Self-assembly of Monodispersed Carnosine Spherical Crystals in

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Self-assembly of Monodispersed Carnosine Spherical Crystals in Reverse Antisolvent Crystallization Process Yanan Zhou, Jingkang Wang, Ting Wang, Na Wang, Yan Xiao, Shuyi Zong, Xin Huang, and Hongxun Hao Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01818 • Publication Date (Web): 03 Apr 2019 Downloaded from http://pubs.acs.org on April 5, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Crystal Growth & Design

Self-assembly of Monodispersed Carnosine Spherical Crystals in Reverse Antisolvent Crystallization Process Yanan Zhou a, b, Jingkang Wang a, b, Ting Wang a, Na Wang a, Yan Xiao a, Shuyi Zonga, Xin Huang a,b *, Hongxun Hao a,b * a

National Engineering Research Center of Industrial Crystallization Technology, School

of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China b

Collaborative Innovation Center of Chemical Science and Engineering(Tianjin), Tianjin

300072, China ABSTRACT: Spherical crystallization is an effective way to increase particle size, raise bulk density, improve flowability and compressibility of crystals with small sizes, especially needle-like and flake-like microcrystals. In this work, reverse antisolvent crystallization method was used to obtain the spherical crystals of carnosine instead of commercially available needle-like carnosine material. Besides, the solubility of carnosine in binary solvents mixture of water + ethanol was measured at temperature ranging from 288.05 K to 323.15 K by using a gravimetric method under atmospheric pressure to optimize this crystallization process and increase the yield of carnosine. Based on this thermodynamic data, single factor analysis in reverse antisolvent crystallization process was investigated, including carnosine aqueous solution *To whom the correspondence should be addressed. Tel.: +86-22-27405754; Fax: +86-22-27374971. E-mail: [email protected] (X. Huang); [email protected] (H. Hao). ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

concentration, feeding rate, volume ratio of solution to antisolvent, temperature and stirring speed. Polarizing microscope, particle size distributions and in situ - particle vision measurement (PVM) were used to characterize and monitor the carnosine spherical crystals during the reverse antisolvent crystallization process. Finally, monodispersed, several hundred micrometer-sized carnosine spherical crystals with higher bulk density (0.224 g/mL) and smaller repose angle (39 °), which indicated the better flowability, were successfully crystallized and a feasible formation mechanism was proposed. Keywords: Carnosine; Spherical Crystals; Reverse Antisolvent Crystallization; Solubility; Process Optimization.

1.

Introduction

Carnosine (β-alanyl-L-histidine, C9H14N4O3, molecular weight: 226.235 g.mol-1, CAS Registry No. 305-84-0), shown in Figure 1, is widely used in areas of medical, cosmetics and food industries because of its ability of reducing activities of liberated fatty acid and phospholipid hydroperoxides, as well as its combination of weak metal chelating, OH. and lipid peroxyl radicals scavenging.1 But as yet, commercially available carnosine material is needle-like crystal and fairly small in size, which always raise difficulties in their downstream processing due to its low bulk density, poor flowability and inferior compressibility.

2

ACS Paragon Plus Environment

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Figure 1. The molecule structure of carnosine. Crystallization is a well-established unit operation for separation, purification of solid products in industrial production.2 Compared with other techniques, crystallization can not only be used to separate and purify the products, but also regulate the related performance of the crystals by controlling the crystal outer shape or inner structure. It is well known that crystallization processes could result in products exhibiting different powder properties such as crystal habit, crystal size, bulk density, flow properties, hygroscopicity and so on,3-5 which can influence the production process as well as the quality and curative effect of solid drugs. Solution crystallization has been widely used in the pharmaceutical industry to improve the powder property of solid drug, such as rotigotine,6 fingolimod hydrochloride7 and ixabepilone,8 by changing the crystal morphology or crystal form. Spherical crystallization, pioneered by Kawashima, is a typical technique to improve the powder property of solid product through formation larger spherical particles by an additives-induced agglomeration process.9 This method is a better choice to improve the powder property of solid product compared with the granulation in the downstream processing due to its advantage of simple operation process and low costs.10, 11 Based on 3



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the characteristics of the spherical crystallization process, it can be subdivided into spherical agglomeration method,12 quasi-emulsion solvent diffusion method,13 ammonia diffusion

method,14

neutralization

technique15

and

crystallo-co-agglomeration

technique.16 No matter which spherical crystallization technique is adopted, antisolvent crystallization is the most common method and has been widely used to improve the powder properties of crystal products. Besides, process analytical technologies have been widely applied in the field of crystallization including monitoring of particle change including size distribution and particles morphology,17, 18 measurement of crystallization thermodynamics and determining the crystallization kinetics,19 such as induction time and metastable zone width, etc. However, up to date, the spherical crystals of carnosine have not been reported in literature and there is little information about the spherical crystallization technology for carnosine. In this study, reverse antisolvent crystallization method was used to produce spherulite formation of carnosine and the spherical crystals of carnosine was first obtained. In the reverse antisolvent crystallization process, carnosine solution was added to the antisolvent to reach high supersaturation at the beginning of the experiment, which can drive the formation of carnosine spherical crystals.20,

21

Besides, the solubility of

carnosine, which provides essential information for the crystallization process,22, 23 was measured at temperature ranging from 288.05 K to 323.15 K by using a gravimetric method under atmospheric pressure to design and optimize the spherical crystallization technology of carnosine. To extend the applicability of the solubility data, the modified 4


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Apelblat equation and the Jouyban-Acree model were used to correlate and analyze the experimental solubility data of carnosine. Based on the accurate and credible solubility data of carnosine, operating parameters for experiment, including carnosine aqueous solution concentration, feeding rate, volume ratio of solution to antisolvent, temperature and stirring speed were systematically investigated by single factor experiments. Moreover, in situ - particle vision measurement (PVM), polarizing microscope, together with particle size distributions were used to characterize and monitor the formation of carnosine spherical crystals by reverse antisolvent crystallization. Finally, monodispersed, several hundred micrometer-sized carnosine spherical crystals with higher powder property were successfully crystallized and a feasible formation mechanism was proposed.

