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Co-Crystal Screening by Vapor Sorption of Organic Solvents

Heiner Veith, Christian Luebbert, Naír Rodríguez-Hornedo, and Gabriele Sadowski*
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sı Supporting Information

ABSTRACT: The formulation of active pharmaceutical ingredients (APIs) as

pharmaceutical co-crystals (CCs) is a promising way to overcome the poor aqueous
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solubility and therewith poor bioavailability of many APIs. Identifying suitable coformers
(CFs) that form CCs with the API is a major challenge during CC development. In this
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work, we developed a material-sparing and simple approach to identify whether a certain

API/CF combination can form CCs. This approach is based on the solvent vapor sorption
of API/CF combinations in a dynamic vapor-sorption apparatus. CC formation is
detected based on the solvent vapor uptake behavior of an API/CF crystal mixture. This
screening approach was applied for carbamazepine (CBZ)/nicotinamide and CBZ/
acetylsalicylic acid systems using ethanol and methanol as the volatile solvents. CC
formation was observed for both systems with both solvents used. Additionally, the
process and success of CC formation by vapor sorption is explained by predicted phase
diagrams using the Perturbed-Chain Statistical Associating Fluid Theory. The developed
approach is beneficial over co-grinding and other batch crystallization approaches in that
it can be performed with only a few milligrams of the API, low solvent consumption, and a solvent sorption versus time behavior for
identifying CC formation.

1. INTRODUCTION growth.8 Given the ubiquitous presence of water vapor in the

The often poor aqueous solubility of active pharmaceutical environment, it is important to recognize that CC formation
ingredients (APIs) can be counteracted by the formulation as might also occur unintentionally in a formulation due to water
co-crystals (CCs).1 CCs are composed of the API and a release from hydrates in the formulation (hydrates of CC
coformer (CF) (could be another API) within a crystalline components or additional excipients).12−14
The use of organic solvent vapors might lead to CC
lattice in a stoichiometric ratio.2 In order to efficiently identify
formation more quickly compared to using water vapor.15,16
possible CF candidates, several screening methods have been
Huskić et al.15 used a benchtop X-ray diffractometer with
developed such as co-grinding (dry or using a solvent-drop),1
saturated solvent vapors of ethanol and methanol to study the
cooling crystallization, and reaction crystallization (often
CC formation of different carbamazepine (CBZ) CCs. Braga et
performed as slurry crystallization).3−6 They all aim to find
al.17 found that different organic solvent vapors lead to the
CCs with minimal resource consumption and time. In a
formation of CCs and solid complexes with different
previous study, we proposed a CC screening method based on
stoichiometries, depending on the relative solubility of the
slurry crystallization.7 This allowed for identifying API/CF
pure components in that solvent. Furthermore, they raised the
screening compositions with the highest chance of CC
question of whether all solid reactions might be caused by
formation.
water vapor in the atmosphere.
Decreasing the amount of organic solvents required for the
The use of water vapor deliquescence of a CC to evaluate its
screening or using water instead of organic solvents will lead to
stability against relative humidity was recently investigated in
a more environmentally friendly screening and production of
our previous work.18 The present work uses predicted
CCs. A method to reduce the amount of the solvent required
thermodynamic phase diagrams to identify conditions under
for the CC screening is the use of solvent vapors instead of a
which CC formation by organic vapor sorption is favorable and
liquid solvent. The CC formation from a physical mixture of
to investigate the influence of temperature and organic solvent
the pure components due to water vapor sorption has been
reported in the literature.8−11 Jayasankar et al.8 showed that
the underlying mechanism by which moisture sorption leads to Received: March 30, 2021
CC formation is based on the hygroscopicity of CC Revised: May 26, 2021
components and the ability of a component to deliquesce Published: June 9, 2021
(form a saturated liquid phase from the sorbed moisture).
Dissolution of both CC components in the deliquesced small
liquid phase generates CC supersaturation, nucleation, and

