CN113842365B - Preparation process of cefazolin sodium for injection - Google Patents
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- C07D501/12—Separation; Purification
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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Abstract
The invention provides a preparation process of cefazolin sodium for injection, which comprises the following steps: (1) Adding dichloromethane into the crude product of cefazolin sodium, adding chitosan, adding sodium ethoxide and 5-ethyl-2-methylpyridine, stirring at the temperature of 8-10 ℃ for 1.5-2.5h, and filtering to obtain a solution A; (2) Adding disodium ethylene diamine tetraacetate and ethanol into the solution A, cooling, crystallizing, drying, dissolving in water again, filtering, sterilizing to obtain cefazolin sodium raw material, adding glycerol, L-cysteine and xylan, and freeze-drying under vacuum to obtain cefazolin sodium for injection; (3) Respectively cleaning and sterilizing the penicillin bottle, the rubber plug and the aluminum cover, subpackaging the cefazolin sodium for injection into the penicillin bottle, pressing the stopper and rolling the cover to obtain the target product. The preparation method of the invention can effectively remove impurities, avoid the introduction of new impurities, reduce the content of related substances and reduce the hygroscopicity of the medicine.
Description
Technical Field
The invention relates to the field of anti-infective drugs, and in particular relates to a preparation process of cefazolin sodium for injection.
Background
Cefazolin sodium is the first generation cephalosporin antibiotics; the antibacterial spectrum is wide, the product has good antibacterial activity to other gram-positive cocci except enterococci and methicillin-resistant staphylococcus, and streptococcus pneumoniae and hemolytic streptococcus are highly sensitive to the product, and the domestic market capacity reaches over 17 billion yuan. The preparation process of cefazolin sodium for injection is easy to introduce new impurities, has high hygroscopicity and is not beneficial to product quality control.
Disclosure of Invention
In view of this, the invention provides a preparation process of cefazolin sodium for injection, which solves the technical problems.
The technical scheme of the invention is realized as follows:
a preparation process of cefazolin sodium for injection comprises the following steps:
(1) Adding dichloromethane into the cefazolin sodium crude product, adding chitosan, and adding a mixture of 1:3-5 of sodium ethoxide and 5-ethyl-2-methylpyridine, stirring for 1.5-2.5h at the temperature of 8-10 ℃, and filtering to obtain a solution A;
(2) Adding a mixture of the solution A and the solution B in a mass ratio of 1:8-10 of disodium ethylene diamine tetraacetate and ethanol, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain the cefazolin sodium raw material, and adding the components in a mass ratio of 1:0.2-0.3:0.7-0.8 of glycerol, L-cysteine and xylan, and performing vacuum freeze-drying to obtain cefazolin sodium for injection;
(3) Respectively cleaning and sterilizing the penicillin bottle, the rubber plug and the aluminum cover, subpackaging the cefazolin sodium for injection into the penicillin bottle, pressing the stopper and rolling the cover to obtain the target product.
Further, in the step (1), the ratio of the mass volume kg/L of the crude cefazolin sodium product to the mass volume kg/L of dichloromethane is 1:4 to 6.
Further, in the step (1), the mass of the chitosan is 1-2% of the mass of the crude product of cefazolin sodium.
Further, in the step (1), the total mass of the sodium ethoxide and the 5-ethyl-2-methylpyridine is 4-6% of the mass of the crude cefazolin sodium product.
Further, in the step (2), the total mass of the added disodium ethylene diamine tetraacetate and the added ethanol is 4.5 to 5.5 times of the mass of the crude product of the cefazolin sodium.
Further, in the step (2), the total mass of the glycerol, the L-cysteine and the xylan is 12-14% of the mass of the cefazolin sodium raw material.
Further, in the step (2), the vacuum freeze-drying temperature is-50 to-45 ℃.
Further, in the step (3), the sterilization temperature of the rubber plug is 121 ℃, and the sterilization time is 30min.
