CN103159787A - Preparation method for high-purity sterilized cefotiam hydrochloride and pharmaceutical composition containing cefotiam hydrochloride - Google Patents
Preparation method for high-purity sterilized cefotiam hydrochloride and pharmaceutical composition containing cefotiam hydrochloride Download PDFInfo
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Abstract
The present invention relates to a preparation method for a high-purity sterilized cefotiam hydrochloride. The method comprises a plurality steps of recrystallization and washing of crude cefotiam hydrochloride to achieve the effect of sterilization, removal of pyrogens and increase of the purity. The obtained cefotiam hydrochloride can be used directly to produce cefotiam hydrochloride powder for injection through sterile dispensing without the need of further sterilization or removal of pyrogens. The invention also relates to a product prepared by the method and a pharmaceutical composition containing the product, especially cefotiam hydrochloride for injection and a preparation method thereof.
Description
Technical field
The invention belongs to medical technical field, be specifically related to the preparation method of the aseptic cefotiam hydrochloride of a kind of high purity.The pharmaceutical composition that the invention still further relates to the product for preparing by the method and comprise this product, especially cefotiam hydrochloridefor inj, and preparation method thereof.
Background technology
Cefotiam hydrochloride; English name: Cefotiam Hydrochloride; chemical name: (6R, 7R)-7-[[(2-amino-4-thiazolyl) ethanoyl] amino]-3-[[1-[2-(dimethylamino) ethyl]-1H-TETRAZOLE-5-yl] sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid dihydrochloride.
Chemical structural formula:
Molecular formula: C
18H
23N
9O
4S
32HCl
Molecular weight: 598.56
Cefotiam hydrochloridefor inj is the sterilized powder that the appropriate sodium carbonate of cefotiam hydrochloride anker is made, and by the research and development of pharmaceutical factory, the military field of Japan, in 1981 first in Japan's listing, preparation listing specification is 0.25g, 0.5g, 1.0g.Cefotiam hydrochloride is second generation cephalosporin, treats clinically respiratory tract infection, abdominal cavity infection, biliary tract infection, urinary tract infection, skin soft-tissue infection etc. all effective.Cefotiam hydrochloride all has stronger scavenging(action) to streptococcus aureus, A group streptococcus, tetrads, intestinal bacilli, the white bacillus of Fei Yankeleishi, cefotiam hydrochloride treatment chronic bronchopneumonia, pulmonary emphysema, pulmonary heart disease companion infect effectively, and be also effective to respiratory tract multi-infections such as spontaneous pneumothorax, pulmonary tuberculosis companion infection, pyothoraxs.
Cefotiam hydrochloridefor inj is sterile packaged preparation, and Cephalosporins bulk material is easily degraded under solution state or produced polymkeric substance, and the clinical application meeting causes the problem of security aspect, so its production technique should adopt direct packaging.
Summary of the invention
The object of the present invention is to provide the preparation method of the aseptic cefotiam hydrochloride of high purity, it comprises the steps:
(1) the cefotiam hydrochloride crude product is added in treatment tank, be dissolved in water for injection, add concentrated hydrochloric acid, sodium bisulfite, EDTA-Na under stirring
2And gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with water for injection, merging filtrate changed in crystallizer;
(2) add dehydrated alcohol and gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, is cooled to 18～22 ℃, adds the crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, solution changes in multi-functional bipyramid and filters, and gets the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection mixed solvent, is cooled to 5～10 ℃, with the cefotiam hydrochloride crystallizing and washing of step (3) gained 3 times;
(5) the described method of same step (2) is processed dehydrated alcohol, is cooled to 5～10 ℃, with the cefotiam hydrochloride crystallizing and washing of step (4) gained 3 times;
(6) be dried to moisture≤7.0%, and get final product.
