The SolidâLiquid Equilibrium and Crystal Habit of l-Carnitine

Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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The Solid−Liquid Equilibrium and Crystal Habit of L‑Carnitine Fumarate Yun Cao,†,‡ Shiyuan Liu,†,‡ Shichao Du,†,‡ Yumin Liu,†,‡ Yingdan Cui,†,‡ Xiaona Li,†,‡ Dandan Han,†,‡ and Junbo Gong*,†,‡ †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China ‡ The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, China S Supporting Information *

ABSTRACT: The solid−liquid equilibrium data of L-carnitine fumarate in methanol + (ethanol/1-propanol/2-propanol) binary mixed systems were determined at temperatures ranging from 288.15 to 328.15 K, while the solubility data of L-carnitine fumarate in (methanol +1-butanol) mixtures were determined from T = (293.15 to 333.15) K because of its low solubility in low temperature. All experimental data were obtained by the gravimetric method under atmospheric pressure. At each composition point, the data increases with the increasing temperature in all determined solutions. A similar trend is also observed when the mole fraction of methanol increases in all binary solvent mixtures for each temperature. It is also found that the solubility data of L-carnitine fumarate in these binary mixtures rank as (methanol + ethanol) > (methanol +1-propanol) > (methanol +2-propanol) > (methanol +1-butanol). The modified Apelblat equation, (CNIBS)/Redlich−Kister model, Solubility−Polarity model, and Jouyban−Acree model were employed to correlate the solubility data determined, and all of them show good agreement with experimental value. Furthermore, the crystal morphology and size distribution of L-carnitine fumarate in different solvents was studied in order to select favorable solvents for good crystal habits.

1. INTRODUCTION L-Carnitine, known as a kind of amino acid, mainly exists in cardiac muscle, liver, and skeletal muscle and can be synthesized by lysine and methionine in liver, kidney, and brain tissues.1 It performs important cellular functions in the normal mitochondria oxidation of fatty acids and in the treatment of cardiovascular diseases and kidney diseases.2−4 Besides, owing to its neuro-protective and antioxidant properties, it could be helpful for the therapy of inherited neurometabolic disorders.5 Because of these multiple biological activities, L-carnitine has been widely used as a clinical drug. However, since it easily absorbs moisture, L-carnitine is commonly replaced by its salt products, such as L-carnitine tartrate, L-carnitine fumarate, and so on.6 In the industrial production of L-carnitine fumarate, recrystallization is used to separate and purify the crude product in order to obtain L-carnitine fumarate with a high purity, and the process design and optimization of solution crystallization strongly rely on a proper solution system, which requires accurate equilibrium solubility data varying with temperature and solution composition. Thus, during the recrystallization process, it is crucial to know the equilibrium solubility data of L-carnitine fumarate. Nevertheless, the solubility of L-carnitine fumarate has not been reported in literature up to date. In this work, because of the wide use of low alcohols in the recrystallization of L-carnitine fumarate and the different properties of them, we choose methanol/ethanol/1-propanol/2-propanol/1-butanol to measure © XXXX American Chemical Society

the solubility of L-carnitine fumarate and study the influence of properties of solvents on the solubility and crystal habit of L-carnitine fumarate. Besides, considering the boiling point of methanol and the common temperature used in industry, we determine the solubility of L-carnitine fumarate in methanol + (ethanol/1-propanol/2propanol) binary mixtures at the temperatures ranging from (288.15 to 328.15) K. What is more, the solubility data in (methanol +1butanol) mixtures was determined from T = (293.15 to 333.15) K owing to L-carnitine fumarate’s low solubility at 288.15 K. All experimental data were obtained by gravimetric method under atmospheric pressure. Four thermodynamic models were adopted to correlate the solubility data. The crystal morphology and size distribution of L-carnitine fumarate in different solvents was studied in a gesture to select solvents favorable to crystal habits. It is hoped that this study can be helpful for the design and optimization of L-carnitine fumarate crystallization process.

2. EXPERIMENTAL SECTION 2.1. Materials. A white crystalline powder of L-carnitine fumarate (molecular formula C11H19NO7, MW 277.27 g/mol, Figure 1) was obtained from Northeast Pharmaceutical Co., Ltd. (Liaoning, China) with mass fraction purity higher than 99.0%. Received: August 29, 2017 Accepted: January 9, 2018

A

DOI: 10.1021/acs.jced.7b00768 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

flask. Then the flasks were transferred into an incubator shaker and oscillated for at least 12 h at a constant temperature to reach the liquid−solid equilibrium. Subsequently, the incubator shaker was stopped, and the solution was kept static for 2 h to wait for the undissolved particles to settle down. The upper saturated solution was then sucked out by a syringe and filtered through a 0.22 μm membrane filter before being transferred into a known mass (m0) beaker. The beaker with saturated solution was weighed (m1) immediately and then put into a vacuum oven (type DZ-1BCII, Yichuan Appearance of Bearing Co., Ltd., China) at 323.15 K to vaporize the solvent. The mass of beaker with solute (m2) was reweighed several times until it did not change any more. Every experiment was repeated three times and the average value was used to calculate the mole fraction of solubility. All the mass was weighed by an analytical balance (model AB 204, Mettler Toledo, Switzerland) with an accuracy of ±0.0001 g. The mole fraction solubility of L-carnitine fumarate could be calculated by eq 1.

Figure 1. Chemical structure of L-carnitine fumarate.

All of the organic solvents used in the experiment, including methanol, ethanol, 1-propanol, 2-propanol and 1-butanol were obtained from Tianjin Yuanli Chemical Co., Ltd. (Tianjin, China). All of them are analytical reagent grade and were used without any further treatment. More details about the chemicals used in this work can be found in Table 1. 2.2. Characterization. If there is any phase transformation of L-carnitine fumarate during the dissolution and drying process, the corresponding solubility data are invalid. X-ray powder diffraction (PXRD) was employed to identify the crystal form of L-carnitine fumarate before and after the experiment to guarantee the reliability of the determined solubility data. The sample was analyzed on a D/MAX 2500 diffractometer using Cu Kα radiation (1.541845 Å). The process was carried out from 2° to 50° at 2θ with a scanning rate of 8° per minute and a step size of 0.02° under the condition of 100 mA current and 40 kV voltage. The melting temperature and the enthalpy of fusion of L-carnitine fumarate were determined by TGA/DSC simultaneous thermal analyzer (TGA/DSC 1, Mettler-Toledo, Switzerland). There are two calibrating weights in the balance room of the TGA/DSC 1 with an automatic calibration function. The temperature and heat were calibrated by standard indium and zinc before the measurement. About (5−10) mg of L-carnitine fumarate was used and scanned from 298.15 to 573.15 K at a rate of 10 K/min, under a dynamic nitrogen atmosphere. SEM was used to study the crystal morphology of products after evaporation of the solvent. The TM 3000 scanning electron microscope (Hitachi High-Technologies Corporation, Japan) was operated at the voltage of 15 kV. The sample was sprayed gold (MSP-1S magnetron sputter magnetron ion sputter metal coating device, Vacuum DEVICE Inc., shinkuu, Japan) with a thickness of 10 nm. The crystal size distribution was determined by wet dispersed laser diffraction measurements with a Mastersizer instrument (MS 3000, Malvern Instruments Ltd.). A total of five measurement cycles were carried out for each sample, and the average value was taken as the final results. 2.3. Apparatus and Procedure. A gravimetric method was used to determine the solubility of L-carnitine fumarate in several solvents.7,8 The temperature was controlled by an incubator shaker (Honor HNY-211B, China) with an uncertainty of ±0.1 K. An excess amount of solute and known amount of solvent whose mole fraction was known were added to a 50 mL conical

x1 =

(m2 − m0)/M1 (m2 − m0)/M1 + (m1 − m2)/M 2

(1)

where (m2 − m0) and (m1 − m2) represent the mass of solute and solvent, respectively; M1 and M2 stand for the molecular weight of solute and binary solvent, respectively. M2 could be calculated by eq 2. M 2 = MA xA + MBx B

(2)

where MA and xA are the molecular weight and mole fraction of methanol, MB and xB represent the molecular weight and mole fraction of ethanol, 1-propanol, 2-propanol, or 1-butanol, respectively.