Further, in the step (3), the sterilization temperature of the aluminum cover is 121 ℃, and the sterilization time is 1800s.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the invention can effectively remove impurities, avoid the introduction of new impurities, reduce the content of related substances and reduce the hygroscopicity of the medicine. The chitosan is used, so that impurities are more fully removed, and meanwhile, the hygroscopicity is reduced; according to the invention, the L-cysteine and the xylan are added, so that the cefazolin sodium is better protected in the vacuum freeze-drying process, the generation of impurities is reduced, and the cefazolin sodium is effectively coated, so that the hygroscopicity is obviously reduced; the invention optimizes the proportion of the sodium ethylate and the 5-ethyl-2-methylpyridine, promotes the cefazolin sodium to be fully dissolved, further removes impurities and is beneficial to reducing the hygroscopicity; the invention optimizes the proportion of the disodium ethylene diamine tetraacetate and the ethanol, further improves the effect of cooling crystallization, better reduces the total impurity content of the product and reduces the hygroscopicity; the invention optimizes the proportion of the glycerol, the L-cysteine and the xylan, further enhances the protection effect, better reduces the product impurities and reduces the hygroscopicity.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention are commercially available unless otherwise specified.
Example 1
A preparation process of cefazolin sodium for injection comprises the following steps:
(1) Adding 500L of dichloromethane into 100kg of cefazolin sodium crude product, adding 1.3kg of chitosan, adding 1kg of sodium ethoxide and 4.2kg of 5-ethyl-2-methylpyridine, stirring for 2.0h at the temperature of 8-10 ℃, and filtering by a 0.45-micrometer filter membrane to obtain a solution A;
(2) Adding 50kg of disodium ethylene diamine tetraacetate and 450kg of ethanol into the solution A, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain a cefazolin sodium raw material, and then adding the raw material with the mass ratio of 1:0.25:0.75 of glycerol, L-cysteine and xylan are added, the total mass of the glycerol, the L-cysteine and the xylan is 13 percent of the mass of the cefazolin sodium raw material, and the mixture is subjected to vacuum freeze-drying at the temperature of between 50 ℃ below zero and 45 ℃ below zero to obtain cefazolin sodium for injection;
(3) Respectively cleaning and sterilizing a penicillin bottle, a rubber plug and an aluminum cover, wherein the sterilization temperature of the rubber plug is 121 ℃, the sterilization time is 30min, the sterilization temperature of the aluminum cover is 121 ℃, and the sterilization time is 1800s; and subpackaging the cefazolin sodium for injection into penicillin bottles, pressing plugs and rolling covers to obtain the target product.
Example 2
A preparation process of cefazolin sodium for injection comprises the following steps:
(1) Adding 400L of dichloromethane into 100kg of cefazolin sodium crude product, adding 1kg of chitosan, adding 1kg of sodium ethoxide and 3kg of 5-ethyl-2-methylpyridine, stirring for 2.5h at the temperature of 8-10 ℃, and filtering by a 0.45-micrometer filter membrane to obtain a solution A;
(2) Adding 50kg of disodium ethylene diamine tetraacetate and 400kg of ethanol into the solution A, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain a cefazolin sodium raw material, and then adding the mixture of the components in a mass ratio of 1:0.2:0.8 of glycerol, L-cysteine and xylan, adding 12 percent of the total mass of the glycerol, the L-cysteine and the xylan into the cefazolin sodium raw material, and performing vacuum freeze-drying at the temperature of between 50 ℃ below zero and 45 ℃ below zero to obtain cefazolin sodium for injection;
(3) Respectively cleaning and sterilizing a penicillin bottle, a rubber plug and an aluminum cover, wherein the sterilization temperature of the rubber plug is 121 ℃, the sterilization time is 30min, the sterilization temperature of the aluminum cover is 121 ℃, and the sterilization time is 1800s; and subpackaging the cefazolin sodium for injection into penicillin bottles, pressing plugs and rolling covers to obtain the target product.
