CN115433208B - Preparation method of ampicillin sodium for injection - Google Patents
Preparation method of ampicillin sodium for injection Download PDFInfo
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- CN115433208B CN115433208B CN202211123121.6A CN202211123121A CN115433208B CN 115433208 B CN115433208 B CN 115433208B CN 202211123121 A CN202211123121 A CN 202211123121A CN 115433208 B CN115433208 B CN 115433208B
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Abstract
The application discloses ampicillin sodium for injection and a preparation method thereof, comprising the following steps: 1) Adding the crude ampicillin sodium product into dichloromethane, sequentially adding chitosan, 5-ethyl-2-methylpyridine and mannitol, stirring at 0-5 ℃, and filtering to obtain a solution A; 2) Adding an adsorbent into the solution A, stirring, filtering, adding disodium ethylenediamine tetraacetate and sodium chloride solid into the filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium; 3) Dissolving refined ampicillin sodium in purified water, filtering with microporous membrane, sterilizing, adding tert-butanol, L-cysteine and xylan, and vacuum freeze drying to obtain ampicillin sodium for injection. The preparation method can reduce the content of the product dimer, reduce the generation of impurities, improve the purity of the product, reduce the hygroscopicity and ensure the quality of the product.
Description
Technical Field
The application relates to the technical field of pharmacy, in particular to a preparation method of ampicillin sodium for injection.
Background
Ampicillin sodium belongs to beta-lactam antibiotics broad-spectrum penicillin, and is mainly used for treating infections of gram-positive cocci, escherichia coli, bacillus proteus, aerogenes, influenza bacillus and the like which are sensitive to penicillin, and for treating infections of urinary systems, respiratory systems, biliary tracts, intestinal tracts and the like. The preparation has the advantages of low toxicity, strong effect, quick in vivo absorption of the medicine, uniform distribution, difficult generation of drug resistance, good physicochemical property, long effective period and the like, so the preparation is widely applied in clinic.
At present, two main methods for industrially producing ampicillin sodium salt are: freeze drying and solvent crystallization. The polymer dimer is one of main allergic sources of the allergic reaction of the ampicillin sodium, and the abnormality of the prior ampicillin sodium in the production control and storage processes can cause the overstandard of related substances such as high molecular polymers and the like, so that medicines are disqualified or on the qualified edge, and serious consequences can be caused when the medicines are used on patients. Meanwhile, when the freeze-drying reagent of ampicillin sodium for injection is prepared, the water solution is extremely unstable after the ampicillin sodium is dissolved in water and is easy to form polymer dimer, so that low-temperature freezing is required to be quickly performed, the product impurities are rapidly increased due to long standing time or freezing time, but the eutectic point temperature of the ampicillin sodium water solution is between minus 30 ℃ and minus 32 ℃, and the freezing box temperature of a freeze dryer for completely freezing the ampicillin sodium water solution is at least required to be minus 35 ℃ to minus 40 ℃, and the cooling and freezing time is longer.
In view of this, the present application has been made.
Disclosure of Invention
The application aims to provide a preparation method of ampicillin sodium for injection, which can greatly reduce the content of dimer of the product and improve the purity of the product by carrying out recrystallization refining on the ampicillin sodium, and simultaneously, the freezing temperature is increased, the freezing time of the solution reaching a eutectic point is shortened, meanwhile, the ampicillin sodium can be well coated, the impurity generation is reduced, the hygroscopicity is reduced, and the product quality is ensured by additionally adding a mixed reagent in the freeze-drying process.
The application is realized by the following technical scheme:
the preparation method of ampicillin sodium for injection comprises the following steps:
1) Adding the crude ampicillin sodium product into dichloromethane, sequentially adding chitosan, 5-ethyl-2-methylpyridine and mannitol, stirring at 0-5 ℃, and filtering to obtain a solution A;
2) Adding an adsorbent into the solution A, stirring, filtering, adding disodium ethylenediamine tetraacetate and sodium chloride solid into the filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium;
3) Dissolving refined ampicillin sodium in purified water, filtering with microporous membrane, sterilizing, adding tert-butanol, L-cysteine and xylan, and vacuum freeze drying to obtain ampicillin sodium for injection.
