CN114796131B - Preparation method of ampicillin sodium for injection - Google Patents
Preparation method of ampicillin sodium for injection Download PDFInfo
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- CN114796131B CN114796131B CN202210496546.5A CN202210496546A CN114796131B CN 114796131 B CN114796131 B CN 114796131B CN 202210496546 A CN202210496546 A CN 202210496546A CN 114796131 B CN114796131 B CN 114796131B
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- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 title claims abstract description 65
- 229960001931 ampicillin sodium Drugs 0.000 title claims abstract description 63
- 238000002347 injection Methods 0.000 title claims abstract description 22
- 239000007924 injection Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 81
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 69
- 238000007710 freezing Methods 0.000 claims abstract description 55
- 230000008014 freezing Effects 0.000 claims abstract description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000001035 drying Methods 0.000 claims abstract description 41
- 238000004108 freeze drying Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 38
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 27
- 229930195725 Mannitol Natural products 0.000 claims abstract description 27
- 239000000594 mannitol Substances 0.000 claims abstract description 27
- 235000010355 mannitol Nutrition 0.000 claims abstract description 27
- 239000003513 alkali Substances 0.000 claims abstract description 26
- 230000008569 process Effects 0.000 claims abstract description 25
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960000723 ampicillin Drugs 0.000 claims abstract description 24
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims abstract description 24
- 235000011089 carbon dioxide Nutrition 0.000 claims abstract description 24
- 238000004090 dissolution Methods 0.000 claims abstract description 21
- 239000008215 water for injection Substances 0.000 claims abstract description 21
- 238000000859 sublimation Methods 0.000 claims abstract description 20
- 230000008022 sublimation Effects 0.000 claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 18
- 238000003756 stirring Methods 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 239000003463 adsorbent Substances 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000000725 suspension Substances 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 17
- 239000000843 powder Substances 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000137 annealing Methods 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 7
- 239000000696 magnetic material Substances 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- 239000008188 pellet Substances 0.000 claims 1
- 230000005496 eutectics Effects 0.000 abstract description 8
- 229920000642 polymer Polymers 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000004457 water analysis Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- 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
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/02—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
-
- 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
- A61K47/02—Inorganic compounds
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- 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
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- 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
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- 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
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- 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
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Abstract
The invention discloses ampicillin sodium for injection and a preparation method thereof, wherein the ampicillin sodium for injection is prepared by a freeze-drying method, and the method comprises the following steps of an alkali dissolving process, solution freezing and sublimation drying, wherein the alkali dissolving process comprises the following specific steps: adding water for injection and mannitol into a reaction container, stirring uniformly, adding ampicillin, stirring to obtain a suspension, adding a 10% sodium hydroxide solution, controlling the pH value of the solution to be 7.8-8.2, adjusting the pH value to be 7.1-7.3 after the reaction is finished, immediately adding dry ice and a magnetic adsorbent, and stirring to remove impurities; wherein: 60-80 parts of ampicillin, 60-70 parts of 10% sodium hydroxide solution, 95-105 parts of water for injection, 10-12 parts of dry ice and 14-16 parts of mannitol. According to the invention, through changing the raw materials in the alkali dissolution process and adding mannitol, the freezing temperature is improved, the freezing time of the solution reaching the eutectic point is shortened, and meanwhile, the dry ice is added, so that the temperature of the solution in the impurity removal and filtration processes before freezing is reduced, the stability of the solution is improved, the polymers generated in the freezing process are reduced, and the product quality is ensured.
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 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. The ampicillin sodium salt is formed by acid-base neutralization reaction of ampicillin and sodium hydroxide.
Currently, there are two main methods for industrially producing ampicillin sodium salt: freeze drying and solvent crystallization. The ampicillin sodium prepared by the conventional freeze drying method is prepared from ampicillin, sodium hydroxide and water for injection, and ampicillin and a sodium hydroxide solution are subjected to a neutralization reaction to generate an ampicillin sodium solution. The ampicillin sodium aqueous solution is extremely unstable and easy to form polymer dimer, which is one of the main allergens of ampicillin sodium anaphylactic reaction. Therefore, the low-temperature freezing needs to be carried out quickly, and the product impurities can be increased sharply if the standing time or the freezing time is longer. The eutectic point temperature of the ampicillin sodium water solution in the traditional process is-30 to-32 ℃, so the temperature of a freezing box of a freeze dryer for completely freezing the ampicillin sodium water solution needs to be at least-35 to-40 ℃, the temperature reduction and freezing time is longer, and about 30 to 60 minutes is needed; meanwhile, after the ampicillin sodium water solution is prepared, the ampicillin sodium water solution needs to be subjected to procedures such as impurity removal, filtration and sterilization by activated carbon and then put into freeze-drying equipment, and the procedures and procedures can be completed only by consuming a certain time, so that impurities are generated.
