CN115433208A - Preparation method of ampicillin sodium for injection - Google Patents
Preparation method of ampicillin sodium for injection Download PDFInfo
- Publication number
- CN115433208A CN115433208A CN202211123121.6A CN202211123121A CN115433208A CN 115433208 A CN115433208 A CN 115433208A CN 202211123121 A CN202211123121 A CN 202211123121A CN 115433208 A CN115433208 A CN 115433208A
- Authority
- CN
- China
- Prior art keywords
- ampicillin sodium
- mass
- sodium
- injection
- drying
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses ampicillin sodium for injection and a preparation method thereof, and the ampicillin sodium for injection comprises the following steps: 1) Adding the ampicillin sodium crude 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 ethylene diamine tetraacetate and sodium chloride solid into filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium; 3) Dissolving refined ampicillin sodium in purified water, filtering and sterilizing with microporous filter membrane, adding tert-butanol, L-cysteine and xylan, and vacuum freeze drying to obtain ampicillin sodium for injection. The preparation method can reduce the dimer content of the product, reduce the generation of impurities, improve the purity of the product, reduce the hygroscopicity and ensure the product quality.
Description
Technical Field
The invention relates to the technical field of pharmacy, and particularly relates to a preparation method of ampicillin sodium for injection.
Background
Ampicillin sodium belongs to broad-spectrum penicillin of beta-lactam antibiotics, is mainly used for treating penicillin-sensitive infections of gram-positive cocci, escherichia coli, proteus, aerobacter, influenza bacillus and the like, and is used for treating infections of urinary systems, respiratory systems, biliary tracts, intestinal tracts and the like. The medicine has the advantages of small toxicity, strong action, quick absorption in vivo, uniform distribution, difficult generation of drug resistance, good physicochemical property, long validity period and the like, so the medicine is widely applied in clinic.
Currently, there are two main methods for industrially producing ampicillin sodium salt: freeze drying and solvent crystallization. The polymer dimer is one of main allergens of ampicillin sodium anaphylactic reaction, and the abnormality of the existing ampicillin sodium in the production control and storage process can cause the overproof of related substances such as high molecular polymers and the like, thereby causing the unqualified medicines or serious consequences when the medicines are used on patients at the qualified edge. Meanwhile, when a freeze-drying reagent of ampicillin sodium for injection is prepared, after ampicillin sodium is dissolved in water, an aqueous solution is extremely unstable and easily forms polymer dimer, so low-temperature freezing is needed rapidly, product impurities are increased rapidly when the reagent is placed for a long time or is frozen for a long time, but the eutectic point temperature of the ampicillin sodium aqueous solution is-30 to-32 ℃, so the temperature of a freezing box of a freeze dryer for completely freezing the ampicillin sodium aqueous solution needs to be at least-35 to-40 ℃, and the temperature reduction and freezing time is long.
In view of this, the present application is specifically made.
Disclosure of Invention
The invention aims to solve the technical problems that impurities in an ampicillin sodium aqueous solution are increased due to the fact that polymers and other related substances exceed standards and the aqueous solution is long in freezing time in the production process of the conventional ampicillin sodium, and aims to provide a preparation method of ampicillin sodium for injection.
The invention is realized by the following technical scheme:
a preparation method of ampicillin sodium for injection comprises the following steps:
1) Adding the ampicillin sodium crude 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 and sterilizing with microporous filter membrane, adding tert-butanol, L-cysteine and xylan, and vacuum freeze drying to obtain ampicillin sodium for injection.
Further, the mass-to-volume ratio of the ampicillin sodium crude product to the dichloromethane is 1:5-6.5.
Further, the mass of the chitosan is 3-4% of the mass of the ampicillin sodium crude product, the mass of the 5-ethyl-2-methylpyridine is 2-3% of the mass of the ampicillin sodium crude product, and the mass of the tertiary butanol is 1-2% of the mass of the ampicillin sodium crude product.
Further, the adsorbent is a silicon dioxide nanotube loaded aluminum oxide nano material, and the addition amount of the adsorbent is 0.8-1.2% of the mass of ampicillin sodium.