© 2021 American Chemical Society https://doi.org/10.1021/acs.cgd.1c00355

4445 Cryst. Growth Des. 2021, 21, 4445−4455
Crystal Growth & Design
vapors on the reaction. Based on this, a CC screening method
using dynamic vapor sorption (DVS) is proposed and
evaluated for the API CBZ with the two CFs [acetylsalicylic
acid (ASA) and nicotinamide (NA)], two solvents (ethanol
and methanol), and temperatures (298 and 313 K).
2. THEORY
Thermodynamic phase equilibria are required to understand
CC formation from the individual pure components in the
presence of a vapor phase. This process can be divided into
two steps, first the moisture uptake as well as dissolution of the
API and CF crystals (deliquescence; see I) and second, the CC
crystallization from the liquid phase (II).8
deliquescence
API(s) + CF(s) ========= ⇒ API(l) + CF(l) (I)
API(l) + CF(l) ⇔ CC(s) (II)
As shown in II, CC formation only occurs from the liquid
phase. The solubilities of API, CF, and CC as well as vapor−
liquid equilibria determine the occurrence of deliquescence,
dissolution of API and CF, generation of CC supersaturation,
and CC formation. Moisture sorption and deliquescence
(water vapor) are investigated in another work.19 The concepts
are analogous to those considered with organic vapor sorption
at their relative saturation (RS) in the surrounding vapor
phase.
2.1. Solubility of the API and Coformer. The solubility
of the API and the CF in a liquid mixture was obtained from
ÅÄÅ
the solid−liquid equilibrium, according to eq 1.20
ÅÅ Δh SL ji T zy
xi = ·expÅÅÅÅ− i ·jjj1 − SL zzz
ÅÅ R ·T k j Ti z{
1
ÅÇ
É
yzÑÑÑÑ
γi
ΔcpSL, i ijj ij TiSL yz TiSL z
·jjlnjjj zz − + 1zzzÑÑÑÑ
z
R jj jk T z{
zÑÑ
k {ÑÖ
− 6.
T (1)
The mole-fraction solubility xi of APIs or CFs depends on
their activity coefficient γi and on their crystal properties (i.e.,
the melting temperature TSL i , the melting enthalpy Δhi , and
SL
the change of heat capacity upon melting ΔcP,i). R is the ideal
SL
gas constant [8.314 J (mol K)−1], and T is the temperature. γi
explicitly accounts for all interactions between the components
in the liquid phase. It is possible to calculate the solubility of
any component even if the component is metastable and might
transform to another crystal form, that is, the solubility line
extends into the metastable region.
2.2. CC Solubility. The equilibrium constant for the
reaction in II is the solubility product Ks,CC according to
K s,CC = ∏ (xi·γi)ν
i
= (xAPI·γAPI)νAPI ·(xCF·γCF)νCF
i (2)
xAPI and xCF are the mole fractions of the dissolved API and CF
in a CC saturated solution, which represent the CC solubility.
The subscript i represents the generalized CC components. γi
are the activity coefficients, and νi are the stoichiometric
coefficients of the API and CF in the CC. The solubility
product can be fitted to the solubility of the CC in any solvent.
Since it does not depend on the solvent, it afterward allows
predicting the CC solubility in any other solvent or solvent
mixture (different activity coefficients lead to different
solubilities in different solvents, but the solubility product
4446
pubs.acs.org/crystal Article
remains constant).21 The temperature dependency of Ks,CC was
calculated using the Gibbs−Helmholtz dependency given in eq
3.21
ij Δh ref i 1 1 yyz
·expjjjj s jjj ref − zzzzzzz
k R kT T {{
ref
K s,CC = K s,CC
(3)
Ks,CC is the temperature-dependent solubility product which
was determined from the reference solubility product Krefs,CC at
the reference temperature Tref with the reference enthalpy
Δhref
s . In case that the reference enthalpy was not available in
the literature, it was determined from the melting enthalpy
ΔhiSL, melting temperature TiSL, and the stoichiometric
coefficient νi of the API and CF in the CC, according to eq 4.
ij νAPI SL y
zz
Δhref = T ref jjjj
SL z
z
z
SL
ΔhAPI νCF ΔhCF
k API CF {
SL
+
ν + νCF T API νAPI + νCF T (4)
Dissolution of CC components in a liquid phase is limited
by the solubility of each component. Dissolution of
components can lead to supersaturation with respect to the
CC when the activity product of dissolved CC components is
greater than the CC solubility product.
[(xAPI·γAPI)νAPI ·(xCF·γCF)νCF ]diss,API,CF > K s,CC (5)
2.3. Vapor−Liquid Equilibrium. The RS of organic
solvents in a vapor phase is defined, according to eq 6
analogously to the definition of relative humidity for water
being the ratio of the solvents’ partial pressure psolvent and the
saturation vapor pressure of the pure solvent pLV
0,solvent. The
vapor pressures of API and CF are negligibly small. In
equilibrium, the chemical potentials of the solvent in the vapor
phase and the liquid phase are the same, and therefore, RS is
also related to the mole fraction of solvent xsolvent and its
activity coefficient γsolvent in the liquid phase, as described in eq
psolvent RS
xsolvent·γsolvent = LV =
p0,solvent 100% (6)
The activity coefficient of the solvent in the liquid phase
(γsolvent) depends on the composition of all components
present in the liquid phase.
2.4. Deliquescence. Deliquescence is the formation of a
liquid phase from a crystalline phase at a certain relative
humidity or RS of a solvent. Crystal molecules dissolve in the
deliquesced liquid phase, which is then saturated with respect
to that crystal solute. Usually, deliquescence is induced by
water vapor (relative humidity), but the same principle can be
applied to volatile compounds such as organic solvents. The
equivalent of deliquescence relative humidity in the case of
organic vapors is deliquescence RS (DRS) and is described as
follows. A solid−liquid−vapor equilibrium calculation was
performed to determine the DRS, above which a liquid phase
forms around a crystalline component i (DRSi). DRSAPI or
DRSCF was calculated by solving eqs 1 and 6 simultaneously.
DRSCC was obtained by solving eqs 2 and 6 simultaneously.
The DRS of a physical mixture of two crystalline components
is lower than the DRS of the individual components. A
prerequisite for any liquid phase formation at this DRS of a
mixture of two (or more) components is that they are in
physical contact with each other. The DRSi/j of a mixture of
two components i and j was calculated by simultaneously
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Cryst. Growth Des. 2021, 21, 4445−4455
Crystal Growth & Design pubs.acs.org/crystal Article

Table 1. PC-SAFT Pure Component Parameters of the Components Investigated in This Work
component Mi/g mol−1 mseg Mi−1/mol g−1 σi/Å ui kB−1/K εAiBi kB−1/K κAiBi Nassoc
i ref
ASA 180.16 0.0183 4.099 416.81 800.0 0.03 3/3 7
CBZ 236.27 0.04223 2.658 151.55 1094.0 0.02 1/1 21
NA 122.12 0.0380 2.178 176.69 2195.3 0.02 2/2 27
ethanol 46.07 0.0571 3.1771 198.24 2653.4 0.0324 1/1 23
methanol 32.04 0.0476 3.23 188.9 2899.5 0.0352 1/1 23

solving the solid−liquid equilibria for the two crystalline Table 2. PC-SAFT Binary Interaction Parameters Used in
components, each in the presence of the other component, and This Work
the vapor−liquid equilibrium of the solvent.
kij,T/K kij,b ref for parameters
2.5. Perturbed-Chain Statistical Associating Fluid
Theory. The activity coefficients considering the interactions ASA/ethanol 0 0.0228 7
of all components in the liquid phase were calculated using the ASA/methanol 0 0.0077 7
Perturbed-Chain Statistical Associating Fluid Theory (PC- CBZ/ethanol −1.48 × 10−4 0.0796 21
SAFT) equation of state.22,23 PC-SAFT calculates the residual CBZ/methanol −1.22 × 10−4 0.0321 21
Helmholtz energy Aresidual from contributions of hard-chain NA/ethanol 8.39 × 10−5 0.021 27
repulsion Ahard‑chain, dispersive attractions like van der Waals NA/methanol 2.91 × 10−4 −0.136 27
forces Adispersion, and hydrogen bond formation Aassociation, CBZ/ASA 0 0 7
according to eq 7. CBZ/NA 1 × 10−3 0.2091 21

Aresidual = Ahard ‐ chain + Adispersion + Aassociation (7)

