11b. The co-crystal 11a was never obtained
from grinding; however, another unknown product was
obtained when FA and PYR were milled in a 1:1 ratio.
Sublimation of a 1:1 mixture of the two starting materials at
170 °C yielded a powder of this unknown product as well as
single crystals of 11b. It is interesting that crystals of 11a (a
fumaric acid:pyridine co-crystal) could be obtained when co-
subliming MA and PYR, but not when subliming FA and PYR.
The reason for this may be the observed higher sublimation
temperature of FA (∼140 °C) compared to MA (∼100 °C).
MA and 3PIC. There are no multicomponent forms of
maleic acid and 3-picoline reported in the CSD. Milling
different ratios of MA and 3PIC together led to the formation
of a powder with an unknown PXRD trace. Crystallizing these
starting materials from solution (using common organic
solvents) led to the formation of another powdered material
with a PXRD trace not matching either starting material, or the
unknown obtained from grinding. Neither of these unknown
materials has been identified, but single crystals of a third
material were finally obtained by co-sublimation at 130 °C.
The crystal structure was determined, which identified the
crystals as a new 1:1 co-crystal salt of 3-picoline and fumaric
acid (12b). In the CSD, there is also a 1:2 co-crystal formed by
FA and 3PIC (12a, refcode: MOGWAI).52 Interestingly, when
FA is dissolved directly in 3PIC, crystals of 12a are obtained
after 24 h, with no 12b forming (similar to what was observed
in the literature). When the powder pattern for 12b was
simulated, it did not correspond to either of the powdered
materials obtained from mechanochemistry or solution
crystallization of MA and 3PIC, and neither did 12a. Thus
far, 12b has only been obtained by sublimation.
From these examples, it is clear that co-sublimation can be
very useful for obtaining new multicomponent crystals. While
isomerization does occur in the gas phase and in solution, the
crystallization mechanism appears to be faster, potentially
leading to the formation of different materials. It is also clear
that the materials formed by mechanochemistry are not always
the same as those formed by sublimation.
Salts by Co-sublimation. It seems unlikely that salts
would form by sublimation, as ions would not be stable in the
gas phase. However, our previous work has shown that salts
can indeed crystallize by co-sublimation.19 In this paper, so far
a number of salts produced by co-sublimation have been
presented. Specifically, the salts 8, 9a, 9b, and 10 and the co-
crystal salts, 6b I, 6b II, 11b, and 12b can all be obtained from
co-sublimation of neutral coformers, and generally crystallize
from sublimation as diffraction-quality single crystals. One
further noteworthy example will be highlighted here.
MA and PYR. As previously stated, no known multi-
component forms of maleic acid and pyridine have been
reported. Milling different ratios of MA and PYR led to the
formation of a material with a PXRD trace not matching either
starting material. Single crystals of this material, a new 1:1 MA-
PYR salt (10), were obtained by sublimation. Heating a 1:1
mixture of the two starting materials in a large Schlenk tube in
vacuo at 120 °C yielded single crystals of 10 on the cold finger
after a few hours, and its crystal structure could be determined.
Unfortunately, these crystals formed concomitantly with two
other types of crystals. These were a 1:2 co-crystal between
fumaric acid and pyridine (11a, CSD refcode: GUKWOZ)50
and a new 1:1 co-crystal salt, also containing fumaric acid and
pyridine (11b). Re-sublimation of the MA-PYR salt obtained
NA and OA. Co-subliming a 1:1 molar ratio of nicotinic acid
and oxalic acid for 7 h at 120 °C led to crystallization of a 1:1
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salt containing the two coformers (13, CSD refcode:
PYG and HMT. The combination of pyrogallol and
hexamethylenetetramine is known to form a 1:1 co-crystal
(14), the structure of which has previously been solved from
powder diffraction data (CSD refcode: BINDIL).54 Grinding a
1:1 molar ratio of the starting materials together produced 14
in quantitative yield. Co-sublimation of the two starting
materials at 110−120 °C for 6 h afforded crystalline material
with a powder pattern matching that of 14. However, one
additional peak was observed which corresponds to a co-crystal
between 1,2-dihydroxybenzene and HMT. Unit cell determi-
nation of single crystals confirmed the presence of this co-
crystal in the products of the co-sublimation experiment (CSD
refcode: CERXIH).55 Pyrogallol clearly partially degrades
during sublimation, but not before the majority co-crystallizes
with HMT.