Furthermore, the total amount of the added disodium ethylene diamine tetraacetate and the solid sodium chloride is 1.0-1.2% of the ampicillin sodium, and the mass ratio of the disodium ethylene diamine tetraacetate to the solid sodium chloride is 1.4-0.6.
Furthermore, the mass of the tertiary butanol is 8-10% of the mass of the refined ampicillin sodium, the mass of the L-cysteine is 2-3% of the mass of the refined ampicillin sodium, and the mass of the xylan is 5-6% of the mass of the refined ampicillin sodium.
Furthermore, the mass of the tertiary butanol is 10 percent of the mass of the refined ampicillin sodium, the mass of the L-cysteine is 2 percent of the mass of the refined ampicillin sodium, and the mass of the xylan is 6 percent of the mass of the refined ampicillin sodium.
Further, the vacuum freeze drying comprises freezing and sublimation, and the freezing process is as follows: 1) Cooling to minus 30 to minus 25 ℃ and freezing for 40 to 50min; 2) Cooling to-45 deg.C, and freezing for 15min; 3) Then heating to-25 ℃ for annealing treatment for 20min; 4) Finally, the temperature is reduced to minus 50 ℃ and frozen for 25 to 30min.
Further, the sublimation drying process is as follows: 1) Vacuumizing the freeze-drying equipment until the vacuum degree reaches more than 50%, heating to 0 ℃ for 60-90min, continuing to heat to 40-45 ℃ for 120-150 min, and finally heating to 60-65 ℃ for 6-7 h to finish primary drying; 2) Then adjusting the vacuum degree of the freeze-drying equipment to 35-40%, raising the temperature to 70-75 ℃ and keeping for 45-60 min to finish secondary drying; 3) And grinding the secondarily dried ampicillin sodium, then putting the secondarily dried ampicillin sodium into a freeze-drying device, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature to be 55-60 ℃ and keeping the temperature for 1-1.5 h to finish drying.
The method comprises the steps of adding a crude ampicillin sodium product into dichloromethane, and sequentially adding chitosan, 5-ethyl-2-methylpyridine and mannitol, wherein the addition of the 5-ethyl-2-methylpyridine can promote ampicillin sodium to be fully dissolved into a solvent, so that impurities and ampicillin sodium are separated, and the addition of chitosan can generate weak adsorption with the impurities, so that the impurities can be removed more easily; meanwhile, the synergistic addition of the chitosan and the mannitol can play a role in adjusting the hygroscopicity of the ampicillin sodium water solution, and further reduce the generation of impurities in the production and crystallization process of ampicillin sodium.
The method adopts an out-phase nucleation salting-out crystallization method, and disodium ethylene diamine tetraacetate and sodium chloride solid are added as seed crystals to play a role in seeding and salting-out, so that an ideal crystal form can be directionally generated, the stability of a product is enhanced, and secondary nucleation and excessive fine powder are avoided; meanwhile, the special proportion of the disodium ethylene diamine tetraacetate and the sodium chloride solid can further improve the effect of cooling and crystallization, better reduce the total impurity content of the product and lower the hygroscopicity.
According to the invention, the silica nanotube loaded aluminum oxide nano material is used as the adsorbent, so that various impurities and polymers in the ampicillin sodium solution can be effectively removed, and the special structure of the silica nanotube nano 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 ampicillin sodium refined by the invention is added with tert-butyl alcohol, L-cysteine and xylan, and then is frozen and dried, thereby preparing the ampicillin sodium for injection.
The eutectic point temperature of the ampicillin sodium solution can be increased from-30 to-32 ℃ to-23 to-20 ℃ after the tert-butyl alcohol solution is added into the ampicillin sodium solution, the freezing temperature of the solution is greatly increased, so that the freezing time of the solution is shortened, the eutectic point temperature can be reached in a few minutes, the solution is quickly frozen, the generation of impurities in the freezing stage of the solution is greatly reduced, and on the other hand, the energy consumption and the cost of production can be reduced as the freezing time is shortened; meanwhile, crystals formed in the freezing process of the tertiary butanol solution have large surface area, so that a large number of tubular passages can be left in the crystals after the ice crystals are sublimated, the flow resistance of water vapor in the ice crystals can be greatly reduced, the sublimation rate of water in the 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 meanwhile, the L-cysteine and the xylan can effectively coat the ampicillin sodium, so that the hygroscopicity is obviously reduced.
