Article pubs.acs.org/jced
Solubility and Caloric Properties of Cinnarizine Raphael Paus, Elena Hart, Yuanhui Ji, and Gabriele Sadowski* Laboratory of Thermodynamics, Department of Biochemical and Chemical Engineering, Technische Universität Dortmund, Emil-Figge-Strasse 70, 44227 Dortmund, Germany ABSTRACT: The solubility of cinnarizine has been investigated in acetonitrile, butyl acetate, 1-butanol, 2-propanol, and water in a temperature range from 288.15 K to 313.15 K. During crystallization from these solvents two different crystal morphologies of cinnarizine were observed. The caloric properties (melting temperature, melting enthalpy, and the difference in the heat capacity of solid and liquid cinnarizin) were measured by differential scanning calorimetry. The temperature-dependent solubility of cinnarizine in different organic solvents and in water was modeled using the perturbed-chain statistical associating fluid theory and was in good agreement with the experimental data.
1. INTRODUCTION Solubility is a key property for the purification, production, and application of active pharmaceutical compounds.1,2 Cinnarizine (CIN), which is an important blood flow promoter,3 is commonly used for the treatment of cerebral arteriosclerosis, post-traumatic cerebral symptoms, and cerebral apoplexy.3,4 The molecular structure of CIN is given in Figure 1.
Therefore, in this work, the temperature-dependent solubility of CIN was measured in acetonitrile, butyl acetate, 1-butanol, 2propanol, and in water. The caloric properties, namely the melting temperature, the melting enthalpy, and the difference in the heat capacity of the solid and liquid CIN were measured. The perturbed-chain statistical associating fluid theory (PCSAFT)7 was used to represent the activity coefficients and the solubility of CIN in a temperature range of 288.15 K to 313.15 K. The results were compared to the ideal solubility. Solventevaporation crystallization experiments in each solvent were carried out and the crystal morphologies of CIN were observed.
2. EXPERIMENTAL SECTION 2.1. Materials. CIN (CAS Number 298-57-7) with a purity of > 99.9 % was purchased from Alfa Aesar (Karlsruhe, Germany). The organic solvents acetonitrile (purity > 99.9 %), butyl acetate (purity > 99.9 %), 1-butanole (purity > 99.8 %), and 2-propanol (purity > 99.8 %) were purchased from VWR/ Merck (Langenfeld, Germany). Deionized, distilled, and filtered (Ø 0.2 μm) water from a Millipore purification system was used for CIN solubility measurements in water. 2.2. Methods. 2.2.1. Solubility Measurements. Solubility measurements of CIN in different solvents were performed in 100 mL double-jacked vessels. An excess of crystalline CIN was added to each solution and the solution was mixed with a magnetic stirrer at 600 rpm. The temperature of the water in the heating jacket was controlled by a Lauda E200 thermostat (Lauda, Königshofen, Germany). The temperature of the solution was monitored by a T900 series thermometer, which was calibrated (accuracy ± 0.01 K) by a calibration thermometer (TPCAL 100/25/DKD) prior to use.
Figure 1. Chemical structure of CIN.
According to the biopharmaceutics classification system (BCS),5 CIN is specified as a BCS class II compound, which means it shows a low solubility in vitro and a high permeability in vivo. Thereby the bioavailability of CIN is limited by the low solubility and slow dissolution. Thus, the knowledge of the CIN solubility in aqueous media is important to evaluate its performance in vivo and in vitro. In addition to that, the knowledge of CIN solubility in organic solvents is important for the design, production, and purification processes, for example, CIN crystallization. In literature, however, only limited data on the solubility of CIN in organic solvents and in water are available. To the best of our knowledge, only one value of CIN solubility in water has been reported.6 Moreover, no temperature-dependent solubility data of CIN have been reported in any solvent. © XXXX American Chemical Society
Received: January 23, 2015 Accepted: June 30, 2015
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current of 15 mA. The data were collected in step-scan mode at a step of 5°/min in the region of 2° to 60°. CIN crystals were prepared by solvent-evaporation crystallization from a saturated solution prepared at 313.15 K. Afterward the solvent was evaporated at room temperature. For this purpose, open glass vials filled with saturated CIN/solvent solutions were stored in an extractor hood for several days until the solvent was fully evaporated. Crystal imaging was carried out using a Leica DM4000 microscope equipped with a polarization filter (Leica, Wetzlar, Germany). 2.2.3. Determination of Caloric Properties. The melting SL SL temperature TCIN , the melting enthalpy ΔhCIN and the difference in the heat capacities of the crystalline solid and liquid cinnarizin ΔcSL p,CIN were measured by using a Q 2000 differential scanning calorimetry (DSC) (TA Instruments, Eschborn, Germany), which was calibrated against the melting enthalpy and melting temperature of pure indium prior to use. For thermal analysis, CIN samples of 5 mg to 10 mg were transferred into hermetically sealed aluminum pans and heated at 2 K/min to a temperature of approximately 20 K above the melting point of cinnarizin. During the measurement, the cell was purged with 50 mL/min nitrogen. For heat-capacity measurements, a modulated operation mode was selected. The modulation period of the oscillating sine curve was fixed to a value of 60 s. The amplitude of the temperature was estimated to a value of 0.318 K. The results were analyzed using TA Universal Analysis software 2000. Each measurement was performed three times, and the average value is reported in the following.