Each component was assumed to be a chain of spheres
(segments), characterized by five pure component parameters:
the segment number divided by the molar mass mseg/Mi, the
segment diameter σi, the dispersion energy ui/kB, the
association energy εAiBi/kB, and the association volume κAiBi.
The combining rules of −Lorentz-Berthelot24,25 were applied
to calculate the segment diameter and the dispersion energy of
mixtures of components i and j (eqs 8 and 9).
1
σij = (σi + σj)
2 (8)

uij = uiuj ·(1 − kij) (9)

The dispersion energy of a mixture was corrected by a binary
Figure 1. Schematic isothermal phase diagram of API/CF/solvent
interaction parameter kij to better describe the experimentally
demonstrating favorable conditions for CC formation (of an example
determined phase behavior. The kij may linearly depend on stoichiometry). The solubility lines shown as thick solid lines separate
temperature with a slope of kij,T and a reference kij,b, according the liquid region L from the regions where crystals and liquid are
to eq 10. present. The three thick solid lines are API, CC, and CF solubility
kij = kij , T ·T[K ] + kij ,b lines (from left to right). Metastable solubility lines of API and CF are
(10) dashed lines. They meet at the metastable eutectic point of API/CF
The combining rules of Wolbach and Sandler were used to 26 (maximum supersaturation point with respect to the CC), where the
calculate the association energy and association volume of liquid solution is saturated with both API and CF (star). The shaded
region represents the region where CC formation is favorable. The
mixtures. dotted lines are iso-RS lines for DRSCC/API, DRSCC/CF, and DRSAPI/CF.
1 A iBi
ε A iBj = (ε + ε AjBj)
2 (11)

ij yz
Pure API, CF, and solvent are found in the corners of the

κ A iBiκ AjBj jjjj zz

z
ternary diagram. The region above the solubility lines

j (1/2)(σi + σj) zz
3
σσ
i j

k {
κ A iBj = represents an unsaturated liquid phase L. The region below
(12) the solubility lines indicates regions where solids do not fully
dissolve and form a saturated solution with compositions on
The pure component parameters used in this work are listed the solubility lines (saturated solutions). The solubility lines of
in Table 1, and the binary parameters used are listed in Table API and CF (very left and right in the diagram) are calculated
2. using eq 1. The CC solubility line in the middle is calculated
using eq 2. In addition to the eutectic points of the API or CF
3. PHASE DIAGRAMS OF CC SYSTEMS with the CC, a metastable eutectic point of API with CF is
An a-priori determination of the most favorable conditions for indicated by a star in Figure 1. This metastable eutectic point
CC formation can be obtained by phase diagram predictions has the maximum supersaturation with respect to the CC,
and the predicted DRS. A schematic ternary phase diagram of where the liquid solution is saturated with both, API and CF.
an API/CF/solvent system, showing CC formation, is shown CC screening aims to form CC from a mixture of API, CF, and
in Figure 1. the appropriate solvent in which both API and CF dissolve. To
4447 https://doi.org/10.1021/acs.cgd.1c00355
Cryst. Growth Des. 2021, 21, 4445−4455
Crystal Growth & Design pubs.acs.org/crystal Article

Figure 2. (a) Schematic solvent sorption isothermal phase diagram for an API/CF/solvent system with CC formation, showing the influence of RS.
The three thick solid lines are deliquescence lines of API, CC, and CF (from left to right). Metastable regions with respect to the CC are shown as
dashed lines intersecting at the DRSAPI/CF (metastable eutectic at maximum CC supersaturation RS is shown as a star). The dashed horizontal line
is the metastable phase boundary in the case that no CC is present. The thin solid lines indicate phase boundaries between solid phases. The
vertical thin dash-dotted line indicates the exemplary CC stoichiometry. Metastable regions are denoted using italic font letters, and the normal font
denotes stable regions. The shaded region shows the CC-formation region from an API/CF mixture. The square indicates an example of API/CF
composition for performing a DVS measurement (1:1 in this case). (b) Scheme of the mass vs time plot from an isothermal DVS measurement of
the API/CF crystal mixture indicated in (a). The dash-dotted line indicates the set RS in the DVS. The solid line is the schematic samples’ solvent
uptake if CC formation occurs, and the dashed line is the schematic samples’ solvent uptake if CC formation does not occur. Since vapor sorption
occurs for reactants only and not for CCs at that RS, as CCs form, there is a loss of mass corresponding to the solvent that goes back to the vapor
phase.

