NOVEL INDUSTRIAL CRYSTALLIZATION METHOD OF CEFUROXIME SODIUM AND PREPARATION THEREOF

Abstract

It discloses a new industrial crystallization method of Cefuroxime Sodium, wherein supercritical fluid extraction technology and traditional crystalline technology are combined to realize the recrystallization of Cefuroxime Sodium. Processes such as extraction, adsorption, crystallization and drying are carried out with a supercritical fluid, a solvent, an extraction cell and a crystallization tank to realize the recrystallization of Cefuroxime Sodium under a specific pressure at a specific temperature.

Claims

1. A novel industrial crystallization method of Cefuroxime Sodium, characterized in that, combining supercritical fluid extraction and traditional crystallization to realize the recrystallization of Cefuroxime Sodium, preferably dissolving Cefuroxime Sodium in an organic solvent, extracting the organic solvent and the solute in the solution of Cefuroxime Sodium by a supercritical fluid, and changing the solubility of the ingredients in the organic solvent and the supercritical fluid by adjusting the temperature and the pressure to make Cefuroxime Sodium crystallize.

2. The method according to claim 1, characterized in that including Cefuroxime Sodium prepared by the method, and a sterile powder for injection containing Cefuroxime Sodium.

3. The method according to claim 2, characterized in that, the solution of Cefuroxime Sodium is subjected to supercritical fluid extraction for 520 minutes under a pressure of 1540 MPa at a temperature of 4060 C., and Cefuroxime Sodium is crystallized and separated from its solution for 2040 minutes under a pressure of 0.55 MPa at a temperature of 2030 C.

4. The method according to claim 3, characterized in that, said solvent for dissolving Cefuroxime Sodium is selected from one of alcohols, aldehydes, esters, ketones, ethers, water and so on or a mixture thereof, an aqueous ethanol is preferable, and an aqueous ethanol with a concentration of 50%80% is more preferable.

5. The method according to claim 4, characterized in that, the working medium for forming the supercritical fluid can be CO.sub.2, alkanes, alkenes and so on, and CO.sub.2 is preferable.

6. The method according to claim 5, characterized in that, devices, such as a working medium cylinder, a compressor, a heat exchanger, a dissolving tank, and a crystallization tank, are used.

7. The method according to claim 6, characterized in that, the surface of the dissolving tank is coated with activated carbon, macroporous absorption resin, and so on, a stirring device is set in the extraction cell, and a freely opened and closed fast interface with a internal filter capable of sterilization is set between the dissolving tank and the crystallization tank.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Hereinafter, the embodiment of the present invention is described in detail combined with the drawing, wherein:

[0035] FIG. 1 shows the schematic diagram of the apparatus used in the present method, wherein, 1 represents a thermostatically controlled heater, 2 represents an extraction cell, 3 represents a crystallization tank, 4 represents a stirrer, 5 represents a sensor, 6 represents a digital monitor, 7 represents a fast interface, 8 represents a cooling system, 9 represents a high pressure pump, 10 represents a cylinder, 11 represents a gas collector, and 12 represents a polystyrene insulator.

EMBODIMENTS OF THE INVENTION

[0036] The present invention is further illustrated by the following embodiments without limiting the scope of the present invention. The present invention is further illustrated referring to the following examples, and a person skilled in the art should appreciate that the present invention is not limited to the embodiments and preparation methods. Moreover, a person skilled in the art is permitted making equivalent replacements, combination, improvement or modification according to the description of the present invention, but these all fall into the scope of the present invention.

[0037] The method for detecting the purity of Cefuroxime Sodium is as follows:

[0038] HPLC is used for detecting the purity of Cefuroxime Sodium, and the chromatographic condition includes:

[0039] Filler: octyl silane bonded silica gel;

[0040] Mobile phase: pH 3.4 acetate buffer (weighing 0.68 g sodium acetate and 5.8 g acetic acid, diluting to 1000 ml with water, and adjusting the pH value to 3.4 with acetic acid)acetonitrile (85:15);

[0041] Detection wavelength: 273 nm;

[0042] Injection volume: 20 l.