2.

Experimental section

2.1. Materials The white to off-white crystalline powder of carnosine with a purity (mass fraction) of 0.9943 was purchased from Tianjin Yuxiang Technology Co., Ltd, China. Methanol, ethanol, 1-propanol, 2-propanol, isobutanol, tert-butanol, acetone, acetonitrile and 1,4-dioxane were supplied by Tianjin Kewei Chemical Co., Ltd, China. They are analytical grade reagents with the purity (mass fraction) higher than 0.995, which were confirmed by gas chromatography. The distilled-deionized water was provided by Nankai 5



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University, China. All the materials were used without any further purification in the experiments. The sources and purities of all the chemicals used in this work are listed in Table 1. Table 1 The sources and purities of all the chemicals used in this work. Chemical name carnosine methanol ethanol 1-propanol 2-propanol isobutanol tert-butanol acetone acetonitrile 1,4-dioxane

Source Tianjin Yuxiang Technology Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China Tianjin Kewei Chemical Co., Ltd, China

Mass purity

Purification method

Analysis method

0.9943

None

HPLC a

＞0.995

None

GC b

＞0.995

None

GC b

＞0.995

None

GC b

＞0.995

None

GC b

＞0.995

None

GC b

＞0.995

None

GC b

＞0.995

None

GC b

＞0.995

None

GC b

＞0.995

None

GC b

High-performance liquid chromatography, which was carried out by Tianjin Yuxiang Technology Co., Ltd, China. b Gas chromatography, which was carried out by Tianjin Kewei Chemical Co., Ltd, China. a

2.2. Solid State Characterization Inorder to verify the crystal form and crystallinity of carnosine samples before and

6


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after the experiments, X-ray powder diffraction patterns (XRPD) were carried out on a D/max-2500 X-ray diffractometer (Rigaku, Japan) using Cu Kα radiation (1.5405 Å). Samples were measured over a diffraction angle (2θ) range of 2-50 ° with a scanning rate of 0.067 °∙sand a step size of 0.02 °. The powder properties of carnosine raw material and the products obtained by the optimal spherical crystallization technology, including bulk density and flow properties, were characterized respectively. The bulk density, also known as apparent density, was determined using the 50 ml graduated cylinder equipped on the powder characteristics tester (BT-100, Bettersize Instruments Ltd., China) without any tapping. The flow ability was assessed by angle of repose using the powder characteristics tester.24 The characterizations were repeated three times and the mean values were used to evaluate the powder properties of carnosine. 2.3. Solubility experiments The solubility of carnosine in binary solvents mixture of water + ethanol was determined at temperature ranging from 288.05 K to 323.15 K under atmospheric pressure by using a gravimetric method whose apparatus and detailed procedures have already been described in previous literature.25 The mole fraction of ethanol (x0 B) was from 0.00 to 0.60 at the interval of 0.10. Furthermore, the experimental solubility data were correlated and analyzed by the modified Apelblat equation and the Jouyban-Acree model, which are widely used to correlate the solubility of a solute at various 7



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temperatures. 2.3.1. Modified Apelblat equation The modified Apelblat equation, a simple semi-empirical model with three empirical parameters A, B and C, is broadly applied to correlate and predict the solubility of solute in solution. It can be expressed as follows: 26 ln x1  A 

B  C ln(T / K ) T/K

(1)

where x1 refers to the molar solubility of solute. T is the absolute temperature. A, B and C stand for the empirical parameters gained from the fitting of experimental solubility data with equation (1) using least square method. 2.3.2. Jouyban-Acree model The Jouyban-Acree model is an accurate model which is used to correlate solubility of a solute in binary solvent mixtures at various temperatures. The model is expressed as equation (2): 27

J i ( x20  x30 )i ln x1  x ln X 2  x ln X 3  x x  T i 0 0 2

0 3

0 0 2 3

N

(2)

where x1 stands for mole fraction of carnosine in saturated solution. x0 2 and x0 3 represent initial mole fraction of water and ethanol in the absence of solute, respectively. And X2, X3 represent mole fraction solubility of carnosine in pure water and ethanol. N refers to the number of “curve-fit” parameters and Ji is the model parameter. T refers to the absolute temperature of solution. 8


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In order to enlarge the application of Jouyban-Acree model in non-ideal systems, it was combined with the modified Apelblat equation to correlate solubility at different temperatures. X2 and X3 can be determined by modified Apelblat equation (3) and (4). b2  c2 ln T T b ln X 3  a3  3  c3 ln T T

ln X 2  a2 

(3) (4)

Because the value of N is 2 for binary solvent mixture, equation (2) can be further simplified into equation (5) by substituting x0 3 with (1- x0 2).

b2 x0  c2 ln T  (a2  a3 ) x20  (b2  b3  J 0  J1  J 2 ) 2 T T 0 2 0 3 （x ）（x ） (3 J1  J 0  5 J 2 ) 2  (8 J 2  2 J1 ) 2 T T 0 4 （x ） (4 J 2 ) 2  (c2  c3 ) x20 ln T T

ln x1  a2 

(5)