obtain pure CC, an API/CF/solvent composition within the
CC + L region, as shown in Figure 1, must be selected.
However, CC will also be present in the entire shaded region,
as shown in Figure 1, but will coexist with API or CF under the
appropriate solubility lines.
CC is formed under non-equilibrium conditions, that is,
below the CC solubility line, where the solution is super-
saturated with respect to the CC. For instance, the case of
dissolution of both API and CF before CC formation extends
beyond the eutectic points (intersections of API solubility line
or CF solubility line, with CC solubility line) and below the
CC solubility line, leading to supersaturation with respect to
the CC and its favorable formation. The supersaturated
conditions, in this case, are shown by the dashed lines, where
the dissolution of CC components leads to supersaturation of
CC and possible CC nucleation and growth. The liquid phase
in this work is generated by the organic solvent vapor at a
certain RS. Therefore, we next consider the conditions under
which vapor sorption of CC components and formation of a
liquid phase can lead to CC formation.
The liquid phase above the solubility curves is in equilibrium
with the vapor phase of a defined RS (eq 6). Iso-RS lines are
connecting compositions of the same solvent activity, that is,
same RS, as shown in Figure 1. These lines are also indicated
in the crystallization region below the solubility lines, although
they are not applicable in thermodynamic equilibrium because
the liquid phase composition at equilibrium corresponds to a
composition on the solubility line.
The diagram in Figure 1 shows the iso-RS lines of
DRSCC/API, DRSCC/CF, and DRSAPI/CF. DRSAPI/CF of the API/
CF mixture is lower than those of CC mixtures with the
individual components DRSCC/CF and DRSCC/API. Of interest is
the DRSAPI/CF, where a liquid phase will evolve when exposing
the API/CF mixture to a RS above DRSAPI/CF (the lowest
possible RS in equilibrium with a liquid phase in contact with
both crystalline API and CF). The evolving liquid phase will
have the composition of the metastable eutectic point of API
and CF, which is the maximum supersaturation with respect to
the CC corresponding to the intersection of the extended API
4448
solubility line and CF solubility line (shown as a star in Figure
1). Supersaturation is a necessary but not sufficient condition
for CC nucleation and growth. If one starts from a physical
mixture of API and CF, the liquid phase region will be
confined by the solubility lines of API and CF. The CC
solubility line is irrelevant in this case as it describes the
thermodynamic equilibrium between a liquid phase and the
CC (which is not present yet).
This phenomenon can be used to screen for CCs, as
illustrated and further explained via a quasi-binary phase
diagram (Figure 2a) and a schematic solvent sorption versus
time behavior from a DVS experiment (Figure 2b). The
deliquescence lines in Figure 2a indicate the RS above which
an API/CF mixture will saturate the liquid phase in
thermodynamic equilibrium (calculated assuming a solid−
liquid−vapor equilibrium). These lines are comparable to the
solubility lines in Figure 1 (calculated assuming a solid−liquid
equilibrium), which indicate the mass fraction of water
necessary to create saturated solutions of API, CF, or CC.
For the sake of clarity, we discuss the case that CC
formation does not occur first. In this case, the deliquescence
lines of API and CF (Figure 2a) are not superimposed by the
CC formation region. The deliquescence lines of the API and
CF remain stable throughout the entire composition range and
intersect at the (in this case) eutectic DRSAPI/CF (also known
as the eutonic composition28). Below this DRSAPI/CF, each
API/CF mixture will remain stable, that is, the two crystals
coexist without any liquid. The API/CF crystal mixture will
deliquesce as soon as it is exposed to RS above DRSAPI/CF. A
liquid phase will either occur in equilibrium with API crystals
(for compositions left of the eutectic composition) or CF
crystals (for compositions right of the eutectic composition).
The API/CF mixture will completely dissolve when exposed to
an RS above the deliquescence lines (L region). A DVS
experiment of an API/CF mixture of the indicated example
composition (square in Figure 2a) will follow the dashed line,
as shown in Figure 2b. The sample will not absorb any vapor
below DRSAPI/CF (t < t1), and the sample will deliquesce as
DRSAPI/CF is exceeded (t > t1). In thermodynamic equilibrium
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Crystal Growth & Design
(t ≈ t2), the sample will have absorbed the amount of solvent,
according to its vapor−liquid equilibrium (eq 6). As the
sample is in the API + L region at that RS, the crystalline API
is in thermodynamic equilibrium with the liquid phase. A
subsequent decrease below DRSAPI/CF leads to evaporation of
the solvent from the sample, leading to supersaturation
regarding API and CF and finally to recrystallization of API
and CF.
We now discuss the case that CC formation will occur. In
this case, a DVS experiment again starting with an API/CF
crystal of the exemplary composition (square, as shown in
Figure 2a) follows the solid line, as shown in Figure 2b. Above
DRSAPI/CF (t > t1), the sample will deliquesce, and a liquid
phase will form. The liquid phase formation is again detected
as the mass uptake, as shown in Figure 2b. The evolving liquid
phase has the composition close to the metastable API/CF
eutectic (see Figure 1), which is supersaturated with respect to
the CC. The liquid phase can reach saturation with both API
and CF at DRSAPI/CF at the maximum supersaturation with
respect to the CC. Slightly above DRSAPI/CF, the liquid phase
will be slightly less supersaturated, according to the