3. THERMODYNAMIC MODELS 3.1. Modified Apelblat Equation. Apelblat assumed that the enthalpy of solution is a linear function of temperature and deduced the Modified Apelblat equation from the Clausius− Clapeyron equation.9 Thus, the Modified Apelblat equation expresses the relationship between solubility data and absolute temperature. It can be expressed as eq 3: B ln x1 = A + + C ln(T /K) (3) T /K where x1 is the molar solubility of L-carnitine fumarate in the solution, T is the absolute temperature, and A, B, and C are empirical parameters. The values of A and B show the variation of the activity coefficient in the solution, and C represents the influence of temperature on the enthalpy of fusion.10 3.2. (CNIBS)/Redlich−Kister Model. The (NIBS)/Redlich−Kister model deduced by Acree et al. is widely applied to

Table 1. Sources and Mass Fraction Purity of Organic Solvents Used in This Papera chemicals L-carnitine

methanol ethanol 1-propanol 2-propanol 1-butanol

fumarate

source

CASRN

molar mass/(g·mol−1)

mass fraction purity

purification method

analysis method

Northeast Pharmaceutical Co., Ltd., China Tianjin Yuanli Co., Ltd., China Tianjin Yuanli Co., Ltd., China Tianjin Yuanli Co., Ltd., China Tianjin Yuanli Co., Ltd., China Tianjin Yuanli Co., Ltd., China

90471-79-7 67-56-1 64-17-5 71-23-8 67-63-0 71-36-3

277.27 32.04 46.07 60.10 60.10 74.12

≥0.990 ≥0.995 ≥0.997 ≥0.998 ≥0.997 ≥0.995

none none none none none none

HPLCb GCc GCc GCc GCc GCc

a

Both the analysis method and the mass fraction purity were provided by the suppliers. bHigh performance liquid chromatography. cGas chromatography. B



Article

describe the solid−liquid equilibrium in binary solvent system.11 It describes the solubility data as a function of solvent composition. The model can be expressed as eq 4:

Hence, by combining the Apelblat model with the Jouyban− Acree model and substituting x30 with (1 − x20), a new simplified model could be obtained by introducing constant terms as follows:

N

ln x1 = x 20 ln(x1)2 + x30 ln(x1)3 + x 20x30∑ Si(x 20 − x30)i

A2 x0 (x 0)2 + A3 ln T + A4 x 20 + A5 2 + A 6 2 T T T 0 3 0 4 (x ) (x ) + A 7 2 + A8 2 + A 9x 20 ln T (10) T T

ln x1 = A1 +

i=0

(4)

where x1 is the mole fraction of the solute in binary solvents, x20 and x30 represent the initial mole fraction of binary solvent without solute, (x1)i is the solubility of solute in monosolvent i. Si is the model parameter and N refers to the quantity of solvents. Furthermore, if we set N equals 2 and replace x30 with (1 − x20), eq 4 can be simplified to eq 5 by introducing constant terms: ln x1 = B1 + B2 x 20 + B3(x 20)2 + B4 (x 20)3 + B5(x 20)4

where A1, A2, A3, A4, A5, A6, A7, A8, and A9 are model parameters.21

4. RESULTS AND DISCUSSION 4.1. TGA/DSC Analysis. X-ray powder diffraction (PXRD) was employed to identify the crystal form of L-carnitine fumarate before and after the experiment. It was found that all of the patterns of samples obtained in this work are the same as that of raw material. Here we set one as sample to discuss (T = 288.15 K, methanol + ethanol (x20 = 0.5)), which is shown in Figure S1. It denotes that the samples did not show any phase transformation during the dissolution and drying process. Meanwhile, the reliability of solubility measurement can be guaranteed. The DSC analysis result of L-carnitine fumarate in this work is shown in Figure 2. The onset temperature was chosen as the

(5)

12

where B1, B2, B3, B4, and B5 are the model parameters. 3.3. Solubility-Polarity Model. The “like dissolves like” rule is an important principle that relates to the polarity between the solvents and solutes. Since the results presented in the literature13,14 show that the dielectric constant is a key index of polarity, we employed a model outwardly like the Arrhenius equation to quantitatively show the relationship between the solubility and the dielectric constant of the mixed solvents in this work, which is called the Solubility−Polarity model:15−17 ⎛ Ex ⎞ x1 = k exp⎜ − ⎟ ⎝ Rεmix (T ) ⎠

(6)

where k and Ex is the pre-exponential factor and the dissolution energy barrier, respectively; R and T refer to the gas constant and the absolute temperature, respectively; εmix(T) represents the relative dielectric constant of binary solvent mixtures at various temperatures which is relevant to the temperature and the composition of the solvents. The relative dielectric constant of nonideal mixed solvents can be calculated by the sum law of cube roots:18 1/3 εmix =

∑ φεi i1/3

(7)

where εi is the relative dielectric constant of monosolvent i and φi refers to the volume fraction of component i in the mixed solvent in absence of solute. Akerlof has already reported that the relative dielectric constant of the monosolvent is a linear function of the absolute temperature:19 εi(T ) = a + bT + cT 2 + dT 3

Figure 2. Thermal analysis (TGA/DSC) of L-carnitine fumarate.

melting point. The value of melting temperature could be determined as 412.2 K (the expanded uncertainty is U = 0.3 K, 0.95 level of confidence) and the mole enthalpy of fusion (ΔfusH) was 51.19 kJ/mol (the expanded uncertainty is U = 1.05 kJ/mol, 0.95 level of confidence). 4.2. Solubility Data. The experimental solubility data of L-carnitine fumarate in several mixed solvents is listed in Tables 2−5 and graphically shown in Figures 3−6. In a gesture to expand the application range of the experimental solubility data, four thermodynamic models, including the modified Apelblat model, the (NIBS)/Redlich−Kister model, the Solubility−Polarity model, and the Jouyban−Acree model, were adopted to correlate the solubility data. The calculated data are depicted in Tables 2−5. To access the applicability and accuracy of the models used in this work, the average relative deviation (ARD) between experimental value and calculated value could be determined by eq 11:

(8)

where the parameter a, b, c, and d, available from the literature,19 are empirical coefficients. 3.4. Jouyban−Acree Model. The Jouyban−Acree model is one of the most accurate models that correlate the solubility data with both temperature and solvent composition.20 It can be expressed as eq 9: ln x1 = x 20 ln(x1)2 + x30 ln(x1)3 +

x 20x30 n ∑ J (x20 − x30)i T i=0 i (9)

where Ji is the model parameter and the meaning of the other parameters is the same as that in the (NIBS)/Redlich−Kister model. Under some circumstances, the Apelblat model can provide a better result for correlation of solubility data in a monosolvent.

