Separation and Purification of (â)-Shikimic Acid and (â)-Quinic Acid by

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Separation and purification of (-)-Shikimic acid and (-)-Quinic acid by the phase diagrams of the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O and the quaternary system of (-)Shikimic acid + (-)-Quinic acid + Ethanol (##50%,##75%)+ H2O Xinying Hao, Qiang Huang, Guopeng Shen, Xiaoru Wu, Guoqin Hu, and Chunlan Ban Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.5b01115 • Publication Date (Web): 24 Jun 2015 Downloaded from http://pubs.acs.org on June 30, 2015

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Industrial & Engineering Chemistry Research

Separation and purification of (-)-Shikimic acid and (-)-Quinic acid by the pha ase diagrams of the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O and the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～～50%,φ～～75%)+ H2O Xinying Hao, Qiang Huang*, Guopeng Shen**, Xiaoru Wu, Guoqin Hu, Chunlan Ban School of Chemical Engineering and Energy, Zhengzhou University, Zhengzhou 450001, PR China

ABSTRACT The solid-liquid phase equilibrium for the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O and the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%,φ～ 75%)+ H2O was measured at T= (298.15, 318.15, 333.15, 348.15) K and the mutual solubility was obtained. Three variable-temperature phase diagrams were constructed according to the experimental solubility. In the phase diagrams, there were in all one invariant point, two univariant curves, and two crystallization regions corresponding to (-)-Shikimic acid, (-)-Quinic acid at each temperature in the studied system. The crystallization regions of the pure two solids increase with the decrease in temperature. The variable-temperature diagrams for quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O can be used to effectively separation and purification of (-)-Shikimic acid and (-)-Quinic acid. Meantime the (solid + liquid) phase equilibrium data can be used for the separation process of (-)-Shikimic acid and (-)-Quinic acid in the industrial production and further theoretical studies. Keywords: Solid-liquid equilibrium, (-)-Shikimic acid, (-)-Quinic acid, Variable-temperature phase diagram, Solubility 1. INTRODUCTION (-)-Shikimic acid ((3R,4S,5R)-(E)-3,4,5-Trihydroxy-1-cyclohexenecarboxylic acid, CASRN 138-59-0) and (-)-Quinic acid (1,3,4,5-tetrahydroxycyclohexane carboxylic acid, CASRN 77-95-2) is a cyclitol derivative, a polyol derivative shown in Figure 1. They are one of the most important fine chemical products and intermediates of drug synthesis, which has the widespread application in medicine, food, chemical industry, agriculture aspects and so on. They are obtained mainly through extraction from natural plants [1, 2] or synthesized by chemical ways [3-6] or microbial fermentation [7, 8]. On the pharmacological function, (-)-Shikimic acid finds many applications in the synthesis of a variety of industrially important chemical products which have innovative and multifunctional roles such as in dermo-cosmetic preparations, anti-enzymatic activity, an exfoliating agent for stratum corneum and antiviral drug (Tamiflu) for the treatment of Swine flu[9]. Studies have shown that the antiviral drug (Tamiflu) synthesized by (-)-Shikimic acid is the only active substance for treatment of flu virus. (-)-Shikimic acid also profoundly inhibited pancreatic lipase activity, thus providing another valuable therapeutic aspect for treating diet induced obesity in humans [9]. Because (-)-Shikimic acid has the nature of the anti-thrombotic it is used as the purposes of inhibiting arterial and venous thrombosis and cerebral thrombosis, it also have a very good anti-inflammatory, anti-viral and anti-tumor effect [10]. (-)-Quinic acid has been reported as an antioxidative [11-13], anti-inflammatory [14] and antimutagenic agent [15, 16] in prior studies, as well as the ability to chelate transition metals in vitro [17]. (-)-Quinic acid also be used as a Drug