The preparation method of the aseptic cefotiam hydrochloride of high purity provided by the present invention comprises the following steps:
(1) cefotiam hydrochloride crude product 6-10kg is added in treatment tank, be dissolved in 20-24kg water for injection, add 1.5-2.5L concentrated hydrochloric acid, 20-40g sodium bisulfite, 10-20g EDTA-Na under stirring
2With the 600-800g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 1-3kg water for injection, merging filtrate changed in crystallizer;
(2) add 90-100kg dehydrated alcohol, 200-500g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stir after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 90-100kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, solution changes in multi-functional bipyramid and filters, and gets the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (40-50kg/5-7kg) mixed solvent, is cooled to 5～10 ℃, with the cefotiam hydrochloride crystallizing and washing of step (3) gained 3 times;
(5) the described method of same step (2) is processed the 40-50kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
The preparation method of the aseptic cefotiam hydrochloride of high purity provided by the present invention comprises the following steps:
(1) cefotiam hydrochloride crude product 6.5kg is added in treatment tank, be dissolved in 22kg water for injection, add 1.95L concentrated hydrochloric acid, 35g sodium bisulfite, 14g EDTA-Na under stirring
2With the 700g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 94.7kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 94.7kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (45kg/6kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed dehydrated alcohol 47.4kg, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
The preparation method of the aseptic cefotiam hydrochloride of high purity provided by the present invention comprises the following steps:
(1) cefotiam hydrochloride crude product 8.5kg is added in treatment tank, be dissolved in 23kg water for injection, add 2L concentrated hydrochloric acid, 35g sodium bisulfite, 14g EDTA-Na under stirring
2With the 800g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 105kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 105kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (50kg/7kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed the 50kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
The preparation method of the aseptic cefotiam hydrochloride of high purity provided by the present invention comprises the following steps:
(1) cefotiam hydrochloride crude product 10kg is added in treatment tank, be dissolved in 24kg water for injection, add 2.2L concentrated hydrochloric acid, 40g sodium bisulfite, 16g EDTA-Na under stirring
2With the 850g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake was used 2kg water for injection detergent active charcoal, merging filtrate changed in crystallizer;
(2) add 115kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 110kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (53kg/7.5kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed the 53kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
The preparation method of the aseptic cefotiam hydrochloride of high purity provided by the present invention comprises the following steps:
(1) cefotiam hydrochloride crude product 6kg is added in treatment tank, be dissolved in 20kg water for injection, add 1.95L concentrated hydrochloric acid, 34g sodium bisulfite, 14g EDTA-Na under stirring
2With the 700g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 90kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 90kg dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (44kg/5.5kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) same step (2) method is processed the 45kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
Above-mentioned preparation method, wherein the concentration expressed in percentage by weight of concentrated hydrochloric acid is 33-37%.
Above-mentioned preparation method, wherein dilute hydrochloric acid is prepared according to the volume ratio of concentrated hydrochloric acid/water=1.18/10 with concentrated hydrochloric acid and water.
Above-mentioned preparation method, wherein step (1) is carried out at 100,000 grades of clean areas, and carry out at ten thousand grades of clean areas step (2)～(6).
The cefotiam hydrochloride crude product refers to not meet the cefotiam hydrochloride drug standard, especially its content and/or related substance and/or polymkeric substance and/or cefotiam hydrochloride aseptic and/or that bacterial endotoxin is against regulation, perhaps meet the cefotiam hydrochloride drug standard, but need further to improve the cefotiam hydrochloride of content and/or minimizing related substance and/or polymkeric substance.
In case of necessity, can repeat above-mentioned preparation process, further to make with extra care and purifying.
By enforcement of the present invention, can improve the purity of cefotiam hydrochloride crude product, play simultaneously degerming except the effect of thermal source, it can be directly used in by the aseptic subpackaged cefotiam hydrochloridefor inj for preparing, and need not further sterilization or except thermal source, guaranteed the stability of medicine and the security of clinical application.
The present invention also provides the product for preparing by aforesaid method, i.e. the aseptic cefotiam hydrochloride of high purity.
The present invention also provides a kind of pharmaceutical composition that comprises the aseptic cefotiam hydrochloride of high purity of the present invention, described pharmaceutical composition comprises described cefotiam hydrochloride and anhydrous sodium carbonate, and described cefotiam hydrochloride is take the weight ratio of cefotiam and anhydrous sodium carbonate as 500: 121.