HEWWAI53) (Figure 8). The salt formed in quantitative
GA and 4PP. The combination of gallic acid and 4-
phenylpyridine is known to form a 1:1 salt (15, CSD refcode:
TICZIQ).56 Salt 15 can easily be made by liquid-assisted
grinding, but in this case, GA degradation entirely prevents
formation of 15 by co-sublimation. It was possible to sublime
the gallic acid monohydrate starting material on its own to
form an anhydrous polymorph of gallic acid (CSD refcode:
IJUMEG06), as reported in the literature.57 However, GA also
tends to decarboxylate and degrade at high temperatures.
During co-sublimation with 4-phenylpyridine, the gallate salt
did not form; instead, powder diffraction shows the formation
of products which do not match the salt or either starting
material. We suspect that these are multicomponent materials
containing GA decomposition products, such as pyrogallol or
dihydroxybenzenes. It was possible to identify one such
product by single-crystal diffraction, namely, a pyrogallol:4-
phenylpyridine co-crystal 16, the structure of which is
described in the Supporting Information.
Figure 8. (a) Powder diffraction pattern for 13 simulated from single-
crystal data obtained from the CSD (refcode: HEWWAI),53
compared to experimental powder patterns of 13 obtained from (b)
co-sublimation and (c) grinding.
yield, and no starting materials sublimed separately or
remained unreacted. Grinding a 1:1 molar ratio of the starting
materials together similarly produced 13 in quantitative yield.
According to the literature, this salt can also be formed by
crystallizing the coformers from solution; however, our
experiments prove that co-sublimation can definitely also be
used for the efficient production of a molecular salt.
Co-crystallization Using Heat-Sensitive Molecules.
Not all coformers are well suited for co-sublimation, as some
compounds can degrade or melt during heating. For example,
maleic acid starts to degrade above 100 °C. Despite this, we
have demonstrated its use in co-sublimation (see above). Being
aware of the heat sensitivity of coformers is crucial in co-
sublimation experiments, so that appropriate measures can be
taken to overcome any degradation. When forming salt 8,
which contains MA, the temperature of co-sublimation had to
be restricted to 100 °C. Co-crystallization was achieved by
using specific ratios of starting materials to ensure sufficient
amounts of each coformer in the gas phase. Of course, this will
not always worksome co-crystals and salts cannot be formed
by co-sublimation at all. Another potential solution to this
problem is to reduce the pressure in the system, which would
allow for sublimation to occur at a lower temperature.
Problems involving heat-sensitive coformers can thus poten-
tially be solved by generating a stronger vacuum, although this
was not explored in this study. Further examples concerning
heat-sensitive coformers are discussed below.
SA and PIP. Consider again the case of succinic acid and
piperazine. It was determined that salt 9b re-sublimed at 140
°C, while salt 9a only re-sublimed at 160 °C. Additionally,
during co-sublimation at 140 °C, salt 9b was obtained, while
9a did not form. It is possible that 9a would also be able to
form if co-sublimation were carried out at 160 °C. However, it
was not possible to use such a high temperature because SA
would melt at this temperature. If co-sublimation could be
carried out at a lower pressure, using a more powerful vacuum
pump, it should be possible to prevent SA from melting before
it sublimes, which could allow for 9a to form by co-
sublimation.
Coformer decomposition or melting can therefore be a
major hindrance during sublimation. However, it is clear that
there are some ways to overcome heat sensitivity (at least
partially), such as carefully controlling temperature, pressure,
and reagent ratios. Additionally, new multicomponent
materials containing decomposition products may be discov-
ered inadvertently.