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Carrier to Solid Tumors for formed (-)-Quinic acid-Conjugated Nanoparticles which has been used to increase the distribution of a drug in tumors, thereby reducing the effective dose and nonspecific toxicity of chemotherapy [18]. Studies have shown that the (-)-Quinic acid could decreased the DNA damage induced by X-ray irradiation and provided a significant radioprotective effect. Meantime, (-)-Quinic acid could be successfully used to synthesis of some impotent (-)-Quinic acid derivatives[19-21]. (-)-Shikimic acid and (-)-Quinic acid are key intermediates in the biosynthesis of aromatic compounds in living systems [22, 23]. During global pandemic of influenza, the limited supply and high cost held the major reasons behind the shortage of (-)-Shikimic acid and (-)-Quinic acid. With the worldwide rapid development, a breakthrough for the higher production of (-)-Shikimic acid and (-)-Quinic acid is obligatory. (-)-Shikimic acid and (-)-Quinic acid metabolic pathway widely exist in many microorganisms [24, 26]. We try to increase the productivity of (-)-Shikimic acid and (-)-Quinic acid by biosynthesis, but we get trouble in the separation of (-)-Shikimic acid and (-)-Quinic acid. However, the separation method are not found in the literature. Phase equilibria and phase diagram are important tools [27, 28] to use for separation and purification of (-)-Shikimic acid and (-)-Quinic acid. However the solid-liquid phase equilibrium and the solubility data for the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O and the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%,φ～75%)+ H2O are not found in the literature. Solubility data are important in crystallization processes design. During the crystallization separation process of (-)-Shikimic acid and (-)-Quinic acid, it is essential to determine the mutual solubility of (-)-Shikimic acid and (-)-Quinic acid in solvent. The solubility of (-)-Shikimic acid and (-)-Quinic acid in ethanol is small so it is not a suitable solvent for the separation process via crystallization. The solubility of (-)-Shikimic acid and (-)-Quinic acid in (H2O + ethanol) binary solvent mixtures decreases with increasing ethanol content at constant temperature. This experimental result showed that ethanol could be used as effective antisolvents in the crystallization process. Therefore the H2O and the (H2O + ethanol) binary solvent mixtures are suitable solvent for the separation process via crystallization, and maybe the (H2O + ethanol) binary solvent mixtures will more suitable. The separation process is made based on the solid-liquid equilibrium and the phase diagram of the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O and the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%,φ～75%)+ H2O. It is very important to measure the mutual solubility of the mixtures system. The objective of this work is to study the solid-liquid phase equilibrium of the ternary system and the quaternary system at (298.15, 318.15, 333.15 and 348.15) by the isothermal solution saturation method. Meantime, demonstrate the temperature dependence of the phase diagram.

(A)

(B)

Fig. 1. Chemical structure of (-)-shikimic acid (A) and (-)-quinic acid (B)

2. EXPERIMENTAL

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2.1. Materials (-)-Shikimic acid and (-)-Quinic acid (mass fraction purity ≥ 0.98) were obtained from Shanghai vibration spectrum Biological Technology Co., Ltd. Ethanol was analytical reagent (AR) grade, having mass fraction purities of 0.997 and was obtained from Sailboats Tianjin Chemical Reagent Co. Ltd. The sources and purity of the materials are listed in table 1. Table 1 The mass fraction purity and suppliers of the materials used. Chemical

Mass fraction purity

Source

(-)-shikimic acid

≥0.98

Shanghai vibration spectrum Biological Technology Co. Ltd.

(-)-quinic acid

≥0.98

Shanghai vibration spectrum Biological Technology Co. Ltd.

Ethanol

≥0.997

Sailboats Tianjin Chemical Reagent Co. Ltd.