Example 3
A preparation process of cefazolin sodium for injection comprises the following steps:
(1) Adding 600L of dichloromethane into 100kg of cefazolin sodium crude product, adding 2kg of chitosan, adding 1kg of sodium ethoxide and 5kg of 5-ethyl-2-methylpyridine, stirring for 1.5h at the temperature of 8-10 ℃, and filtering by a 0.45-micrometer filter membrane to obtain a solution A;
(2) Adding 50kg of disodium ethylene diamine tetraacetate and 500kg of ethanol into the solution A, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain a cefazolin sodium raw material, and then adding the mixture of the components in a mass ratio of 1:0.3:0.7 of glycerol, L-cysteine and xylan, adding 14 percent of the total mass of the glycerol, the L-cysteine and the xylan into the cefazolin sodium raw material, and performing vacuum freeze-drying at the temperature of between 50 ℃ below zero and 45 ℃ below zero to obtain cefazolin sodium for injection;
(3) Respectively cleaning and sterilizing a penicillin bottle, a rubber plug and an aluminum cover, wherein the sterilization temperature of the rubber plug is 121 ℃, the sterilization time is 30min, the sterilization temperature of the aluminum cover is 121 ℃, and the sterilization time is 1800s; and subpackaging the cefazolin sodium for injection into penicillin bottles, pressing plugs and rolling covers to obtain the target product.
Comparative example 1
Referring to example 1, the process of step (1) was adjusted: chitosan replaces activated carbon.
The method comprises the following specific steps: adding 500L of dichloromethane into 100kg of cefazolin sodium crude product, adding 1.3kg of activated carbon, adding 1kg of sodium ethoxide and 4.2kg of 5-ethyl-2-methylpyridine, and stirring at the temperature of 8-10 ℃ for 2.0h to obtain a solution A. The other steps were identical to example 1.
Comparative example 2
Referring to example 1, the process of step (2) was adjusted: no L-cysteine and no xylan were added.
The method specifically comprises the following steps: adding 50kg of disodium ethylene diamine tetraacetate and 450kg of ethanol into the solution A, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain a cefazolin sodium raw material, adding glycerol, adding 13% of glycerol by mass of the cefazolin sodium raw material, and performing vacuum freeze-drying at the temperature of between 50 ℃ below zero and 45 ℃ below zero to obtain the cefazolin sodium for injection. The other steps were in accordance with example 1.
Comparative example 3
Referring to example 1, the process of step (1) was adjusted: wherein the mass ratio of the sodium ethoxide to the 5-ethyl-2-methylpyridine is 1:1.
the method specifically comprises the following steps: adding 500L of dichloromethane into 100kg of cefazolin sodium crude product, adding 1.3kg of chitosan, adding 2.6kg of sodium ethoxide and 2.6kg of 5-ethyl-2-methylpyridine, and stirring at the temperature of 8-10 ℃ for 2.0h to obtain a solution A. The other steps were in accordance with example 1.
Comparative example 4
Referring to example 1, the process of step (2) was adjusted: wherein the mass ratio of the disodium ethylene diamine tetraacetate to the ethanol is 1:14.
the method specifically comprises the following steps: adding 38kg of disodium ethylene diamine tetraacetate and 532kg of ethanol into the solution A, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain a cefazolin sodium raw material, and then adding the mixture of the materials in a mass ratio of 1:0.25:0.75 percent of glycerin, L-cysteine and xylan are added, the total mass of the glycerin, the L-cysteine and the xylan is 13 percent of the mass of the cefazolin sodium raw material, and the cefazolin sodium for injection is obtained by vacuum freeze-drying at the temperature of between 50 ℃ below zero and 45 ℃ below zero. The other steps were in accordance with example 1.