N

ARD = C

x exp − x cal 1 ∑ i exp i N i=1 xi

(11) DOI: 10.1021/acs.jced.7b00768 J. Chem. Eng. Data XXXX, XXX, XXX−XXX


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Table 2. Mole Fraction Solubility of L-Carnitine Fumarate in (Methanol + Ethanol) Binary Mixtures at Different Initial Mole Fractions of Methanol (x20) and Different Temperatures (P = 0.1 MPa)a 103x1cal

a

T/K

103x1exp

Apelblat

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.216 0.329 0.488 0.769 1.019 1.469 2.050 2.467 2.732

0.154 0.283 0.481 0.757 1.11 1.53 1.97 2.41 2.78

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.277 0.414 0.588 0.911 1.22 1.76 2.36 2.80 3.24

0.216 0.373 0.602 0.915 1.31 1.77 2.28 2.79 3.26

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.361 0.527 0.743 1.10 1.49 2.15 2.82 3.42 3.79

0.266 0.461 0.745 1.13 1.61 2.16 2.76 3.34 3.86

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.483 0.710 0.976 1.37 1.86 2.63 3.49 3.95 4.55

0.383 0.632 0.982 1.44 2.00 2.63 3.31 3.98 4.58

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.665 0.956 1.28 1.72 2.37 3.29 4.39 5.07 5.53

0.496 0.820 1.27 1.86 2.56 3.35 4.18 4.96 5.65

288.15 293.15 298.15 303.15 308.15

0.941 1.31 1.67 2.19 3.06

0.693 1.12 1.70 2.44 3.31

(NIBS)/ Redlich−Kister x20 = 0.000 0.219 0.332 0.480 0.761 1.02 1.48 2.05 2.45 2.68 x20 = 0.100 0.271 0.0414 0.0588 0.0911 0.122 0.175 0.236 0.284 0.326 x20 = 0.200 0.356 0.529 0.754 1.11 1.50 2.13 2.83 3.36 3.87 x20 = 0.300 0.486 0.710 0.974 1.36 1.87 2.64 3.48 4.04 4.58 x20 = 0.400 0.675 0.965 1.27 1.71 2.38 3.33 4.38 4.98 5.52 x20 = 0.500 0.943 1.31 1.67 2.19 3.06

103x1cal Solubility− Polarity

JouybanAcree

0.302 0.428 0.559 0.794 1.14 1.66 2.24 2.33 2.22

0.214 0.345 0.527 0.770 1.08 1.44 1.86 2.30 2.76

0.376 0.527 0.686 0.967 1.38 1.97 2.65 2.81 2.75

0.270 0.424 0.637 0.918 1.27 1.69 2.17 2.71 3.26

0.470 0.654 0.848 1.18 1.67 2.37 3.16 3.42 3.44

0.351 0.538 0.794 1.13 1.54 2.04 2.62 3.26 3.95

0.594 0.818 1.06 1.46 2.04 2.86 3.80 4.18 4.33

0.467 0.700 1.01 1.42 1.92 2.53 3.23 4.03 4.90

0.757 1.03 1.33 1.82 2.52 3.48 4.59 5.15 5.49

0.633 0.926 1.31 1.81 2.43 3.17 4.05 5.05 6.16

0.972 1.31 1.68 2.28 3.12

0.869 1.24 1.73 2.34 3.11

T/K

103x1exp

Apelblat

313.15 318.15 323.15 328.15

4.28 5.55 6.24 6.84

4.27 5.25 6.18 6.97

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

1.31 1.77 2.19 2.87 4.02 5.39 7.00 7.90 8.91

1.03 1.57 2.28 3.17 4.22 5.39 6.64 7.88 9.04

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

1.79 2.31 2.87 3.75 5.12 6.84 8.91 10.1 11.3

1.39 2.09 2.99 4.11 5.41 6.88 8.43 10.0 11.5

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

2.32 2.99 3.73 4.96 6.56 8.65 11.1 13.2 15.0

1.94 2.80 3.89 5.24 6.85 8.70 10.8 13.0 15.3

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

3.04 3.84 4.84 6.39 8.33 10.6 13.5 16.7 21.0

2.90 3.83 5.00 6.47 8.31 10.6 13.4 16.8 21.0

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

3.79 4.89 6.17 7.87 10.1 12.9 16.1 21.1 27.8

3.94 4.91 6.16 7.78 9.91 12.7 16.4 21.2 27.7

(NIBS)/ Redlich−Kister x20 = 0.500 4.23 5.55 6.24 6.81 x20 = 0.600 1.30 1.75 2.19 2.86 3.97 5.40 7.04 7.93 8.68 x20 = 0.700 1.77 2.31 2.87 3.77 5.14 6.86 8.89 10.2 11.4 x20 = 0.800 2.35 2.99 3.74 4.96 6.59 8.63 11.1 13.1 15.3 x20 = 0.900 3.03 3.83 4.83 6.38 8.29 10.7 13.5 16.8 20.7 x20 = 1.00 3.79 4.89 6.17 7.87 10.1 12.9 16.1 21.1 27.9

Solubility− Polarity

JouybanAcree

4.27 5.59 6.39 7.02

4.03 5.13 6.40 7.84

1.26 1.68 2.15 2.88 3.90 5.27 6.85 8.00 9.06

1.20 1.67 2.28 3.05 4.00 5.15 6.53 8.15 10.0

1.65 2.18 2.77 3.68 4.93 6.55 8.46 10.1 11.8

1.65 2.25 3.00 3.95 5.13 6.57 8.30 10.4 12.8

2.19 2.85 3.61 4.74 6.27 8.23 10.5 12.8 15.5

2.26 3.00 3.93 5.10 6.54 8.32 10.5 13.1 16.2

2.92 3.77 4.75 6.17 8.06 10.4 13.2 16.5 20.6

3.04 3.94 5.07 6.48 8.23 10.4 13.1 16.3 20.3

3.95 5.03 6.31 8.11 10.5 13.3 16.7 21.4 27.7

4.02 5.08 6.41 8.08 10.2 12.8 16.0 20.0 25.0

x20 is the initial mole fraction of methanol; x1exp is the experimental solubility; x1cal is the calculated solubility by eqs 3, 5, 6, and 10, respectively. The standard uncertainty of temperature is u(T) = 0.1 K. The relative standard uncertainty of the solubility measurement is ur(x) = 0.03. The relative standard uncertainty of pressure is ur(P) = 0.05. The relative standard uncertainty in mole fraction of methanol (2) in the solvent mixtures is ur(x20) = 0.005. D



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Table 3. Mole Fraction Solubility of L-Carnitine Fumarate in (Methanol +1-Propanol) Binary Mixtures at Different Mole Fractions of Methanol (x20) and Different Temperatures (P = 0.1 MPa)a 103x1cal

a

T/K

103x1exp

Apelblat

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.0967 0.145 0.209 0.313 0.414 0.609 0.901 0.946 1.24

0.0801 0.134 0.211 0.317 0.453 0.619 0.809 1.02 1.23

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.120 0.172 0.259 0.384 0.522 0.742 1.10 1.35 1.62