H2 O

De-ionised water

Prepared in laboratory

2.2. Experimental Methods The solid-liquid phase equilibrium and the solubility data were determined by the isothermal solution saturation method and we used the analyzed quantitatively by HPLC method to measure the compositions of the saturated solutions [29, 30]. The saturated solutions were acquired by adding an excess (-)-Shikimic acid and/or (-)-Quinic acid to solvent (H2O, ethanol:H2O=1:1(V:V) or ethanol:H2O=3:1(V:V)). The mixture was placed in a water jacketed glass vessel (20 mL) kept at the desired temperature by circulating water that was provided by a constant-temperature bath (type 501, Shanghai Bilon Instruments Co. Ltd. China) and a micro-thermometer (with uncertainty of ±0.05 K) was used to determine the temperature of the system inside the vessel and a condenser was attached to the flask to avoid solvent from evaporating. An electric magnetic stirrer (type 95-2, Henan Zhicheng Technology Development Co. Ltd. China) was employed to achieve continuous stirring for the mixing of the solution. The equilibrium was confirmed by both measuring repetitively the composition of (-)-Shikimic acid and (-)-Quinic acid after 3 additional days and approaching equilibrium from supersaturation at a higher temperature. Equilibration had been reached when the composition of the liquid phase was constant then maintained the same temperature and turned off the stirring 5 h in order to make the undissolved solids to settle down at the bottom of the glass test tube. 1g-1.2g clear upper saturated solution was taken by a pipette and transferred into a volumetric flask pre-weighed by using an analytical balanceand (Shanghai Heng Ping Scientific Instrument Co. Ltd) with an uncertainty of ±0.0001g and analyzed quantitatively by HPLC (Agilent Technology, USA). In order to get different compositions of the liquid phase, the same experimental procedure was made by varying the ratio of (-)-Shikimic acid to (-)-Quinic acid. 2.3. Analysis The equilibrium solutions is analyzed quantitatively by HPLC with a Waters Synergy C18 column (150 mm×2.0 mm I.D.) by using the following mobile phase: consisted of methanol-0.02 mol/L dipotassium phosphate solution (1:99, v/v) and adjusted PH = 2.8 with phosphoric acid, at the flow rate of 0.8 ml/min. The temperature was conditioned at 30℃. The injection volume was 20 µL using partial loop mode for sample injection. The detection wavelength was set at 216nm. (-)-Shikimic acid and (-)-Quinic acid concentrations were determined after appropriate dilution by measuring the peak area and interpolation from a previously constructed the peak area ratios versus concentrations calibration curve. Each analysis is repeated three times, and the average value is used as the final value of the analysis. 3



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3. RESULTS AND DISCUSSION 3.1. Solid-liquid phase equilibrium data The equilibrium solubility data for the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～75%) + H2O, the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O and the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O at T= (298.15, 318.15, 333.15, 348.15) K are presented in Tables 2-4, respectively. The corresponding phase diagrams are shown in Figs. 2-4. In Figs. 2-4: points S, Q represent the pure solids of (-)-Shikimic acid and (-)-Quinic acid, points A, B represent the pure solvent of H2O and Ethanol, respectively. Points S1, S2, S3 and S4 represent the equilibrium solubility of (-)-Quinic acid in ethanol:H2O=3:1(V:V) (or ethanol:H2O=1:1(V:V) or H2O) at 298.15K, 318.15K, 333.15K and 348.15K, respectively. Points S’1 , S’2 , S’3 and S’4 stand for the solubility of (-)-Shikimic acid at different temperatures. S1C1, S2C2, S3C3 or S4C4 are solubility curves, which show that the compositions of saturated solution are in equilibrium with pure solid of (-)-Quinic acid at 298.15K, 318.15K, 333.15K and 348.15K, respectively. Solubility curves S’1 C1, S’2 C2, S’3 C3 or S ’4 C4 indicate that the compositions of saturated solutions are in equilibrium with the pure solid (-)-Shikimic acid at 298.15K, 318.15K, 333.15K and 348.15K, respectively. Points C1, C2, C3 and C4 are invariant points, which show the two pure solids (-)-Shikimic acid and (-)-Quinic acid saturated with equilibrium solution. The compositions of the invariant points are shown in Tables 2-4. Figs. 2-4 further illustrate that solid solution is not appeared in the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～75%) + H2O, the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O and the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O at T= (298.15, 318.15, 333.15, 348.15) K. The equilibrium phase diagram was divided into three crystallization regions: (-)-Shikimic acid crystallization regions (SS’1 C1, SS’2 C2, SS’3 C3 and SS’4 C4), (-)-Quinic acid crystallization regions (QS1C1, QS2C2, QS3C3 and QS4C4) and mixture solids of (-)-Shikimic acid and (-)-Quinic acid crystallization regions (SC1Q, SC2Q, SC3Q and SC4Q). The phase diagram has two invariant curves and one invariant point at each temperature. Figs. 2-4 further demonstrate the temperature influence on the equilibrium phase diagram for the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～75%) + H2O, the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O and the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O. The solubility values of (-)-Shikimic acid and (-)-Quinic acid increase with the increase in temperature from T = 298.15K to 348.15K, and the co-saturated point moves upward. The crystalline fields of two pure solids increase as the temperature decreases. The crystallization field of (-)-Shikimic acid is larger than that of (-)-Quinic acid at the same temperature. Table 2 Solubility data in mass fraction (wi)