Example 1

[0043] (1) 5.43 kg crude Cefuroxime Sodium with a purity of 93.4% was weighed and placed in the extraction cell, adding a mixed solvent of 50 kg 50% aqueous ethanol, and stirring until Cefuroxime Sodium dissolved at a temperature of 40 C.;

[0044] (2) Pumping CO.sub.2 fluid to 15 MPa by a high pressure liquid pump, stirring and maintaining the pressure and the temperature for 5 minutes, and then turning off the high pressure pump;

[0045] (3) Adding seed crystal to the crystallization tank, lifting the height of the extraction cell to 30 cm, thereafter opening the fast interface between the two cells, so that the liquid in the extraction cell entered the crystallization tank, and closing the fast interface;

[0046] (4) Adjusting the pressure of the crystallization tank to 0.5 MPa and the temperature to 20 C., maintaining the temperature and the pressure for 20 minutes;

[0047] (5) After the system was cooled down and the pressure was dropped, 4.52 kg crystalline of Cefuroxime Sodium with high purity was prepared by drying under reduced pressure, and a sterile powder of Cefuroxime Sodium was obtained after sterile packing;

[0048] (6) As determined by HPLC, the Cefuroxime Sodium had a purity of 99.5% with a crystallization ratio of 88.7%.

Example 2

[0049] (1) 5.66 kg crude Cefuroxime Sodium with a purity of 93.4% was weighed and placed in the extraction cell, adding a mixed solvent of 60 kg 80% aqueous ethanol, and stirring until Cefuroxime Sodium dissolved at a temperature of 60 C.;

[0050] (2) Pumping CO.sub.2 fluid to 40 MPa by a high pressure liquid pump, stirring and maintaining the pressure and the temperature for 20 minutes, and then turning off the high pressure pump;

[0051] (3) Adding seed crystal to the crystallization tank, lifting the height of the extraction cell to 30 cm, thereafter opening the fast interface between the two cells, so that the liquid in the extraction cell entered the crystallization tank, and closing the fast interface;

[0052] (4) Adjusting the pressure of the crystallization tank to 5 MPa and the temperature to 30 C., and maintaining the temperature and the pressure for 40 minutes;

[0053] (5) After the system was cooled down and the pressure was dropped, 4.66 kg crystalline of Cefuroxime Sodium with a high purity was prepared by drying under reduced pressure and a sterile powder of Cefuroxime Sodium was obtained after sterile packing;

[0054] (6) As determined by HPLC, the Cefuroxime Sodium had a purity of 99.6% with a crystallization ratio of 87.8%.

Example 3

[0055] (1) 6.97 kg crude Cefuroxime Sodium with a purity of 93.4% was weighed and placed in the extraction cell, adding a mixed solvent of 70 kg 70% aqueous ethanol, and stirring until Cefuroxime Sodium dissolved at a temperature of 50 C.;

[0056] (2) Pumping CO.sub.2 fluid to 30 MPa by a high pressure liquid pump, stirring and maintaining the pressure and the temperature for 10 minutes, and then turning off the high pressure pump;

[0057] (3) Adding seed crystal to the crystallization tank, lifting the height of the extraction cell to 30 cm, thereafter opening the fast interface between the two cells, so that the liquid in the extraction cell entered the crystallization tank, and closing the fast interface;

[0058] (4) Adjusting the pressure of the crystallization tank to 1 MPa and the temperature to 25 C., and maintaining the temperature and the pressure for 30 minutes;

[0059] (5) After the system was cooled down and the pressure was dropped, 5.65 kg crystalline of Cefuroxime Sodium with a high purity was prepared by drying under reduced pressure and a sterile powder of Cefuroxime Sodium was obtained after sterile packing;

[0060] (6) As determined by HPLC, the Cefuroxime Sodium had a purity of 99.9% with a crystallization ratio of 86.7%.

Example 4

[0061] (1) 4.47 kg crude Cefuroxime Sodium with a purity of 93.4% was weighed and placed in the extraction cell, adding a mixed solvent of 50 kg 75% aqueous ethanol, and stirring until Cefuroxime Sodium dissolved at a temperature of 55 C.;

[0062] (2) Pumping CO.sub.2 fluid to 20 MPa by a high pressure liquid pump, stirring and maintaining the pressure and the temperature for 15 minutes, and then turning off the high pressure pump;

[0063] (3) Adding seed crystal to the crystallizaion tank, lifting the height of the extraction cell to 25 cm, thereafter opening the fast interface between the two cells, so that the liquid in the extraction cell entered the crystallization tank, and closing the fast interface;

[0064] (4) Adjusting the pressure of the crystallization tank to 4 MPa and the temperature to 25 C., and maintaining the temperature and the pressure for 35 minutes;

[0065] (5) After the system was cooled down and the pressure was dropped, 3.85 kg crystalline of Cefuroxime Sodium with a high purity was prepared by drying under reduced pressure and a sterile powder of Cefuroxime Sodium was obtained after sterile packing;

[0066] (6) As determined by HPLC, the Cefuroxime Sodium had a purity of 99.7% with a crystallization ratio of 91.9%.

