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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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vapors on the reaction. Based on this, a CC screening method remains constant).21 The temperature dependency of Ks,CC was
using dynamic vapor sorption (DVS) is proposed and calculated using the Gibbs−Helmholtz dependency given in eq
evaluated for the API CBZ with the two CFs [acetylsalicylic 3.21
ij Δh ref i 1 1 yyz
·expjjjj s jjj ref − zzzzzzz
acid (ASA) and nicotinamide (NA)], two solvents (ethanol
k R kT T {{
and methanol), and temperatures (298 and 313 K). ref
K s,CC = K s,CC
(3)
2. THEORY
Thermodynamic phase equilibria are required to understand Ks,CC is the temperature-dependent solubility product which
CC formation from the individual pure components in the was determined from the reference solubility product Krefs,CC at
presence of a vapor phase. This process can be divided into the reference temperature Tref with the reference enthalpy
two steps, first the moisture uptake as well as dissolution of the Δhref
s . In case that the reference enthalpy was not available in
API and CF crystals (deliquescence; see I) and second, the CC the literature, it was determined from the melting enthalpy
crystallization from the liquid phase (II).8 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
deliquescence
SL z
z
z
API(s) + CF(s) ========= ⇒ API(l) + CF(l) (I) SL
ΔhAPI νCF ΔhCF
k API CF {
SL
+
API(l) + CF(l) ⇔ CC(s) (II) ν + νCF T API νAPI + νCF T (4)
As shown in II, CC formation only occurs from the liquid Dissolution of CC components in a liquid phase is limited
phase. The solubilities of API, CF, and CC as well as vapor− by the solubility of each component. Dissolution of
liquid equilibria determine the occurrence of deliquescence, components can lead to supersaturation with respect to the
dissolution of API and CF, generation of CC supersaturation, CC when the activity product of dissolved CC components is
and CC formation. Moisture sorption and deliquescence greater than the CC solubility product.
(water vapor) are investigated in another work.19 The concepts
[(xAPI·γAPI)νAPI ·(xCF·γCF)νCF ]diss,API,CF > K s,CC (5)
are analogous to those considered with organic vapor sorption
at their relative saturation (RS) in the surrounding vapor 2.3. Vapor−Liquid Equilibrium. The RS of organic
phase. solvents in a vapor phase is defined, according to eq 6
2.1. Solubility of the API and Coformer. The solubility analogously to the definition of relative humidity for water
of the API and the CF in a liquid mixture was obtained from being the ratio of the solvents’ partial pressure psolvent and the
ÅÄÅ
the solid−liquid equilibrium, according to eq 1.20 saturation vapor pressure of the pure solvent pLV
ÅÅ Δh SL ji T zy
0,solvent. The
ÅÅ R ·T k j Ti z{
1
ÅÇ
equilibrium, the chemical potentials of the solvent in the vapor
É
yzÑÑÑÑ
γi phase and the liquid phase are the same, and therefore, RS is
z
R jj jk T z{
activity coefficient γsolvent in the liquid phase, as described in eq
zÑÑ
k {ÑÖ
− 6.
T (1)
psolvent RS
The mole-fraction solubility xi of APIs or CFs depends on xsolvent·γsolvent = LV =
p0,solvent 100% (6)
their activity coefficient γi and on their crystal properties (i.e.,
the melting temperature TSL i , the melting enthalpy Δhi , and
SL
The activity coefficient of the solvent in the liquid phase
the change of heat capacity upon melting ΔcP,i). R is the ideal
SL
(γsolvent) depends on the composition of all components
gas constant [8.314 J (mol K)−1], and T is the temperature. γi present in the liquid phase.
explicitly accounts for all interactions between the components 2.4. Deliquescence. Deliquescence is the formation of a
in the liquid phase. It is possible to calculate the solubility of liquid phase from a crystalline phase at a certain relative
any component even if the component is metastable and might humidity or RS of a solvent. Crystal molecules dissolve in the
transform to another crystal form, that is, the solubility line deliquesced liquid phase, which is then saturated with respect
extends into the metastable region. to that crystal solute. Usually, deliquescence is induced by
2.2. CC Solubility. The equilibrium constant for the water vapor (relative humidity), but the same principle can be
reaction in II is the solubility product Ks,CC according to applied to volatile compounds such as organic solvents. The
equivalent of deliquescence relative humidity in the case of
K s,CC = ∏ (xi·γi)ν
i
= (xAPI·γAPI)νAPI ·(xCF·γCF)νCF
organic vapors is deliquescence RS (DRS) and is described as
i (2)
follows. A solid−liquid−vapor equilibrium calculation was
xAPI and xCF are the mole fractions of the dissolved API and CF performed to determine the DRS, above which a liquid phase
in a CC saturated solution, which represent the CC solubility. forms around a crystalline component i (DRSi). DRSAPI or
The subscript i represents the generalized CC components. γi DRSCF was calculated by solving eqs 1 and 6 simultaneously.