After the system was kept at constant temperature for at least 96 h to ensure thermodynamic equilibrium (equilibrium was assumed after a constant CIN concentration was achieved), the solubility of CIN in different solvents was measured. For this purpose, syringes (10 mL) and needles were used for sampling. If necessary, the syringes and needles were preheated to prevent crystallization of CIN during sampling. The stirrer was stopped for 10 min prior to sampling. The solution (2 mL to 3 mL) was filtered by a preheated polytetrafluoroethylene (used for the organic solvents) and polypropylene filter (used for the aqueous solution) with a mesh size of Ø 0.45 μm and 0.2 μm, respectively, and then either filled into preweighted glass vials (in the case of the organic solutions) or immediately analyzed by a Eppendorf BioSpectrometer (in the case of water solutions). The mass of the organic solid-free saturated solutions of CIN was recorded using a laboratory balance (accuracy of ± 0.0001 g). Solvent evaporation was conducted by storage of the samples in a ventilated hood at room temperature. After the organic solvent was evaporated, the mass of the dry solid was recorded after the mass of the sample remained constant. As CIN is poorly soluble in water, the concentration of the dissolved cinnarizin in water was determined using the UV−vis spectrometer at a wavelength of 258 nm. To determine the concentrations of CIN, standard solutions in aqueous phosphate buffer (fixed pH of 4.8) with different concentrations of cinnarizin were prepared to generate the required absorbance/concentration calibration curves (the coefficient of determination R2 was higher than 0.996). To convert the measured cinnarizin concentrations in mg/L into mole fractions, the following correlation for the temperaturedependent water density was used eq 1.8 ϱ w (T ) =
3. SOLID−LIQUID EQUILIBRIUM MODELING According to solid−liquid equilibrium (SLE), the chemical potential of the pure crystalline CIN equals that of CIN in its saturated solution. On the basis of the SLE,9 the solubility of crystalline CIN in each solvent was described according to eq 4.
5.459 (1 + (1 − (T /647.13))0.081)
0.30542
(1)
In eq 1 ϱw(T) is the density of water in mol/L and T is the temperature in K. Because of the low CIN concentrations in water, it was assumed that the density of the solution was equal to the density of pure water. The mole fraction solubility of CIN, xLCIN, in water was calculated according to eq 2 L xCIN
=
L xCIN =
cCIN MCIN
+ ϱ w (T )
)
=
mCIN MCIN mCIN MCIN
+
mOS MOS
⎧ SL ⎛ ⎪ ΔhCIN T ⎞ ⎜1 − SL ⎟ exp⎨ − ⎪ RT ⎝ TCIN ⎠ ⎩
SL ⎞ ⎤⎫ ΔcpSL,CIN ⎡ ⎛ TCIN ⎪ T SL ⎢ln⎜ ⎟ − CIN + 1⎥⎬ ⎥⎦⎪ R ⎢⎣ ⎝ T ⎠ T ⎭
(4)
In eq 4, xLCIN is the solubility of CIN in the solvent in mole fraction, γLCIN is the activity coefficient of cinnarizin in its saturated solution, T is the temperature of the system in Kelvin SL and R is the ideal gas constant in J/(mol K). ΔhSL CIN and TCIN are the melting enthalpy in J/mol and the melting temperature in K of the crystalline CIN, and ΔcSL p,CIN is the difference in the heat capacities of crystalline solid and liquid cinnarizin in J/ (mol K), respectively. The latter is commonly assumed to be temperature independent and has a considerable influence on the accuracy of solubility calculations for active pharmaceutical ingredients (APIs).10−13 The perturbed-chain statistical associating fluid theory (PCSAFT)7 was applied in this work to correlate the activity coefficients of CIN obtained from solubility data according to eq 4.