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.159 0.256 0.348 0.498 0.681 0.962 1.36 1.67 2.11

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.220 0.362 0.477 0.694 0.954 1.26 1.73 2.22 2.72

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.321 0.514 0.693 0.951 1.31 1.71 2.28 2.76 3.47

288.15 293.15 298.15 303.15 308.15

0.481 0.727 0.986 1.36 1.83

(NIBS)/ Redlich−Kister

x20 = 0.000 0.0933 0.131 0.204 0.313 0.411 0.632 0.942 0.840 1.04 x20 = 0.100 0.0898 0.122 0.154 0.186 0.250 0.262 0.385 0.385 0.562 0.523 0.784 0.737 1.04 1.07 1.33 1.36 1.64 1.73 x20 = 0.200 0.146 0.162 0.230 0.261 0.348 0.351 0.508 0.503 0.718 0.693 0.983 0.931 1.31 1.32 1.68 1.82 2.12 2.30 x20 = 0.300 0.217 0.224 0.330 0.364 0.487 0.486 0.696 0.686 0.965 0.943 1.30 1.24 1.71 1.71 2.19 2.25 2.74 2.76 x20 = 0.400 0.332 0.321 0.488 0.510 0.697 0.685 0.967 0.957 1.31 1.31 1.72 1.70 2.22 2.29 2.80 2.73 3.46 3.25 x20 = 0.500 0.452 0.478 0.687 0.722 0.998 0.975 1.39 1.35 1.86 1.82


Jouyban− Acree

0.137 0.188 0.263 0.379 0.522 0.678 0.920 0.873 0.900

0.0894 0.141 0.214 0.313 0.442 0.603 0.797 1.02 1.28

0.175 0.240 0.333 0.477 0.655 0.851 1.15 1.12 1.19

0.120 0.185 0.277 0.399 0.558 0.756 0.994 1.27 1.59

0.228 0.311 0.429 0.609 0.833 1.08 1.46 1.47 1.58

0.164 0.250 0.367 0.522 0.722 0.970 1.27 1.62 2.02

0.302 0.410 0.560 0.789 1.07 1.40 1.87 1.94 2.14

0.231 0.344 0.497 0.698 0.954 1.27 1.66 2.11 2.62

0.407 0.548 0.744 1.04 1.40 1.82 2.43 2.60 2.94

0.331 0.484 0.687 0.952 1.29 1.70 2.20 2.79 3.47

0.559 0.748 1.01 1.39 1.87

0.485 0.694 0.969 1.32 1.77

T/K

103x1exp

Apelblat

313.15 318.15 323.15 328.15

2.33 3.08 3.57 4.15

2.39 2.98 3.58 4.17

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.736 1.04 1.39 1.90 2.55 3.26 4.26 4.62 5.34

0.645 0.985 1.43 1.97 2.61 3.31 4.03 4.72 5.35

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

1.15 1.50 2.00 2.70 3.58 4.65 6.00 6.51 7.55

0.970 1.45 2.07 2.83 3.70 4.67 5.67 6.66 7.57

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

1.77 2.21 2.89 3.85 5.05 6.49 8.34 9.46 11.9

1.63 2.23 3.00 3.94 5.08 6.44 8.01 9.81 11.8

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

2.69 3.30 4.19 5.44 7.10 8.96 11.4 14.9 18.9

2.61 3.34 4.27 5.46 7.00 8.97 11.5 14.8 19.0

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

3.79 4.89 6.17 7.87 10.1 12.9 16.1 21.1 27.8

3.94 4.91 6.16 7.78 9.91 12.7 16.4 21.2 27.7



Jouyban− Acree

2.42 3.21 3.54 4.11

2.32 2.98 3.76 4.67

0.785 1.04 1.39 1.89 2.52 3.27 4.29 4.89 5.82

0.721 1.01 1.39 1.87 2.47 3.20 4.09 5.14 6.37

1.13 1.48 1.95 2.62 3.47 4.48 5.84 6.87 8.39

1.09 1.49 2.01 2.67 3.49 4.48 5.69 7.12 8.80

1.66 2.16 2.80 3.71 4.88 6.26 8.07 9.83 12.3

1.66 2.23 2.96 3.86 4.98 6.34 7.99 9.96 12.3

2.51 3.22 4.13 5.37 6.99 8.93 11.4 14.3 18.3

2.56 3.36 4.37 5.63 7.17 9.05 11.3 14.0 17.3

3.91 4.95 6.24 7.96 10.2 13.0 16.3 21.2 27.8

3.96 5.09 6.50 8.24 10.4 13.0 16.1 19.9 24.4

x20 is the initial mole fraction of methanol; x1exp is the experimental solubility; x1cal is the calculated solubility by eqs 3, 5, 6, and 10, respectively. The standard uncertainty of temperature is u(T) = 0.1 K. The relative standard uncertainty of the solubility measurement is ur(x) = 0.08. The relative standard uncertainty of pressure is ur(P) = 0.05. The relative standard uncertainty in mole fraction of methanol (2) in the solvent mixtures is ur(x20) = 0.005. E



Article

Table 4. Mole Fraction Solubility of L-Carnitine Fumarate in (Methanol +2-Propanol) Binary Mixtures at Different Mole Fractions of Methanol (x20) and Different Temperatures (P = 0.1 MPa)a 103x1cal T/K

103x1exp

Apelblat

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.0524 0.115 0.150 0.246 0.348 0.410 0.622 0.827 1.05

0.0681 0.105 0.158 0.230 0.327 0.453 0.614 0.815 1.06

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.0906 0.160 0.210 0.325 0.432 0.595 0.882 1.14 1.36

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.144 0.204 0.303 0.386 0.556 0.795 1.05 1.37 1.62

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.164 0.264 0.382 0.540 0.744 0.996 1.40 1.87 2.30

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.262 0.372 0.522 0.740 1.03 1.39 1.96 2.48 2.93

288.15 293.15 298.15 303.15 308.15

0.387 0.548 0.772 1.01 1.43

(NIBS)/ Redlich−Kister

x20 = 0.000 0.0524 0.127 0.164 0.266 0.354 0.435 0.639 0.904 1.11 x20 = 0.100 0.0799 0.0867 0.133 0.147 0.210 0.207 0.317 0.304 0.459 0.429 0.639 0.561 0.855 0.821 1.11 1.06 1.38 1.29 x20 = 0.200 0.118 0.132 0.187 0.192 0.285 0.277 0.417 0.387 0.587 0.555 0.797 0.757 1.05 1.08 1.33 1.36 1.64 1.65 x20 = 0.300 0.161 0.190 0.248 0.267 0.370 0.384 0.537 0.523 0.758 0.745 1.04 1.04 1.39 1.44 1.82 1.83 2.33 2.20 x20 = 0.400 0.213 0.266 0.340 0.380 0.519 0.537 0.759 0.728 1.07 1.02 1.45 1.44 1.90 1.94 2.42 2.48 2.98 2.98 x20 = 0.500 0.347 0.373 0.522 0.544 0.760 0.753 1.08 1.02 1.48 1.40