Further, the mass volume ratio of the crude ampicillin sodium product to the dichloromethane is 1:5-6.5.
Further, the mass of the chitosan is 3-4% of the mass of the crude product of ampicillin sodium, the mass of the 5-ethyl-2-methylpyridine is 2-3% of the mass of the crude product of ampicillin sodium, and the mass of the tertiary butanol is 1-2% of the mass of the crude product of ampicillin sodium.
Furthermore, the adsorbent adopts a silica nanotube loaded aluminum oxide nano material, and the addition amount of the adsorbent is 0.8-1.2% of the mass of the ampicillin sodium.
Further, the total addition amount of the disodium edetate and the sodium chloride solid is 1.0-1.2% of ampicillin sodium, and the mass ratio of the disodium edetate to the sodium chloride solid is 1:0.4-0.6.
Further, the tertiary butanol is 8-10% of refined ampicillin sodium, the L-cysteine is 2-3% of refined ampicillin sodium, and the xylan is 5-6% of refined ampicillin sodium.
Further, the mass of tertiary butanol is 10% of the mass of refined ampicillin sodium, the mass of L-cysteine is 2% of the mass of refined ampicillin sodium, and the mass of xylan is 6% of the mass of refined ampicillin sodium.
Further, the vacuum freeze-drying comprises freezing and sublimation, and the freezing process is specifically as follows: 1) Cooling to-30 to-25 ℃ and freezing for 40-50 min; 2) Cooling to-45deg.C, and freezing for 15min; 3) Then heating to-25 ℃ for annealing treatment for 20min; 4) Finally cooling to minus 50 ℃ and freezing for 25-30 min.
Further, the sublimation drying process is specifically as follows: 1) Vacuumizing the freeze-drying equipment until the vacuum degree reaches more than 50%, heating to 0 ℃ for 60-90min, continuously heating to 40-45 ℃ for 120-150 min, heating to 60-65 ℃ for 6-7 h, and finishing primary drying; 2) Then the vacuum degree of the freeze-drying equipment is regulated to 35-40%, the temperature is raised to 70-75 ℃ and kept for 45-60 min, and secondary drying is completed; 3) Grinding the secondarily dried ampicillin sodium, then putting the powder into freeze-drying equipment, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature at 55-60 ℃ for 1-1.5 h to finish drying.
According to the application, the crude product of ampicillin sodium is added into dichloromethane, and then chitosan, 5-ethyl-2-methylpyridine and mannitol are sequentially added, wherein the addition of the 5-ethyl-2-methylpyridine can promote the ampicillin sodium to be fully dissolved into a solvent so as to be beneficial to the separation of impurities and the ampicillin sodium, and the addition of the chitosan can produce weak adsorption with the impurities, so that the removal of the impurities is more beneficial; meanwhile, the chitosan and mannitol are added cooperatively to play a role in adjusting the hygroscopicity of the ampicillin sodium aqueous solution, so that the generation of impurities in the production and crystallization process of the ampicillin sodium is further reduced.
According to the application, a heterogeneous nucleation salting-out crystallization method is adopted, and disodium ethylenediamine tetraacetate and sodium chloride solid are added to serve as seed crystals, so that the effect of seeding salting-out is achieved, an ideal crystal form can be generated in a directional manner, the stability of a product is enhanced, and secondary nucleation and excessive fine powder generation are avoided; meanwhile, the special proportion of the disodium ethylenediamine tetraacetate and sodium chloride solid can further improve the cooling crystallization effect, better reduce the total impurity content of the product and reduce the hygroscopicity.
According to the application, the silica nanotube-loaded aluminum oxide nano material is used as an adsorbent, so that various impurities and polymers in the ampicillin sodium solution can be effectively removed, and the special structure of the silica nanotube can protect the adsorbed impurities from being desorbed in the solution, so that the impurity content in the ampicillin sodium product can be reduced.