a

for quaternary system of (-)-shikimic acid + (-)-quinic acid +

ethanol:H20=3:1(V:V) at T= (298.15, 318.15, 333.15, 348.15) K and P= 101.32 kPa. b 298.15K Liquid

phase

318.15K Liquid

Solid

100w1

100w2

phase

0.00

11.51

3.30

11.30

c

phase

333.15K Liquid

Solid

100w1

100w2

phase

S

0.00

18.56

S

3.04

18.14

c

phase

348.15K Solid c

Liquid

phase

Solid

100w1

100w2

phase c

100w1

100w2

phase

S

0.00

25.00

S

0.00

32.17

S

S

2.81

24.40

S

2.55

31.42

S

4


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a b c

5.44

11.16

S

5.78

17.75

S

6.35

23.76

S

7.44

11.01

S

9.05

17.30

S

10.73

22.88

S

8.64

10.92

S+Q

12.39

16.84

S

16.57

21.83

S

8.82

8.86

Q

15.00

16.47

S+Q

21.08

21.07

S+Q

9.16

4.44

Q

15.11

14.60

Q

21.93

12.69

9.56

0.00

Q

15.32

12.04

Q

21.32

17.92

15.61

8.20

Q

22.27

15.85

4.11

Q

16.25

0.00

Q

6.41

30.31

S

11.52

28.85

S

16.34

27.49

S

21.15

26.11

S

Q

25.55

24.83

S+Q

Q

28.52

12.86

Q

7.55

Q

27.45

17.15

Q

22.61

3.78

Q

26.32

21.82

Q

23.14

0.00

Q

30.05

6.80

Q

30.79

3.38

Q

31.62

0.00

Q

w1, the mass fraction (-)-quinic acid; w2, the mass fraction (-)-shikimic acid. Standard uncertainties u are u(T) = 0.05, ur(P) = 0.02, ur(w1) = 0.005, ur(w2) = 0.008. S, (-)-shikimic acid; Q, (-)-quinic acid.

Table 3 Solubility data in mass fraction (wi)

a

for quaternary system of (-)-shikimic acid + (-)-quinic acid +

ethanol:H20=1:1(V:V) at T= (298.15, 318.15, 333.15, 348.15) K and P= 101.32 kPa. b 298.15K Liquid

phase

318.15K Liquid

Solid c

phase

333.15K Solid

100w1

100w2

phase

S

0.00

27.48

16.17

S

4.07

100w1

100w2

phase

0.00

16.58

5.08

Liquid c

phase

348.15K Solid c

Liquid

phase

Solid

100w1

100w2

phase c

100w1

100w2

phase

S

0.00

35.71

S

0.00

43.08

S

26.57

S

7.61

33.80

S

6.81

40.81

S

9.26

15.79

S

8.81

25.57

S

11.34

32.33

S

10.01

40.27

S

14.22

15.11

S

12.65

24.49

S

15.29

30.87

S

13.55

38.73

S

17.54

14.86

S+Q

16.97

23.25

S

21.34

29.16

S

20.51

36.77

S

17.78

13.38

Q

21.09

22.40

S

27.98

27.08

S

29.04

34.15

S

18.22

10.60

Q

25.38

21.36

S+Q

33.33

25.34

S+Q

38.89

31.10

S

18.68

7.82

Q

26.91

16.17

Q

34.40

21.60

Q

46.16

28.91

S+Q

19.25

4.42

Q

28.18

11.68

Q

35.94

15.80

Q

46.30

24.89

Q

19.89

0.00

Q

29.87

6.75

Q

37.31

10.20

Q

46.44

21.54

Q

31.62

0.00

Q

38.69

5.90

Q

46.75

14.77

Q

40.02

0.00

Q

46.97

8.63

Q

47.11

5.09

Q

47.23

0.00

Q

a b c


Table 4 Solubility data in mass fraction (wi) a for ternary system of (-)-shikimic acid + (-)-quinic acid + H20 at T= (298.15, 318.15, 333.15, 348.15) K and P= 101.32 kPa. b 298.15K Liquid

