Solubility of Trehalose in Water+ Methanol Solvent System from

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Solubility of Trehalose in Water + Methanol Solvent System from (293.15 to 313.15) K Linjie Jiang,‡ Suye Li,‡,§ Jinxia Jiang,†,§ Yangang Liang,†,§ and Peng Wang*,‡,† †

School of Chemical Engineering, and ‡Advanced Institute of Materials Science, Changchun University of Technology, Changchun, Jilin 130012, People’s Republic of China ABSTRACT: The solubility of trehalose in the water + methanol solvent system was measured with the mole fraction of water ranging from 0.000 to 0.700, at temperatures from (293.15 to 313.15) K, using the gravimetric method. Two kinds of crystals were collected and measured by differential scanning calorimetry and X-ray diffraction to prove the change of crystal habit for dihydrate trehalose from granular to powderlike at low water content. The turning points of every solubility curve were the critical points of crystal habit transition from the granular dihydrate trehalose (higher than the critical points) to the powderlike dihydrate trehalose (lower than the critical points). The mole fraction of the critical water content ranged from 0.160 to 0.250. The combination version of the Jouyban−Acree and van’t Hoff models was used to separately correlate the solubility data lower and higher than the critical points by nonlinear surface fit. The root-mean-square deviation (rmsd) values for the powderlike and the granular dihydrate trehalose solubility data were 1.4900·10−4 and 3.5919·10−4, respectively, which shows the model correlated the data well.

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INTRODUCTION Trehalose, a nonreducing disaccharide which is widespread in plants, animals and microbes, is formed by two glucose units linked in an α,α-1,1-glycosidic linkage.1 Depending on the given thermodynamic conditions, trehalose mainly has two kinds of polymorphs: dihydrate and anhydrous forms.2 The dihydrate trehalose can be easily obtained by crystallization from supersaturated solutions and is the most stable one. There are four different forms of anhydrous trehalose reported until now.3 The β-form which is stable at room temperature and less hydroscopic has been obtained when keeping the dihydrate trehalose under vacuum at 130 °C for 4 h,4 or from the transformation of dihydrate trehalose to anhydrous trehalose using ethanol.3,5,6 The α-form which could be easily rehydrated back to dihydrate trehalose has been observed when keeping the dihydrate trehalose under vacuum at 85 °C for 4 h.4 The γform, the mixture of dihydrate and β-form trehalose, has been shown by the shape of the calorimetric curve for the dihydrate trehalose at 5 K·min−1 to 20 K·min−1.4 The ε-form has been obtained still by thermal treatment according to Sussich’s report.7 The importance of observing polymorphic forms and solvated varieties has been recognized by most academic and industrial research groups.8 In our previous work, we determined the solubility of trehalose in a water + ethanol solvent system, and a white flocculent suspension which is the anhydrous form was observed in low water content. Most researches simply involve water + methanol solvents and water + ethanol solvents to determine the solubility results.9 So it is necessary to determine the solubility of trehalose in the water + methanol solvent system. © XXXX American Chemical Society

In this work, the solubility of trehalose in the water + methanol solvent system was measured with the mole fraction of water ranging from 0.000 to 0.700, at temperatures from (293.15 to 313.15) K, using the gravimetric method. The critical points of crystal habit transition were also recorded. Below the critical points, the white flocculent suspension which was distinguished from that higher than the critical points was also observed in the water + methanol solvent system. This phenomenon was very similar to that in the water + ethanol solvent system observed in our previous work. In the water + ethanol solvent system, the white flocculent suspension has been proven to be the β-form of anhydrous trehalose, and the crystals suspended in the higher water content solutions were the dihydrate form.4,5 The combination version of the Jouyban−Acree and van’t Hoff models was used to correlate the solubility data at different temperatures and water content by a nonlinear surface fit.