The refined ampicillin sodium is added with tertiary butanol, L-cysteine and xylan and then freeze-dried, so that the ampicillin sodium for injection is prepared.
The temperature of the eutectic point of the solution of ampicillin sodium can be increased from the original temperature of-30 to-32 ℃ to the temperature of-23 to-20 ℃ after the solution of tert-butanol is added into the solution of ampicillin sodium, so that the freezing temperature of the solution is greatly increased, the freezing time of the solution is shortened, the temperature of the eutectic point can be reached in a short period of minutes, the solution can be quickly frozen, the generation of impurities in the freezing stage of the solution is greatly reduced, and on the other hand, the freezing time is shortened, and the energy consumption and the cost of production can be reduced; meanwhile, the crystal formed in the freezing process of the tert-butyl alcohol solution has a larger surface area, so that a large number of tubular channels can be reserved inside after the ice crystals sublimate, the flow resistance of water vapor in the ice crystals can be greatly reduced, the sublimation rate of water in a product is improved, the generation of impurities is further reduced, and the hygroscopicity of the product is reduced.
The addition of the L-cysteine and the xylan can better protect the ampicillin sodium in the freeze-drying process, reduce the generation of impurities, and simultaneously the L-cysteine and the xylan can effectively coat the ampicillin sodium, thereby obviously reducing the hygroscopicity.
The freezing treatment method adopted by the application is that the temperature is kept for 40-50 min at minus 35-minus 30 ℃ and is slightly lower than the initial freezing temperature, and the temperature is kept at the temperature, so that the internal temperature of the product can be automatically balanced, the temperature gradient in the product is eliminated, and then the temperature is reduced to minus 45 ℃, so that the internal temperature gradient of the product is relatively smaller in the freezing process, the growth speed of ice crystals is relatively faster, thereby forming fine crystals and being beneficial to sublimation; after the product is completely frozen, the temperature is raised to minus 25 ℃ for annealing, the shape of ice crystals can be changed, the condition of uneven distribution of the size of the ice crystals is eliminated, the drying speed is improved, and finally, the temperature is reduced to minus 50 ℃ for freezing for 25-30 min. The whole freezing process of the freezing treatment method only needs about 2 hours, so that the solution can be completely frozen, the generation of impurities in the freezing stage of the solution is greatly reduced, and the energy consumption and the cost of production are reduced.
The sublimation drying process of the application firstly carries out primary drying to remove water in the form of ice crystals, and secondary drying is to further remove bound water adsorbed in solid lattice gaps, and after secondary drying, products are ground into powder and then are dried again, so that the defect of unstable quality of the prepared products can be further overcome, and ampicillin sodium for injection with small hygroscopicity and good quality stability is obtained.
Compared with the prior art, the application has the following advantages and beneficial effects:
1. according to the preparation method of ampicillin sodium for injection, provided by the embodiment of the application, the addition of the 5-ethyl-2-methylpyridine can promote the ampicillin sodium to be fully dissolved into a solvent so as to be beneficial to separation of impurities and the ampicillin sodium, and the addition of chitosan can be weakly adsorbed with the impurities, so that the removal of the impurities is facilitated; meanwhile, the chitosan and mannitol are cooperatively added to play a role in adjusting the hygroscopicity of the ampicillin sodium aqueous solution, so that the generation of impurities in the production and crystallization process of the ampicillin sodium is further reduced;
2. according to the preparation method of ampicillin sodium for injection, provided by the embodiment of the application, by adopting a heterogeneous nucleation salting-out crystallization method, disodium ethylenediamine tetraacetate and sodium chloride solid are added as seed crystals to play a role of seeding salting-out, so that an ideal crystal form can be generated in a directional manner, the stability of a product is enhanced, and secondary nucleation and excessive fine powder generation are avoided; meanwhile, the special proportion of the disodium ethylenediamine tetraacetate to the sodium chloride solid can further improve the cooling crystallization effect, better reduce the total impurity content of the product and reduce the hygroscopicity;
3. according to the preparation method of ampicillin sodium for injection, provided by the embodiment of the application, the silica nanotube loaded aluminum oxide nano material is used as the adsorbent, so that various impurities and polymers in an ampicillin sodium solution can be effectively removed, and the special structure of the silica nanotube can protect adsorbed impurities from being desorbed in the solution, so that the impurity content in an ampicillin sodium product can be reduced;
4. according to the preparation method of ampicillin sodium for injection, provided by the embodiment of the application, the addition of tertiary butanol can improve the eutectic point temperature of an ampicillin sodium solution, shorten the solution freezing time, greatly reduce the generation of impurities in the solution freezing stage, and simultaneously reduce the energy consumption and the cost of production;
5. according to the preparation method of ampicillin sodium for injection, provided by the embodiment of the application, the addition of the L-cysteine and the xylan can better protect the ampicillin sodium in the freeze-drying process, so that the generation of impurities is reduced, and meanwhile, the L-cysteine and the xylan can effectively coat the ampicillin sodium, so that the hygroscopicity is obviously reduced.