are the activity coefficients, and νi are the stoichiometric DRSCC was obtained by solving eqs 2 and 6 simultaneously.
coefficients of the API and CF in the CC. The solubility The DRS of a physical mixture of two crystalline components
product can be fitted to the solubility of the CC in any solvent. is lower than the DRS of the individual components. A
Since it does not depend on the solvent, it afterward allows prerequisite for any liquid phase formation at this DRS of a
predicting the CC solubility in any other solvent or solvent mixture of two (or more) components is that they are in
mixture (different activity coefficients lead to different physical contact with each other. The DRSi/j of a mixture of
solubilities in different solvents, but the solubility product two components i and j was calculated by simultaneously
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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
ij yz
Pure API, CF, and solvent are found in the corners of the
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
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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 solubility line and CF solubility line (shown as a star in Figure
CC + L region, as shown in Figure 1, must be selected. 1). Supersaturation is a necessary but not sufficient condition
However, CC will also be present in the entire shaded region, for CC nucleation and growth. If one starts from a physical
as shown in Figure 1, but will coexist with API or CF under the mixture of API and CF, the liquid phase region will be
appropriate solubility lines. confined by the solubility lines of API and CF. The CC
CC is formed under non-equilibrium conditions, that is, solubility line is irrelevant in this case as it describes the
below the CC solubility line, where the solution is super- thermodynamic equilibrium between a liquid phase and the
saturated with respect to the CC. For instance, the case of CC (which is not present yet).
dissolution of both API and CF before CC formation extends This phenomenon can be used to screen for CCs, as
beyond the eutectic points (intersections of API solubility line illustrated and further explained via a quasi-binary phase
or CF solubility line, with CC solubility line) and below the diagram (Figure 2a) and a schematic solvent sorption versus
CC solubility line, leading to supersaturation with respect to time behavior from a DVS experiment (Figure 2b). The
the CC and its favorable formation. The supersaturated deliquescence lines in Figure 2a indicate the RS above which
conditions, in this case, are shown by the dashed lines, where an API/CF mixture will saturate the liquid phase in
the dissolution of CC components leads to supersaturation of thermodynamic equilibrium (calculated assuming a solid−
CC and possible CC nucleation and growth. The liquid phase liquid−vapor equilibrium). These lines are comparable to the
in this work is generated by the organic solvent vapor at a solubility lines in Figure 1 (calculated assuming a solid−liquid
certain RS. Therefore, we next consider the conditions under equilibrium), which indicate the mass fraction of water
which vapor sorption of CC components and formation of a necessary to create saturated solutions of API, CF, or CC.
liquid phase can lead to CC formation. For the sake of clarity, we discuss the case that CC
The liquid phase above the solubility curves is in equilibrium formation does not occur first. In this case, the deliquescence
with the vapor phase of a defined RS (eq 6). Iso-RS lines are lines of API and CF (Figure 2a) are not superimposed by the
connecting compositions of the same solvent activity, that is, CC formation region. The deliquescence lines of the API and
same RS, as shown in Figure 1. These lines are also indicated CF remain stable throughout the entire composition range and
in the crystallization region below the solubility lines, although intersect at the (in this case) eutectic DRSAPI/CF (also known
they are not applicable in thermodynamic equilibrium because as the eutonic composition28). Below this DRSAPI/CF, each
the liquid phase composition at equilibrium corresponds to a API/CF mixture will remain stable, that is, the two crystals
composition on the solubility line. coexist without any liquid. The API/CF crystal mixture will
The diagram in Figure 1 shows the iso-RS lines of deliquesce as soon as it is exposed to RS above DRSAPI/CF. A
DRSCC/API, DRSCC/CF, and DRSAPI/CF. DRSAPI/CF of the API/ liquid phase will either occur in equilibrium with API crystals
CF mixture is lower than those of CC mixtures with the (for compositions left of the eutectic composition) or CF
individual components DRSCC/CF and DRSCC/API. Of interest is crystals (for compositions right of the eutectic composition).