The present invention also provides the preparation method of aforementioned pharmaceutical compositions, and described method comprises cefotiam hydrochloride (in cefotiam) and the anhydrous sodium carbonate weight ratio with 500: 121 is mixed; Empty cillin bottle fills nitrogen, packing, gland; After the assay was approved, packing.
Embodiment
Below by specific embodiment and experimental data, the present invention and advantage thereof are further described, will be appreciated that these embodiment are not limited to the present invention.
Embodiment 1
(1) cefotiam hydrochloride crude product 6.5kg is added in treatment tank, be dissolved in 22kg water for injection, add 1.95L concentrated hydrochloric acid, 35g sodium bisulfite, 14g EDTA-Na under stirring
2With the 700g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 94.7kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 94.7kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (45kg/6kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed dehydrated alcohol 47.4kg, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) the first vacuum of wet product was taken out 12 hours, then 25 ± 2 ℃ of vacuum-dryings 48 hours, after inspection by sampling moisture qualified (≤7.0%), was total to get the aseptic cefotiam hydrochloride 5.46kg of high purity.
Embodiment 2
(1) cefotiam hydrochloride crude product 8.5kg is added in treatment tank, be dissolved in 23kg water for injection, add 2L concentrated hydrochloric acid, 35g sodium bisulfite, 14g EDTA-Na under stirring
2With the 800g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 105kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 105kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (50kg/7kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed the 53.5kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) wet product 25 ± 2 ℃ of vacuum-dryings 60 hours, after inspection by sampling moisture qualified (≤7.0%), is total to get the aseptic cefotiam hydrochloride 7.31kg of high purity.
Embodiment 3
(1) cefotiam hydrochloride crude product 10kg is added in treatment tank, be dissolved in 24kg water for injection, add 2.2L concentrated hydrochloric acid, 40g sodium bisulfite, 16g EDTA-Na under stirring
2With the 850g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake was used 2kg water for injection detergent active charcoal, merging filtrate changed in crystallizer;
(2) add 115kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 110kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (53kg/7.5kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed the 56kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) wet product 25 ± 2 ℃ of vacuum-dryings 60 hours, after inspection by sampling moisture qualified (≤7.0%), is total to get the aseptic cefotiam hydrochloride 8.37kg of high purity.
Embodiment 4
(1) cefotiam hydrochloride crude product 6kg is added in treatment tank, be dissolved in 20kg water for injection, add 1.95L concentrated hydrochloric acid, 34g sodium bisulfite, 14g EDTA-Na under stirring
2With the 700g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 90kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 90kg dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (44kg/5.5kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) same step (2) method is processed the 46kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) the first vacuum of wet product was taken out 12 hours, then 25 ± 2 ℃ of vacuum-dryings 48 hours, after inspection by sampling moisture qualified (≤7.0%), was total to get the aseptic cefotiam hydrochloride 5.08kg of high purity.
Embodiment 5
Specification: 0.5g (in cefotiam)
Prescription:
According to above-mentioned prescription, get the aseptic cefotiam hydrochloride of high purity of embodiment 1, itself and anhydrous sodium carbonate are mixed, empty cillin bottle fills nitrogen, packing in 100 grades of clean areas, gland is packed after the assay was approved, and be get final product.
Embodiment 6
Specification: 1.0g (in cefotiam)
Prescription:
According to above-mentioned prescription, get the aseptic cefotiam hydrochloride of high purity of embodiment 2, itself and anhydrous sodium carbonate are mixed, empty cillin bottle fills nitrogen, packing in 100 grades of clean areas, gland is packed after the assay was approved, and be get final product.
Embodiment 7
Specification: 2.0g (in cefotiam)
Prescription:
According to above-mentioned prescription, get the aseptic cefotiam hydrochloride of high purity of embodiment 3, itself and anhydrous sodium carbonate are mixed, empty cillin bottle fills nitrogen, packing in 100 grades of clean areas, gland is packed after the assay was approved, and be get final product.