Detailed Description
The present application will be described in further detail with reference to the following examples, for the purpose of making the objects, technical solutions and advantages of the present application more apparent, and the description thereof is merely illustrative of the present application and not intended to be limiting.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, it will be apparent to one of ordinary skill in the art that: no such specific details are necessary to practice the application. In other instances, well-known methods have not been described in detail in order to avoid obscuring the present application.
Throughout the specification, references to "one embodiment," "an embodiment," "one example," or "an example" mean: a particular feature, structure, or characteristic described in connection with the embodiment or example is included within at least one embodiment of the application. Thus, the appearances of the phrases "in one embodiment," "in an example," or "in an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combination and/or sub-combination in one or more embodiments or examples.
Example 1
The preparation method of ampicillin sodium for injection provided by the embodiment of the application comprises the following steps:
1) Adding 600g of ampicillin sodium crude product into 3000ml of dichloromethane, sequentially adding 18g of chitosan, 12g of 5-ethyl-2-methylpyridine and 6g of mannitol, stirring at 0-5 ℃, and filtering to obtain a solution A;
2) Adding 4.8g of silica nanotube-loaded aluminum oxide nano-material adsorbent into the solution A, stirring, filtering, adding 4g of disodium ethylenediamine tetraacetate and 2g of sodium chloride solid into the filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium;
3) Dissolving 100g of refined ampicillin sodium in purified water, filtering and sterilizing by a microporous filter membrane, and adding 8g of tertiary butanol, 2g L-cysteine and 5g of xylan;
4) Freezing the solution: firstly, cooling to-30 to-25 ℃ and freezing for 40-50 min; then cooling to-45 ℃ and freezing for 15min; then heating to-25 ℃ for annealing treatment for 20min; finally cooling to minus 50 ℃ and freezing for 25-30 min;
5) Sublimation drying: vacuumizing the freeze-drying equipment until the vacuum degree reaches more than 50%, heating to 0 ℃ for 60-90min, continuously heating to 40-45 ℃ for 120-150 min, heating to 60-65 ℃ for 6-7 h, and finishing primary drying; then the vacuum degree of the freeze-drying equipment is regulated to 35-40%, the temperature is raised to 70-75 ℃ and kept for 45-60 min, and secondary drying is completed; grinding the secondarily dried ampicillin sodium, then putting the powder into freeze-drying equipment, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature at 55-60 ℃ for 1-1.5 h to finish drying, thereby obtaining the ampicillin sodium for injection. The prepared ampicillin sodium product for injection was tested and the results are shown in table 1 below.