By simplifying equation (5) with a constant term, Jouyban-Acree model could be transformed into equation (6): 2 A2 x0 （x 0）  A3 ln T  A4 x20  A5 2  A6 2 T T T 0 3 0 4 （x ）（x ）  A7 2  A8 2  A9 x20 ln T T T

ln x1  A1 

(6)

where A1 to A9 are model parameters; the meaning of other term is same as above. This hybrid model shows the relationship of solubility, temperature and composition of initial solvent specifically.28 2.4. Development and optimization process of spherical crystals for carnosine The development of carnosine spherical crystals technology was investigated by 9



reverse antisolvent crystallization through the following procedures. Firstly, 36 mL of several pure organic solvents, including methanol, ethanol, 1-propanol, 2-propanol, isobutanol, tert-butanol, acetone, acetonitrile and 1,4-dioxane, were added into a 100 mL water-jacketed vessel at 303.15 K respectively. The temperatures of the glass vessels were controlled by circulating water from a thermostat (CF41, Julabo, Germany). Then, the solid carnosine was dissolved in water at room temperature to prepare 0.15 g/mL carnosine aqueous solution. Finally, 12 mL carnosine solution was dropped into the water-jacketed vessels containing organic solvents respectively by a peristaltic pump (BT100-1F, Longer, China) at an addition rate of 250 μL/min. During the adding process of carnosine solution, a mechanical stirrer with an overhead 2-blade impeller stirring was adjusted to 300 rpm to fully mix the carnosine solution with organic solvent. Once the adding process of carnosine solution finished, a drop of slurry was taken out by a plastic dropper and analyzed under a polarized optical microscopy (BX51, Olympus, Japan). After that, the products were filtered and dried in a vacuum oven at 298.15 K for further characterization. The reverse antisolvent crystallization apparatuses for the development of carnosine spherical crystals are shown in Figure 2. Moreover, systematical optimizations for the reverse antisolvent crystallization were carried out by single factor analysis method to gain monodispersed, pure carnosine spherical crystals. The operating parameters, including carnosine aqueous solution concentration, feeding rate, volume ratio of solution to antisolvent, temperature and 10


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stirring speed were optimized separately. Finally, 22 experiments, as shown in Table 2, were performed and each product was qualitatively evaluated for its size distribution and particles morphology by a particle size analyzer (Mastersizer 3000, Malvern Instruments Ltd., U.K.) and a polarized optical microscopy (BX51, Olympus, Japan), respectively.

Figure 2. The schematic diagram for the reverse antisolvent crystallization in the development and optimization process of spherical crystals for carnosine: (1) measuring cylinder; (2) peristaltic pump; (3) thermostat; (4) 100 mL water-jacketed vessel; (5) mechanical stirrer; (6) stirring paddle; (7) PVM probe; (8) computer. Table 2 Operating conditions of the single factor experiments for optimizing the crystallization process of carnosine spherical crystals. Experiment

Concentration of carnosine solution

Feeding rate of carnosine solution

Volume ratio of solution to antisolvent

Temperature

Stirring speed

Concentration of carnosine solution 1

0.100 g/mL

250 μL/min

1:3

303.15 K

300 rpm

2

0.125 g/mL

250 μL/min

1:3

303.15 K

300 rpm

11



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3

0.150 g/mL

250 μL/min

1:3

303.15 K

300 rpm

4

0.175 g/mL

250 μL/min

1:3

303.15 K

300 rpm

5

0.200 g/mL

250 μL/min

1:3

303.15 K

300 rpm

Feeding rate of carnosine solution 6

0.175 g/mL

100 μL/min

1:3

303.15 K

300 rpm

7

0.175 g/mL

150 μL/min

1:3

303.15 K

300 rpm

8

0.175 g/mL

200 μL/min

1:3

303.15 K

300 rpm

4

0.175 g/mL

250 μL/min

1:3

303.15 K

300 rpm

9

0.175 g/mL

300 μL/min

1:3

303.15 K

300 rpm

10

0.175 g/mL

350 μL/min

1:3

303.15 K

300 rpm

Volume ratio of solution to antisolvent 11

0.175 g/mL

100 μL/min

1:2

303.15 K

300 rpm

6

0.175 g/mL

100 μL/min

1:3

303.15 K

300 rpm

12

0.175 g/mL

100 μL/min

1:4

303.15 K

300 rpm

13

0.175 g/mL

100 μL/min

1:5

303.15 K

300 rpm

14

0.175 g/mL

100 μL/min

1:6

303.15 K

300 rpm

Temperature of crystallization 15

0.175 g/mL

100 μL/min

1:3

298.15 K

300rpm

6

0.175 g/mL

100 μL/min

1:3

303.15 K

300 rpm

16

0.175 g/mL

100 μL/min

1:3

308.15 K

300 rpm

17

0.175 g/mL

100 μL/min

1:3

313.15K

300 rpm

18

0.175 g/mL

100 μL/min

1:3

318.15K

300rpm

12


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Stirring speed 19

0.175 g/mL

100 μL/min

1:3

303.15 K

100 rpm

20

0.175 g/mL

100 μL/min

1:3

303.15 K

200 rpm

6

0.175 g/mL

100 μL/min

1:3

303.15 K

300 rpm

21

0.175 g/mL

100 μL/min

1:3

303.15 K

400 rpm

22

0.175 g/mL

100 μL/min

1:3

303.15 K

500 rpm

2.5. Formation mechanism of carnosine spherical crystals In this work, particle vision measurement (PVM, V819, Mettler Toledo, Switzerland) was employed to monitor the self-assembly process of carnosine spherical crystals during the crystallization process with the optimal values of operating parameters. The PVM was operated throughout the crystallization processes and the images of particles morphology were recorded at an update rate of 2 images per second.

3.