In view of this, the present application is specifically made.
Disclosure of Invention
The invention aims to solve the technical problems that the prior process and the freezing time for preparing ampicillin sodium by using a freeze-drying method are long, and the impurities in the ampicillin sodium water solution are increased due to the solution, 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 adopts a freeze-drying method for preparation, and comprises the steps of adopting a sodium hydroxide solution to dissolve ampicillin in alkali, freezing the solution and carrying out sublimation drying, wherein the alkali dissolving process comprises the following raw materials in parts by weight: 60-80 parts of ampicillin, 60-70 parts of 10% sodium hydroxide solution, 95-105 parts of water for injection, 10-12 parts of dry ice and 14-16 parts of mannitol.
In another specific embodiment, the alkali dissolution process comprises the following raw materials in parts by weight: 70 parts of ampicillin, 70 parts of 10% sodium hydroxide solution, 100 parts of water for injection, 10 parts of dry ice and 15 parts of mannitol.
In another embodiment, the alkali dissolution process is as follows: adding water for injection and mannitol into a reaction container, stirring uniformly, adding ampicillin, stirring to obtain a suspension, adding a 10% sodium hydroxide solution, controlling the pH value of the solution to be 7.8-8.2, adjusting the pH value to be 7.1-7.3 after the reaction is finished, immediately adding dry ice and a magnetic adsorbent, and stirring to remove impurities.
According to the invention, mannitol is added in the alkali dissolution process, firstly, the eutectic point of a mannitol solution is about-2 to-3 ℃, the eutectic point temperature of an ampicillin sodium solution can be reduced, after the mannitol solution is added in the ampicillin sodium solution, the eutectic point temperature is increased from-30 to-32 ℃ to-23 to-20 ℃, 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 rapid freezing of the solution is realized, 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 by shortening the freezing time;
secondly, in the crystallization process of the mannitol solution during freezing, crystals formed in the freezing process have a 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 is greatly reduced, and the sublimation rate is obviously improved.
Finally, mannitol itself is often used as a protective agent and excipient with a lyophilized drug, and mannitol is completely non-hygroscopic, thus enabling to improve production stability and storage stability of ampicillin sodium.
According to the invention, dry ice is added after the alkali dissolution reaction is finished, firstly, the solution temperature is sharply reduced and kept at a lower temperature by absorbing heat in the solution through solid sublimation of the dry ice, so that the stability of the aqueous solution can be improved in the processes of impurity removal and filtration of the adsorbent, meanwhile, the solution is put into the freeze-drying equipment at the lower temperature, the shortening of the freezing time of the solution can be further promoted, the initial temperature of the product put into the freeze-drying equipment is lower, the temperature gradient of the upper part and the lower part of the solution is smaller, the growth speed of the ice crystal is higher, and thus small ice crystals can be formed, and the subsequent drying efficiency is improved; second, sublimation of dry ice solids to produce CO 2 Section (C)CO separation 2 Overflow from the solution, part of the CO 2 Can be dissolved in water to form carbonic acid or free molecules, and then frozen, and when entering into sublimation drying process, the water vapor is volatilized and simultaneously the free CO is evaporated 2 Or CO produced by heating carbonic acid 2 The crystal can volatilize along with the crystal, so that a large number of gas pores are left in the crystal, flowing gaps of water vapor are further increased, the volatilization of combined water adsorbed in gaps of solid lattices can be promoted, a certain driving force for the water vapor to escape from a product is provided, the full drying is realized, and the sublimation rate is greatly improved; finally, CO 2 The volatilization of the water content enables the heat transfer mode of the drying process to be no longer dominated by heat conduction, and meanwhile, the heat convection mode is indirectly increased, so that the speed of water analysis can be accelerated.
In another embodiment, the freezing process of the solution is as follows: separating the magnetic adsorbent from the ampicillin sodium solution generated by alkali dissolution by using a magnetic field, precisely filtering, filling into a freeze-drying device, firstly cooling to-35-30 ℃, quickly freezing for 25-30 min, then cooling to-50 ℃, continuously quickly freezing for 30min, then heating to-25-20 ℃, annealing for 15min, and then cooling to-50 ℃ and freezing for 30-45 min.