Comparative example 5
Referring to example 1, the process of step (2) was adjusted: wherein the mass ratio of the glycerol to the L-cysteine to the xylan is 1:1:1.
the method comprises the following specific steps: adding 50kg of disodium ethylene diamine tetraacetate and 450kg of ethanol into the solution A, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain a cefazolin sodium raw material, and then adding the raw material with the mass ratio of 1:1:1, adding glycerol, L-cysteine and xylan, wherein the total mass of the glycerol, the L-cysteine and the xylan is 13 percent of the mass of the cefazolin sodium raw material, and performing vacuum freeze-drying at the temperature of between 50 ℃ below zero and 45 ℃ below zero to obtain the cefazolin sodium for injection. The other steps were in accordance with example 1.
Cefazolin sodium for injection prepared in the above examples 1-3 and comparative examples 1-5 is tested for related substances and hygroscopicity by referring to the Chinese pharmacopoeia 2020 edition.
The hygroscopicity was determined as follows:
(1) Taking a certain amount of sample and placing it in a precisely weighed place (m) 1 ) In a glass weighing bottle with a plug (the outer diameter is 50mm, the height is 15 mm), precisely weighing (m) 2 )；
(2) The weighing bottle mouth is placed in a climatic box (the set temperature is 25 +/-1 ℃) and the relative humidity is (80% +/-2%).
(3) Standing for 24h;
(4) The weighing bottle cap is closed, and the bottle is precisely weighed (m) 3 )。
(5) Calculated weight gain percentage = (m) 3 -m 2 )/(m 2 -m 1 )×100％
The moisture absorption and weight increment is not less than 15 percent, namely the moisture absorption is very high;
the moisture absorption weight is less than 15% and not less than 2%, namely the moisture absorption is realized;
the moisture-attracting weight gain is less than 2% and not less than 0.2%, namely the moisture-attracting property is slightly increased.
The results are as follows:
| total impurities (%) | Hygroscopicity (%) | |
| Crude product | 0.68 | 10.54 |
| Example 1 | 0.02 | 2.21 |
| Example 2 | 0.05 | 3.14 |
| Example 3 | 0.03 | 2.82 |
| Comparative example 1 | 0.27 | 3.05 |
| Comparative example 2 | 0.49 | 5.57 |
| Comparative example 3 | 0.18 | 3.65 |
| Comparative example 4 | 0.11 | 4.37 |
| Comparative example 5 | 0.13 | 4.58 |
The results show that the preparation method of the invention can effectively remove impurities, avoid the introduction of new impurities, reduce the content of related substances and reduce the hygroscopicity of the medicine.
Among them, example 1 compared with comparative example 1, the present invention using chitosan more sufficiently removes impurities while contributing to a reduction in hygroscopicity.
Compared with the comparative example 2, the invention adds L-cysteine and xylan, better protects cefazolin sodium in the vacuum freeze-drying process, reduces the generation of impurities, effectively coats the cefazolin sodium and obviously reduces the hygroscopicity.
Compared with the comparative example 3, the invention optimizes the proportion of the sodium ethoxide and the 5-ethyl-2-methylpyridine, promotes the cefazolin sodium to be fully dissolved, further removes impurities and is beneficial to reducing hygroscopicity.
Compared with the comparative example 4, the invention optimizes the proportion of the disodium ethylene diamine tetraacetate and the ethanol, further improves the effect of cooling and crystallization, and better reduces the total impurity content of the product and the hygroscopicity.