Results and discussion

3.1. X-ray powder diffraction analysis

Figure 3. X-ray powder diffraction pattern of carnosine. 13



The XRPD patterns for the carnosine raw material and the products obtained by process of spherical crystals were found to be the same, which are shown in Figure 3. The results demonstrate that both the crystal form and the crystallinity of carnosine didn’t change during the experimental process. 3.2. Solubility experiments

Figure 4. Mole fraction solubility of carnosine in binary solvent mixture of water and ethanol depending on temperature T and the initial mole fraction of water (x0 2) at atmospheric pressure (p = 0.1 MPa). The experimental data for solubility of carnosine in water + ethanol binary solvents mixture at temperature ranging from (288.05 to 323.15) K is depicted in Table 3 and graphically shown in Figure 4. The results show that the solubility of carnosine depends on both temperature and solvent composition. It can be clearly seen from the figure that the solubility of carnosine monotonously increases with the increasing of temperature at a 14


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given composition of the binary solvents mixture, which indicates that the dissolving process of carnosine is endothermic throughout the entire tested temperature ranges.29 In addition, the solubility data of carnosine decreases apparently with the increasing of the mole fraction of ethanol. This may be explained by the effect of polarity of solvents and intermolecular interaction between solute and solvents. These results can be used to guide the design and optimization of the crystallization process for carnosine spherical crystals. Table 3 The mole fraction solubility of carnosine x1 in (water + ethanol) mixture in temperature ranges from (288.05 to 323.15) K at atmospheric pressure (p = 0.1 MPa).a,b 103x1Exp

x0 2

103x1 Exp

x0 2

288.05 K

293.05 K

0.4014

0.165

0.4014

0.181

0.5005

0.418

0.5005

0.459

0.6006

0.800

0.6006

0.896

0.7005

1.76

0.7005

1.93

0.8003

3.45

0.8003

3.85

0.9003

6.87

0.9003

8.31

1.0000

21.7

1.0000

22.4

298.2 K 0.4014 0.5005

303.25 K

0.199 0.498

0.4014

0.217

0.5005

0.561

15



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0.6006

1.00

0.6006

1.21

0.7005

2.23

0.7005

2.53

0.8003

4.38

0.8003

5.29

0.9003

9.57

0.9003

11.5

1.0000

23.6

1.0000

24.9

308.15 K

313.25 K

0.4014

0.246

0.4014

0.265

0.5005

0.608

0.5005

0.654

0.6006

1.32

0.6006

1.47

0.7005

3.00

0.7005

3.43

0.8003

6.32

0.8003

7.26

0.9003

13.2

0.9003

15.1

1.0000

26.5

1.0000

28.7

318.2 K

323.15 K

0.4014

0.287

0.4014

0.315

0.5005

0.697

0.5005

0.777

0.6006

1.68

0.6006

1.87

0.7005

3.86

0.7005

4.51

0.8003

8.41

0.8003

9.93

0.9003

16.9

0.9003

19.7

1.0000

30.1

1.0000

32.4

16


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x0 2 is the initial mole fraction of water in the binary solvent mixture; x1Exp is the experimental solubility. b The standard uncertainty of T is u(T) = 0.05 K. The relative standard uncertainty of the solubility is ur(x1) = 2 %. The relative standard uncertainty of the binary solvent mixture composition x0 2 is ur(x0 2) = 0.03 %. The standard uncertainty of pressure is u (p) = 0.3 kPa. a

Two thermodynamic models including the modified Apelblat equation and the Jouyban-Acree model were used to correlate and analyze the experimental solubility data of carnosine. The parameters of these models are listed in Tables 4–5. To evaluate the applicability and accuracy of the models applied in this work, the average relative deviation (ARD) was used to evaluate the accuracy of correlation. It is defined as follows: ARD 

1 N



N i 1

xiExp  xiCal xiExp

(7)

where xiExp stands for the experimental solubility data of carnosine. xiCal refers to the solubility data of carnosine calculated by the modified Apelblat equation or the Jouban-Acree model. N represents the number of the experimental data points. Table 4 Parameters of the modified Apelblat equation for the solubility of carnosine in binary solvent mixtures of water + ethanol at p = 101.3 kPa.a x0 2

A

B

C

ARD %

0.4014

-24.56

-743.4

3.253

0.7534

0.5005

-8.346

-1339

0.9206

0.9229

0.6006

-31.21

-833.2

4.760

1.1914

0.7005

-172.6

5394

26.04

1.38

0.8003

-169.2

4993

25.81

1.3633

17



a

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0.9003

52.14

-4896

-7.083

1.0544

1.0000

-161.6

6241

24.04

0.5134

The standard uncertainty of pressure is u (p) = 0.3 kPa.

Table 5 Parameters of the Jouban-Acree model for the solubility of carnosine in binary solvent mixtures of water + ethanol at p = 101.3 kPa.a Parameters

Parameters

A1

17.72

A4

-149.5

A7

3033

A2

-3646

A5

1.013e4

A8

-551.5

A3

-3.409

A6

-5050

A9

23.57

ARD % a

Parameters

6.218

The standard uncertainty of pressure is u (p) = 0.3 kPa.

Figure 5. Experimental and correlated mole fraction solubility of carnosine in binary solvent mixture of water and ethanol at different initial mole fraction of water (x0 2): (■) x0 2=0.4014; (○) x0 2=0.5005; (▲) x0 2=0.6006; (◇) x0 2=0.7005; (●) x0 2=0.8003; (▽) x0 2=0.9003; (◆) x0 2=1.0000. The values of ARD of the modified Apelblat equation and the Jouban-Acree model are also listed in Table 4 and Table 5, respectively. It can be found that the ARD % values 18


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of the modified Alpebalt equation and the Jouban-Acree model are less than 1.4 % and 6.3 %, respectively, which means that both thermodynamic models could give accurate correlated values of the solubility data in the tested temperature range. Furthermore, the modified Alpebalt equation could predict the solubility data of carnosine better than the Jouban-Acree model and the fitted curves using the modified Apelblat equation are depicted in Figure 5. 3.3. Development and optimization process of spherical crystals for carnosine

Figure 6. The polarizing microscope images of raw material (a) and the products (b) obtained in development process of spherical crystals, in which ethanol acting as antisolvent. In the development of carnosine spherical crystals, spherulitic agglomeration of carnosine was first observed in reverse antisolvent crystallization process, in which water served as solvent and ethanol acted as antisolvent. However, as shown in Figure 6, the obtained product was a mixture of spherical and needle shaped carnosine crystals, whose crystal size distribution exhibited a bimodal distribution, as shown in Figure 7. The products of the rest of the preliminary experiments, in which methanol, 1-propanol, 19



2-propanol, isobutanol, tert-butanol, acetone, acetonitrile and 1,4-dioxane acted as antisolvents, were needle-like microcrystals. The particle size distributions of these needle-like carnosine crystals were almost the same as that of the raw material, which are shown in Figure 7.