the DRSAPI/CF, where a liquid phase will evolve when exposing The API/CF mixture will completely dissolve when exposed to
the API/CF mixture to a RS above DRSAPI/CF (the lowest an RS above the deliquescence lines (L region). A DVS
possible RS in equilibrium with a liquid phase in contact with experiment of an API/CF mixture of the indicated example
both crystalline API and CF). The evolving liquid phase will composition (square in Figure 2a) will follow the dashed line,
have the composition of the metastable eutectic point of API as shown in Figure 2b. The sample will not absorb any vapor
and CF, which is the maximum supersaturation with respect to below DRSAPI/CF (t < t1), and the sample will deliquesce as
the CC corresponding to the intersection of the extended API DRSAPI/CF is exceeded (t > t1). In thermodynamic equilibrium
4448 https://doi.org/10.1021/acs.cgd.1c00355
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(t ≈ t2), the sample will have absorbed the amount of solvent, 4. MATERIALS AND METHODS
according to its vapor−liquid equilibrium (eq 6). As the 4.1. Materials. CBZ form III was obtained from Alfa Aesar (USA)
sample is in the API + L region at that RS, the crystalline API (purity > 98%). NA (form I, purity > 99%), USP grade ASA form I,
is in thermodynamic equilibrium with the liquid phase. A and ethanol (purity ≥ 99.9%) were purchased from Sigma-Aldrich
subsequent decrease below DRSAPI/CF leads to evaporation of (Germany). Methanol (purity ≥ 99.9%) was obtained from VWR
the solvent from the sample, leading to supersaturation Chemicals (Germany). All chemicals were used without further
purification. Table 3 shows the melting properties required for
regarding API and CF and finally to recrystallization of API
solubility calculations of CBZ, ASA, and NA.
and CF.
We now discuss the case that CC formation will occur. In
Table 3. Melting Properties of the Components Considered
this case, a DVS experiment again starting with an API/CF
in This Work
crystal of the exemplary composition (square, as shown in
Figure 2a) follows the solid line, as shown in Figure 2b. Above component TSL/K ΔhSL/kJ mol−1 ΔcSL
p /J mol
−1 −1
K ref
DRSAPI/CF (t > t1), the sample will deliquesce, and a liquid ASA (form I) 408.15 25.6 0 31
phase will form. The liquid phase formation is again detected CBZ (form III) 447.95 26.82 65.17 32−34
as the mass uptake, as shown in Figure 2b. The evolving liquid NA (form I) 401.15 28.0 78.12 31,35
phase has the composition close to the metastable API/CF
eutectic (see Figure 1), which is supersaturated with respect to Table 4 shows the solubility product used for the calculation of the
the CC. The liquid phase can reach saturation with both API CC solubility. CBZ with NA forms a 1:1 CC,36 and CBZ with ASA
forms a 1:1 CC.37
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 Table 4. CC Solubility Products and Reference Enthalpies
corresponding iso-RS line in Figure 1. Therefore, conditions of CCs Used in This Work
are favorable for the CC to crystallize as supersaturation is component Ks,CC Δhref/kJ mol−1 Tref (K) ref
generated. As soon as the CC is formed, the CC deliquescence CBZ/ASA 7.87 × 10 −4
18.28a
298.15 7
line now becomes the determining one. Therefore, the liquid CBZ/NA 7.26 × 10−4 27.6038 298.15 21
phase already formed at that point is not stable anymore and a
The reference enthalpy for the CC solubility product of CBZ/ASA
will again evaporate (region CC + CF). The solvent mass was estimated by eq 4.39
fraction in the sample decreases, although RS is kept constant
(Figure 2b). This characteristic vapor-sorption profile indicates 4.2. Experimental Method for CC Screening. Physical crystal
the transformation of the prepared API/CF crystal mixture mixtures were prepared in a 2 mL tube with a NA mass fraction of
into a more thermodynamically stable crystal form. The 0.48 for CBZ/NA and an ASA mass fraction of 0.49 for CBZ/ASA
thermodynamically most stable form has the lowest (the gravimetric data are found in Table SI1 in Supporting
solubility,29 resulting in a higher DRS value than the Information) and were mixed using a vortex mixer for 30 s. The
crystal size was not investigated. These compositions were randomly
DRSAPI/CF.30 Next to CC formation, a change in polymorphism
selected to prove that the screening is composition-independent. 13−
or formation of solvates (or hydrates with water) of the API or 49 mg of these mixtures was transferred into the measurement pans
CF might also be indicated by a similar vapor-sorption profile. (see Table SI2 in Supporting Information for detailed gravimetric
The proposed screening approach uses DVS measurements data). The DVS Resolution from Surface Measurement Systems
and the examination of the vapor-sorption profile to assess the (United Kingdom) was used to determine the mass change in the
formation of a CC easily. To reliably find the CC and presence of RS. The accuracy of the balance is ±0.1 μg. The
introduce the maximum supersaturation with respect to 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%
CC, the RS should be thus slightly above DRSAPI/CF to observe RS steps if the mass uptake was below 0.01% min−1 for at least 45 min
the characteristic sorption profile. per step. As soon as a considerable mass uptake of the solvent was
In principle, solvent-drop grinding might seem similar to the observed, the RS was kept at that level for up to 2000 min.