(2)
In eq 2 cCIN is the measured CIN concentration in g/L and MCIN is the molar mass of CIN in g/mol, respectively. The mole-fraction solubility of CIN, which was determined by the gravimetric method, was calculated according to eq 3. L xCIN
L γCIN
−
cCIN MCIN
(
1
(3)
In eq 3, mCIN is the mass of CIN and mOS is the mass of the organic solvent. MOS is the molar mass of the organic solvent. For each temperature, the solubility measurement was performed three times and the average value is reported in what follows. 2.2.2. Characterization of CIN Crystals. X-ray diffraction studies of the excess solid in solution were performed by using a Rigaku MiniFlex 600 diffractometer (Rigaku Europe SE, Berlin, Germany), with Cu Kα irradiation, voltage of 40 kV, and
4. PC-SAFT In PC-SAFT, the residual Helmholtz energy ares of a system can be described as a sum of different contributions7,14 as shown in eq 5: B
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a res = a hc + adisp + aassoc
Table 2. Measured Solubility of CIN in Water as a Function of Temperature at 0.1 MPa
(5) disp
Here, contributions due to van der Waals attractions (a , disp means dispersion interactions)7 as well as association (aassoc)14 are added to the repulsion of the hard-chain reference system (ahc). The detailed expressions of these contributions can be found in previous works.7,14−16 PC-SAFT considers a compound as a chain of mseg i spherical segments with a diameter σi. To characterize a compound, three pure-component parameters (segment number mseg, segment diameter σi, and dispersion energy parameter (ui/kB)) are required. For an associating compound (as the most APIs are) which may form hydrogen bonds, two additional parameters, namely the association-energy parameter (εAiBi/kB) and the association-volume parameter kAiBi are required. Thus, five purecomponent parameters have to be determined to describe an associating component. Additionally, the number of the association sites Nassoc , which can potentially form hydrogen i bonds, has to be specified for each molecule (in the case of CIN, Niassoc was assumed to be two: one electron donor and one electron acceptor). For the calculation of thermodynamic properties of a binary mixture, consisting of a solute compound i and a solvent j, simple Berthelot−Lorentz combining rules17 can be used to calculate the segment diameter σij and the dispersion energy uij according to eqs 6 and 7. σij =
1 (σi + σj) 2
T/Ka
CIN solubility in mole fraction xLCIN (standard uncertainties u(x) in brackets) 5.23·10−8 5.61·10−8 6.63·10−8 7.71·10−8 9.35·10−8 1.22·10−7 1.32·10−7
288.8 298.5 298.3 303.0 307.8 309.7 312.6 a
(4.06·10−9) (5.48·10−9) (9.69·10−9) (1.00·10−9) (3.43·10−9) (4.11·10−9) (2.97·10−9)
Standard uncertainty of the temperature was within 0.1 K.
(6)
uij = (1 − kij) uiuj
(7)
Here, one additional binary interaction parameter kij eq 7 that corrects for the dispersion energy in the mixture has to be determined. As suggested in previous works,1,18−20 the use of temperature-dependent binary interaction parameters turned out to be advantageous eq 8. kij(T ) = kij ,slope·T /K + kij ,intercept
(8)
Figure 2. Morphologies of CIN crystals prepared by solventevaporation crystallization in (a) acetonitrile, (b) butyl acetate, (c) 1-butanol, (d) 2-propanol, and (e) water.