Figure 7. The particle size distributions of raw material (a) and the products (b) obtained in development process of spherical crystals, in which ethanol acting as antisolvent. Based on the correlated results of the Jouban-Acree model, the supersaturation, which was represented by the ratio of solution concentration to solubility, was calculated during the adding of carnosine solution into ethanol without considering the appearing of crystals and plotted in Figure 8. It can be obviously seen from Figure 8 that the supersaturation was enormous at the beginning of the experiment and decreased with the increasing of carnosine solution in the system. The huge supersaturation at the beginning of reverse antisolvent crystallization process was the driving force for the formation of carnosine spherical crystals. 20


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Figure 8. The change of supersaturation during the adding of carnosine solution into the water-jacketed vessels containing ethanol without considering the appearing of crystals. In order to gain monodispersed, pure carnosine spherical crystals with higher powder properties, the operating parameters for the reverse antisolvent crystallization process, including carnosine aqueous solution concentration, feeding rate, volume ratio of solution to antisolvent, temperature and stirring speed were systematically optimized by single factor method. Finally, monodispersed, several hundred micrometer-sized carnosine spherical crystals were successfully crystallized by reverse antisolvent crystallization process with the optimized experiment parameters. 3.3.1. Carnosine aqueous solution concentration All of the experiments in this section were conducted at a stirring speed of 300 rpm with a volume ratio (solution: antisolvent) of 1:3. And the feeding rate of carnosine solution as well as the experimental temperature were all set to 250 μL/min and 303.15 K, respectively. The effect of carnosine solution concentration (ranging from 0.100 g/mL to 21



0.200 g/mL) on the overall shape and crystal size distribution of products was investigated and the results are shown in Figure S1 of the Supporting Information and Figure 9. It can be obviously seen from Figure S1 that both the amount and the size of spherical carnosine crystals increased with the increasing of carnosine solution concentration firstly and then reduced after the concentration exceed a certain value,30 which was in accordance with the particle size distributions of crystal products. This is due to the fact that the solids loading in the slurry increased with the increasing of carnosine solution concentration, which could increase the frequency of particle collision. On the one hand, the increasing of particle collision frequency could facilitate the forming of aggregates. On the other hand, the increasing of particle collision frequency might also cause the attrition and breakage of spherical crystals in the system, as shown in Figure S1(e). So, the carnosine solution concentration was set to 0.175 g/mL in the following optimization experiments, considering the overall shape and crystal size distribution of products obtained in the investigated reverse antisolvent crystallization process.

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Figure 9. The particle size distributions of the products obtained in optimization process of spherical crystals with different carnosine aqueous solution concentration: (a) 0.100 g/mL; (b) 0.125 g/mL; (c) 0.150 g/mL; (d) 0.175 g/mL; (e) 0.200 g/mL. 3.3.2. Feeding rate All of the experiments in this section were conducted at a stirring speed of 300 rpm with a volume ratio (solution: antisolvent) of 1:3. And the carnosine solution concentration as well as the experimental temperature were all set to 0.175 g/mL and 303.15 K, respectively. Figure S2 presents the polarizing microscope images of the products obtained in optimization process with different feeding rate of carnosine solution: (a) 100 μL/min; (b) 150 μL/min; (c) 200 μL/min; (d) 250 μL/min; (e) 300 μL/min; (f) 350 μL/min. It was found that the amount of needle shaped carnosine crystals decreased with the decreasing of feeding rate. The supersaturation change with the adding amount of carnosine solution before crystal nucleation was the same. However, the supersaturation change speed was dissimilar with different feeding rate of carnosine 23



solution. The bigger the feeding rate would result in the faster supersaturation change speed which could further lead to the production of redundant crystal nucleus. These excessive crystal nucleus would result in the decreasing of supersaturation in the system, which was disadvantage to the further growth of spherical crystals. There was scarcely any needle shaped carnosine crystals when the feeding rate was 100 μL/min. Furthermore, the size of carnosine spherical crystals increased with the decreasing of feeding rate, which could be confirmed by the particle size distributions of the products (Figure 10). Therefore, the feeding rate was set to 100 μL/min in the following single factor experiments, considering the amount and size of spherical crystals obtained in the investigated reverse antisolvent crystallization process.

Figure 10. The particle size distributions of the products obtained in optimization process of spherical crystals with different feeding rate of carnosine solution: (a) 100 μL/min; (b) 150 μL/min; (c) 200 μL/min; (d) 250 μL/min; (e) 300 μL/min; (f) 350 μL/min. 3.3.3. Volume ratio of solution to antisolvent 24


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All of the experiments in this section were conducted at a stirring speed of 300 rpm with the experimental temperature of 303.15 K. And the carnosine solution concentration as well as the feeding rate were all set to 0.175 g/mL and 100 μL/min, respectively. The morphology and crystal size distribution of products obtained under various volume ratios are reported in Figures S3 and Figure 11, respectively. As shown in Figure S3, when the ratio was increased from 1:6 to 1:2 gradually, the amount of needle shaped carnosine crystals reduced drastically. This might be the result of the increasing supersaturation with the decreased ratio from 1:2 to 1:6 at the same adding amount of carnosine solution, which could further lead to the production of redundant crystal nucleus. These excessive crystal nucleus could also retarded the further growth of spherical crystals. Within the ranges of this research, the bigger the volume ratio was, the better the products would. It can be obviously seen from Figure S3(a)-(b) that the overall shapes of products obtained in reverse antisolvent crystallization process (volume ratio = 1:2 and 1:3) were exactly the same except the uniformity. This was further confirmed by the crystal size distribution (Figure 11), indicating that there was no needle shaped carnosine crystal when volume ratio was reduced to 1:2 and 1:3. In addition, the size of crystals obtained at the ratio of 1:2 is more homogeneous than that obtained under 1:3, which also has a narrower crystal size distribution. However, as the yield of reverse antisolvent crystallization process mainly depends on volume ratio of solution to antisolvent, which can be interpreted in terms of solubility data of carnosine.23 The yield decreases apparently with the increasing of the mole fraction of ethanol. Thus, volume 25



ratio is set to 1:3 in the following optimizing experiments, considering both the crystal shape and yield of the products.