The freezing treatment method adopted by the invention firstly keeps the temperature of minus 35 to minus 30 ℃ for 40 to 50min, the temperature is slightly lower than the initial freezing temperature, the temperature is kept at the temperature, 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 small in the freezing process, the growth speed of ice crystals is relatively high, and therefore, fine crystals are formed, and the sublimation is facilitated; after the product is completely frozen, the temperature is raised to-25 ℃ for annealing, the shape of the ice crystals can be changed, the condition that the size distribution of the ice crystals is uneven is eliminated, the drying speed is increased, and finally the temperature is lowered to-50 ℃ for freezing for 25-30 min. The freezing treatment method of the invention only needs about 2 hours in total in the whole freezing process, can completely freeze the solution, greatly reduces the generation of impurities in the freezing stage of the solution, and simultaneously reduces the energy consumption and the cost of production.
In the sublimation drying process, firstly, water in the form of ice crystals is removed by primary drying, then, bound water adsorbed in gaps of solid lattices is further removed by secondary drying, and after the secondary drying, the product is ground and then is dried for the first time, so that the defect of unstable quality of the prepared product can be further overcome, and the ampicillin sodium for injection with small hygroscopicity and good quality stability can be obtained.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, the addition of 5-ethyl-2-methylpyridine can promote ampicillin sodium to be fully dissolved in a solvent, so that impurities can be separated from ampicillin sodium, and the addition of chitosan can generate weak adsorption with the impurities, so that the impurities can be removed more easily; meanwhile, the synergistic addition of the chitosan and the mannitol can play a role in adjusting the hygroscopicity of the ampicillin sodium water solution, so that the generation of impurities in the production and crystallization process of ampicillin sodium is further reduced;
2. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, an out-phase nucleation salting-out crystallization method is adopted, and disodium ethylenediamine tetraacetic acid and sodium chloride solids are added as seed crystals to play a role in seeding and salting-out, so that an ideal crystal form can be generated directionally, the stability of a product is enhanced, and secondary nucleation and excessive fine powder generation are avoided; meanwhile, the special proportion of the disodium ethylene diamine tetraacetate and the sodium chloride solid can further improve the effect of cooling and crystallization, better reduce the total impurity content of the product and lower the hygroscopicity;
3. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, silica nanotubes loaded with alumina nano materials are used as an adsorbent, so that various impurities and polymers in ampicillin sodium solution can be effectively removed, and the special structure of the silica nanotubes can protect adsorbed impurities from being desorbed in the solution, so that the impurity content in ampicillin sodium products can be reduced;
4. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, the addition of tertiary butanol can improve the eutectic point temperature of ampicillin sodium solution, shorten the freezing time of the solution, greatly reduce the generation of impurities in the freezing stage of the solution, and simultaneously reduce the energy consumption and cost of production;
5. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, the addition of L-cysteine and xylan can better protect ampicillin sodium in the freeze-drying process, so that the generation of impurities is reduced, and meanwhile, L-cysteine and xylan can effectively coat ampicillin sodium, so that the hygroscopicity is obviously reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not used as limiting the present invention.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to those of ordinary skill in the art that: it is not necessary to employ these specific details to practice the present invention. In other instances, well-known methods have not been described in detail in order not to obscure the present invention.