5. RESULTS AND DISCUSSION 5.1. Solubility Data. The measured solubilities of CIN (including the standard uncertainty) in the organic solvents
Table 3. Melting Temperature, Melting Enthalpy (Standard Uncertainties in Brackets) and the Difference in the Solid and Liquid Heat Capacities of CIN
Table 1. Measured Solubility of CIN in Organic Solvents As Function of Temperature at 0.1 MPa CIN solubility in mole fraction xLCIN (standard uncertainties u(x) in brackets) T/Ka
acetonitrile
1-butanol
butyl acetate
2-propanol
288.5
8.77·10−4 (1.02·10−5) 1.05·10−3 (5.45·10−6) 1.37·10−3 (5.10·10−5) 1.58·10−3 (5.28·10−6) 2.04·10−3 (5.76·10−5) 2.73·10−3 (9.73·10−5)
2.73·10−3 (1.70·10−4) 3.51·10−3 (4.16·10−5) 4.12·10−3 (1.94·10−5) 4.99·10−3 (3.30·10−5) 6.07·10−3 (8.05·10−5) 8.04·10−3 (1.79·10−4)
1.53·10−2 (4.20·10−4) 1.97·10−2 (4.30·10−4) 2.26·10−2 (1.48·10−4) 2.72·10−2 (4.95·10−5) 3.37·10−2 (2.37·10−4) 4.25·10−2 (9.10·10−5)
6.40·10−4 (3.08·10−5) 8.11·10−4 (4.11·10−5) 9.94 ·10−04 (1.93·10−5) 1.27·10−3 (2.78·10−5) 1.65·10−3 (2.53·10−5) 2.08·10−3 (5.67·10−5)
293.5 298.4 303.3 308.3 313.2
a
TSL CIN/K
ΔhSL CIN/(kJ/mol)
ΔcSL pCIN/(J/mol K)
393.98 (0.38)
37.13 (2.13)
113.6
(acetonitrile, butyl acetate, 1-butanol, and 2-propanol) are summarized in Table 1. The solubility of CIN in water (including the standard uncertainty) is summarized in Table 2. As observed from Table 1 and Table 2, the solubility of CIN in each solvent depends on temperature and increases with increasing temperature. CIN shows the highest solubility in butyl acetate, whereas CIN is nearly insoluble in water. The measured temperature-dependent solubility data for CIN follows the trend butyl acetate > 1-butanol > acetonitrile > 2propanol > water. For the solubility of CIN in water, the measured data are in a good accordance with data reported in literature.6 Tarsa et al.6 reported a solubility of 2 μg/mL for CIN in water (temperature not reported). In this work, a solubility of 2.5 μg/mL (1.22·10−7 in mole fraction) was measured at 309.7 K.
Standard uncertainty of the temperature was within 0.1 K. C
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Table 5. Binary Interaction Parameters kij between APIs and Solvents and Average Relative Deviations (ARDs) between Calculated and Experimental API Solubilities CIN/acetonitrile CIN/butyl acetate CIN/1-butanol CIN/2-propanol CIN/water
kij,slope·1003
kij,intercept
ARD (%)
0.17014 0.06605 0.0669 0.05616 0.29313
−0.01764 −0.01265 −0.005296 0.000101 −0.12732
3.15 1.75 2.32 1.64 12.63
standard uncertainties are summarized in Table 3. As shown in Table 3, the melting temperature TSL CIN and the melting enthalpy ΔhSL of CIN were estimated to be 120.83 °C (393.98 K) and CIN 37.13 kJ/mol, respectively. Baired et al.26 reported similar values of 121 °C for the melting temperature TSL CIN and 40.87 kJ/mol for the melting enthalpy ΔhSL CIN, respectively. The small difference between the measured values in this work and those reported in literature is within the uncertainty of the measurements. For the determination of the heat capacity of the solid and liquid CIN ΔcSL pAPI, in this work, the approach proposed by Neau et al.10 was applied. For this purpose, the difference in the heat capacity of the solid and liquid CIN ΔcSL pAPI was measured below and above its melting temperature and then it was extrapolated to its melting temperature by regression as shown in Figure 3. For CIN the heat capacity of both, the solid and liquid CIN, is a function of temperature. The difference in the heat capacity, which is also given in Table 3, was estimated to be 113.6 J/(mol K) and was further used for CIN solubility calculations according to eq 4. 5.4. Solubility Correlations with PC-SAFT. In this work, the PC-SAFT parameters of CIN, including the binary interaction parameters between CIN and the organic solvents, were estimated simultaneously by fitting them to the measured solubility data of CIN in the organic solvents. The suitability of this approach was already demonstrated for several pharmaceuticals in the work of Ruether and Sadowski.1 As the association volume κAiBi has a small influence on the modeling results,1 it was fixed to a common value of 0.02. Thus, four pure-component parameters and the corresponding binary interaction parameters (two for each CIN/solvent system) were estimated. The fitted parameters of CIN and the solvent parameters used within this work are summarized in Table 4. The corresponding binary interaction parameters between CIN and the different solvents are summarized in Table 5. On the basis of the estimated parameters, the solubilities of CIN in the organic solvents were modeled in a temperature range from 285 K to 320 K. The results are shown in Figure 4a. It can be seen in this figure that PC-SAFT can well represent
Figure 3. Measured temperature-dependent heat capacities of the solid (circles) and liquid (squares) CIN. For cLpCIN the following regressed equation was used: 1.024469·T/K + 149.057648 (R2 = 0.997). For cSpCIN the following regressed equation was used: 1.482757·T/K − 145.052239 (R2 = 0.998). For cSpCIN and cLpCIN the maximal standard uncertainties of the measurements were 18.6 J/(mol K) and 17.3 J/ (mol K), respectively.