The freezing treatment method adopted by the invention is characterized in that the temperature is kept at minus 35 to minus 30 ℃ for 25 to 30min, 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 50 ℃, 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 are beneficial to sublimation; after the product is completely frozen, the temperature is raised to-25 to-20 ℃ for annealing, the shape of the ice crystal can be changed, the condition of uneven size distribution of the ice crystal is eliminated, and the drying speed is improved.
In another embodiment, 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 into powder, then putting the powder into a freeze-drying device, vacuumizing the freeze-drying device 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.
The drying process of the invention is divided into three steps, the primary drying is mainly to remove water in the form of ice crystals, the secondary drying is to further remove the bound water adsorbed in the solid crystal lattice gaps, after the secondary drying, the product is ground into powder and then is dried again, the defect that the quality of the prepared product is unstable can be further overcome, and the product with small hygroscopicity and good quality stability can be obtained.
The invention adopts mesoporous silicon dioxide to coat Fe 3 O 4 The magnetic material of the particles replaces active carbon to be used as an adsorbent, a decarburization process is not needed, separation of the magnetic material can be rapidly realized through a magnetic field, and time consumed by a process before freezing is shortened.
The dry ice is granular, the contact area of the dry ice and the solution is large, the sublimation rate is high, the temperature of the solution is low, the speed is high, the stability of the ampicillin sodium solution is improved, and impurities are prevented from being generated.
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, mannitol is added in the alkali dissolution process, so that the eutectic point temperature of an ampicillin sodium solution can be reduced, the freezing time of the solution is shortened, the eutectic point temperature can be reached in a few minutes, the solution is rapidly frozen, and the generation of impurities in the freezing stage of the solution is greatly reduced;
2. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, mannitol solution forms crystals with larger surface area in the process of crystallization during freezing, so that a large number of tubular channels can be left in the mannitol solution after ice crystals are sublimated, the flow resistance of water vapor is greatly reduced, and the sublimation rate is obviously improved;
3. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, dry ice is added to enable the temperature of the solution to be sharply reduced and kept at a lower temperature, so that the stability of the solution in the impurity removal and filtration processes of the adsorbent is improved;
4. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, dry ice solid is sublimated to generate CO 2 Part of CO 2 Overflow from the solution, part of CO 2 Can be dissolved in water to form carbonic acid or free molecules, and then frozen, and when entering into sublimation drying process, the free CO is volatilized at the same time 2 Or CO produced by heating carbonic acid 2 The crystal can volatilize along with the crystal, so that a large number of gas pores are left in the crystal, flowing gaps of water vapor are further increased, the volatilization of combined water adsorbed in gaps of solid lattices can be promoted, a certain driving force for the water vapor to escape from a product is provided, the full drying is realized, and the sublimation rate is greatly improved;
5. according to the preparation method of ampicillin sodium for injection provided by the embodiment of the invention, the freezing treatment is firstly kept at-35 to-30 ℃ for 25-30 min, 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-50 ℃, 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 are beneficial to sublimation; after the product is completely frozen, the temperature is raised to-25 to-20 ℃ for annealing, the shape of the ice crystal can be changed, the condition of uneven size distribution of the ice crystal is eliminated, and the drying speed is improved.
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 limitations of 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 one 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 phrase "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. Further, those of ordinary skill in the art will appreciate that the illustrations provided herein are for illustrative purposes and are not necessarily drawn to scale. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the description of the present invention, the terms "front", "rear", "left", "right", "upper", "lower", "vertical", "horizontal", "upper", "lower", "inner", "outer", etc. indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience of description and simplicity of description, but do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed in a particular orientation, and be operated, and therefore, should not be construed as limiting the scope of the present invention.