phase

318.15K Liquid

Solid

100w1

100w2

phase

0.00

18.68

S

c

phase

333.15K Liquid

Solid

100w1

100w2

phase

0.00

29.96

S

c

phase

348.15K Solid

100w1

100w2

phase

0.00

39.57

S

5


c

Liquid

phase

Solid

100w1

100w2

phase c

0.00

49.38

S


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3.86

18.07

S

5.46

28.60

S

4.24

38.21

S

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6.95

46.37

S

8.31

17.41

S

11.16

27.09

S

9.24

36.36

S

13.19

43.35

S

11.55

16.93

S

15.77

25.88

S

14.27

34.50

S

19.56

40.26

S

15.38

16.37

S

21.01

24.50

S

18.13

33.07

S

25.78

37.25

S

21.46

15.47

S

26.35

23.09

S

23.38

31.13

S

32.38

34.05

S

24.77

14.99

S

30.40

22.02

S

28.88

29.10

S

35.88

32.35

S

29.34

14.32

S+Q

34.96

20.81

S+Q

34.48

27.03

S

38.48

31.09

S

30.08

11.70

Q

36.89

16.21

Q

39.03

25.35

S+Q

41.09

29.83

S

30.70

9.79

Q

39.35

10.37

Q

41.13

21.00

Q

42.78

29.01

S+Q

32.08

5.01

Q

40.57

7.47

Q

44.35

14.33

Q

43.38

27.93

Q

33.45

0.00

Q

41.80

4.52

Q

46.40

10.08

Q

45.88

23.39

Q

43.56

0.00

Q

48.13

6.50

Q

49.48

16.86

Q

49.61

3.42

Q

51.64

12.94

Q

51.22

0.08

Q

54.33

8.06

Q

56.15

4.74

Q

58.76

0.00

Q

a b c


Fig. 2. Phase diagram for the quaternary system of (-)-shikimic acid + (-)-quinic acid + ethanol:H2O=3:1(V:V) at T= (298.15, 318.15, 333.15, 348.15) K and P= 101.32 kPa. O, ethanol:H20=3:1(V:V); S, pure solid of (-)-shikimic acid; Q, pure solid of (-)-quinic acid; A, pure solvent of H2O; B, pure solvent of Ethanol; C (C1, C2, C3, C4) co-saturated point of (-)-shikimic acid and (-)-quinic acid; (S1, S2, S3, S4), solubility of (-)-quinic acid in ’ ’ ’ ethanol:H20=3:1(V:V); S’(S’ 1 , S2 , S3 , S4 ) solubility of (-)-shikimic acid in ethanol:H20=3:1(V:V).

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Fig. 3. Phase diagram for the quaternary system of (-)-shikimic acid + (-)-quinic acid + ethanol:H2O=1:1(V:V) at T= (298.15, 318.15, 333.15, 348.15) K and P= 101.32 kPa. O, ethanol:H2O=1:1(V:V); S, pure solid of (-)-shikimic acid; Q, pure solid of (-)-quinic acid; A, pure solvent of H2O; B, pure solvent of Ethanol; C (C1, C2, C3, C4) co-saturated point of (-)-shikimic acid and (-)-quinic acid; (S1, S2, S3, S4), solubility of (-)-quinic acid in ’ ’ ’ ethanol:H20=1:1(V:V); S’(S’ 1 , S2 , S3 , S4 ), solubility of (-)-shikimic acid in ethanol:H2O=1:1(V:V).

Fig. 4. Phase diagram for the ternary system of (-)-shikimic acid + (-)-quinic acid + H20 at T= (298.15, 318.15, 333.15, 348.15) K and P= 101.32 kPa. A, H2O; S, pure solid of (-)-shikimic acid; Q, pure solid of (-)-quinic acid; C (C1, C2, C3, C4) co-saturated point of (-)-shikimic acid and (-)-quinic acid; (S1, S2, S3, S4), solubility of (-)-quinic ’ ’ ’ acid in H2O; S’(S’ 1 , S2 , S3 , S4 ), solubility of (-)-shikimic acid in H2 O.