Figure 11. The particle size distributions of the products obtained in optimization process of spherical crystals with different volume ratio of solution to antisolvent: (a) 1:2; (b) 1:3; (c) 1:4; (d) 1:5; (e) 1:6. 3.3.4. Temperature All of the experiments in this section were conducted at a stirring speed of 300 rpm with a volume ratio of 1:3. And the carnosine solution concentration as well as the feeding rate were all set to 0.175 g/mL and 100 μL/min, respectively. Figure S4 describes the polarizing microscope images of the products obtained at different temperatures: (a) 298.15 K; (b) 303.15 K; (c) 308.15 K; (d) 313.15 K; (e) 318.15 K. It can be seen from the patterns that the crystals changed from compact to sparse and the needle shaped crystals increased as temperature increased from 298.15 K to 318.15 K. This is due to the fact that no additive was used in this work to encourage the spherulite formation and water was 26


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acted as the role of bridging agent to induce agglomeration process of needle shaped carnosine crystals. Thus, the decreased of solution viscosity with the increasing of temperature could weaken the bridging action of water and resulted in more needle shaped crystals.31 There were almost no needle shaped carnosine crystals at 298.15 K and 303.15 K. However, the conglutination of two or three spherical crystals appeared (Figure S4(a)) when the reverse antisolvent crystallization experiment was carried out at 298.15 K due to the higher solution viscosity at the lower temperature. Therefore, 303.15 K is the best temperature among the temperature investigated to gain monodispersed carnosine spherical without out needle shaped crystals nor conglutination phenomenon. This was confirmed by the only unimodal distribution curve of the products at 303.15 K, as shown in Figure 12.

Figure 12. The particle size distributions of the products obtained in optimization process of spherical crystals at different temperature: (a) 298.15 K; (b) 303.15 K; (c) 308.15 K; (d) 313.15 K; (e) 318.15 K. 27



3.3.5. Stirring speed

Figure 13. The particle size distributions of the products obtained in optimization process of spherical crystals with different stirring speed: (a) 100 rpm; (b) 200 rpm; (c) 300 rpm; (d) 400 rpm; (e) 500 rpm. All of the experiments in this section were conducted at 303.15 K with a volume ratio of 1:3. And the carnosine solution concentration as well as the feeding rate were all set to 0.175 g/mL and 100 μL/min, respectively. The results of the stirring speed effect on the overall shape and crystal size distribution of products are shown in Figures S5 and Figure 13, respectively. As shown in Figure S5, the crystals obtained were almost all spherical crystals under the stirring speed investigated. When the stirring speed was increased from 100 rpm to 500 rpm at an interval of 100 rpm, the average size decreased from 315 μm to 158 μm due to an increase in the shear force. 32 However, the crystal size distribution became narrow gradually with the increasing of stirring speed which may be the result of better mixing at the higher stirring speed could avoid local supersaturation 28


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and inhibit the nucleation process. Considering both average size and particle size distribution of the products, the stirring speed is set to 300 rpm. In conclusion, the crystal morphology and particle size distribution were influenced by the process conditions and the operating parameters were optimized as follows: the concentration of carnosine solution was 0.175 g/mL, the feeding rate of carnosine solution was 100 μL/min, volume ratio of solution to antisolvent was 1:3, temperature was 303.15 K, and the stirring speed was 300 rpm. Finally, monodispersed, several hundred micrometer-sized carnosine spherical crystals were successfully crystallized. Besides, the powder properties of raw materials and the products obtained under optimized operating condition, including mean particle size, coefficient of variance (CV), bulk density and flow properties were characterized respectively. It can be seen from the results listed in Table 6 that the mean particle size of products obtained under optimized operating condition was 211 μm, which was much bigger than that of needle-like raw crystals. Furthermore, CV is frequently used to evaluate the uniformity of particles. The smaller the CV value is, the more uniform the products would. The CV value of products obtained under optimized operating condition was much smaller than that of needle-like raw crystals, which means that the particle size distribution of products is much more uniform. In addition, the monodispersed, several hundred micrometer-sized carnosine spherical crystals show a bulk density as high as 0.224 g/mL, whereas the needle-like raw crystals show a significantly lower value of bulk density (0.047 g/mL). In addition, the 29



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repose angle of spherulitic particles (39 °) is much smaller than that of the needle-like raw material (58 °), which indicated that the obtained spherulitic particles have a much better flowability than the needle-like raw material. Table 6 Characterization of powder property of raw material and the products obtained by reverse antisolvent crystallization process with the optimal values of operating parameters. Product obtained from condition 6 (table 2) Tianjin Yuxiang Technology Co., Ltd a CV

Morphology spherulitic particles needle-like crystals

Mean particle size (μm)

CVa

Bulk density (g/mL)

Angle of repose (°)

211

30.24

0.224

39

31.9

97.05

0.047

58

is calculated by the equation CV = 100(PD84 − PD16)/2PD50.