CONCLUSION
■
We have shown that co-sublimation is an efficient crystal-
lization technique for the formation of co-crystals, salts, and
the intermediate co-crystal salts. When two starting materials
have similar sublimation rates and temperatures, co-sublima-
tion can be a quick and easy way to determine whether a
multicomponent crystal exists, and potentially to obtain single
crystals of the material. In fact, even when sublimation
temperatures differ, co-sublimation can still be successful.
When this temperature difference is very large, the gas-phase
coformer concentrations can be manipulated by changing
coformer stoichiometries, pre-forming multicomponent crys-
tals by mechanochemistry, or by heating the starting materials
at two different temperatures. In this way, even multiple
polymorphic forms can be obtained by co-sublimation. Our
simple sublimation apparatus did not allow for sufficiently
precise temperature control to selectively form particular
polymorphs, but a new polymorph of a known co-crystal salt
was identified from single crystals obtained by co-sublimation
(6b II). Co-sublimation is more challenging when one of the
coformers can isomerize or degrade during sublimation, but we
have demonstrated how these problems can be overcome and
H
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Notes
have successfully produced multicomponent crystals contain-
ing maleic acid by co-sublimation. When coformer decom-
position could not be prevented, degradation products, as well
as multicomponent crystals formed with them, could easily be
identified by SCXRD.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank the Wilhelm Frank
Scholarship Fund and Stellenbosch University for funding, as
well as Dr. Leigh Loots for assistance regarding refinement of
the crystal structure of 16.
Mechanochemistry is a rapid and efficient crystallization
technique convenient for screening for multicomponent
materials. Unfortunately, single crystals are not produced. On
the other hand, co-sublimation successfully produced multi-
component crystals in most of the examples presented here,
and often formed diffraction-quality single crystals. We also
observed that the products formed during co-sublimation are
not always the same as those obtained from mechanochemistry
(or solution crystallization), which has allowed us to discover
new multicomponent crystals (10, 11b, and 12b), one of
which has not been obtained using any other technique (12b).
It would be interesting to attempt a number of failed co-
grinding experiments by co-sublimation, but unfortunately,
these are rarely published. Further study into the mechanisms
of gas-phase crystal growth is definitely warranted.
Co-sublimation is more laborious than mechanochemical
grinding and will therefore not replace it as a routine
technique. However, sublimation is clearly a valuable co-
crystallization technique for the discovery and identification of
new multicomponent materials. We encourage the incorpo-
ration of co-sublimation into screening protocols in addition to
other crystallization methodologies, especially when working
on complex or problematic systems. In our opinion, a
multitechnique approach is always best.
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̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.0c01148.
■
̌
̌
́
sı
Full details of all experimental procedures and analysis of
powder X-ray data and FTIR spectra. Single-crystal X-
ray diffraction data for 6a, 6b I, 6b II, 8, 9a, 9b, 10, 11b,
12b, and 16 (PDF)
Accession Codes
CCDC 2023387−2023396 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Jean Lombard − Department of Chemistry and Polymer Science,
Stellenbosch University, Matieland 7602, Republic of South
Africa; orcid.org/0000-0002-9225-8994; Email: jeanl@
sun.ac.za
Authors
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Sugden, I. J.; Hernandez, H. H.; Naumov, P.; Mohamed, S. Efficient
Screening for Ternary Molecular Ionic Cocrystals Using a
Complementary Mechanosynthesis and Computational Structure
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Prohens, R. Combined Virtual/Experimental Multicomponent Solid
Forms Screening of Sildenafil: New Salts, Cocrystals, and Hybrid
Salt−Cocrystals. Cryst. Growth Des. 2018, 18, 7618−7627.
Delia A. Haynes − Department of Chemistry and Polymer
Science, Stellenbosch University, Matieland 7602, Republic of
South Africa; orcid.org/0000-0002-8390-5432
Tanya le Roex − Department of Chemistry and Polymer Science,
Stellenbosch University, Matieland 7602, Republic of South
Africa; orcid.org/0000-0002-1874-1996
Complete contact information is available at:
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I
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