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EXPERIMENTAL SECTION Materials. Commercial food grade dihydrate trehalose was obtained from Hayashibara Co., Ltd. (Okayama, Japan), and its purity is higher than 98.0 % (mass fraction), and used without further purification. The analytical reagent grade of methanol used in our study is higher than 99.5 % (mass fraction) and the other solvent used in this experiment was deionized water which was prepared by Merck Millipore Mingche-D 24UV Received: July 1, 2014 Accepted: November 13, 2014

A

dx.doi.org/10.1021/je5006054 | J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

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ultrapure water system (electrical resistivity was 18.2 MΩ·cm at 25 °C). Apparatus and Procedures. The gravimetric method was also used to measure the solubility of trehalose. The procedures were the same as we used in our previous work.5 In our experiments, different amounts of water and methanol were added in the crystallizer which was maintained at a constant temperature by a thermostatic water bath (Shanghai Laboratory Instrument Works Co., Ltd. 501A, China), and then excess trehalose weighed by a analytical balance (0.1 mg precision) was added. The mixed solution was stirred fully with a magnetic stirring apparatus (IKA, RCT B S25, Germany) for 2 h which was the reasonable equilibrium time according to our research on the dissolution equilibrium time of trehalose. Also the time for the dissolution of dihydrate trehalose at the water content below and above the critical points was less than 2 h. The suspension was settled for 20 min, and then about 3 mL of clear liquor with no visible particles was weighed. The sample was dried during 24 h at 60 °C. In this paper, the molecular weight of dihydrate trehalose was used to calculate the solubility of trehalose. Every experimental point was measured at least three times, and represented by the average value. For the above experiments, the relative expanded uncertainty of measurement was estimated to be 7 %. Calorimetric measurements were carried out with a PerkinElmer Diamond differential scanning calorimeter (DSC), and the underlying scan rate was 10 K· min−1. X-ray diffraction (XRD) patterns were obtained with D/ MAX-2200PC X-ray diffractometer at room temperature. The samples were scanned in the range of 2θ from 10° to 30° at a scanning rate of 1°·min−1. Models and Calculations. The combination version of the Jouyban−Acree and van’t Hoff models proposed by A. Jouyban and W. E. Acree Jr.10 was used to correlate the solubility data of trehalose in the binary water + methanol solvent system at different temperatures, and its expression can be written as follows,11−13

Figure 1. Experimental and correlated mole fraction solubility of trehalose (xA) versus mole fraction of water in a water + methanol solvent system (x1) at different solvent compositions and temperatures.

⎛ ⎛ B ⎞ B ⎞ ln(xA ) = x1⎜A1 + 1 ⎟ + (1 − x1)⎜A 2 + 2 ⎟ ⎝ ⎠ ⎝ T T⎠ x (1 − x1) + 1 [J0 + J1(2x1 − 1) + J2 (2x1 − 1)2 ] T (1)

where x1 is the mole fraction of water in mixed solvent, in solute-free basis, xA is the calculated solubility of trehalose in mole fraction according to the selected model, A1, B1, A2, B2, J0, J1, and J2 terms are the model parameters obtained by nonlinear surface fit of the solubility at different temperatures and water content. Equation 2 was used to calculate the root-mean-square deviation (rmsd).

Figure 2. Experimental and correlated logarithm mole fraction solubility of trehalose (ln(xA)) versus mole fraction of water (x1) in water + ethanol and water + methanol solvent system. (a) Water + ethanol, (b) water + methanol: pink □―, T = 293.15 K; black ○  , T = 298.15 K; red △―, T = 303.15 K; green ▽―, T = 308.15 K; blue ◇―, T = 313.15 K.