3.5. Formation mechanism of carnosine spherical crystals As shown in Figure 14 a, the monodispersed, several hundred micrometer-sized carnosine spherical crystals were successfully prepared by reverse antisolvent crystallization process without any additives, and the crystallization process was monitored using PVM (Figure 14 b-f). The formation process of carnosine spherical crystals may be divided into four steps. Firstly, the carnosine in solution nucleated and grew into small spherical crystals (Figure 14 b) with the addition of the solution into ethanol. After that, these small spherical crystals agglomerated to some extent until the agglomerates (Figure 14 c) became compact. Then the irregular agglomerates began to branch and grow in all directions. At the same time, these irregular agglomerates can also break into needle-like crystals and sparse highly-spherical crystals due to the agitation 30


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shear force. Finally, the sparse spherical crystals agglomerated with the needle-like crystals and rearranged into monodispersed carnosine spherical crystals (Figure 14 f). It is more properly to describe the formation of carnosine spherical crystals as a spherulitic growth - spherulitic agglomeration - spherulitic breakage - spherulitic reagglomeration process, as shown in the schematic diagrams in Figure 15.

Figure 14. (a) SEM image of products obtained by reverse antisolvent crystallization 31



process with the optimal values of operating parameters, (b-f) PVM images at 7 min, 30 min, 37 min and 47 min, 90 min respectively.

Figure 15. The schematic diagrams of self-assembly process for carnosine spherical crystals: (a) individual nucleus; (b) small spherical crystals; (c) agglomerates of small spherical crystals; (d) the agglomerates after branching and growing in all directions; (e) needle-like crystals and sparse spherical crystals with high sphericity; (f) monodispersed carnosine spherical crystals. 4.

Conclusions

In this work, reverse antisolvent crystallization method, which can realize high 32


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supersaturation at the beginning of the crystallization process, was used to produce spherical crystals of carnosine. The solubility of carnosine was measured at temperature ranging from 288.05 K to 323.15 K and the solubility data was fitted by the modified Apelblat equation and the Jouyban-Acree model successfully. Besides, monodispersed, several hundred micrometer-sized carnosine spherical crystals with higher powder properties were successfully prepared through systematical optimization by single factor method. The results indicated that solution concentration, feeding rate, volume ratio, temperature and stirring speed can affect the particle size distribution and crystal shape during the optimization process of spherical crystals. This is due to the fact that the supersaturation of the system changed with these operating parameters which could further influence crystal nucleation, growth, agglomeration and breakage process. Finally, a spherulitic growth - spherulitic agglomeration - spherulitic breakage - spherulitic reagglomeration mechanism was proposed to interpret the formation of carnosine spherical crystals. The developed and optimized spherical crystallization technology in this work is simple, quick and convenient, which could provide an effective method to improve the powder properties of the solid product in an easy manner.

33



AUTHOR INFORMATION Corresponding Author *Tel:86-22-27405754. Fax: 86-22-27314971 E-mail: E-mail: [email protected]; [email protected]. Notes The authors declare no competing financial interest. Acknowledgment

The authors are grateful to the ﬁnancial supported from National Key Research and Development Program of China (no. 2016YFB0600504).

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List of abbreviations Abbreviation

Full name

ARD

average relative deviation

CV

coefficient of variance

PVM

particle vision measurement

S

ratio of solution concentration to solubility

SEM

scanning electron microscope

XRPD

X-ray powder diffraction patterns

35



Supporting Information

Figure S1. The polarizing microscope images of the products obtained with different carnosine aqueous solution concentration. Figure S2. The polarizing microscope images of the products obtained with different feeding rate of carnosine solution. Figure S3. The polarizing microscope images of the products obtained with different volume ratio of solution to antisolvent. Figure S4. The polarizing microscope images of the products obtained at different temperature. Figure S5. The polarizing microscope images of the products obtained with different stirring speed.

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References (1) Babizhayev, M. A., L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities. Biochem. J., 1994, 304 , 509-516. (2) Tung, H. H.; Paul, E. L.;

Midler, M.; Mccauley, J. A. Crystallization of organic compounds. Wiley,

2009. (3) Ouyang, J.; Wang, J.; Wang, Y.; Yin, Q.; Hao, H., Fhermodynamic study on dynamic water and organic vapor sorption on amorphous valnemulin hydrochloride. Front. Chem. Sci. Eng., 2015, 9, 94-104. (4) Zu, C.; Zhao, X.; Du, X., Enhanced water-solubility of Licorice extract microparticle prepared by antisolvent precipitation process. Adv. Powder Technol., 2014, 25 , 787-794. (5) Zhou, Y.; Wang, J.; Xiao, Y.; Wang, T.; Huang, X., The effects of polymorphism on physicochemical properties and pharmacodynamics of solid drugs. Curr. Pharm. Design., 2018, 24, 1-8. (6) Wolff, H. M.; Quere, L.; Riedner, J., Novel polymorphic form of rotigotine and process for production. United States patent US 20100311806. 2010 Dec. (7) Gidwani, R. M.; Hiremath, C., Crystalline fingolimod citrate for the treatment of relapsing-remitting multiple sclerosis. Europe patent Eur 2896609. 2015 Jul. (8) Lux, G.; Biljan, T.; Crowe, M. D.; Piran, M.; Canavesi, A., Solid state forms of ixabepilone. WIPO patent WO 2011153221. 2011 Dec. (9) Kawashima, Y.; Okumura, M.; Takenaka, H., Spherical Crystallization: Direct Spherical Agglomeration of Salicylic Acid Crystals during Crystallization. Science, 1982, 216, 1127-1128. (10) Yang, J.; Wang, Y.; Hao, H.; Xie, C.; Bao, Y.; Yin, Q.; Gong, J.; Jiang, C.; Hou, B.; Wang, Z., Spherulitic Crystallization of L-tryptophan: Characterization, Growth Kinetics and Mechanism. Cryst. Growth Des., 2015, 15, 5124-5132. (11) Yang, J.; Hu, C. T.; Shtukenberg, A.; Yin, Q.; Kahr, B., L-Malic Acid Crystallization: Polymorphism, Semi-Spherulites, Twisting, and Polarity. CrystEngComm., 2018, 20, 1383-1389 . (12) Mahanty, S.; Sruti, J.; Patra, C. N.; Rao, M. B., Particle design of drugs by spherical crystallization techniques. Int. J. Pharm. Sci. Nanotech., 2010, 3, 912-918. (13) Kawashima, Y.; Niwa, T.; Handa, T.; Takeuchi, H.; Iwamoto, T.; Itoh, K., . Preparation of controlled-release microspheres of ibuprofen with acrylic polymers by a novel quasi-emulsion solvent diffusion method. J. Pharm. Sci., 1989, 78, 68-72. (14) Ueda, M.; Nakamura, Y.; Makita, H.; Imasato, Y.; Kawashima, Y., Particle Design of Enoxacin by Spherical Crystallization Technique. I.: Principle of Ammonia Diffusion System (ADS). Chemical & pharmaceutical bulletin, 1990, 38, 2537-2541. (15) Garg, J.; Khatry, S.; Arora, S., Spherical crystallization: An overview. Int. J. Pharm. Technol., 2012, 4, 1909-1928. (16) Pawar, A. P.; Paradkar, A. R.; Kadam, S. S.; Mahadik, K. R., Crystallo-co-agglomeration: A novel technique to obtain ibuprofen-paracetamol agglomerates. Aaps Pharmscitech, 2004, 5, 57-64. (17) Guo, N.; Hou, B.; Wang, N.; Xiao, Y.; Huang, J.; Guo, Y.; Zong, S.; Hao, H., In Situ Monitoring and Modeling of the Solution-Mediated Polymorphic Transformation of Rifampicin: From Form II to Form I. J. Pharm. Sci-US., 2017, 107, 344-352. 37