proposed screening approach, but the solvent-drop grinding DRSAPI/CF ranges were indirectly determined from the DVS
lacks defined conditions of RS and temperature during the measurements. The highest RS at which no significant solvent uptake
grinding. Therefore, the increased mobility required for CC 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
formation might occur either due to mechanical energy input,
DRSAPI/CF upper border. If the absorbed solvent mass fraction
the presence of a liquid phase, the RS in the surrounding, or decreased after it initially increased, the CC screening experiment was
increasing temperature. These unknown conditions prevent considered as being successful. Powder X-ray diffraction (PXRD)
the targeted use of a particular phenomenon for CC screening (Miniflex 600, Rigaku, Japan) was used to check for CC formation
in a phase diagram. after the DVS screening experiment. A Cu anode with Kα radiation in
The proposed CC screening approach is advantageous reflection mode is used with a tube voltage of 40 kV and an electric
compared to conventional approaches since the DVS 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
isotherms can be readily analyzed during the vapor-sorption important to mention that all samples were dried for at least 1 h at 0%
experiment (mass change with time: increase and subsequent RS prior to the PXRD measurements. The diffractograms were
decrease). The CC screening can be performed with a few compared to reference diffractograms obtained from the Cambridge
milligrams of API only and even in cases where the solubilities Structural Database (CSD).
of API and CF are very different. Another important advantage
of the CC screening using the solvent vapors is that less 5. RESULTS AND DISCUSSION
organic solvent is needed compared to experiments performed The CC screening approach was evaluated for the CCs of
in the batch crystallization process. CBZ/NA and CBZ/ASA using the solvents ethanol and
4449 https://doi.org/10.1021/acs.cgd.1c00355
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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.
4451 https://doi.org/10.1021/acs.cgd.1c00355
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influence on the CC screening was investigated using the CC CBZ/NA using methanol, as shown in Figure 9, due to very
system of CBZ/ASA also at 298.15 K. The predicted ethanol low solvent sorption below this value (see Figure SI2 in
DRSCBZ/ASA at 298.15 K is 92.7%. This value is higher Supporting Information).
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
■
thorough investigation might be expedient. A solvent change
from methanol to ethanol with slower CC crystallization and AUTHOR INFORMATION
therefore a more comprehensive CC crystallization clearly
showed CC formation. Corresponding Author
To conclude, two factors must be considered when selecting Gabriele Sadowski − Laboratory of Thermodynamics, TU
a suitable solvent vapor for successful CC screenings. The first Dortmund University, D-44227 Dortmund, Germany;
point is to use solvents, resulting in a low DRSAPI/CF value to orcid.org/0000-0002-5038-9152; Phone: +49 (0)231
decrease the amount of solvent needed and allow for a rapid 755 2635; Email: gabriele.sadowski@tu-dortmund.de;
solvent uptake by the initial API/CF crystal mixture. As a rule Fax: +49 (0)231 755 2572
of thumb, solvents with high API or CF solubility result in low
DRSAPI/CF values. Second, if the solvent mass decrease after an Authors
initial solvent uptake occurs too fast, the yield of the CC Heiner Veith − Laboratory of Thermodynamics, TU
formation might be too low to detect CCs via PXRD afterward. Dortmund University, D-44227 Dortmund, Germany;
Nevertheless, the characteristic vapor-sorption profile very orcid.org/0000-0003-4526-4547
quickly shows that a transformation from the prepared API/CF Christian Luebbert − Laboratory of Thermodynamics, TU
mixture to another thermodynamically more stable form Dortmund University, D-44227 Dortmund, Germany;
occurred. orcid.org/0000-0001-5555-4965
Naír Rodríguez-Hornedo − Department of Pharmaceutical
6. CONCLUSIONS Sciences, University of Michigan, 48109-1065 Ann Arbor,
A vapor-phase-assisted CC screening approach was developed. Michigan, United States
The CC screening was successfully performed for crystal Complete contact information is available at:
mixtures of the example systems CBZ/NA and CBZ/ASA https://pubs.acs.org/10.1021/acs.cgd.1c00355
using the solvents ethanol or methanol. The resulting vapor-
sorption profiles allows to quickly evaluate if any trans- Notes
formation of the prepared API/CF crystal mixture occurred. The authors declare no competing financial interest.