Comparative Example 1

[0067] (1) 1.44 kg crude Cefuroxime Sodium with a purity of 93.4% was weighed and placed in the reactor, adding 20 kg water, and stirring until Cefuroxime Sodium dissolved at a temperature of 60 C.;

[0068] (2) Adding acetone to the above solution, while cooling down to room temperature and standing for 6 hours;

[0069] (3) 0.67 kg Cefuroxime Sodium was obtained by drying under reduced pressure;

[0070] (4) As determined by HPLC, the Cefuroxime Sodium had a purity of 95.2% with a crystallization ratio of 47.4%.

Experimental Example 1

[0071] In order to examine the flowability of the refined Cefuroxime Sodium prepared in Example 1, the angle of repose was measured by a funnel method.

[0072] Test method: The particles were placed in a fixed funnel, and were felled freely to a horizontal plane to form a disk-shaped stacked body with a bottom radius of r, and the height of the stacked body was measured as H. The results were calculated according to the equation of tan =H/r and were shown in the following table:

TABLE-US-00001 TABLE 1 Flowability test results of Cefuroxime Sodium Test items Height H Radius r Angle of repose The first time 30 mm 61.5 mm 25.9 The second time 30 mm 61.2 mm 26.1 The third time 30 mm 60.9 mm 26.2 Average value 30 mm 61.3 mm 26.1 Conclusion: In general, less than 30 of the angle of repose indicates a good flowability of powders or granules. The angle of repose of above described crystalline powder of Cefuroxime Sodium is 26.1, which is less than 30, suggesting it has a good flowability and is suitable for packing as a sterile powder for injection.

Experimental Example 2

[0073] Referring to the quality standard of the raw material in Part 2 of Chinese Pharmacopoeia 2010 Edition, the quality research on crystalline powder of Cefuroxime Sodium was conducted in Example 14 and Comparative Example 1, and the results were shown as follows:

TABLE-US-00002 TABLE 2 Quality results of Cefuroxime Sodium Comparative Test items Example 1 Example 2 Example 3 Example 4 Example 1 Appearance White White White White Pale yellow crystalline crystalline crystalline crystalline crystalline powder powder powder powder powder pH pH = 7.3 pH = 7.5 pH = 7.4 pH = 7.0 pH = 7.5 Clarity of Compliance Compliance Compliance Compliance Compliance the solution Color of Compliance Compliance Compliance Compliance Greater than the yellow No. 6 solution Related Single Single Single Single Single substances impurity: 0.046% impurity: 0.051% impurity: 0.065% impurity: 0.057% impurity: 1.22% Total Total Total Total Total impurity: 0.101% impurity: 0.096% impurity: 0.114% impurity: 0.095% impurity: 3.45% Cefuroxime 0.031% 0.012% 0.022% 0.019% 0.24% polymer Solvent Compliance Compliance Compliance Compliance Compliance residue 2-ethyl 0.024% 0.078% 0.039% 0.096% 0.258% hexanoic acid Water 1.16% 0.99% 1.42% 0.96% 0.99% Visible Compliance Compliance Compliance Compliance Compliance foreign matter Insoluble Compliance Compliance Compliance Compliance Compliance particles Heavy Compliance Compliance Compliance Compliance Compliance metal Abnormal Compliance Compliance Compliance Compliance Compliance toxicity Bacterial Compliance Compliance Compliance Compliance Compliance endotoxin Content 94.6% 94.7% 95.0% 94.8% 90.5% (counted on Cefuroxime) Conclusion: Each test items of the crystalline powder of Cefuroxime Sodium in Example 1~4 was in line with the regulation, while the color of the solution, related substances, cefuroxime polymer and content in Comparative Example 1 didn't comply with the regulation, Therefore, the crystalline powder of Cefuroxime Sodium prepared by this technology met the quality requirements of Part 2 of Chinese Pharmacopoeia 2010 edition.

INDUSTRIAL PRACTICABILITY

[0074] What can see from the results of the examples and experimental examples described above, the crystalline powder of Cefuroxime Sodium prepared by the new industrial crystallization technology and apparatus of the present invention has high yield and high purity, with each index in line with the regulation. The crystalline powder of Cefuroxime Sodium is suitable for preparing as sterile powder for injection, and possessing good value in industry.

[0075] The present invention has been described above in detail through the embodiments and examples. However, it should be understood that the description does not make any restrictions to the scope of the present invention. Without departing from the sprit and scope of the present invention, various modifications, improvement, and replacements is permitted, and will be seen in the scope of the present invention.