Throughout the specification, reference to "one embodiment," "an embodiment," "one example" or "an example" means: the particular features, structures, or characteristics described in connection with the embodiment or example are included in at least one embodiment of the invention. Thus, the appearances of the phrases "one embodiment," "an embodiment," "one example" or "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 invention comprises the following steps:
1) Adding 600g of crude ampicillin sodium 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 alumina nano material adsorbent into the solution A, stirring, filtering, adding 4g of disodium ethylenediamine tetraacetic acid 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 using a microporous filter membrane, and adding 8g of tert-butyl alcohol, 2g L-cysteine and 5g of xylan;
4) Freezing the solution: firstly, cooling to minus 30 to minus 25 ℃ and freezing for 40 to 50min; then cooling to-45 deg.C 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, continuing to heat to 40-45 ℃ for 120-150 min, and finally heating to 60-65 ℃ for 6-7 h to finish primary drying; then adjusting the vacuum degree of the freeze-drying equipment to 35-40%, raising the temperature to 70-75 ℃ and keeping for 45-60 min to finish secondary drying; and grinding the secondarily dried ampicillin sodium into powder, then putting the powder into a freeze-drying device, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature to be 55-60 ℃ for 1-1.5 h to finish drying to obtain the ampicillin sodium for injection. The ampicillin sodium product for injection is detected, and the results are shown in the following table 1.
TABLE 1
Example 2
The preparation method of ampicillin sodium for injection provided by the embodiment of the invention comprises the following steps:
1) Adding 600g of crude ampicillin sodium 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 nanomaterial adsorbent into the solution A, stirring, filtering, adding 4.4g of disodium ethylene diamine 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 using a microporous filter membrane, and adding 9g of tert-butyl alcohol, 2.5g of L-cysteine and 5g of xylan;
4) Freezing the solution: firstly, cooling to minus 30 to minus 25 ℃ and freezing for 40 to 50min; then cooling to-45 deg.C 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, continuing to heat to 40-45 ℃ for 120-150 min, and finally heating to 60-65 ℃ for 6-7 h to complete primary drying; then adjusting the vacuum degree of the freeze-drying equipment to 35-40%, raising the temperature to 70-75 ℃ and keeping for 45-60 min to finish secondary drying; and grinding the secondarily dried ampicillin sodium into powder, then putting the powder into a freeze-drying device, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature to be 55-60 ℃ for 1-1.5 h to finish drying to obtain the ampicillin sodium for injection. The ampicillin sodium product for injection is obtained by detecting, and the results are shown in the following table 2.
TABLE 2
Example 3
The preparation method of ampicillin sodium for injection provided by the embodiment of the invention comprises the following steps:
1) Adding 600g of crude ampicillin sodium 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 ethylene diamine 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 using a microporous filter membrane, and adding 10g of tert-butyl alcohol, 3g L-cysteine and 6g of xylan;
4) Freezing the solution: firstly, cooling to minus 30 to minus 25 ℃ and freezing for 40 to 50min; then cooling to-45 deg.C 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, continuing to heat to 40-45 ℃ for 120-150 min, and finally heating to 60-65 ℃ for 6-7 h to finish primary drying; then adjusting the vacuum degree of the freeze-drying equipment to 35-40%, raising the temperature to 70-75 ℃ and keeping for 45-60 min to finish secondary drying; and grinding the secondarily dried ampicillin sodium into powder, then putting the powder into a freeze-drying device, vacuumizing until the vacuum degree reaches 18-22%, and then controlling the temperature to be 55-60 ℃ for 1-1.5 h to finish drying to obtain the ampicillin sodium for injection. The ampicillin sodium product for injection is detected, and the results are shown in the following table 1.
TABLE 3
Comparative example 1
This comparative example differs from example 1 in that: in the step 1), chitosan, 5-ethyl-2-methylpyridine and mannitol are not added. The ampicillin sodium product obtained was tested and the results are given in table 4 below.
TABLE 4
Comparative example 2
The comparative example differs from example 1 in that: disodium edetate and sodium chloride solids are not added in the step 2). The ampicillin sodium product thus obtained was examined and the results are shown in Table 5 below.
TABLE 5
Comparative example 3
The comparative example differs from example 1 in that: tert-butanol, L-cysteine and xylan were not added in step 3).
The ampicillin sodium product thus obtained was examined and the results are shown in Table 6 below.