Jouyban− Acree

0.0549 0.0820 0.126 0.183 0.262 0.389 0.558 0.608 0.623

0.0639 0.102 0.158 0.234 0.335 0.464 0.623 0.814 1.03

0.0754 0.112 0.170 0.244 0.348 0.512 0.731 0.810 0.851

0.0894 0.140 0.212 0.311 0.440 0.606 0.811 1.06 1.34

0.105 0.154 0.232 0.331 0.469 0.683 0.968 1.09 1.18

0.126 0.194 0.289 0.417 0.585 0.799 1.07 1.39 1.76

0.151 0.218 0.323 0.456 0.642 0.926 1.30 1.49 1.66

0.180 0.270 0.395 0.563 0.781 1.06 1.41 1.83 2.33

0.220 0.314 0.458 0.641 0.894 1.27 1.77 2.07 2.36

0.257 0.378 0.543 0.763 1.05 1.41 1.86 2.42 3.08

0.328 0.463 0.662 0.918 1.27

0.369 0.532 0.751 1.04 1.41

T/K

103x1exp

Apelblat

313.15 318.15 323.15 328.15

2.03 2.62 3.34 4.14

1.99 2.60 3.32 4.16

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.543 0.753 1.03 1.40 1.88 2.67 3.58 4.31 5.16

0.450 0.694 1.03 1.47 2.02 2.68 3.44 4.29 5.20

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

0.796 1.14 1.48 2.00 2.66 3.76 4.92 6.17 7.38

0.699 1.04 1.50 2.09 2.83 3.74 4.82 6.07 7.47

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

1.23 1.65 2.28 3.04 4.01 5.15 6.84 8.45 10.8

1.22 1.67 2.27 3.03 4.00 5.22 6.71 8.54 10.8

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

2.11 2.65 3.47 4.51 5.95 7.85 10.3 12.3 15.7

1.96 2.65 3.53 4.65 6.05 7.80 9.94 12.6 15.7

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

3.79 4.89 6.17 7.87 10.1 12.9 16.1 21.1 27.8

3.94 4.91 6.16 7.78 9.91 12.7 16.4 21.2 27.7



Jouyban− Acree

1.78 2.45 2.92 3.41

1.89 2.48 3.22 4.10

0.503 0.699 0.980 1.34 1.83 2.54 3.45 4.17 5.00

0.538 0.759 1.05 1.44 1.93 2.56 3.36 4.34 5.53

0.794 1.08 1.49 2.00 2.71 3.68 4.93 6.06 7.45

0.805 1.11 1.51 2.04 2.71 3.56 4.64 5.98 7.63

1.29 1.72 2.31 3.06 4.08 5.45 7.16 8.94 11.3

1.25 1.69 2.26 3.00 3.94 5.14 6.65 8.54 10.9

2.16 2.83 3.69 4.80 6.28 8.21 10.6 13.4 17.3

2.07 2.73 3.58 4.67 6.06 7.82 10.1 12.9 16.4

3.76 4.79 6.06 7.72 9.90 12.6 15.9 20.4 26.9

3.73 6.45 6.14 7.87 10.1 12.9 16.4 20.9 26.6

a 0 x2 is the initial mole fraction of methanol; x1exp is the experimental solubility; x1cal is the calculated solubility by eqs 3, 5, 6, and 10, respectively. The standard uncertainty of temperature is u(T) = 0.1 K. The relative standard uncertainty of the solubility measurement is ur (x)0.0524 ≤ 103x ≤ 0.0906 = 0.33, [ur(x) 103x ≥ 0.115]max = 0.10. The relative standard uncertainty of pressure is ur(P) = 0.05. The relative standard uncertainty in mole fraction of methanol (2) in the solvent mixtures is ur(x20) = 0.005.

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Table 5. Mole Fraction Solubility of L-Carnitine Fumarate in (Methanol +1-Butanol) Binary Mixtures at Different Mole Fractions of Methanol (x20) and Different Temperatures (P = 0.1 MPa)a 103x1cal T/K

103x1exp

Apelblat

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.103 0.132 0.208 0.294 0.379 0.441 0.703 0.833 1.21

0.114 0.151 0.201 0.269 0.361 0.485 0.653 0.881 1.19

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.152 0.188 0.275 0.402 0.503 0.559 1.04 1.17 1.46

0.129 0.189 0.270 0.378 0.517 0.693 0.910 1.17 1.48

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.180 0.283 0.323 0.521 0.706 0.709 1.22 1.41 2.10

0.216 0.277 0.358 0.469 0.620 0.827 1.11 1.51 2.06

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.249 0.352 0.517 0.684 0.868 0.955 1.56 2.14 2.47

0.247 0.345 0.475 0.647 0.870 1.16 1.52 1.98 2.55

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.306 0.449 0.662 0.912 1.19 1.26 2.03 2.63 3.66

0.374 0.480 0.624 0.819 1.09 1.45 1.96 2.66 3.64

293.15 298.15 303.15 308.15 313.15

0.510 0.685 0.863 1.17 1.64

0.432 0.623 0.877 1.21 1.63

(NIBS)/ Redlich−Kister x20 = 0.000 0.132 0.151 0.229 0.296 0.381 0.501 0.728 0.724 0.793 x20 = 0.100 0.119 0.184 0.267 0.401 0.509 0.656 0.953 1.14 1.56 x20 = 0.200 0.148 0.245 0.339 0.526 0.675 0.848 1.24 1.60 2.29 x20 = 0.300 0.219 0.342 0.454 0.682 0.896 1.10 1.62 2.12 2.86 x20 = 0.400 0.342 0.486 0.627 0.888 1.20 1.46 2.12 2.73 3.38 x20 = 0.500 0.523 0.692 0.883 1.18 1.64

103x1cal


Jouyban− Acree

0.0799 0.133 0.180 0.238 0.375 0.468 0.586 0.642 0.738

0.101 0.144 0.202 0.280 0.381 0.512 0.679 0.888 1.15

0.106 0.173 0.233 0.310 0.481 0.603 0.759 0.846 0.982

0.139 0.197 0.275 0.378 0.512 0.685 0.904 1.18 1.52

0.143 0.230 0.309 0.410 0.629 0.791 1.00 1.13 1.33

0.188 0.265 0.368 0.503 0.678 0.902 1.19 1.54 1.98

0.197 0.312 0.418 0.554 0.838 1.06 1.34 1.55 1.84

0.254 0.356 0.490 0.666 0.893 1.18 1.55 2.01 2.58

0.280 0.433 0.578 0.766 1.14 1.44 1.84 2.17 2.59

0.346 0.480 0.657 0.887 1.18 1.56 2.04 2.64 3.37

0.409 0.618 0.822 1.09 1.59

0.478 0.658 0.895 1.20 1.60

T/K

103x1exp

Apelblat

318.15 323.15 328.15 333.15

1.88 2.93 3.74 4.34

2.15 2.79 3.55 4.45

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.736 0.993 1.15 1.61 2.37 2.77 3.87 4.72 5.81