Compared with the comparative example 5, the invention optimizes the proportion of the glycerol, the L-cysteine and the xylan, further strengthens the protection effect, better reduces the impurities of the product and reduces the hygroscopicity.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A preparation process of cefazolin sodium for injection is characterized by comprising the following steps:
(1) Adding dichloromethane into the cefazolin sodium crude product, adding chitosan, and then adding the mixture of the dichloromethane and the chitosan in a mass ratio of 1:3-5 of sodium ethoxide and 5-ethyl-2-methylpyridine, stirring for 1.5-2.5h at the temperature of 8-10 ℃, and filtering to obtain a solution A;
(2) Adding a mixture of 1:8-10 of disodium ethylene diamine tetraacetate and ethanol, cooling, crystallizing, drying, dissolving in water, filtering, sterilizing to obtain the cefazolin sodium raw material, and then adding the mixture of 1:0.2-0.3:0.7-0.8 of glycerol, L-cysteine and xylan, and performing vacuum freeze-drying to obtain cefazolin sodium for injection;
(3) Respectively cleaning and sterilizing the penicillin bottle, the rubber plug and the aluminum cover, subpackaging the cefazolin sodium for injection into the penicillin bottle, pressing the stopper and rolling the cover to obtain a target product.
2. The preparation process of cefazolin sodium for injection according to claim 1, wherein in step (1), the mass volume kg/L ratio of the crude cefazolin sodium to dichloromethane is 1:4 to 6.
3. The preparation process of cefazolin sodium for injection according to claim 2, wherein in the step (1), the mass of chitosan is 1-2% of the mass of the crude product of cefazolin sodium.
4. The preparation process of cefazolin sodium for injection according to claim 3, wherein in the step (1), the total mass of the sodium ethoxide and the 5-ethyl-2-methylpyridine is 4-6% of the mass of the crude cefazolin sodium product.
5. The process for preparing cefazolin sodium for injection according to claim 4, wherein in step (2), the total mass of the disodium edetate and the ethanol added is 4.5-5.5 times of the mass of the crude product of cefazolin sodium.
6. The process for preparing cefazolin sodium for injection according to claim 5, wherein in the step (2), the total mass of the glycerol, the L-cysteine and the xylan is 12-14% of the mass of the cefazolin sodium raw material.
7. The process for preparing cefazolin sodium for injection according to claim 6, wherein in the step (2), the vacuum freeze-drying temperature is-50 to-45 ℃.
8. The process for preparing cefazolin sodium for injection according to claim 7, wherein in the step (3), the rubber plug is sterilized at 121 ℃ for 30min.
9. The process for preparing cefazolin sodium for injection according to claim 8, wherein in the step (3), the sterilization temperature of the aluminum cap is 121 ℃ and the sterilization time is 1800s.
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| CN110894197A (en) * | 2019-09-25 | 2020-03-20 | 上海欣峰制药有限公司 | Preparation method of cefazolin sodium for injection |
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| CN113398072A (en) * | 2020-09-10 | 2021-09-17 | 广东金城金素制药有限公司 | Cefazolin sodium for injection and preparation method thereof |
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| WO2002030469A2 (en) * | 2000-10-12 | 2002-04-18 | Orchid Chemicals And Pharmaceuticals Limited | Beta-lactam antibiotic-polysaccharide complex |
| CN104610282B (en) * | 2015-02-14 | 2017-03-15 | 石药集团中诺药业（石家庄）有限公司 | A kind of method of purification of cefazolin |
| CN106432276A (en) * | 2016-09-21 | 2017-02-22 | 陕西顿斯制药有限公司 | Cefazolin sodium compound prepared according to novel intelligent crystallization technology and preparation of cefazolin sodium compound |
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| CN103550247A (en) * | 2013-10-15 | 2014-02-05 | 海南卫康制药(潜山)有限公司 | Cefpiramide sodium composition freeze-dried injection for injection |
| CN110894197A (en) * | 2019-09-25 | 2020-03-20 | 上海欣峰制药有限公司 | Preparation method of cefazolin sodium for injection |
| CN111548357A (en) * | 2020-04-16 | 2020-08-18 | 华北制药河北华民药业有限责任公司 | High-purity cefazolin sodium and preparation method of pharmaceutical preparation thereof |
| CN113398072A (en) * | 2020-09-10 | 2021-09-17 | 广东金城金素制药有限公司 | Cefazolin sodium for injection and preparation method thereof |
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