As reported in the literature,21 no polymorphic forms of cinnarizin were observed (verified by DSC and X-ray diffraction measurements). 5.2. Crystal Morphology. CIN crystals were prepared by the solvent-evaporation crystallization from its saturated solution in different solvents at 313.15 K to room temperature. The morphologies of the dried crystals were monitored. The morphologies of CIN crystals are shown in Figure 2 panels a to e. The needle-shaped CIN crystals were obtained from all considered organic solvents (see Figure 2a−d). Here, the fast evaporation of the organic solvents (compared to water) might lead to a higher CIN supersaturation and a higher number of crystal seeds in solution. In addition to that the molecular interactions between the solute and solvent play an important role on the crystal shape.22−25 As the solubility of CIN in the organic solvents is considerably higher than that in water, the molecular interactions between CIN and the organic solvent are significantly stronger than those between CIN and water. A significant solute/solvent interaction often leads to a favored crystal growth in one direction and as a result to a needle-shape crystal22,23,25 which might explain the observed crystal morphology of CIN in the organic solvents as shown in Figure 2 panels a to d. In contrast, an insignificant interaction between solvent and solute sometimes leads to platy crystals formed from solution.25 As it can be seen from Figure 2e, CIN crystallized from water was found to form platy crystals which are step-lined ordered. As water shows a high polarity, the interactions between CIN molecules with water might be very weak favoring crystal growth in different directions. 5.3. Caloric Properties. The measured melting temperSL ature TSL CIN and melting enthalpy ΔhCIN of CIN including the
Table 4. Molecular weights and pure-component PC-SAFT parameters of CIN and solvents used in this work M
a
σi
ui/kB
εAiBi/kB
substance
[g/mol]
miseg
Å
K
K
CIN acetonitrile butyl acetate 1-butanol 2-propanol water
368.51 41.052 116.16 74.123 60.096 18.015
13.561 2.3290 3.9608 2.7515 3.0929 1.2047
3.086 3.1898 3.5427 3.6139 3.2085 2.7927a
231.02 311.31 242.52 259.59 208.42 353.95
983.4 0 2544.6 2253.9 2425.7
κAiBi
Niassoc
ref
0.02
1/1
0.02 0.006692 0.024675 0.0451
1/1 1/1 1/1 1/1
this work 27 7 15 15 28
σwater = 2.7927 + 10.11·exp(−0.01775·T) − 1.417·exp(−0.01146·T).28 D
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Figure 4. (a) Solubility of CIN in different organic solvents. The symbols represent the experimental solubilities of CIN in butyl acetate (gray stars), 1-butanol (gray triangles), acetonitrile (gray squares), and 2-propanol (gray circles). (b) Solubility of CIN in water (gray circles). The full lines describe the calculated cinnarizin solubilities using PC-SAFT, and the dashed line is the calculated ideal solubility of cinnarizin (γLCIN = 1).
Funding
the solubility of CIN in all the organic solvents. The overall average relative deviation (ARD) in solubility is smaller than 4 % (see Table 5). Subsequently, the solubility of CIN in water was correlated in the same temperature range. For this purpose, the already determined pure-component parameters of CIN were used and the binary interaction parameters between CIN and water were estimated by fitting them to the measured CIN solubility in water as summarized in Table 2. The estimated binary interaction parameters between CIN and water are also shown in Table 5. The calculated CIN solubilities in water are shown in Figure 4b. Again, PC-SAFT can successfully model the solubility of CIN in water as a function of temperature. The average relative deviation is lower than 13% (see Table 5) although the solubility of CIN in water is lower than 1.5·10−7 (mole fraction) in the considered temperature range. As shown in Figure 4a, the experimental solubility of CIN in different organic solvents is significantly lower than the ideal solubility (γLCIN = 1). It becomes obvious that the activity coefficients of CIN cannot be neglected for accurate solubility calculations. When neglecting the activity coefficients of CIN in the solvent, the calculated CIN solubility would be always the same irrespective of the solvent, which definitely disagrees with the experimental data as shown in Figure 4a.