TABLE 1
Example 2
The preparation method of ampicillin sodium for injection provided by the embodiment of the application comprises the following steps:
1) Adding 600g of ampicillin sodium crude product into 3600ml of dichloromethane, sequentially adding 21g of chitosan, 15g of 5-ethyl-2-methylpyridine and 9g of mannitol, stirring at 0-5 ℃, and filtering to obtain a solution A;
2) Adding 6g of silica nanotube-loaded aluminum oxide nano-material adsorbent into the solution A, stirring, filtering, adding 4.4g of disodium ethylenediamine tetraacetate and 2.2g of sodium chloride solid into the filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium;
3) Dissolving 100g of refined ampicillin sodium in purified water, filtering and sterilizing by a microporous filter membrane, and adding 9g of tertiary butanol, 2.5g of L-cysteine and 5g of xylan;
4) Freezing the solution: firstly, cooling to-30 to-25 ℃ and freezing for 40-50 min; then cooling to-45 ℃ and freezing for 15min; then heating to-25 ℃ for annealing treatment for 20min; finally cooling to minus 50 ℃ and freezing for 25-30 min;
5) Sublimation drying: vacuumizing the freeze-drying equipment until the vacuum degree reaches more than 50%, heating to 0 ℃ for 60-90min, continuously heating to 40-45 ℃ for 120-150 min, heating to 60-65 ℃ for 6-7 h, and finishing primary drying; then the vacuum degree of the freeze-drying equipment is regulated to 35-40%, the temperature is raised to 70-75 ℃ and kept for 45-60 min, and secondary drying is completed; grinding the secondarily dried ampicillin sodium, then putting the powder into freeze-drying equipment, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature at 55-60 ℃ for 1-1.5 h to finish drying, thereby obtaining the ampicillin sodium for injection. The prepared ampicillin sodium product for injection was tested and the results are shown in table 2 below.
TABLE 2
Example 3
The preparation method of ampicillin sodium for injection provided by the embodiment of the application comprises the following steps:
1) Adding 600g of ampicillin sodium crude product into 3900ml of dichloromethane, sequentially adding 24g of chitosan, 18g of 5-ethyl-2-methylpyridine and 12g of mannitol, stirring at 0-5 ℃, and filtering to obtain a solution A;
2) Adding 7.2g of silica nanotube-loaded aluminum oxide nano-material adsorbent into the solution A, stirring, filtering, adding 4.8g of disodium ethylenediamine tetraacetate and 2.4g of sodium chloride solid into the filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium;
3) Dissolving 100g of refined ampicillin sodium in purified water, filtering and sterilizing by a microporous filter membrane, and adding 10g of tertiary butanol, 3g L-cysteine and 6g of xylan;
4) Freezing the solution: firstly, cooling to-30 to-25 ℃ and freezing for 40-50 min; then cooling to-45 ℃ and freezing for 15min; then heating to-25 ℃ for annealing treatment for 20min; finally cooling to minus 50 ℃ and freezing for 25-30 min;
5) Sublimation drying: vacuumizing the freeze-drying equipment until the vacuum degree reaches more than 50%, heating to 0 ℃ for 60-90min, continuously heating to 40-45 ℃ for 120-150 min, heating to 60-65 ℃ for 6-7 h, and finishing primary drying; then the vacuum degree of the freeze-drying equipment is regulated to 35-40%, the temperature is raised to 70-75 ℃ and kept for 45-60 min, and secondary drying is completed; grinding the secondarily dried ampicillin sodium, then putting the powder into freeze-drying equipment, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature at 55-60 ℃ for 1-1.5 h to finish drying, thereby obtaining the ampicillin sodium for injection. The prepared ampicillin sodium product for injection was tested and the results are shown in table 1 below.
TABLE 3 Table 3
Comparative example 1
The difference between this comparative example and example 1 is that: in the step 1), chitosan, 5-ethyl-2-methylpyridine and mannitol are not added. The resulting ampicillin sodium product was tested and the results are shown in table 4 below.
TABLE 4 Table 4
Comparative example 2
The difference between this comparative example and example 1 is that: no disodium ethylenediamine tetraacetate and no sodium chloride solids were added in step 2). The resulting ampicillin sodium product was tested and the results are shown in table 5 below.
TABLE 5
Comparative example 3
The difference between this comparative example and example 1 is that: no t-butanol, L-cysteine and xylan were added in step 3).
The resulting ampicillin sodium product was tested and the results are shown in table 6 below.