3.2. Variable-temperature phase diagrams applications to real industrial separation process. The mass ratio for the mixture solids of (-)-Shikimic acid and (-)-Quinic acid equal to 9:1 (point F). Separation process is as follows which shows in Figs. 5,6.For the quaternary system of

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(-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～75%) + H2O. The co-saturated point of (-)-Shikimic acid and (-)-Quinic acid almost on a straight line of passing through the origin which indicates that it is not suitable for separation process. For the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O (Figs. 5). A certain amount of water was added to the co-saturated solution (point A) to make it reached the point B, some pure (-)-Shikimic acid was separated out by filtration and then the solution reached the point C at T=298.15K, an amount of water was evaporated to make the solution reached the point D, pure (-)-Quinic acid was separated out by hot filtration and then the solution reached the point A at T=348.15K, repeating steps from A to C, then adding the mixture solids of (-)-Shikimic acid and (-)-Quinic acid make the solution reached the point E, pure (-)-Shikimic acid was separated out by hot filtration and then the solution reached the point A at T=348.15K, then repeating the steps A to B to C to D to A to B to C to E to A. The steps (A to B to C to D to A) need to circulate operation 17 times in order to make the volume of the system not increase.The efficiency was relatively lower and the energy consumption was relatively larger which indicates that it is not suitable for the separation process. For the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O (Figs. 6). A certain amount of solvent (50% ethanol) was added to the co-saturated solution (point A) to make it reached the point B, some pure (-)-Quinic acid was separated out by filtration and then the solution reached the point C at T=298.15K, an amount of solvent was evaporated to make the solution reached the point D (first the 95% ethanol was evaporated then the water was evaporated), a certain amount of solvent (95% ethanol) was added to make the solution reached the point E (meantime the solvent become 50% ethanol), then adding the mixture solids of (-)-Shikimic acid and (-)-Quinic acid make the solution reached the point G, pure (-)-Shikimic acid was separated out by hot filtration and then the solution reached the point A at T=348.15K. We can continue to separation out the pure of (-)-Shikimic acid and (-)-Quinic acid by repeating the steps (A to B to C to D to E to G to A), and the volume of the system will unchanged after a circulation. This result indicates that it is suitable for the real industrial separation (-)-Shikimic acid and (-)-Quinic acid process.

FIGURE 5. Variable-temperature phase diagrams for the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O applications to real industrial separation process.

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FIGURE 6. Variable-temperature phase diagrams for the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O applications to real industrial separation process.

4. CONCLUSIONS The solid-liquid phase equilibrium and the solubility of the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～75%) + H2O, the quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O and the ternary system of (-)-Shikimic acid + (-)-Quinic acid + H2O at T= (298.15, 318.15, 333.15, 348.15) K were determined experimentally and the corresponding variable-temperature phase diagrams were constructed. The equilibrium phase diagram consists of three crystallization regions ((-)-Shikimic acid, (-)-Quinic acid, and a mixture of (-)-Shikimic acid and (-)-Quinic acid), two equilibrium solubility curves, and one co-saturated point. The solubility values of (-)-Shikimic acid and (-)-Quinic acid increase with the increase in temperature. The crystallization field of (-)-Shikimic acid is larger than that of (-)-Quinic acid at the same temperature. The variable-temperature phase diagrams for quaternary system of (-)-Shikimic acid + (-)-Quinic acid + Ethanol (φ～50%) + H2O can be used to effectively separation (-)-Shikimic acid and (-)-Quinic acid process. The phase diagrams of the ternary and quaternary systems could provide the fundamental basis and serve as a guide for the separation of (-)-Shikimic acid and (-)-Quinic acid from the mixtures of (-)-Shikimic acid and (-)-Quinic acid, which is meaningful for industrial production and further theoretical studies. AUTHOR INFORMATION Corresponding Author Tel.: +86 371 67781292. *E-mail address: [email protected], **E-mail address: [email protected]

Notes The authors declare no competing financial interest.

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