The authors would like to acknowledge the financial support from the Alexander von Humboldt-Foundation (YJ) and German Science Foundation (Leibniz Award to G. Sadowski). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS All PC-SAFT calculations were performed using the Software SolCalc developed at TU Dortmund.
(1) Ruether, F.; Sadowski, G. Modeling the solubility of pharmaceuticals in pure solvents and solvent mixtures for drug process design. J. Pharm. Sci. 2009, 98, 4205−4215. (2) Blagden, N.; De Matas, M.; Gavan, P.; York, P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv. Drug Delivery Rev. 2007, 59, 617−630. (3) Shi, S.; Chen, H.; Lin, X.; Tang, X. Pharmacokinetics, tissue distribution and safety of cinnarizine delivered in lipid emulsion. Int. J. Pharm. 2010, 383, 264−270. (4) Singh, B. N. The Mechanism of Action of Calcium-Antagonists Relative to Their Clinical-Applications. Br. J. Clin. Pharmacol. 1986, 21, 109−121. (5) Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. A Theoretical Basis for a Biopharmaceutic Drug Classification - the Correlation of in-Vitro Drug Product Dissolution and in-Vivo Bioavailability. Pharm. Res. 1995, 12, 413−420. (6) Tarsa, P. B.; Towler, C. S.; Woollam, G.; Berghausen, J. The influence of aqueous content in small scale salt screening-Improving hit rate for weakly basic, low solubility drugs. Eur. J. Pharm. Sci. 2010, 41, 23−30. (7) Gross, J.; Sadowski, G. Perturbed-chain SAFT: An equation of state based on a perturbation theory for chain molecules. Ind. Eng. Chem. Res. 2001, 40, 1244−1260. (8) Perry, R. H.; Green, D. W.; Maloney, J. O. Perry’s Chemical Engineers Handbook; McGraw-Hill: New York, 1997. (9) Prausnitz, J. M.; Lichtenthaler, R. N.; de Azevedo, E. G. Molecular Thermodynamics of Fluid-Phase Equilibria; Prentice Hall: NJ, 1999. (10) Neau, S. H.; Bhandarkar, S. V.; Hellmuth, E. W. Differential molar heat capacities to test ideal solubility estimations. Pharm. Res. 1997, 14, 601−605. (11) Granberg, R. A.; Rasmuson, A. C. Solubility of paracetamol in pure solvents. J. Chem. Eng. Data 1999, 44, 1391−1395. (12) Grant, D. J. W.; Higuchi, T. Solubility Behavior of Organic Compounds; John Wiley & Sons: New York, 1990. (13) Snow, R. L.; Ott, J. B.; Goates, J. R.; Marsh, K. N.; Oshea, S.; Stokes, R. H. (Solid + Liquid) and (Vapor + Liquid) Phase-Equilibria and Excess-Enthalpies for (Benzene + N-Tetradecane), (Benzene + NHexadecane), (Cyclohexane + N-Tetradecane), and (Cyclohexane + N-Hexadecane) at 293.15,298.15, and 308.15 K - Comparison of G-
6. CONCLUSIONS The solubility of CIN in acetonitrile, butyl acetate, 1-butanol, and 2-propanol as well as in water was investigated in a temperature range from 288.15 K to 313.15 K. CIN crystals were prepared by solvent evaporation from these five solvents. It was found, that the crystals prepared from saturated aqueous solution showed a platy morphology, whereas the crystals prepared from the saturated organic solutions were needleshaped. Caloric properties of CIN, namely the melting temperature, the melting enthalpy, and the difference in the heat capacity of the solid and liquid CIN were estimated by DSC. The solubilities of CIN in all considered solvents were found to be significantly lower than the ideal solubility (γLCIN = 1), which demonstrates that the activity coefficients of CIN cannot be neglected for accurate solubility calculations. They (and therewith the solubilities) were successfully correlated by PCSAFT.
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