Example 1
The preparation method of ampicillin sodium for injection provided by the embodiment of the invention comprises the following steps:
1) Weighing the following raw materials: 70g ampicillin, 10% sodium hydroxide solution (density 1.1 g/cm) 3 ) 63.5ml, 100ml of water for injection, 10g of dry ice and 15g of mannitol;
2) Alkali dissolution: adding water for injection and mannitol into a reaction container, stirring uniformly, adding ampicillin, stirring to obtain a suspension, adding 10% sodium hydroxide solution, and controlling the solutionThe pH value is 7.8, after the reaction is finished, the pH value is adjusted to 7.1, and then dry ice and mesoporous silicon dioxide are immediately added to coat Fe 3 O 4 Removing impurities from the magnetic material of the particles;
3) Freezing: separating a magnetic adsorbent from an ampicillin sodium solution generated by alkali dissolution by using a magnetic field, precisely filtering, filling the solution into freeze-drying equipment, firstly cooling to-35-30 ℃, quickly freezing for 25-30 min, then cooling to-50 ℃, continuously quickly freezing for 30min, then heating to-25-20 ℃, annealing for 15min, and then cooling to-50 ℃ and freezing for 30-45 min;
4) Sublimation drying:
4.1, vacuumizing by using a freeze-drying device 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;
4.2 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;
4.3 taking out the ampicillin sodium, grinding the ampicillin sodium into powder, then placing the powder into a freeze-drying device, vacuumizing the freeze-drying device until the vacuum degree reaches 18-22%, then controlling the temperature at 55-60 ℃ and keeping the temperature for 1-1.5 h, and finishing drying to obtain the ampicillin sodium product. The ampicillin sodium product obtained was tested and the results are given in table 1 below:
TABLE 1
Example 2
The preparation method of ampicillin sodium for injection provided by the embodiment of the invention comprises the following steps:
1) Weighing the following raw materials: ampicillin 60g,10% sodium hydroxide solution (density 1.1 g/cm) 3 ) 54.5ml, 95ml of water for injection, 10g of dry ice and 14g of mannitol;
2) Alkali dissolution: adding water for injection and mannitol into a reaction container, stirring uniformly, adding ampicillin, stirring to obtain a suspension, adding 10% sodium hydroxide solution,controlling the pH value of the solution to be 7.7, adjusting the pH value to be 7.1 after the reaction is finished, immediately adding dry ice and mesoporous silica to coat Fe 3 O 4 Removing impurities from the magnetic material of the particles;
3) Freezing: separating a magnetic adsorbent from an ampicillin sodium solution generated by alkali dissolution by using a magnetic field, precisely filtering, filling into a freeze-drying device, firstly cooling to-35-30 ℃, quickly freezing for 25-30 min, then cooling to-50 ℃, continuously quickly freezing for 30min, then heating to-25-20 ℃, annealing for 15min, and then cooling to-50 ℃ and freezing for 30-45 min;
4) Sublimation drying:
4.1, vacuumizing by using a freeze-drying device 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;
4.2 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;
4.3 taking out the ampicillin sodium, grinding the ampicillin sodium into powder, then placing the powder into a freeze-drying device, vacuumizing the freeze-drying device until the vacuum degree reaches 18-22%, then controlling the temperature at 55-60 ℃ and keeping the temperature for 1-1.5 h, and finishing drying to obtain the ampicillin sodium product. The ampicillin sodium product obtained is detected, 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) Weighing the following raw materials: ampicillin 80g,10% sodium hydroxide solution (density 1.1 g/cm) 3 ) 63.5ml, 105ml of water for injection, 10g of dry ice and 15g of mannitol;
2) Alkali dissolution: adding water for injection and mannitol into a reaction container, stirring uniformly, adding ampicillin, stirring to obtain a suspension, and adding 10% of hydroxideControlling the pH value of the sodium solution to be 7.8, adjusting the pH value to 7.1 after the reaction is finished, and immediately adding dry ice and mesoporous silica to coat Fe 3 O 4 Removing impurities from the magnetic material of the particles;
3) Freezing: separating a magnetic adsorbent from an ampicillin sodium solution generated by alkali dissolution by using a magnetic field, precisely filtering, filling the solution into freeze-drying equipment, firstly cooling to-35-30 ℃, quickly freezing for 25-30 min, then cooling to-50 ℃, continuously quickly freezing for 30min, then heating to-25-20 ℃, annealing for 15min, and then cooling to-50 ℃ and freezing for 30-45 min;
4) Sublimation drying:
4.1, vacuumizing by using a freeze-drying device 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;
4.2 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;
4.3 taking out the ampicillin sodium, grinding the ampicillin sodium into powder, then putting the powder into a freeze-drying device, vacuumizing the freeze-drying device until the vacuum degree reaches 18-22%, then controlling the temperature to be 55-60 ℃ and keeping the temperature for 1-1.5 h, and completing drying to obtain the ampicillin sodium product. The ampicillin sodium product obtained was tested and the results are given in table 3 below:
TABLE 3
Comparative example 1
The preparation method of ampicillin sodium for injection provided by the comparative example of the invention comprises the following steps:
1) 1) weighing raw materials: 70g ampicillin, 10% sodium hydroxide solution (density 1.1 g/cm) 3 ) 63.5ml of water for injection and 100ml of water for injection;
2) Alkali dissolution: adding water for injection and ampicillin into a reaction container, stirring to obtain a suspension, adding 10% sodium hydroxide solution, controlling the pH value of the solution to be 7.8, and adding activated carbon to remove impurities;
3) Freezing: decarburizing an ampicillin sodium solution generated by alkali dissolution, precisely filtering, filling into a freeze-drying device, cooling to-50 ℃, and freezing for 2.5h;
4) Sublimation drying:
4.1, vacuumizing by using a freeze-drying device 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;
4.2 then adjusting the vacuum degree of the freeze-drying equipment to 35-40%, raising the temperature to 70-75 ℃, keeping the temperature for 45-60 min, and finishing secondary drying to obtain the ampicillin sodium product. The ampicillin sodium product obtained was tested and the results are given in table 4 below:
TABLE 4
Comparative example 2
The preparation method of ampicillin sodium for injection provided by the comparative example of the invention comprises the following steps:
1) Weighing the following raw materials: 70g ampicillin, 10% sodium hydroxide solution (density 1.1 g/cm) 3 ) 63.5ml, 100ml of water for injection and 15g of mannitol;
2) Alkali dissolution: adding water for injection and mannitol into a reaction container, stirring uniformly, adding ampicillin, stirring to obtain a suspension, adding 10% sodium hydroxide solution, controlling the pH value of the solution to be 7.7, adjusting the pH value to be 7.1 after the reaction is finished, and adding activated carbon to remove impurities;
3) Freezing: decarburizing an ampicillin sodium solution generated by alkali dissolution, precisely filtering, filling into a freeze-drying device, cooling to-50 ℃, and freezing for 3 hours;
4) Sublimation drying:
4.1, carrying out vacuum pumping treatment on 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;
4.2 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; obtaining ampicillin sodium product. The ampicillin sodium product obtained was tested and the results are given in table 4 below:
TABLE 4
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 (5)
1. The preparation method of ampicillin sodium for injection adopts a freeze-drying method, comprises the steps of dissolving ampicillin in sodium hydroxide solution, freezing the solution and sublimation-drying, and is characterized in that the alkali dissolving process comprises the following raw materials in parts by weight: 60-80 parts of ampicillin, 60-70 parts of 10% sodium hydroxide solution, 95-105 parts of water for injection, 10-12 parts of dry ice and 14-16 parts of mannitol;
the alkali dissolution process is as follows: adding water for injection and mannitol into a reaction container, stirring uniformly, adding ampicillin, stirring to obtain a suspension, adding a 10% sodium hydroxide solution, controlling the pH value of the solution to be 7.8-8.2, adjusting the pH value to be 7.1-7.3 after the reaction is finished, immediately adding dry ice and a magnetic adsorbent, stirring to remove impurities, wherein the magnetic adsorbent is prepared by coating Fe with mesoporous silica 3 O 4 A magnetic material of the particles;
the freezing process of the solution is as follows: separating a magnetic adsorbent from an ampicillin sodium solution generated by alkali dissolution by using a magnetic field, precisely filtering, filling into a freeze-drying device, firstly cooling to-35-30 ℃, quickly freezing for 25-30 min, then cooling to-50 ℃, continuously quickly freezing for 30min, then heating to-25-20 ℃, annealing for 15min, and then cooling to-50 ℃ and freezing for 30-45 min;
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%, heating to 70-75 ℃ and keeping for 45-60 min to complete 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.
2. The preparation method of ampicillin sodium for injection as claimed in claim 1, wherein the alkali dissolution process comprises the following raw materials in parts by mass: 70 parts of ampicillin, 70 parts of 10% sodium hydroxide solution, 100 parts of water for injection, 10 parts of dry ice and 15 parts of mannitol.
3. The preparation method of ampicillin sodium for injection as claimed in claim 1, wherein the alkali dissolution process comprises the following raw materials in parts by mass: 60 parts of ampicillin, 60 parts of 10% sodium hydroxide solution, 95 parts of water for injection, 10 parts of dry ice and 14 parts of mannitol.
4. The method for preparing ampicillin sodium for injection as claimed in claim 1, 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.
5. The method for producing ampicillin sodium for injection as claimed in claim 1, wherein the dry ice is in the form of pellets.
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