TABLE 6
Comparative example 4
The difference between this comparative example and example 1 is that: in the step 1), chitosan, 5-ethyl-2-methylpyridine and mannitol are not added; step 2) is not added with disodium ethylenediamine tetraacetate and sodium chloride solid; no t-butanol, L-cysteine and xylan were added in step 3). The resulting ampicillin sodium product was tested and the results are shown in table 7 below.
TABLE 7
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the application, and is not meant to limit the scope of the application, but to limit the application to the particular embodiments, and any modifications, equivalents, improvements, etc. that fall within the spirit and principles of the application are intended to be included within the scope of the application.
Claims (6)
1. The preparation method of ampicillin sodium for injection is characterized by comprising the following steps:
1) Adding the crude ampicillin sodium product into dichloromethane, sequentially adding chitosan, 5-ethyl-2-methylpyridine and mannitol, stirring at 0-5 ℃, and filtering to obtain a solution A; the mass of the chitosan is 3-4% of the mass of the crude ampicillin sodium product, the mass of the 5-ethyl-2-methylpyridine is 2-3% of the mass of the crude ampicillin sodium product, and the mass of the mannitol is 1-2% of the mass of the crude ampicillin sodium product;
2) Adding a silica nanotube-loaded aluminum oxide nano material adsorbent into the solution A, stirring, filtering, adding disodium ethylenediamine tetraacetate and sodium chloride solid into the filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium; the total addition amount of the disodium ethylenediamine tetraacetate and the sodium chloride solid is 1.0-1.2% of the ampicillin sodium;
3) Dissolving refined ampicillin sodium in purified water, filtering and sterilizing by a microporous filter membrane, and then adding tertiary butanol, L-cysteine and xylan, wherein the mass of tertiary butanol is 8-10% of that of the refined ampicillin sodium, the mass of L-cysteine is 2-3% of that of the refined ampicillin sodium, and the mass of xylan is 5-6% of that of the refined ampicillin sodium; vacuum freeze drying to obtain ampicillin sodium for injection;
the vacuum freeze drying comprises freezing and sublimation, wherein the freezing process is specifically as follows: 1) Cooling to-30 to-25 ℃ and freezing for 40-50 min; 2) Cooling to-45deg.C, and freezing for 15min; 3) Then heating to-25 ℃ for annealing treatment for 20min; 4) Finally cooling to-50 ℃ and freezing for 25-30 min;
the sublimation drying process comprises the following steps: 1) Vacuumizing the freeze-drying equipment until the vacuum degree reaches more than 50%, heating to 0 ℃ for 60-90min, continuously heating to 40-45 ℃ for 120-150 min, heating to 60-65 ℃ for 6-7 h, and finishing primary drying; 2) Then, the vacuum degree of the freeze-drying equipment is adjusted to 35-40%, the temperature is raised to 70-75 ℃ and kept for 45-60 min, and secondary drying is completed; 3) And (3) regulating the vacuum degree of the freeze-drying equipment to 18-22%, regulating the temperature to 55-60 ℃ and keeping for 1-1.5 h, and finishing drying.
2. The preparation method of ampicillin sodium for injection according to claim 1, wherein the mass-volume ratio of the ampicillin sodium crude product to dichloromethane is 1:5-6.5.
3. The method for preparing ampicillin sodium for injection according to claim 1, wherein the addition amount of the adsorbent is 0.8-1.2% of the mass of ampicillin sodium.
4. The method for preparing ampicillin sodium for injection according to claim 1, wherein the mass ratio of disodium ethylenediamine tetraacetate to sodium chloride solid is 1:0.4-0.6.
5. The method for preparing ampicillin sodium for injection according to claim 1, wherein the mass of tertiary butanol is 10% of the mass of refined ampicillin sodium, the mass of L-cysteine is 2% of the mass of refined ampicillin sodium, and the mass of xylan is 6% of the mass of refined ampicillin sodium.
6. The method for preparing ampicillin sodium for injection according to claim 1, wherein the specific steps of step 3) are as follows: grinding the ampicillin sodium subjected to the secondary drying in the step 2), then putting the ground ampicillin sodium into freeze-drying equipment, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature at 55-60 ℃ for 1-1.5 h.
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