0.658 0.921 1.26 1.70 2.25 2.92 3.74 4.71 5.84

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

1.09 1.42 1.82 2.33 3.24 4.19 5.48 6.93 7.77

0.906 1.31 1.85 2.52 3.33 4.30 5.40 6.63 7.96

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

1.52 2.13 2.93 3.61 5.03 6.47 7.75 9.40 11.3

1.50 2.11 2.88 3.83 4.97 6.30 7.81 9.47 11.3

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

2.36 3.38 4.36 5.78 7.82 10.0 12.6 16.4 21.2

2.49 3.33 4.41 5.81 7.60 9.89 12.8 16.5 21.1

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

4.89 6.17 7.87 10.1 12.9 16.1 21.1 27.8 40.7

5.43 6.38 7.72 9.59 12.2 15.9 21.2 28.9 40.1



Jouyban− Acree

2.01 2.58 3.10 3.74

2.10 2.73 3.51 4.48

0.616 0.908 1.20 1.58 2.27 2.88 3.71 4.54 5.53

0.680 0.929 1.25 1.67 2.21 2.89 3.74 4.79 6.09

0.964 1.38 1.81 2.38 3.34 4.24 5.47 6.82 8.37

1.01 1.36 1.83 2.42 3.17 4.12 5.31 6.78 8.59

1.57 2.17 2.84 3.70 5.06 6.42 8.29 10.5 13.0

1.57 2.11 2.79 3.67 4.79 6.18 7.91 10.1 12.7

2.67 3.56 4.60 5.96 7.91 10.0 12.9 16.7 20.8

2.61 3.46 4.55 5.93 7.66 9.82 12.5 15.8 19.8

4.76 6.09 7.78 9.97 12.8 16.1 20.8 27.4 34.0

4.68 6.13 7.97 10.3 13.2 16.7 21.1 26.5 33.0

a 0 x2 is the initial mole fraction of methanol; x1exp is the experimental solubility; x1cal is the calculated solubility by, eqs 3, 5, 6, and 10, respectively. The standard uncertainty of temperature is u (T) = 0.1 K. The relative standard uncertainty of the solubility measurement is ur (x)0.103 ≤ 103x ≤ 0.132 = 0.19, [ur(x) 103x ≥ 0.152]max = 0.07. The relative standard uncertainty of pressure is ur (P) = 0.05. The relative standard uncertainty in mole fraction of methanol (2) in the solvent mixtures is ur (x20) = 0.005.

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Figure 3. Experimental solubility (x1) of L-carnitine fumarate in the {methanol (2) + ethanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (288.15 to 328.15) K.

Figure 6. Experimental solubility (x1) of L-carnitine fumarate in the {methanol (2) + 1-butanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (293.15 to 333.15) K.

dilution crystallization can be used for the purification of fumarate in this case. The dielectric constants of monosolvents used in this work are depicted in Table 6. The relative dielectric constants of the mixed solvents in this work at various temperature are also listed in Table 7 and shown in Figures 7−10. Figures 7−10 indicate that the Solubility−Polarity model can well describe the relationship of the solubility and dielectric constant. It can be seen that the dielectric constants of the five monosolvents can be arranged in a decreasing way: methanol > ethanol >1-propanol >2-propanol >1-butanol. Meanwhile, in binary solvents, the dielectric constants increase with the mole fraction of methanol increasing. Owing to the positive relationship between dielectric constants and polarity, the order of the polarity, which stands for the strength of solute−solvent van der Waals interactions, should be the same as that of the dielectric constants. From Figure 1, L-carnitine fumarate can be considered as a polar molecule judged by its structure, thus a solvent with higher polarity could display better solvency for the solute according to the rule of “like dissolves like”.23 What is more, when L-carnitine fumarate dissolves in selected organic solvents, due to the hydroxyl groups and carboxyl groups of L-carnitine fumarate, the solute molecules and the solvent molecules can form not only van der Waals force but also an intermolecular hydrogen bond. A summation of hydrogen-bond donor/acceptor properties of monosolvents used in this work is listed in Table 6. It has been reported that the proton donor is more important than the proton acceptor for estimating hydrogenbond strength.24 Considering the steric hindrance effect,25 the order of the hydrogen bond strength between L-carnitine fumarate and these solvents, might be (L-carnitine fumarate + methanol) > (L-carnitine fumarate + ethanol) > (L-carnitine fumarate + 1-propanol) > (L-carnitine fumarate + 2-propanol) > (L-carnitine fumarate + 1-butanol), which is exactly the same as the solubility sequence. Meanwhile, with mole fraction of methanol increasing, the polarity of solvents and the intermolecular hydrogen-bond strength between solute and solvent will also increase, which gives rise to the increment of solubility. 4.3. Crystal Habit. Crystal habit is one of the important indicators that needs to be considered during the production process. It not only has a great influence on the subsequent treatment process of products, but also can affect the bulk density, mechanical strength, flowability, and so on, thus affecting the storage and use of products.26 Both the internal crystal structure and the external growth environment can affect the crystal habit. Since the former is often difficult to control and L-carnitine

Figure 4. Experimental solubility (x1) of L-carnitine fumarate in the {methanol (2) + 1-propanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (288.15 to 328.15) K.

Figure 5. Experimental solubility (x1) of L-carnitine fumarate in the {methanol (2) + 2-propanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (288.15 to 328.15) K.

The parameters and value of ARD of the four models are given in Tables S1−S4, from which we can come to a conclusion that all of the four thermodynamic models can give satisfactory correlation results, especially the (CNIBS)/Redlich−Kister model. Figures 3−6 display that the solubility of L-carnitine fumarate increases with increasing temperature at a constant solvent composition in all selected solvents, in particular the most obvious change being in monomethanol. It indicates that the cooling crystallization method is suitable for the recrystallization to purify L-carnitine fumarate in monomethanol. Meanwhile, the solubility of L-carnitine fumarate changes significantly with the solvent composition in the four mixed solvents. Therefore, H



Article

Table 6. Physical Properties of Solvents Used in This Work22 solvent

∑αa

∑βb

dielectric constantc

densityd

viscositye

surface tensionf


0.43 0.37 0.37 0.33 0.37

0.47 0.48 0.48 0.56 0.48

32.61 24.85 20.52 19.26 17.33

0.79 0.79 0.80 0.78 0.81

0.54 1.07 1.95 2.04 2.54

31.77 31.62 33.57 30.13 35.88

a

Summation of the hydrogen bond donor propensities of the solvent. bSummation of the hydrogen bond acceptor propensities of the solvent. Dielectric constant at 298.15 K in the unit of D. dDensity at 293.15 K in the unit of kg·m−3. eViscosity at 298.15 K in the unit of mPa·s. fSurface tension of the solvent at 298.15 K in the unit of mN·m−1. c

Table 7. Relative Dielectric Constant (εmix) of Binary Solvents at Various Temperature Used in This Work.a εmix

x10

T /K

0.00

0.10

0.20

0.30

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

26.08 25.45 24.85 24.28 23.74 23.22 22.73 22.26 21.82

26.62 25.97 25.36 24.78 24.23 23.70 23.21 22.73 22.29

27.20 26.54 25.91 25.32 24.75 24.22 23.72 23.25 22.80

27.83 27.15 26.51 25.90 25.32 24.78 24.28 23.80 23.36

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

22.07 21.29 20.52 19.78 19.05 18.33 17.64 16.97 16.31

22.67 21.88 21.11 20.36 19.63 18.92 18.23 17.56 16.91

23.35 22.55 21.77 21.02 20.29 19.58 18.89 18.22 17.58

24.11 23.30 22.52 21.76 21.03 20.32 19.64 18.98 18.35

288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15

20.90 20.07 19.26 18.48 17.71 16.97 16.25 15.54 14.86

21.53 20.70 19.89 19.10 18.33 17.59 16.87 16.17 15.49

22.24 21.40 20.59 19.80 19.03 18.29 17.57 16.88 16.20

23.05 22.20 21.38 20.59 19.83 19.09 18.37 17.68 17.02

293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

18.00 17.33 16.69 16.06 15.46 14.88 14.31 13.76 13.23

18.58 17.91 17.26 16.63 16.02 15.43 14.87 14.32 13.79

19.26 18.57 17.92 17.28 16.67 16.08 15.51 14.96 14.43

20.04 19.35 18.68 18.04 17.42 16.83 16.26 15.71 15.19

0.40

0.50

(Methanol + Ethanol) 28.52 29.27 27.82 28.54 27.16 27.86 26.53 27.22 25.95 26.62 25.40 26.06 24.88 25.54 24.40 25.06 23.96 24.62 (Methanol +1-Propanol) 24.97 25.96 24.16 25.14 23.37 24.35 22.61 23.59 21.88 22.86 21.18 22.16 20.50 21.49 19.85 20.85 19.22 20.24 (Methanol +2-Propanol) 23.97 25.04 23.12 24.18 22.30 23.36 21.51 22.56 20.74 21.80 20.01 21.07 19.30 20.37 18.62 19.71 17.97 19.07 (Methanol +1-Butanol) 20.96 22.06 20.26 21.35 19.58 20.66 18.93 20.00 18.31 19.38 17.71 18.78 17.14 18.21 16.60 17.67 16.08 17.15

0.60

0.70

0.80

0.90

1.00

30.09 29.34 28.63 27.98 27.36 26.79 26.27 25.78 25.34

30.99 30.21 29.48 28.81 28.18 27.60 27.06 26.58 26.14

31.98 31.17 30.42 29.72 29.07 28.48 27.94 27.45 27.01

33.08 32.24 31.46 30.73 30.07 29.46 28.91 28.42 27.99

34.31 33.43 32.61 31.86 31.18 30.55 30.00 29.50 29.07

27.11 26.28 25.48 24.72 23.99 23.30 22.64 22.02 21.43

28.46 27.61 26.81 26.05 25.32 24.64 24.00 23.39 22.83

30.05 29.20 28.39 27.63 26.91 26.24 25.62 25.04 24.51

31.97 31.10 30.29 29.53 28.82 28.17 27.58 27.04 26.55

34.31 33.43 32.61 31.86 31.18 30.55 30.00 29.50 29.07

26.29 25.42 24.59 23.80 23.05 22.33 21.64 20.99 20.37

27.76 26.89 26.06 25.27 24.52 23.81 23.15 22.52 21.93

29.52 28.64 27.81 27.03 26.30 25.61 24.96 24.37 23.81

31.66 30.78 29.95 29.18 28.47 27.81 27.20 26.64 26.14

34.31 33.43 32.61 31.86 31.18 30.55 30.00 29.50 29.07

23.40 22.66 21.97 21.30 20.67 20.07 19.50 18.97 18.47

25.04 24.29 23.58 22.91 22.27 21.68 21.12 20.59 20.10

27.12 26.35 25.62 24.95 24.31 23.72 23.17 22.66 22.20

29.81 29.02 28.28 27.60 26.96 26.38 25.85 25.38 24.95

33.43 32.61 31.86 31.18 30.55 30.00 29.50 29.07 28.71

a

x20 is the initial mole fraction of methanol in selected binary solvents. The relative dielectric constant (εmix) of binary solvents at various temperatures are calculated by eqs 7 and 8.

flowability. In view of this, we have investigated the effect of different solvents on the crystal habit of L-carnitine fumarate during the cooling crystallization at the rate of 0.1 K/min, and thus provide a basis for the further selection of solvent in the industrial crystallization process.

change, we often obtained the desired crystal habit by the change of crystallization temperature or solvent or the addition of specific media and other methods. In the industrial crystallization process of L-carnitine fumarate, poor products are often obtained with small particle size, low apparent bulk density, and poor I



Article

Figure 7. Correlation of ln x versus −1/εmix in {methanol (2) + ethanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (288.15 to 328.15) K: ■, T = 288.15 K; red ●, T = 293.15 K; light blue ▲, T = 298.15 K; pink ▼, T = 303.15 K; green ◆, T = 308.15 K; dark blue ◀, T = 313.15 K; purple ▶, T = 318.15 K; purple ∗, T = 323.15 K; maroon ★, T = 328.15 K.

Figure 9. Correlation of ln x versus −1/εmix in {methanol (2) + 2-propanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (288.15 to 328.15) K: black ■, T = 288.15 K; red ●, T = 293.15 K; light blue ▲, T = 298.15 K; pink ▼, T = 303.15 K; green ◆, T = 308.15 K; dark blue ◀, T = 313.15 K; purple ▶, T = 318.15 K; purple ∗, T = 323.15 K; maroon ★, T = 328.15 K.

Figure 8. Correlation of ln x versus −1/εmix in {methanol (2) + 1-propanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (288.15 to 328.15) K: black ■, T = 288.15 K; red ●, T = 293.15 K; light blue ▲, T = 298.15 K; pink ▼, T = 303.15 K; green ◆, T = 308.15 K; dark blue ◀, T = 313.15 K; purple ▶, T = 318.15 K; purple ∗, T = 323.15 K; maroon ★, T = 328.15 K.

Figure 10. Correlation of ln x versus −1/εmix in {methanol (2) + 1-butanol (3)} binary solvent mixtures at atmosphere pressure (P = 0.1 MPa) from T = (293.15 to 333.15) K: black ■, T = 288.15 K; red ●, T = 293.15 K; light blue ▲, T = 298.15 K; pink ▼, T = 303.15 K; green ◆, T = 308.15 K; dark blue ◀, T = 313.15 K; purple ▶, T = 318.15 K; purple ∗, T = 323.15 K; maroon ★, T = 328.15 K.

4.3.1. Crystal Morphology Analysis. Figure 11 shows fumarate crystals from monosolvents used in this work. It can be seen that crystals grown in mono methanol/ ethanol/1-propanol exhibit thin flake-like shape, and pile up in an unorganized manner. When adopting mono 2-propanol/ 1-butanol as solvent, the thickness of products is increased, and the aggregation is reduced. The morphology of products obtained from (methanol + ethanol/1-propanol/2-propanol/1-butanol) binary solvents are shown in Figure 12. Thereinto, Figure 12 panels a and b show crystals produced using (methanol +1-butanol) binary mixtures with different mole fraction of methanol. It can be seen that crystals produced with higher methanol mole fraction are thinner and easier to agglomerate together than that produced with lower methanol mole fraction. Figure 12 panels c−e display products from three other binary solvents with the mole fraction of

methanol equals to 0.3. The morphology of them are similar to that in the corresponding poor solvent. On this basis, 1-butanol and (methanol +1-butanol) binary solvents with mole fraction of methanol less than 0.3 can serve as favorable solvents to a good crystal habit. It has been reported that the molecular structure and polarity of solvents have an important effect on the crystal growth process and habit.27,28 The dielectric constants of solvents in this study are listed in Table 7. It can be seen that the dielectric constants can be arranged in a decreasing way: methanol > ethanol > 1-propanol > 2-propanol > 1-butanol. What is more, the dielectric constants increase with the mole fraction of methanol increasing in the binary solvents. The larger dielectric constant of solvent will result in a relative stronger interaction between solvent and solute molecules and stronger absorption on the crystal planes of L-carnitine fumarate, which will inhibit the growth of crystal and

L-carnitine

J



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Figure 11. SEM images of L-carnitine fumarate grown in different monosolvents: (a) methanol; (b) ethanol; (c) 1-propanol; (d) 2-propanol; (e) 1-butanol.