corresponding iso-RS line in Figure 1. Therefore, conditions
are favorable for the CC to crystallize as supersaturation is
generated. As soon as the CC is formed, the CC deliquescence
line now becomes the determining one. Therefore, the liquid
phase already formed at that point is not stable anymore and
will again evaporate (region CC + CF). The solvent mass
fraction in the sample decreases, although RS is kept constant
(Figure 2b). This characteristic vapor-sorption profile indicates
the transformation of the prepared API/CF crystal mixture
into a more thermodynamically stable crystal form. The
thermodynamically most stable form has the lowest
solubility,29 resulting in a higher DRS value than the
DRSAPI/CF.30 Next to CC formation, a change in polymorphism
or formation of solvates (or hydrates with water) of the API or
CF might also be indicated by a similar vapor-sorption profile.
The proposed screening approach uses DVS measurements
and the examination of the vapor-sorption profile to assess the
formation of a CC easily. To reliably find the CC and
introduce the maximum supersaturation with respect to the
CC, the RS should be thus slightly above DRSAPI/CF to observe
the characteristic sorption profile.
In principle, solvent-drop grinding might seem similar to the
proposed screening approach, but the solvent-drop grinding
lacks defined conditions of RS and temperature during the
grinding. Therefore, the increased mobility required for CC
formation might occur either due to mechanical energy input,
the presence of a liquid phase, the RS in the surrounding, or
increasing temperature. These unknown conditions prevent
the targeted use of a particular phenomenon for CC screening
in a phase diagram.
The proposed CC screening approach is advantageous
compared to conventional approaches since the DVS
isotherms can be readily analyzed during the vapor-sorption
experiment (mass change with time: increase and subsequent
decrease). The CC screening can be performed with a few
milligrams of API only and even in cases where the solubilities
of API and CF are very different. Another important advantage
of the CC screening using the solvent vapors is that less
organic solvent is needed compared to experiments performed
in the batch crystallization process.
4449
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4. MATERIALS AND METHODS
4.1. Materials. CBZ form III was obtained from Alfa Aesar (USA)
(purity > 98%). NA (form I, purity > 99%), USP grade ASA form I,
and ethanol (purity ≥ 99.9%) were purchased from Sigma-Aldrich
(Germany). Methanol (purity ≥ 99.9%) was obtained from VWR
Chemicals (Germany). All chemicals were used without further
purification. Table 3 shows the melting properties required for
solubility calculations of CBZ, ASA, and NA.
Table 3. Melting Properties of the Components Considered
in This Work
component TSL/K ΔhSL/kJ mol−1 ΔcSL
p /J mol
−1 −1
K ref
ASA (form I) 408.15 25.6 0 31
CBZ (form III) 447.95 26.82 65.17 32−34
NA (form I) 401.15 28.0 78.12 31,35
Table 4 shows the solubility product used for the calculation of the
CC solubility. CBZ with NA forms a 1:1 CC,36 and CBZ with ASA
forms a 1:1 CC.37
Table 4. CC Solubility Products and Reference Enthalpies
of CCs Used in This Work
component Ks,CC Δhref/kJ mol−1 Tref (K) ref
CBZ/ASA 7.87 × 10 −4
18.28a
298.15 7
CBZ/NA 7.26 × 10−4 27.6038 298.15 21
a
The reference enthalpy for the CC solubility product of CBZ/ASA
was estimated by eq 4.39
4.2. Experimental Method for CC Screening. Physical crystal
mixtures were prepared in a 2 mL tube with a NA mass fraction of
0.48 for CBZ/NA and an ASA mass fraction of 0.49 for CBZ/ASA
(the gravimetric data are found in Table SI1 in Supporting
Information) and were mixed using a vortex mixer for 30 s. The
crystal size was not investigated. These compositions were randomly
selected to prove that the screening is composition-independent. 13−
49 mg of these mixtures was transferred into the measurement pans
(see Table SI2 in Supporting Information for detailed gravimetric
data). The DVS Resolution from Surface Measurement Systems
(United Kingdom) was used to determine the mass change in the
presence of RS. The accuracy of the balance is ±0.1 μg. The
isothermal (313.15 or 298.15 K) measurement program started with
65% RS (85% RS for systems with NA). The RS was increased in 5%
RS steps if the mass uptake was below 0.01% min−1 for at least 45 min
per step. As soon as a considerable mass uptake of the solvent was
observed, the RS was kept at that level for up to 2000 min.
DRSAPI/CF ranges were indirectly determined from the DVS
measurements. The highest RS at which no significant solvent uptake
was observed was taken as the DRSAPI/CF lower border, and the lowest
RS at which a significant solvent uptake was observed was taken as the
DRSAPI/CF upper border. If the absorbed solvent mass fraction
decreased after it initially increased, the CC screening experiment was
considered as being successful. Powder X-ray diffraction (PXRD)
(Miniflex 600, Rigaku, Japan) was used to check for CC formation
after the DVS screening experiment. A Cu anode with Kα radiation in
reflection mode is used with a tube voltage of 40 kV and an electric
current of 15 mA. Each diffractogram was collected between 5 and
35° 2θ at a scanning rate of 5° 2θ per minute in steps of 0.02°. It is
important to mention that all samples were dried for at least 1 h at 0%
RS prior to the PXRD measurements. The diffractograms were
compared to reference diffractograms obtained from the Cambridge
Structural Database (CSD).
5. RESULTS AND DISCUSSION
The CC screening approach was evaluated for the CCs of
CBZ/NA and CBZ/ASA using the solvents ethanol and
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methanol at 313.15 K. The CBZ/ASA CC screening using