TABLE 6
Comparative example 4
This comparative example differs from example 1 in that: chitosan, 5-ethyl-2-methylpyridine and mannitol are not added in the step 1); disodium ethylene diamine tetraacetate and sodium chloride solid are not added in the step 2); tert-butanol, L-cysteine and xylan were not added in step 3). The ampicillin sodium product obtained was tested, and the results are shown in table 7 below.
TABLE 7
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, 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 (10)
1. A preparation method of ampicillin sodium for injection is characterized by comprising the following steps:
1) Adding the ampicillin sodium crude 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 ethylene diamine tetraacetate and sodium chloride solid into filtrate, cooling, crystallizing, washing and drying to obtain refined ampicillin sodium;
3) Dissolving refined ampicillin sodium in purified water, filtering and sterilizing with microporous membrane, adding tert-butanol, L-cysteine and xylan, and vacuum freeze drying to obtain ampicillin sodium for injection.
2. The preparation method of ampicillin sodium for injection as claimed in claim 1, wherein the mass volume ratio of the crude ampicillin sodium to the dichloromethane is 1:5-6.5.
3. The method for preparing ampicillin sodium for injection as claimed in claim 1, wherein the mass of chitosan is 3-4% of the mass of the crude product of ampicillin sodium, the mass of 5-ethyl-2-methylpyridine is 2-3% of the mass of the crude product of ampicillin sodium, and the mass of mannitol is 1-2% of the mass of the crude product of ampicillin sodium.
4. The preparation method of ampicillin sodium for injection as claimed in claim 1, wherein the adsorbent is silica nanotubes loaded with alumina nanomaterial, and the addition amount of the adsorbent is 0.8-1.2% of the mass of ampicillin sodium.
5. The method for preparing ampicillin sodium for injection as claimed in claim 1, wherein the total amount of added disodium edetate and sodium chloride solids is 1.0-1.2% of ampicillin sodium, and the mass ratio of disodium edetate to sodium chloride solids is 1.4-0.6.
6. A process for producing ampicillin sodium for injection as claimed in claim 1, wherein the mass of t-butanol is 8 to 10% of the mass of the purified ampicillin sodium, the mass of L-cysteine is 2 to 3% of the mass of the purified ampicillin sodium, and the mass of xylan is 5 to 6% of the mass of the purified ampicillin sodium.
7. The method of claim 6, wherein the mass of t-butanol is 10% of the mass of the purified ampicillin sodium, the mass of L-cysteine is 2% of the mass of the purified ampicillin sodium, and the mass of xylan is 6% of the mass of the purified ampicillin sodium.
8. The method for preparing ampicillin sodium for injection as claimed in claim 1, wherein the vacuum freeze-drying comprises freezing and sublimation, and the freezing process comprises the following steps: 1) Cooling to minus 30 to minus 25 ℃ and freezing for 40 to 50min; 2) Cooling to-45 deg.C, and freezing for 15min; 3) Then heating to-25 ℃ for annealing treatment for 20min; 4) Finally, the temperature is reduced to minus 50 ℃ and frozen for 25 to 30min.
9. The method for preparing ampicillin sodium for injection as claimed in claim 8, wherein the sublimation drying process is as follows: 1) Vacuumizing the freeze-drying equipment until the vacuum degree reaches more than 50%, heating to 0 ℃ for 60-90min, continuing to heat to 40-45 ℃ for 120-150 min, and finally heating to 60-65 ℃ for 6-7 h to finish primary drying; 2) Then adjusting the vacuum degree of the freeze-drying equipment to 35-40%, raising the temperature to 70-75 ℃ and keeping for 45-60 min to finish secondary drying; 3) The vacuum degree of the freeze-drying equipment is adjusted to 18-22%, the temperature is adjusted to 55-60 ℃ and kept for 1-1.5 h, and the drying is finished.