Figure 12. SEM images of L-carnitine fumarate grown in different binary solvents: (a) 0.3 methanol + 0.7 1-butanol; (b) 0.7 methanol + 0.3 1-butanol; (c) 0.3 methanol + 0.7 ethanol; (d) 0.3 methanol + 0.7 1-propanol; (e) 0.3 methanol + 0.7 2-propanol.

induce crystals to agglomerate together. Meanwhile, due to the different intensity of the interactions between solvent and solute molecules on different crystal planes, the resistance of solvent on these surfaces is different. With the decrease of the dielectric constant of solvent, the interaction between solvent and solute becomes weaker and the self-association between solute molecules is more likely to occur. Thus, the degree of agglomeration of crystals decreases and the growth rate of each crystal face becomes closer and closer, leading to a lower length-diameter ratio. So crystals produced in mono-1-butanol/2-propanol and binary solvents with low mole fraction of methanol are thicker, and the degree of coalescence is lighter than that grown in other monosolvents and binary solvents with high mole fraction of methanol. 4.3.2. Crystal Size Distribution Analysis. The crystal size distributions of crystals from monosolvents are displayed in Figure 13. The corresponding volume-weighted mean diameters determined along with the D(10)-, D(50)- and D(90)-cumulative undersize are listed in Table 8. As shown in Figure 13 and Table 8, the particle size of crystals in those monosolvents can be

arranged in a decreasing way: methanol > ethanol > 1-butanol > 1-propanol > 2-propanol. Meanwhile, crystals produced in methanol show the narrowest distribution range with unimodal distribution, while in other monosolvents, the distribution curve broadens, and especially in ethanol/1-butanol, the size distributions of products are bimodal. This is in line with the crystal morphology analysis findings as shown in section 4.3.1. When grown in methanol, the stronger interaction between solute and solvent molecules inhibits the growth of crystal and leads crystals to agglomerate into larger particles, while in ethanol/1-propanol/2-propanol, the relative weaker interaction between solute and solvent molecules yields smaller agglomerated particles with uneven particle size. Hence, the size distributions of crystals produced in these solvents is broad, and even bimodal. In contrast, when 1-butanol is adopted as solvent, the weakest interaction between solute and solvent molecules results in the lightest degree of agglomeration and the weakest resistance of solvent on crystal surfaces. Consequently, the single particle size of products from 1-butanol is larger than K



Article

Figure 13. Particle size distribution curve of L-carnitine fumarate crystals grown in monosolvents: black ■, methanol; red ●, ethanol; blue ▲, 1-propanol; pink ▼, 2-propanol; green ◆, 1-butanol.

Figure 15. Particle size distribution curve of L-carnitine fumarate crystals grown in binary solvents with a mole fraction of methanol of 0.3: black ■, (methanol + ethanol); red ●, (methanol + 1-propanol); blue ▲, (methanol + 2-propanol); pink ▼, (methanol + 1-butanol).

Table 8. Volume Weighted Mean Diameters and Radial Distance of L-Carnitine Fumarate Crystals Grown in Monosolvents

Table 9. Volume-Weighted Mean Diameters and Radial Distance of L-Carnitine Fumarate Crystals Grown in Binary Solvents volume-weighted mean diameters/μm

volume-weighted mean diameters/μm a

solvent

D(10)

D(50)

D(90)

span


146 35.6 50.9 20.4 35.1

220 137 118 76.9 131

321 238 204 177 220

0.792 1.475 1.298 2.042 1.413

a Index of particle size distribution width, can be calculated by (D90 − D10)/D50.

solvent

mole fraction of methanol

methanol + ethanol methanol + 1-propanol methanol + 2-propanol methanol + 1-butanol methanol + 1-butanol

0.3 0.3 0.3 0.3 0.7

D(10) D(50) D(90) spana 42.6 37.3 17.9 26.8 55.6

171 155 94.8 138 151

260 243 223 234 238

1.266 1.332 2.168 1.507 1.212

Index of particle size distribution width, can be calculated by (D90 − D10)/D50. a

solvents is between that of products grown in corresponding monosolvents. What is more, the particle size increases with the mole fraction of methanol increasing, and the crystal size distribution becomes narrower. This is because as the mole fraction of methanol increases, the interaction between solute and solvent molecules increases, which inhibits the growth of crystal and induces more crystals to agglomerate into large particles.

5. CONCLUSIONS The solubility of L-carnitine fumarate in (methanol + ethanol/1propanol/2-propanol) was determined within the temperature range of 288.15−328.15 K at atmospheric pressure by the gravimetric method. Meanwhile, the solubility in (methanol + 1butanol) was determined by the same method from T = (293.15 to 333.15) K due to its low solubility in low temperature. It is found that the solubility increases with the increasing temperature and the mole fraction of methanol in all solutions. Moreover, the solubility data of L-carnitine fumarate in mixed solutions ranks as (methanol + ethanol) > (methanol + 1-propanol) > (methanol + 2-propanol) > (methanol + 1-butanol), partly depending on the polarity of the solvents and intermolecular hydrogen-bond strength between solute and solvent molecules. The modified Apelblat equation, (CNIBS)/Redlich−Kister model, Solubility−Polarity model, and Jouyban−Acree model were applied to correlate the solubility data in all solutions, and all of them could show satisfactory correlation results. Besides, the crystal morphology and size distribution of L-carnitine

Figure 14. Particle size distribution curve of L-carnitine fumarate crystals grown in (methanol + 1-butanol) binary solvents: black ■, mole fraction of methanol is 0.7; red ●, mole fraction of methanol is 0.3.

that from other monosolvents. However, the presence of agglomerated particles leads to uneven particle size distribution. Figures 14 and 15 are crystal size distributions of L-carnitine fumarate grown in binary solvents. The corresponding volumeweighted mean diameters determined along with the D(10)-, D(50)- and D(90)-cumulative undersize are listed in Table 9. It can be seen that the crystal size of products grown in binary L



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fumarate in different solvents were studied in order to select solvents favorable to crystal habits. It is hoped that the experimental solubility value and the crystal habit study can be helpful for the design and optimization of the L-carnitine fumarate crystallization process.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.7b00768. Calculated parameters with the average relative deviation (ARD) of four models (modified Apelblat model, (CNIBS)/Redlich−Kister model, Solubility−Polarity model, and Jouyban−Acree model); figure of the X-ray power diffraction pattern of L-carnitine fumarate before and after the experiment (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: 86-22-27405754. Fax: +86-22-27374971. ORCID

Shichao Du: 0000-0002-8369-2983 Junbo Gong: 0000-0002-3376-3296 Notes

The authors declare no competing financial interest. Funding

The works was supported by the National Natural Science Foundation of China (NNSFC 81361140344 and NNSFC 21376164), the National 863 Program (2015AA021002), the Major Science and Technology Program for Water Pollution Control and Treatment (No. 2015ZX07202-013), the Tianjin Science and Technology Project (15JCZDJC33200) and the Project of Developing the Sea through Science and Technology of Tianjin (KJXH2015-01).

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REFERENCES

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