(18) Wu, H.; Wang, J.; Xiao, Y.; Huang, X.; Guo, Y.; Zong, S.; Liu, Q.; Hao, Y.; Hao, H., Manipulation of Crystal Morphology of Zoxamide Based on Phase Diagram and Crystal Structure Analysis. Cryst. Growth Des., 2018, 18, 5790-5799. (19) Barrett, P.; Glennon, B., Characterizing the Metastable Zone Width and Solubility Curve Using Lasentec FBRM and PVM. Chem. Eng. Res. Des., 2002, 80, 799-805. (20) Shtukenberg, A. G.; Punin, Y. O.; Gunn, E.; Kahr, B., Spherulites. Chem. Rev., 2011, 112, 1805-1838. (21) Wu, S.; Ma, B.; Fang, Z.; Jian, C.; Luo, Y., Spherulite Formation of Lipophilic Surfactant Induced by Noncrystalline Amphiphilic Diblock Copolymer. Cryst. Growth Des., 2008, 8, 4589-4595. (22) Qi, R.; Wang, J.; Ye, J.; Hao, H.; Bao, Y., The solubility of cefquinome sulfate in pure and mixed solvents. Front. Chem. Sci. Eng., 2016, 10, 245-254. (23) Zhou, Y.; Wang, J.; Fang, B.; Guo, N.; Xiao, Y.; Hao, H.; Bao, Y.; Huang, X., Solubility and dissolution thermodynamic properties of 2-Cyano-4′-methylbiphenyl in binary solvent mixtures. J. Mol. Liq., 2017, 236, 298-307. (24) Geldart, D., Assessing the Flowability of Powders using Angle of Repose. Powder Handling & Processing, 1990, 2, 341-345. (25) Zhou, Y.; Hao, H.; Yang, J.; Zhu, P.; Wang, T.; Hou, B.; Xie, C.; Wang, J., Solid−liquid phase equilibrium and mixing properties of 2-Cyano-4′-methylbiphenyl in pure solvents. J. Chem. Thermodyn., 2016, 103, 134-141. (26) Apelblat, A.; Manzurola, E., Solubilities of o -acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p -toluic acid, and magnesium- ja:math -aspartate in water from T =(278 to 348) K. J. Chem. Thermodyn., 1999, 31, 85-91. (27) Li, K.; Du, S.; Wu, S.; Cai, D.; Wang, J.; Zhang, D.; Zhao, K.; Yang, P.; Yu, B.; Guo, B.; Li, D.; Gong, J., J. Chem. Thermodyn., 2016, 96, 12-23. (28) Wang, S.; Qin, L.; Zhou, Z.; Wang, J., Solubility and Solution Thermodynamics of Betaine in Different Pure Solvents and Binary Mixtures. J. Chem. Eng. Data, 2012, 57, 2128–2135. (29) Li, J.; Wang, Z.; Bao, Y.; Wang, J., Solid–Liquid Phase Equilibrium and Mixing Properties of Cloxacillin Benzathine in Pure and Mixed Solvents. Ind. Eng. Chem. Res., 2013, 52, 3019-3026. (30) Tierney, T. B.; Rasmuson, Å. C.; Hudson, S. P., Size and shape control of micron-sized salicylic acid crystals during antisolvent crystallization. Org. Process Res. Dev., 2017, 21, 1732-1740. (31) Han, L.; Chen, H.; Luo, P., Viscosity behavior of cationic gemini surfactants with long alkyl chains. Surf. Sci., 2004, 564, 141-148. (32) Lin, R.; Meng, W. W.; Selomulya, C.; Lu, J.; Chen, X. D., Controlling the Size of Taurine Crystals in the Cooling Crystallization Process. Ind. Eng. Chem. Res., 2013, 52, 13449-13458.

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For Table of Contents Only

Self-assembly of Monodispersed Carnosine Spherical Crystals in Reverse Antisolvent Crystallization Process Yanan Zhou a, b, Jingkang Wang a, b, Ting Wang a, Na Wang a, Yan Xiao a, Shuyi Zonga, Xin Huang a,b *, Hongxun Hao a,b *

Synopsis Monodispersed, several hundred micrometer-sized carnosine spherical crystals with higher bulk density and better flowability were successfully prepared by reverse antisolvent crystallization process without any additives and a feasible formation mechanism was proposed.

39


Self-assembly of Monodispersed Carnosine Spherical Crystals in

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