10. The method for preparing ampicillin sodium for injection as claimed in claim 9, wherein the specific steps in step 3) are as follows: grinding the ampicillin sodium subjected to secondary drying in the step 2) into powder, then putting the powder into a freeze-drying device, vacuumizing until the vacuum degree reaches 18-22%, and then keeping the temperature at 55-60 ℃ for 1-1.5 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211123121.6A CN115433208B (en) | 2022-09-15 | 2022-09-15 | Preparation method of ampicillin sodium for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211123121.6A CN115433208B (en) | 2022-09-15 | 2022-09-15 | Preparation method of ampicillin sodium for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115433208A true CN115433208A (en) | 2022-12-06 |
| CN115433208B CN115433208B (en) | 2023-10-03 |
Family
ID=84249749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211123121.6A Active CN115433208B (en) | 2022-09-15 | 2022-09-15 | Preparation method of ampicillin sodium for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115433208B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115350141A (en) * | 2022-09-15 | 2022-11-18 | 四川制药制剂有限公司 | Preparation method of cefazolin sodium for injection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525978A (en) * | 2012-02-07 | 2012-07-04 | 海南卫康制药(潜山)有限公司 | Children amoxicillin-potassium clavulanate composition |
| CN114796131A (en) * | 2022-05-09 | 2022-07-29 | 四川制药制剂有限公司 | Preparation method of ampicillin sodium for injection |
-
2022
- 2022-09-15 CN CN202211123121.6A patent/CN115433208B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525978A (en) * | 2012-02-07 | 2012-07-04 | 海南卫康制药(潜山)有限公司 | Children amoxicillin-potassium clavulanate composition |
| CN114796131A (en) * | 2022-05-09 | 2022-07-29 | 四川制药制剂有限公司 | Preparation method of ampicillin sodium for injection |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115350141A (en) * | 2022-09-15 | 2022-11-18 | 四川制药制剂有限公司 | Preparation method of cefazolin sodium for injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115433208B (en) | 2023-10-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115433208A (en) | Preparation method of ampicillin sodium for injection | |
| CN114796131B (en) | Preparation method of ampicillin sodium for injection | |
| KR20140139123A (en) | High-purity cyclopeptide crystal as well as preparation method and use thereof | |
| JPH01146825A (en) | Antibiotic solution and freeze drying method | |
| JP2767171B2 (en) | Crystal manufacturing method | |
| WO2021203377A1 (en) | Bendamustine composition and use thereof | |
| CN105997941B (en) | Amphiphilic micelle nanocapsule and preparation method and application thereof | |
| CN102058548B (en) | Ambroxol hydrochloride composition for injection and preparation method thereof | |
| CN108309944B (en) | Pantoprazole sodium for injection and preparation method thereof | |
| CN107661298B (en) | Isaconazole sulfate for injection and freeze-drying process thereof | |
| JP2015166347A (en) | Process for isolating tigecycline | |
| CN113956250A (en) | Berberine hydrochloride pharmaceutical co-crystal and preparation method and application thereof | |
| CN105748482A (en) | Cefoperazone sodium and tazobactam sodium pharmaceutical composition for injection | |
| KR880001299B1 (en) | Process for preparing sodium 7beta-(2d-2amino-2-carboxyethlthioacetamido)-7alpha-methoxy-3-(-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxyl-ateheptahydrate | |
| CN113456598A (en) | Shugeng sodium gluconate freeze-dried powder injection and preparation method thereof | |
| CN114028345B (en) | Aspoxicillin freeze-dried agent for injection and preparation process thereof | |
| CN111378002A (en) | Novel cycloastragenol crystal form A and preparation method thereof | |
| CN109718209B (en) | Freeze-drying method of risperidone microspheres with low ethanol residues | |
| EP1880997A1 (en) | Crystal of 1-methylcarbapenem compound | |
| WO2022025091A1 (en) | Lyophilized formulation containing cephalosporin having catechol group, and method for producing same | |
| CN115737573B (en) | Cephalosporium oxydanum freeze-dried powder for injection and preparation method thereof | |
| CN117618325A (en) | Preparation method of high-purity ampicillin sodium and sulbactam sodium for injection | |
| CN115350141A (en) | Preparation method of cefazolin sodium for injection | |
| CN117243901A (en) | Development of parecoxib sodium freeze-dried injection for injection | |
| CN104610411B (en) | Method for purifying compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |