CN108721211B - Preparation method of florfenicol injection - Google Patents
Preparation method of florfenicol injection Download PDFInfo
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- CN108721211B CN108721211B CN201810975378.1A CN201810975378A CN108721211B CN 108721211 B CN108721211 B CN 108721211B CN 201810975378 A CN201810975378 A CN 201810975378A CN 108721211 B CN108721211 B CN 108721211B
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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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
- A61K9/0012—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
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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
- A61K9/08—Solutions
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention particularly relates to a preparation method of a florfenicol injection, which comprises the following steps: mixing florfenicol with dimethylacetamide and polyethylene glycol, adding water to a constant volume of 100L, stirring, mixing and filtering to obtain a florfenicol injection; the particle size Dv (90) of the florfenicol is 30-75 mu m. The florfenicol injection finished product prepared by the method has high water solubility, low residual solvent content and simple process operation.
Description
Technical Field
The invention relates to the field of veterinary drugs, in particular to a preparation method of florfenicol injection.
Background
Florfenicol, also known as florfenicol or florfenicol, is a monofluoro derivative of thiamphenicol with a molecular formula of C12H14C12FNO4S, the molecular weight of which is 358.2, is mostly crystal powder, is white, has no peculiar smell and is nontoxic. It is very soluble in Dimethylformamide (DMF), has good solubility in methanol and acetone, is slightly soluble in acetic acid, and is very slightly soluble in chloroform and water, and the structural formula is as follows:
florfenicol produces a broad spectrum antibacterial effect by inhibiting the activity of peptidyl transferase, and the antibacterial range of florfenicol includes various gram negative bacteria, positive bacteria, mycoplasma, chlamydia and the like. Clinically, it is mainly used for treating colibacillus and rickettsiaSensitive bacteria such as salmonella, staphylococcus aureus, haemophilus and the like have stronger effects. Compared with other chloramphenicol antibiotics, the florfenicol reduces acetylation of the phthalein transferase in bacteria by substituting hydroxyl on the third position of a propane carbon chain of the chloramphenicol antibiotic by F, but does not lose activity under the action of a secondary enzyme, and increases antibacterial activity of the phthalein transferase. Since chloramphenicol has a very serious anemia-causing aplastic anemia, it has been regulated in many countries not to be used for the prevention and treatment of diseases in food animals and the like. Chloramphenicol has been reported to cause aplastic anemia primarily due to its aromatic ring para-nitro group, which in the case of florfenicol is replaced by O2N, so that the use of florfenicol does not cause aplastic anemia, which is the same reaction as chloramphenicol. The use of florfenicol to replace chloramphenicol in the clinic is therefore of great promise, both in the treatment and prevention of animal diseases such as food animals and in clinical veterinary applications.
The solubility of florfenicol in water is extremely low, and is only about 1.30mg/ml at room temperature, which not only affects the oral absorption of florfenicol, but also further affects the bioavailability thereof; causes poor clinical use effect, large dosage, high cost and easy drug residue and induces recurrent infection of drug-resistant strains.
In view of the above, solving the problem of poor solubility of florfenicol in water has been a hot spot of research in the field of veterinary medicine. There are two major types of methods currently reported for increasing the water solubility of florfenicol: the physical method comprises the beta-cyclodextrin inclusion compound, the hydroxypropyl-beta-cyclodextrin inclusion compound, the preparation of solid dispersion and the like, the process is complex, a large amount of special auxiliary materials are needed, and the requirements of preparation and clinical use are difficult to meet; the other method is a chemical method, namely the florfenicol is prepared into an inactive prodrug which is metabolized into the florfenicol to play a role after entering the body of an animal, and the florfenicol is characterized in that the water solubility is far greater than that of a physical method, but the pharmacokinetic characteristics of the drug are changed due to structural change to generate some unexpected effects.
Disclosure of Invention
Because florfenicol has poor solubility in water, a large amount of solvent is needed to be used for dissolving when being prepared into injection, the concentration of the injection is low, and the dosage of the solvent in the injection can be reduced by improving the solubility; meanwhile, the florfenicol used for preparing the injection also needs to meet the characteristics of less impurities and low solvent residue.
The applicant finds that the particle size of original florfenicol is generally larger than 200 mu m, the original florfenicol is blocky, and the particle size is too large, so that impurities and solvents are easily wrapped, and the product has large impurity and solvent residues, small solubility in water and low bioavailability; the particle size is too small, the product viscosity is high, the centrifugation or suction filtration operation in the crystallization process is influenced, solid and liquid are difficult to completely separate in the centrifugation or suction filtration operation of the product, and then the product quality is unqualified due to overlarge residue of impurities and solvents in a product detection report, and meanwhile, the requirement on equipment such as centrifugation is increased due to the too small particle size, and the production cost is increased.
Further research shows that the particle size Dv (90) of the florfenicol is controlled within the range of 30-75 mu m, the product has a proper particle size within the particle size range, the viscosity of the product is not increased due to too small particle size within the particle size range, a large amount of impurities are not wrapped due to too large particle size, and the solubility of the product in water reaches 3500-strain 3850 ug/ml.
The term "D90" in this application refers to the corresponding particle size when the cumulative particle size distribution of a sample reaches 90%. Its physical meaning is that 90% of the particles have a particle size less than it, e.g., "D90 ═ 100" means "90% of the particles no greater than 100 microns". All numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be a difference of around 5% in the value of each number or a reasonable difference as considered by the person skilled in the art.
The florfenicol is used for preparing a florfenicol injection, and the preparation method comprises the following steps: according to the weight portion, the florfenicol, dimethylacetamide and polyethylene glycol are mixed, water is added for constant volume to 100L, and the florfenicol injection is obtained after stirring, mixing and filtering.
Wherein, the concentration of the florfenicol injection is 0.9-1.1g/10 ml; preferably 1g/10 ml. The dosage of other components, such as dimethylacetamide and polyethylene glycol, can be referred to the relevant regulations of the 2010 version of Chinese animal pharmacopoeia.
The invention also provides a preparation method of the florfenicol, which comprises the following steps:
1) dissolving a florfenicol crude product in a benign solvent to form a mixed solution;
2) adding a poor solvent into the mixed solution, cooling to a first temperature, and stirring while keeping the temperature;
3) cooling to a second temperature, and stirring while keeping the temperature;
4) centrifuging and drying to obtain the finished product.
The florfenicol crude product is prepared by adopting the prior disclosed technology, and the purity of the florfenicol crude product is generally 98.5-99.5% of a florfenicol solid sample to be refined. The first temperature and the second temperature described above are not important to be construed as being equivalent to each other, and may be replaced by a temperature a, a temperature B, or other names capable of distinguishing the temperatures. As can be seen by the embodiments of the present invention, the second temperature is lower than the first temperature.
The mixed solution of the florfenicol comprises but is not limited to a mixed solution of a crude florfenicol product and a benign solvent; in addition, the mixed solution can also be a mixed solution of an original florfenicol drug and a benign solvent, and the crude florfenicol product can be directly converted into the florfenicol with higher purity and better solubility by using the method.
Further, the crude florfenicol in the step 1) can also be understood as high-purity florfenicol, such as crude drug, which is only called crude product relative to the final prepared product.
The method for preparing the florfenicol-rich mixed solution in the step 1) is a conventional method, and the preparation method used in one embodiment of the invention is as follows: heating and dissolving the florfenicol in a benign solvent to obtain a florfenicol mixed solution.
In one embodiment of the present invention, in step 1), the benign solvent is methanol, acetamide or acetone; preferably acetamide.
Wherein, the benign solvent is a solvent with high florfenicol solubility.
In one embodiment of the invention, in the step 2), the concentration of florfenicol in the mixed solution is 50-110 mg/ml.
In one embodiment of the invention, in the step 2), the volume ratio of the benign solvent to the poor solvent is 1: 3-5; the poor solvent is water.
Wherein the poor solvent is a solvent with low florfenicol solubility.
In one embodiment of the invention, in the step 2), the first temperature is 25-30 ℃; the cooling rate is 6-15 ℃/h.
In the step 2), the heat preservation and stirring time is 30-50 min.
In one embodiment of the present invention, in the step 3), the second temperature is 0 to 7 ℃.
In the step 3), the heat preservation and stirring time is 40-60 min; the cooling rate is 6-10 ℃/h.
In an embodiment of the present invention, in the step 4), when the solid-liquid separation is finally performed, a centrifugal method may be used, or other conventional means such as filtration may be used. And then washed at least once with the poor solvent. Vacuum drying at 60-70 deg.C for 6-10 hr; preferably, the vacuum degree is more than or equal to 0.08 MPa.
The invention has the beneficial effects that:
the florfenicol finished product prepared by the method has low impurity content and low solvent residue, and the solubility in water can reach more than 3500 ug/ml; due to the high solubility, the florfenicol injection has high clarity in the process of preparing injection, can reduce the pressure of filtration and prolong the service cycle of the filter element.
Compared with the prior art, the invention does not add a stabilizer in the preparation process, the whole preparation process is simple, the product has fewer impurities and is safer without adding the stabilizer, and the particle size obtained by the product preparation is controlled to be 30-75 mu m.
The invention can effectively enhance the solubility in water, simultaneously can keep a larger particle size and reduce the requirements on separation equipment such as centrifugation and the like by improving the process conditions, particularly selecting acetamide as a benign solvent.
Drawings
FIG. 1 is a flow chart of the preparation of florfenicol injection.
Detailed Description
In order to fully illustrate the preparation idea and concept of the present patent, the preparation method of the present patent is verified in the following examples, which are only for illustration and representative of specific examples and should not be interpreted or interpreted as a limitation of the protection of the present invention.
Example 1
The preparation process of the florfenicol injection comprises the following steps:
concentrating the liquid medicine:
1) the container and the utensil used for preparing the liquid are washed twice by the water for injection.
2) The injection water used for preparing the solution must be kept fresh (no more than 8 hours).
3) According to the prescription requirement, adding florfenicol, dimethylacetamide and polyethylene glycol-400, stirring to make them fully dissolved, fully mixing them uniformly. Adding water to 100L, stirring for 15 min, mixing, and filtering.
3) The concentrated liquid medicine passes through a titanium rod filter and is filtered to a diluting preparation tank.
Diluting and preparing liquid:
1) and (4) notifying QA personnel to sample, detecting the content, and introducing nitrogen into the liquid preparation tank for protection after the content is qualified.
And (3) filtering:
1) before filtration, the sterilizing filter is subjected to complete inspection, and is cleaned after being qualified.
2) And filters (0.45um and 0.22um) of the filtering system, pipelines and the like are installed.
3) And (3) circularly filtering the liquid medicine by using a filter, wherein the filtering time is 10min, sampling at a sampling port to check visible foreign matters, and filling and sealing the liquid medicine after the foreign matters are qualified.
4) During the filtering process of the liquid medicine, after the filter element is changed midway or the pipeline is disconnected and reconnected, the integrity test is needed to be done again, the QA checks the visible foreign matters, and the filtering can be continued after the color is qualified.
5) The filtering speed should be checked at any time during the filtering process, and the filtering system should be checked when the filtering speed is too fast or too slow. And cleaning and disinfecting according to the online cleaning and disinfecting procedures of the preparation system.
6) And after the filtration is finished, the integrity of the filter is checked, and the requirement is met.
The specific amounts are shown in the following table:
the florfenicol is prepared by the following method:
the materials and instruments used in the examples were those commercially available.
Example 2
A preparation method of florfenicol comprises the following specific preparation steps:
adding 300L of methanol into a 2000L reaction kettle, starting stirring, adding a florfenicol crude product, heating to 80 ℃, cooling to 25 ℃ at the speed of 6 ℃/h after the solid is completely dissolved to prepare a methanol mixed solution of the florfenicol, pumping the mixed solution into a refining tank, starting stirring, simultaneously dripping 900L of water, starting stirring, cooling to 25 ℃ at the speed of 6 ℃/h, keeping stirring at 25 ℃ for 30min, cooling to the initial 5 ℃ at the speed of 6 ℃/h, keeping stirring at 5 ℃ for 40min, and centrifuging. The solids obtained by centrifugation were rinsed with 180Kg of water. Drying the wet product in vacuum at 60 deg.C for 6 hr with vacuum degree not less than 0.08 MPa. The purification yield of the final product was 93.1%, the solvent residual methanol was 120ppm, and the Dv (90) was controlled to 56 μm. The florfenicol crystal prepared by the method has the solubility in water up to 3531 mu g/ml.
Example 3
A preparation method of florfenicol comprises the following specific preparation steps:
adding 300L of acetamide into a 2000L reaction kettle, starting stirring, adding a florfenicol crude product, heating to 80 ℃, cooling to 28 ℃ at the speed of 10 ℃/h after the solid is completely dissolved to prepare a methanol mixed solution of the florfenicol, pumping the mixed solution into a refining tank, starting stirring while dropping 1200L of water, starting stirring, cooling to the 28 ℃ at the speed of 10 ℃/h, keeping stirring at the 28 ℃ for 40min, cooling to the initial 7 ℃ at the speed of 10 ℃/h, keeping stirring at the 7 ℃ for 60min, and centrifuging. The solids obtained by centrifugation were rinsed with 200Kg of water. Drying the wet product in vacuum at 70 deg.C for 6-10 hr with vacuum degree not less than 0.08 MPa. The final product had a purification yield of 94.8%, residual acetamide in the solvent of 107ppm and Dv (90) of 40 μm. The florfenicol crystal prepared by the method has the solubility in water up to 3749 mu g/ml.
Example 4
A preparation method of florfenicol comprises the following specific preparation steps:
adding 300L of acetamide into a 2000L reaction kettle, starting stirring, adding a florfenicol crude product, heating to 80 ℃, cooling to 25 ℃ at the speed of 6 ℃/h after the solid is completely dissolved to prepare a methanol mixed solution of the florfenicol with the concentration of 110mg/ml, pumping the mixed solution into a refining tank, starting stirring and simultaneously dripping 1500L of water, starting stirring, cooling to the 25 ℃, keeping stirring at the 25 ℃ for 30min, cooling to the beginning 2 ℃ at the speed of 10 ℃/h, keeping stirring at the 2 ℃ for 60min, and centrifuging. The solids obtained by centrifugation were rinsed with 180Kg of water. Drying the wet product in vacuum at 70 deg.C for 6-10 hr with vacuum degree not less than 0.08 MPa. The final product had a purification yield of 94.6%, residual acetamide in solvent 155ppm, and Dv (90) controlled at 68 μm. The florfenicol crystal prepared by the method has the solubility in water up to 3537 mu g/ml.
The applicant investigated the effect of different influencing factors on the solubility of florfenicol crystals in water, the influencing factors being as follows:
example 5
The effect of the concentration of florfenicol in benign solvent on the dissolution of the finally prepared crystals in water was prepared in the same manner as in example 2, but the concentration of acetamide mixture of florfenicol was changed, and the results are shown in table 1:
as can be seen from Table 1, the solubility of the compound is not much different from 1300 μ g/ml of the original drug when the concentration is 30mg/ml, and the solubility of the compound can reach more than 3500mg/ml when the concentration is 50-100 mg/ml.
Example 6
The effect of florfenicol in benign solvents on the dissolution of the finally obtained crystals in water was prepared as in example 2, with the results shown in table 2:
example 7
The volume ratio of the benign solvent to the poor solvent affects the dissolution of the finally obtained crystals in water, which is the same as example 2, and the results are shown in Table 3:
example 8
The effect of the first temperature on the dissolution of the finally obtained crystals in water was obtained in the same manner as in example 2, and the results are shown in Table 4:
the effect of the second temperature on the dissolution of the finally obtained crystals in water was obtained in the same manner as in example 2, and the results are shown in Table 5:
example 9
The applicant further inspects the influence of the cooling rate on the product, and finds that the important influence on the reduction of the solvent residue of the product is realized when the cooling rate is controlled at 6-15 ℃/h and 6-10 ℃/h respectively. The preparation method is the same as example 2, and the results are shown in Table 6:
therefore, the invention discloses a method for preparing florfenicol in an amplification way, and the process conditions can be adopted to effectively control the particle size of the product, thereby achieving the purpose of controlling the key quality attributes of the product, such as the purity, the solvent residue, the solubility in water and the like.
Although the preferred embodiments have been described above, other parameter values, types of drugs, etc. are not shown in the embodiments, but are not intended to be used and are omitted here.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be made by those skilled in the art without inventive work within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.
Claims (6)
1. The preparation method of florfenicol is characterized by comprising the following steps:
1) dissolving a florfenicol crude product in a benign solvent to form a mixed solution;
2) adding a poor solvent into the mixed solution, cooling to a first temperature, and stirring while keeping the temperature;
3) cooling to a second temperature, and stirring while keeping the temperature;
4) centrifuging and drying to obtain a finished product;
in the step 1), the benign solvent is methanol, acetamide or acetone;
in the step 2), the concentration of florfenicol in the mixed solution is 50-110 mg/ml;
in the step 2), the volume ratio of the benign solvent to the poor solvent is 1: 3-5; the poor solvent is water;
in the step 2), the first temperature is 25-30 ℃, and the cooling rate is 6-15 ℃/h;
in the step 3), the second temperature is 0-7 ℃, and the cooling rate is 6-10 ℃/h.
2. The process for the preparation of florfenicol according to claim 1, characterized in that: in step 1), the benign solvent is acetamide.
3. The process for the preparation of florfenicol according to claim 1, characterized in that: in the step 2), the heat preservation and stirring time is 30-50 min.
4. The process for the preparation of florfenicol according to claim 1, characterized in that: in the step 3), the heat preservation and stirring time is 40-60 min.
5. The process for the preparation of florfenicol according to claim 1, characterized in that: in the step 4), the drying temperature is 60-70 ℃, and the drying time is 6-10 h.
6. A preparation method of florfenicol injection is characterized by comprising the following steps: mixing florfenicol with dimethylacetamide and polyethylene glycol, adding water to a constant volume of 100L, stirring, mixing and filtering to obtain a florfenicol injection;
the particle size Dv (90) of the florfenicol is 30-75 mu m;
the solubility of the florfenicol in water can reach more than 3500 ug/ml;
the florfenicol is obtained by the preparation method of any one of claims 1-5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20100110590A (en) * | 2009-04-03 | 2010-10-13 | 주식회사 동부한농 | Pharmaceutical composition containing florfenicol |
| CN103980166A (en) * | 2014-04-17 | 2014-08-13 | 天津大学 | New florfenicol crystal form and preparation method thereof |
| CN105125483A (en) * | 2015-08-27 | 2015-12-09 | 浙江大飞龙动物保健品有限公司 | Florfenicol injection solution for veterinary use and preparation method of injection solution |
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- 2018-08-24 CN CN201810975378.1A patent/CN108721211B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20100110590A (en) * | 2009-04-03 | 2010-10-13 | 주식회사 동부한농 | Pharmaceutical composition containing florfenicol |
| CN103980166A (en) * | 2014-04-17 | 2014-08-13 | 天津大学 | New florfenicol crystal form and preparation method thereof |
| CN105125483A (en) * | 2015-08-27 | 2015-12-09 | 浙江大飞龙动物保健品有限公司 | Florfenicol injection solution for veterinary use and preparation method of injection solution |
Non-Patent Citations (2)
| Title |
|---|
| 增加药物在制剂中溶解度的常用方法;王祖兵;《兽药与饲料添加剂》;20011231;第6卷;第24页 * |
| 氟苯尼考在猪体内混饲给药药动学研究;陈进;《营养与日粮》;20110731(第267期);第32-35页 * |
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