ethanol was additionally performed at 298.15 K. PC-SAFT was
used to explain the CC screening based on predicted
thermodynamic phase diagrams.
5.1. Prediction of Deliquescence in Presence of
Solvent Vapors. An important value for the CC screening
process is DRSAPI/CF. The DRSAPI/CF is the RS above which
liquid phase formation occurs. This liquid phase will have the
maximum CC supersaturation as it is saturated with respect to
API and CF. All DRSAPI/CF values were predicted using PC-
SAFT (eqs 1 and 6) prior to the experiments and are listed in
Table 5. The predicted ethanol DRSCBZ/NA value is 91.6%

Table 5. Predicted DRSAPI/CF Values and Predicted RS of

Full Dissolution Compared to Measured DRSAPI/CF Values
Obtained from Vapor Sorption Measurements Figure 3. Predicted phase diagram of CBZ/NA/ethanol with CBZ/
NA CC formation at 313.15 K. Compositions are given in mass
predicted measured
solvent CC T/K DRSAPI/CF/% DRSAPI/CF/% fractions. The solubility lines shown as thick solid lines separate the
region L from the regions where crystals are present. Upper corner
ethanol CBZ/NA 313.15 91.6 90 < DRS < 95a
from left to right: the solubility lines of CBZ, CC, and NA (the latter
ethanol CBZ/ASA 313.15 85.3 85 < DRS < 90 is hard to see). Metastable parts of the solubility lines of CBZ and NA
ethanol CBZ/ASA 298.15 92.7 85 < DRS < 94 are shown as dashed lines intersecting at the metastable eutectic point
methanol CBZ/NA 313.15 83.6 DRS < 85a of API/CF shown as a star. The square indicates the solid
methanol CBZ/ASA 313.15 77.4 80 < DRS < 85 composition for the screening experiment.
a
Plots of the DVS measurements are shown in Figures SI1 and SI2 in
Supporting Information.
beginning of the experiment (the sample did not deliquesce at
lower RS; measurement can be found in Figure SI1 in
which is a lot higher than the ethanol DRSCBZ/ASA (85.3%). Supporting Information). Subsequently, the mass fraction of
Lower temperatures increase the predicted DRS values the solvent absorbed increases to the value of wethanol = 0.19
significantly (e.g., to 92.7% for ethanol DRSCBZ/ASA at 298.15 after 2000 min until the mass fraction decreases again to a
K). DRSAPI/CF values for methanol were significantly lower value of wethanol = 0.096 at 3000 min. The observations during
than those for ethanol. the DVS experiment fit to the vapor-sorption profile expected
For all investigated cases, the predicted DRSAPI/CF values fit from the predicted phase diagram and predicted DRS values.
into the measured DRS ranges. We thus conclude that PC- To further confirm the result of the experiment, the
SAFT can predict the DRSAPI/CF of organic solvents (at least diffractograms of the prepared sample prior to the DVS
within a range of ±5% RS since this was the accuracy limit for experiment and after the DVS experiment are compared to the
most measurements). Therefore, PC-SAFT predicted phase reference diffractograms of CBZ, NA, and its CC, as shown in
diagrams are used in the following to get a broader Figure 5. The initially obtained sample diffractograms confirm
understanding for the DVS measurements. that CC formation did not occur prior to the DVS
5.2. CC Screening Using DVS. 5.2.1. CBZ/NA/Ethanol measurement, while CC characteristic peaks (highlighted as
(313.15 K). First, the CC screening via vapor sorption was the shaded regions in Figure 5) were found after the DVS
investigated for the system CBZ/NA using ethanol. Although measurement. A comparison of the measured diffractogram
the CC screening can be performed without knowing a phase with different reference CBZ polymorph diffractograms can be
diagram, predicted phase diagrams are useful in designing CC found in Figure SI8 in Supporting Information. Thus, the mass
screens successfully. The predicted ternary phase diagram, as increase and subsequent mass decrease of the sample can be
shown in Figure 3, indicates the solubility of CBZ, NA, and the clearly assigned to CC formation during the DVS measure-
CC in ethanol at 313.15 K. The metastable eutectic point of ment.
CBZ and NA lies within the CC formation region (star). The 5.2.2. CBZ/ASA/Ethanol (313.15 K). The CBZ/ASA CC was
prepared crystal mixture (square) has a significantly higher NA also investigated using ethanol vapor to check whether the CC
mass fraction (wNA = 0.48) than the stoichiometry of the CC screening also works for other CCs. The ethanol DRSCBZ/ASA
(wNA = 0.34). was predicted to be 85.3%. The mass fraction of ASA in the
The influence of RS on the deliquescence is studied in the prepared sample (wASA = 0.49) was again higher than the
phase diagram at 313.15 K, as shown in Figure 4a. According stoichiometric mass fraction of ASA in the CC (wASA = 0.43).
to the prediction, the deliquescence of the CBZ/NA crystal The predicted phase diagrams for this and further studied
mixture will occur above 91.6% RS. CC is expected to systems can be found in Figures SI3−SI6 in the Supporting
crystallize from the evolving liquid phase due to super- Information. According to these phase diagrams, deliquescence
saturation with respect to the CC (the liquid phase has the and subsequent CC formation were expected for these systems.
composition shown as the star in Figure 3), and parts of the In the DVS experiment, as shown in Figure 6, the RS
liquid phase will evaporate afterward because DRSCBZ/NA is increased from 65% RS in 5% RS steps until a significant mass
lower than DRSCC/NA. Finally, the sample will consist of increase was observed. A slight increase in mass was observed
crystalline CC in contact with a CC-saturated liquid phase. at 85% RS, which directly decreased afterward. This indicates
The results of the experimental CC screening using DVS are that the ethanol DRSCBZ/ASA is indeed close to the predicted
shown in Figure 4b. The RS is increased to 95% directly at the one of 85.3% RS. At 90% RS, a significant amount of ethanol
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Cryst. Growth Des. 2021, 21, 4445−4455
Crystal Growth & Design pubs.acs.org/crystal Article

Figure 4. (a) Predicted phase diagram of CBZ/NA/ethanol with CBZ/NA CC formation at 313.15 K, showing the influence of the RS. The three
thick solid lines are deliquescence lines of CBZ, CC, and NA (from left to right). Metastable parts of the deliquescence lines of the CBZ (left) and
NA (right) are shown as dashed lines intersecting at the ethanol DRSCBZ/NA (metastable eutectic RS shown as a star). The thin solid lines indicate
phase boundaries, and the vertical thin dash-dotted line is the CC stoichiometry. The thin dashed horizontal line is the metastable phase boundary
in the case that no CC is present. The square indicates the prepared sample composition. (b) DVS measurement of a CBZ/NA crystal mixture with
ethanol at 313.15 K. The dash-dotted line indicates the target RS of ethanol (0−95% RS). The solid line is the mass fraction of ethanol absorbed by
the sample. The star indicates the ethanol DRSCBZ/NA.

was absorbed, leading to a maximum ethanol mass fraction of

wethanol = 0.33 after approximately 1200 min. Afterward, the
ethanol mass fraction decreased until the end of the
experiment to a mass fraction of wethanol = 0.3. The mass
increases slightly from wethanol = 0.305 to wethanol = 0.309 within
1700 and 2200 min, which might be a kinetic effect of the
interplay of deliquescence and CC crystallization. Never-
theless, the course of the solvent mass fraction increase and a
subsequent decrease leads us to conclude that CC formation
did occur during the experiment.
Again, the diffractogram showed significant CC peaks after
the DVS measurement, which could not be seen in the
diffractogram obtained before the measurement (see Figure 7).
5.3. Temperature Influence on the CC Screening.
5.3.1. CBZ/ASA/Ethanol (298.15 K). The temperature
Figure 5. Diffractograms from bottom to top: CBZ from III reference
(CBMZPN01); NA form I reference (NICOAM); prepared crystal
mixture of CBZ/NA; CC of CBZ/NA reference (UNEZES);
measured diffractogram after the screening process using methanol;
and measured diffractogram after the screening process using ethanol.
The characteristic peaks of the CC of CBZ/NA reference are
highlighted as gray bars. Reference diffractograms were obtained from
the CSD stating their identifiers.

Figure 7. Diffractograms from bottom to top: CBZ from III reference

Figure 6. DVS measurement of a CBZ/ASA crystal mixture with
ethanol at 313.15 K. The dash-dotted line indicates the target RS of
ethanol (0−65−70−75−80−85−90% RS). The solid line is the mass
fraction of ethanol absorbed by the sample. The ethanol DRSCBZ/ASA
is indicated by a star.
(CBMZPN01), ASA form I reference (ACSALA), measured
diffractogram of the prepared crystal mixture of CBZ/ASA, CC of
CBZ/ASA reference (TAZRAO), measured diffractogram after the
screening process using methanol at 313.15 K, and measured
diffractogram after the screening process using ethanol at 313.15 K
and 298.15 K. The characteristic peaks of the CC of CBZ/ASA
reference are highlighted as the shaded background. Reference
diffractograms were obtained from the CSD stating their identifiers.

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Cryst. Growth Des. 2021, 21, 4445−4455
Crystal Growth & Design
influence on the CC screening was investigated using the CC
system of CBZ/ASA also at 298.15 K. The predicted ethanol
DRSCBZ/ASA at 298.15 K is 92.7%. This value is higher
compared to the value of 85.3% at 313.15 K. Thus, CC
formation was expected to occur above 92.7% RS at 298.15 K.
The results of the DVS screening experiment are shown in
Figure 8. The sample did not absorb ethanol at 85% RS, which
Figure 8. DVS measurement of a CBZ/ASA crystal mixture with
ethanol at 298.15 K. The dash-dotted line indicates the target RS of
ethanol (0−85−94−97% RS). The solid line is the mass fraction of
ethanol absorbed by the sample. The ethanol DRSCBZ/ASA is indicated
by a star.
is in accordance with the predicted DRSCBZ/ASA. Instead, the
solvent absorption did occur at 94% RS. By looking at the
slope of the solvent absorption from 3000 until 3700 min, it
might be safe to assume that the mass fraction of ethanol did
increase almost linearly from the beginning of setting 94% RS.
Therefore, the fluctuations from approximately 2300 min to
3000 min are assumed to be a measurement disturbance of the
balance.
After 1500 min at 94% RS, the sample was removed from
the DVS, and a PXRD measurement was performed. As
expected, CC formation could not be detected since no mass
fraction decrease could be observed during the experiment
(diffractograms are shown in Figure SI7 in Supporting
Information). The exposure of the sample to 97% RS led to
a significant increase in the ethanol mass fraction and a
subsequent decrease thereof. This is a clear sign of
deliquescence and subsequent transformation of the prepared
CBZ/ASA mixture. The mass fraction increase at around 4000
min allowed us to conclude that the liquid phase is stable in
thermodynamic equilibrium next to the CC (as confirmed by
the phase diagram in Figure SI4 in Supporting Information).
The CC significant peaks were observed in the diffractogram at
the end of the CC screening at 97% RS, while they were not
observed for the prepared sample (as compared in Figure 7).
When comparing the measurement at 298.15 K with the one at
313.15 K, it is concluded that the CC screening is feasible for
both temperatures. Nevertheless, higher temperatures might be
advantageous due to the increased kinetics of the deliques-
cence and CC crystallization.
5.4. Solvent Influence on the CC Screening.
5.4.1. CBZ/NA/Methanol (313.15 K). According to the
prediction, the methanol DRSCBZ/NA is 83.6%. A preliminary
DVS measurement changing the RS from 0−85−90−95−97%
RS was performed to identify the boundary conditions for the
CC screening (see Figure SI2 in Supporting Information). This
measurement confirmed the predicted DRSCBZ/NA value. 95%
RS was chosen to perform the CC screening experiment for
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CBZ/NA using methanol, as shown in Figure 9, due to very
low solvent sorption below this value (see Figure SI2 in
Supporting Information).
Figure 9. DVS measurement of a CBZ/NA crystal mixture with
methanol at 313.15 K. The dash-dotted line indicates the RS of
methanol (0−95% RS). The solid lines are the mass fraction of
methanol absorbed by the sample. The star indicates the methanol
DRSCBZ/NA.
The methanol mass fraction increased rapidly as soon as
95% RS was established and afterward decreased to almost
zero. Thus, CBZ/NA transformation occurred after initial
deliquescence. This deliquescence and CC formation occurred
within 40 min of storage at 95% RS. A significantly lower
amount of solvent absorption for methanol (wmethanol,max =
0.02) compared to ethanol (wethanol,max = 0.19) led us to assume
a more thorough conversion to the CC when using ethanol.
The CC significant peaks were found in the diffractogram
(Figure 5) after the CC screening using both, ethanol or
methanol. Nevertheless, the significant CBZ peaks after the CC
screening using methanol are well visible, and therefore, CBZ
seemed not to be converted entirely into the CC using
methanol (as opposed to ethanol). This might be the
consequence of rapid CC crystallization kinetics in methanol,
resulting from the higher CBZ/NA solubility in methanol
compared to ethanol. The predicted mole fraction of CBZ and
NA in methanol is xCBZ = 0.034 and xNA = 0.156 compared to
the liquid phase formed with ethanol of xCBZ = 0.013 and xNA =
0.079. Thus, the possibility that a CBZ and NA molecule meet
to form a CC is significantly higher in methanol. Deliquescence
at the contact points of CBZ and NA crystals quickly leads to
CC formation and subsequent liquid phase evaporation (see
the significant decline in solvent mass in Figure 9). This
prevents the complete conversion of all CBZ and NA crystals
to the CC for the use of methanol. Nevertheless, the time for
the CC screening using methanol was significantly lower
compared to using ethanol for the system CBZ/NA.
5.4.2. CBZ/ASA/Methanol (313.15 K). The influence of the
solvent was also investigated for the CBZ/ASA system using
methanol. The predicted DRSCBZ/ASA for methanol is 77.4%.
Therefore, CC formation with methanol is expected above this
value. The CC screening experiment is shown in Figure 10.
The methanol mass fraction increased, in agreement to the
prediction, as soon as the sample was exposed to 80% RS of
methanol. The deliquescence is occurring slowly due to the
low driving force for deliquescence (a ratio of set RS to the
DRSCBZ/ASA). As soon as the RS increases to 85%, the mass
increased rapidly to a methanol mass fraction of 0.02.
Afterward, the methanol mass fraction decreased rapidly
https://doi.org/10.1021/acs.cgd.1c00355
Cryst. Growth Des. 2021, 21, 4445−4455
Crystal Growth & Design
Figure 10. DVS measurement of a CBZ/ASA crystal mixture with
methanol at 313.15 K. The dash-dotted line indicates the target RS of
methanol (0−65−70−75−80−85% RS). The solid line is the mass
fraction of methanol absorbed by the sample. The ethanol
DRSCBZ/ASA is indicated by the star.
again. Thus, a transformation of CBZ/ASA into a thermody-
namically more stable CC was expected.
The diffractogram in Figure 7 shows only a very small peak
of the significant CC at 9° 2θ after the measurement. Thus,
CC formation did occur but only to a very small extent. A
significantly lower amount of solvent absorption for methanol
(wmethanol,max = 0.02) compared to using ethanol (wethanol,max =
0.33) let us to assume a more thorough conversion to CC
using ethanol again. Comparable to the system CBZ/NA, this
may result from the faster CC crystallization in methanol than
that in ethanol (higher solubility of CBZ/ASA in methanol
compared to ethanol, as shown in Figures SI3 and SI6). The
fast crystallization from the liquid phase results in CBZ crystals
and NA crystals that are not in contact with each other (due to
CC crystals separating API and CF crystals). This might result
in a less comprehensive transformation of CBZ/ASA during
the CC screening with methanol compared to using ethanol.
Nevertheless, the DVS experiment with methanol very quickly
showed that there exists a more thermodynamically stable form
than the initially prepared API/CF crystal mixture, and a more
thorough investigation might be expedient. A solvent change
from methanol to ethanol with slower CC crystallization and
therefore a more comprehensive CC crystallization clearly
showed CC formation.
To conclude, two factors must be considered when selecting
a suitable solvent vapor for successful CC screenings. The first
point is to use solvents, resulting in a low DRSAPI/CF value to
decrease the amount of solvent needed and allow for a rapid
solvent uptake by the initial API/CF crystal mixture. As a rule
of thumb, solvents with high API or CF solubility result in low
DRSAPI/CF values. Second, if the solvent mass decrease after an
initial solvent uptake occurs too fast, the yield of the CC
formation might be too low to detect CCs via PXRD afterward.
Nevertheless, the characteristic vapor-sorption profile very
quickly shows that a transformation from the prepared API/CF
mixture to another thermodynamically more stable form
occurred.
6. CONCLUSIONS
A vapor-phase-assisted CC screening approach was developed.
The CC screening was successfully performed for crystal
mixtures of the example systems CBZ/NA and CBZ/ASA
using the solvents ethanol or methanol. The resulting vapor-
sorption profiles allows to quickly evaluate if any trans-
formation of the prepared API/CF crystal mixture occurred.
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The transformation of the prepared API/CF crystal mixture
into a more thermodynamically stable form is accompanied by
a characteristic solvent mass uptake and subsequent mass loss
during exposure to a constant relative solvent saturation.
PC-SAFT-predicted phase diagrams were used to explain the
underlying phenomenon of CC formation through the
exposure of solvent vapors. Furthermore, the DRS above
which the CC formation occurs could be predicted by PC-
SAFT, in excellent agreement with the experiments.
The investigations showed that CC screening at an elevated
temperature (313.15 K) is advantageous compared to the CC
screening at room temperature (298.15 K). Moreover,
investigations showed that solvents that allow high solubilities
of API and CF are preferred. These solvents shorten the time
necessary for screening. Thus, CF/solvent pairs with
considerable CF solubility should be selected for this
screening. This lowers the RS required for deliquescence,
dissolution of CC components, nucleation, and CC growth.
The CC screening approach is advantageous compared to
conventional slurry screenings as it allows for high CC
supersaturations, which result in a high chance of CC
formation. Furthermore, the screening result can be readily
observed from vapor-sorption analysis (mass increase and
subsequent decrease). The CC screening can be performed
using only a few milligrams of the API, and due to the use of
the vapor phase, it also requires very small amounts of organic
solvent. This leads to a more environmentally friendly CC
screening.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.1c00355.
Prepared samples used for CC screening; dynamic vapor
sorption measurements to obtain DRSCBZ/NA; predicted
phase diagrams; and measured diffractograms for CBZ/
ASA CC screening at 298.15 K (PDF)
■
AUTHOR INFORMATION
Corresponding Author
Gabriele Sadowski − Laboratory of Thermodynamics, TU
Dortmund University, D-44227 Dortmund, Germany;
orcid.org/0000-0002-5038-9152; Phone: +49 (0)231
755 2635; Email: gabriele.sadowski@tu-dortmund.de;
Fax: +49 (0)231 755 2572
Authors
Heiner Veith − Laboratory of Thermodynamics, TU
Dortmund University, D-44227 Dortmund, Germany;
orcid.org/0000-0003-4526-4547
Christian Luebbert − Laboratory of Thermodynamics, TU
Dortmund University, D-44227 Dortmund, Germany;
orcid.org/0000-0001-5555-4965
Naír Rodríguez-Hornedo − Department of Pharmaceutical
Sciences, University of Michigan, 48109-1065 Ann Arbor,
Michigan, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.1c00355
Notes
The authors declare no competing financial interest.
https://doi.org/10.1021/acs.cgd.1c00355
Cryst. Growth Des. 2021, 21, 4445−4455
Crystal Growth & Design

■
pubs.acs.org/crystal Article

NOTATION Polymorphs, Salts, and Cocrystals: What’s in a Name? Cryst. Growth

Des. 2012, 12, 2147−2152.
A, Helmholtz energy/J (3) Childs, S. L.; Rodríguez-Hornedo, N.; Reddy, L. S.; Jayasankar,
ΔcSL P,i , difference of the heat capacity of the solid and the A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, B. C.
liquid component i at its melting point/kJ K−1 kg−1 Screening strategies based on solubility and solution composition
ΔhSL, melting enthalpy/kJ kg−1 generate pharmaceutically acceptable cocrystals of carbamazepine.
kb, Boltzmann constant/J K−1 CrystEngComm 2008, 10, 856.
kij, binary interaction parameter (4) Malamatari, M.; Ross, S. A.; Douroumis, D.; Velaga, S. P.
Ks,CC, co-crystal solubility product Experimental cocrystal screening and solution based scale-up
mseg, number of segments of component i cocrystallization methods. Adv. Drug Delivery Rev. 2017, 117, 162−
Mi, molar mass of component i/g mol−1 177.
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(7) Veith, H.; Schleinitz, M.; Schauerte, C.; Sadowski, G.
xi, mole fraction of component i

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Thermodynamic Approach for Co-crystal Screening. Cryst. Growth
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API active pharmaceutical ingredient by which moisture generates cocrystals. Mol. Pharmaceutics 2007, 4,
ASA acetylsalicylic acid 360−372.
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κAiBi association volume parameter Pacheco, R.; Gómez-Amoza, J. L.; Souto, C.; Concheiro, A.; Rowe, R.
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σi segment diameter/Å

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