N

rmsd =

∑i = 1 (xical − xiexp)2 N

(2)

where N is the number of the experimental solubility data, superscript cal is the calculated values and exp is the experimental one.

that the solubility of trehalose increases with the mole fraction of water and temperature. To clearly show the difference of solubility curves below and above the critical water content, the curves of ln(xA) versus x1 were plotted as shown in Figure 2b. From Figure 2b, it can be seen that there were the turning points (x1 = 0.160 to 0.250) for every curve corresponding to the critical mole fraction of water that increased with temperature. After filtration, the white flocculent suspension

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RESULTS AND DISCUSSION The 2D scatter plot of trehalose solubility and calculated solubility curves in water + methanol solvent system from (293.15 to 313.15) K is shown in Figure 1. Figure 1 showed B



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Table 1. Experimental solubility xAexp (mole fraction) of trehalose in water + methanol solvent system at mole fraction of water x1 lower and higher than the turning point at different temperatures Ta lower than the turning point

higher than the turning point

x1

103xAexp

x1

103xAexp

mol/mol

mol/mol

mol/mol

mol/mol

T = 293.15 K 0.000 0.050 0.080 0.100 0.140 0.150

0.349 0.394 0.526 0.534 1.164 1.708

0.000 0.050 0.100 0.150 0.171

0.313 0.446 0.587 1.084 1.945

0.000 0.050 0.101 0.151 0.190

0.379 0.403 0.728 0.874 2.051

0.000 0.100 0.150 0.200 0.211

0.339 0.674 1.019 1.860 2.077

0.000 0.100 0.150 0.200 0.240

0.383 0.719 1.139 1.982 3.171

0.200 0.300 0.400 0.499 0.600 0.700

1.445 1.582 2.439 3.977 6.828 11.022

0.181 0.201 0.301 0.400 0.500 0.600 0.700

1.906 1.844 2.111 3.240 5.194 8.746 14.102

0.201 0.300 0.400 0.501 0.600 0.701

2.455 2.777 4.084 7.156 11.805 18.955

0.220 0.300 0.400 0.500 0.600 0.700

3.132 3.829 5.670 9.563 15.890 25.228

0.250 0.300 0.400 0.500 0.600 0.700

4.499 5.294 8.105 13.653 22.704 33.315

T = 298.15 K

T = 303.15 K

Figure 3. Spectrograms of DSC: (a) granular dihydrate trehalose part and (b) powderlike dihydrate trehalose part.

T = 308.15 K

T = 313.15 K

a The standard uncertainty for temperature is u(T) = 0.05 K, the relative standard uncertainty for solvent mole fraction of water is ur(x1) = 0.02, and the relative expanded uncertainty for the solubility is Ur(xAexp) = 0.07 for all the solubility data.

Table 2. Model Parameters Fitted from Experimental Trehalose Solubility Data A1 B1 A2 B2 J0 J1 J2 Adj. R2

Figure 4. Spectrograms of XRD: (a) granular dihydrate trehalose part and (b) powderlike dihydrate trehalose part.

below the critical points was powder−like, while above those, it was granular. And the two kinds of crystals were determined by DSC and XRD measurements. The spectrograms are shown in Figures 3 and 4. From Figure 3 panels a and b, the first endothermic peaks which appeared around 100 °C were attributed to the dehydration of dihydrate trehalose.6 And the C

lower than the turning point

higher than the turning point

−41.25 5.899·104 −4.655 −9.985·102 −8.604·104 −6.292·104 −2.592·104 0.9583

15.28 −5.356·103 10.46 −4.520·103 −1.821·103 1.945·103 −2.004·103 0.9982



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Figure 5. Experimental and correlated mole fraction solubility of trehalose (xA) versus mole fraction of water (x1) in the water + methanol and water + ethanol solvent systems at 308.15 K. (A) Below the critical points and (B) above the critical points: black ■ , water + ethanol; red ○―, water + methanol.