4453 https://doi.org/10.1021/acs.cgd.1c00355
Cryst. Growth Des. 2021, 21, 4445−4455
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■
pubs.acs.org/crystal Article
■
Thermodynamic Approach for Co-crystal Screening. Cryst. Growth
Des. 2019, 19, 3253−3264.
ABBREVIATIONS (8) Jayasankar, A.; Good, D. J.; Rodríguez-Hornedo, N. Mechanisms
API active pharmaceutical ingredient by which moisture generates cocrystals. Mol. Pharmaceutics 2007, 4,
ASA acetylsalicylic acid 360−372.
CBZ carbamazepine (9) Ervasti, T.; Aaltonen, J.; Ketolainen, J. Theophylline-
CC co-crystal nicotinamide cocrystal formation in physical mixture during storage.
CF coformer Int. J. Pharm. 2015, 486, 121−130.
DRS deliquescence relative saturation (10) Maheshwari, C.; Jayasankar, A.; Khan, N. A.; Amidon, G. E.;
DVS dynamic vapor sorption Rodríguez-Hornedo, N. Factors that influence the spontaneous
formation of pharmaceutical cocrystals by simply mixing solid
L liquid phase
reactants. CrystEngComm 2009, 11, 493−500.
NA nicotinamide (11) Sarceviča, I.; Orola, L.; Nartowski, K. P.; Khimyak, Y. Z.;
PC-SAFT perturbed-chain statistical associating fluid theory Round, A. N.; Fábián, L. Mechanistic and Kinetic Insight into
PXRD powder X-ray diffraction Spontaneous Cocrystallization of Isoniazid and Benzoic Acid. Mol.
RS relative humidity
■
Pharmaceutics 2015, 12, 2981−2992.
(12) Arora, K. K.; Tayade, N. G.; Suryanarayanan, R. Unintended
GREEK SYMBOLS water mediated cocrystal formation in carbamazepine and aspirin
γi activity coefficient of component i tablets. Mol. Pharmaceutics 2011, 8, 982−989.
εAiBi/kB association energy parameter/K (13) Landín, M.; Pérez-Marcos, B.; Casalderrey, M.; Martínez-
κAiBi association volume parameter Pacheco, R.; Gómez-Amoza, J. L.; Souto, C.; Concheiro, A.; Rowe, R.
C. Chemical stability of acetylsalicylic acid in tablets prepared with
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different commercial brands of dicalcium phosphate dihydrate. Int. J.
νi stoichiometric coefficient of component i
Pharm. 1994, 107, 247−249.
σi segment diameter/Å
■
(14) Arora, K. K.; Thakral, S.; Suryanarayanan, R. Instability in
theophylline and carbamazepine hydrate tablets: cocrystal formation
SUBSCRIPTS due to release of lattice water. Pharm. Res. 2013, 30, 1779−1789.
i, j component i, component j (15) Huskić, I.; Christopherson, J.-C.; Užarević, K.; Frišcǐ ć, T. In situ
■
monitoring of vapour-induced assembly of pharmaceutical cocrystals
SUPERSCRIPTS using a benchtop powder X-ray diffractometer. Chem. Commun. 2016,
52, 5120−5123.
LV liquid−vapor (16) Ji, C.; Hoffman, M. C.; Mehta, M. A. Catalytic Effect of Solvent
SL solid−liquid Vapors on the Spontaneous Formation of Caffeine−Malonic Acid
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