XRD spectrograms between the powder-like and granular trehalose crystals obtained in water + methanol solvent system might be the different crystal habit of them. So the trehalose we obtained below the critical points was still dihydrate trehalose only with a different crystal habit from that above the critical points. To get the theoretical values of solubility of two kinds of crystals accurately, we divided the solubility data into two parts from the turning points and correlated the data using the combination version of the Jouyban−Acree and van’t Hoff models, respectively. The Adj. R2 (adjusted coefficient of determination) and correlated parameters are listed in Table 2. All of the experimental solubility data are listed in Table 1. The rmsd values for the powder-like dihydrate trehalose part and the granular dihydrate trehalose part were 1.4900·10−4 and 3.5919·10−4, respectively, which shows a good mathematical representation of the experimental solubility data of trehalose in water + methanol solvent system. In Table 2, it was obvious that the combination version of the Jouyban−Acree and van’t Hoff models was more suitable for the data above the boundary. A comparison between the solubility curves of trehalose in water + ethanol and water + methanol solvent systems is shown in Figure 2. From Figure 2, at the same temperature, the critical water content in water + methanol system was higher than that in the water + ethanol system with relatively low critical water content (x1 = 0.040 to 0.050).5 It also can be seen that the solubility curves below the critical points in the water + methanol solvent system increased with temperature, while that in the water + ethanol solvent system decreased with temperature. This indicates that the influence of polymorphism (in water + ethanol solvent system) and crystal habit (in water + methanol solvent system) on solubility behaviors of trehalose could be different. From Figure 5, the solubility data of trehalose in the water + methanol solvent system is higher than that of trehalose in the water + ethanol solvent system above the critical points, but the data intersected below the critical points. The comparison of critical points between the two

Figure 6. Comparison of critical points between water + methanol and water + ethanol solvent systems.

range of the first peak temperature varied from 91 to 103 °C because of the purity of the crystals.14 So the powderlike and the granular trehalose crystals obtained in water + methanol solvent system were both dihydrate forms. The last endothermic peaks in Figure 3 panels a and b around 215 °C were due to the melting of the β-form of anhydrous trehalose. From Figure 3, the DSC spectrogram of the powderlike dihydrate trehalose was similar to that of the granular one except for the residue in Figure 3a at 125 °C. The reason was that the transformed trehalose contained some α-form of anhydrous trehalose,6 while after the dehydration of the powderlike dihydrate trehalose, only β-form anhydrous trehalose was generated. In addition, from Figure 4, the XRD spectrogram of the granular dihydrate trehalose agreed with that in the literature.4 Except for the differences at the range of 21° to 23° of 2θ, the XRD spectrograms of the two kinds of crystals were similar. The cause of the discrepancy of DSC and D



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(5) Wang, P.; Jiang, J.; Jia, X. a.; Jiang, L.; Li, S. Solubility of trehalose in water + ethanol solvent system from (288.15 to 318.15) K. J. Chem. Eng. Data 2014, 59, 1872−1876. (6) Verhoeven, N.; Neoh, T. L.; Furuta, T.; Yamamoto, C.; Ohashi, T.; Yoshii, H. Characteristics of dehydration kinetics of dihydrate trehalose to its anhydrous form in ethanol by DSC. Food Chem. 2012, 132, 1638−1643. (7) Sussich, F.; Cesàro, A. Transitions and phenomenology of α,αtrehalose polymorphs interconversion. J. Therm. Anal. Calorim. 2000, 62, 757−768. (8) Garnier, S.; Petit, S.; Coquerel, G. Dehydration mechanism and crystallisation behaviour of lactose. J. Therm. Anal. Calorim. 2002, 68, 489−502. (9) Zou, F.; Zhuang, W.; Wu, J.; Zhou, J.; Liu, Q.; Chen, Y.; Xie, J.; Zhu, C.; Guo, T.; Ying, H. Experimental measurement and modelling of solubility of inosine-5′-monophosphate disodium in pure and mixed solvents. J. Chem. Thermodyn. 2014, 77, 14−22. (10) Jouyban, A.; Shayanfar, A.; Acree, W. E., Jr Solubility prediction of polycyclic aromatic hydrocarbons in non-aqueous solvent mixtures. Fluid Phase Equilib. 2010, 293, 47−58. (11) Sardari, F.; Jouyban, A. Solubility of 3-ethyl-5-methyl-(4RS)-2((2-aminoeth-oxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl3,5-pyridinedicarboxylate monobenzenesulfonate (amlodipine besylate) in ethanol + water and propane-1,2-diol + water mixtures at various temperatures. J. Chem. Eng. Data 2012, 57, 2848−2854. (12) Eghrary, S. H.; Zarghami, R.; Martinez, F.; Jouyban, A. Solubility of 2-butyl-3-benzofuranyl 4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl ketone hydrochloride (amiodarone HCl) in ethanol + water and Nmethyl-2-pyrrolidone + water mixtures at various temperatures. J. Chem. Eng. Data 2012, 57, 1544−1550. (13) Tang, F.; Wu, S.; Wu, F.; Zhao, S. Solubility of cefpiramide sodium in binary ethanol + water and 2-propanol + water solvent mixtures. J. Chem. Eng. Data 2014, 59, 56−60. (14) Chen, T.; Fowler, A.; Toner, M. Literature review: Supplemented phase diagram of the trehalose−water binary mixture. Cryobiology 2000, 40, 277−282.

solvent systems is shown in Figure 6. The critical points in the water + methanol solvent system increased with temperature, while that in the water + ethanol solvent system had little change basically.

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CONCLUSIONS The solubility of trehalose with the mole fraction of water ranging from 0.000 to 0.700 at different temperatures was determined using the gravimetric method in the water + methanol solvent system, and the solubility curves increased with water content and temperature. The analysis of DSC and XRD spectrograms showed that the two kinds of crystals suspended in the solution were both dihydrate forms in different crystal habit. The critical points of crystal habit transition from the granular dihydrate trehalose to the powderlike one were from 0.160 to 0.250 (mole fraction of water in solvent). The solubility curves lower and higher than the critical points were different. Comparing with the solubility curves of trehalose in the water + ethanol solvent system, the critical water content increased obviously. The critical points in the water + methanol solvent system had an obvious growth trend with temperature, while it was almost invariable in the water + ethanol solvent system. The solubility data of trehalose in the water + methanol solvent system was higher than that of trehalose in the water + ethanol solvent system above the critical points, but the data intersected and had the opposite trend below the critical points due to the different effect of polymorphism and crystal habit on solubility behaviors of trehalose. We used the combination version of the Jouyban− Acree and van’t Hoff models to separately fit the solubility data below and above the crystal habit transition points by nonlinear surface fit. The adj. R2 values for the powderlike and the granular dihydrate trehalose were 95.83 % and 99.82 %, respectively, which showed the model correlated the solubility data well especially for the latter. The rmsd values for the data lower and higher than the turning points were 1.4900·10−4 and 3.5919·10−4, respectively.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +86-431-85717211. Author Contributions §

S.L., J.J., and Y.L. contributed equally to this work.

Funding

This work was financially supported by Changchun University of Technology Foundation for Scientific Research and Development (LG06). Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Elbein, A. D.; Pan, Y. T.; Pastuszak, I.; Carroll, D. New insights on trehalose: A multifunctional molecule. Glycobiology 2003, 13, 17R− 27R. (2) Furuki, T.; Kishi, A.; Sakurai, M. De- and rehydration behavior of α,α-trehalose dihydrate under humidity-controlled atmospheres. Carbohydr. Res. 2005, 340, 429−438. (3) Ohashi, T.; Yoshii, H.; Furuta, T. Innovative crystal transformation of dihydrate trehalose to anhydrous trehalose using ethanol. Carbohydr. Res. 2007, 342, 819−825. (4) Sussich, F.; Urbani, R.; Princivalle, F.; Cesàro, A. Polymorphic amorphous and crystalline forms of trehalose. J. Am. Chem. Soc. 1998, 120, 7893−7899. E


Solubility of Trehalose in Water+ Methanol Solvent System from

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