Embodiment 8
Specification: 1.0g (in cefotiam)
Prescription:
According to above-mentioned prescription, get the aseptic cefotiam hydrochloride of high purity of embodiment 4, itself and anhydrous sodium carbonate are mixed, empty cillin bottle fills nitrogen, packing in 100 grades of clean areas, gland is packed after the assay was approved, and be get final product.
The check of experimental example 1-cefotiam hydrochloride of the present invention
Get embodiment 1-4, test according to following quality standard respectively, the results are shown in Table 1.
[proterties] this product is white to light yellow crystalline powder, odorless.
This product is easily molten in water, methane amide, and is almost insoluble in acetone, methylene dichloride, acetonitrile and ethanol.
Specific optical rotation is got this product, and is accurately weighed, is dissolved in water and dilutes and make the solution that approximately contains 10mg in every 1ml, and measure (2005 editions two appendix VI E of Chinese Pharmacopoeia) specific optical rotation is+60 ° to+72 ° in accordance with the law.
Uptake factor is got this product, and is accurately weighed, be dissolved in water and dilute and make the solution that approximately contains 20 μ g in every 1ml, according to spectrophotometry (2005 editions two appendix IV A of Chinese Pharmacopoeia) at 259nm place mensuration optical density, uptake factor
Be 255～285.
The aqueous solution of [discriminating] (1) this product shows muriatic identification (2005 editions two appendix III of Chinese Pharmacopoeia).
(2) the infrared Absorption collection of illustrative plates of this product should consistent with the collection of illustrative plates of reference substance (2005 editions two appendix IVC of Chinese Pharmacopoeia).
(3) in the color atlas that records under the assay item, need testing solution main peak retention time should be consistent with reference substance solution main peak retention time.
[inspection] acidity is got this product, adds water and makes the solution that approximately contains cefotiam 0.1g in every 1ml.Measure (2005 editions appendix VI H of Chinese Pharmacopoeia), the pH value should be 1.2～1.7 in accordance with the law.
Clarity and colour of solution is got 5 parts of this product, adds respectively water and makes the solution that approximately contains 0.1g in 1ml, inspects immediately, and solution should be clarified colourless; As aobvious muddy, compare with No. 1 turbidity standard (2005 editions two appendix IX B of Chinese Pharmacopoeia), all must not be denseer; As colour developing, compare with yellow or No. 5 standard color solutions of yellow-green colour (2005 editions two appendix IX A first methods of Chinese Pharmacopoeia), all must not be darker.
Moisture is got this product, measures according to aquametry (2005 editions two appendix VIII M first method A of Chinese Pharmacopoeia), and (through anhydrous sodium sulfate drying 24 hours)-methyl alcohol (2: 1) is as solvent take methane amide, and moisture content must not cross 7.0%.
It is appropriate that related substance is got this product, accurately weighed, adds moving phase and dissolve and dilute and make the solution that every 1ml approximately contains cefotiam 0.5mg, shakes up, as need testing solution.Precision measures need testing solution 1ml, puts in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution.According to chromatographic condition under the assay item, precision measures contrast solution 20 μ l injection liquid chromatographies, regulates detection sensitivity, and making principal constituent chromatographic peak peak height is 10%～30% of full range; Precision measures each 20 μ l of contrast solution and need testing solution again, and injection liquid chromatography respectively records color atlas to 2.5 times of principal constituent peak retention time.In the need testing solution color atlas, if any impurity peaks, maximum assorted peak area must not be greater than contrast solution main peak area (1.0%), and each impurity peak area summation should be greater than 3 times (3.0%) of contrast solution main peak area.
The cefotiam polymkeric substance is measured according to size exclusive chromatography (two appendix V H of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability are weighting agent with sephadex G-10 (40～120 μ m), and internal diameter is 1.0cm, and the post height is 30.0cm.Take the 0.1mol/L phosphate buffered saline buffer [sodium dihydrogen phosphate of 0.1mol/L disodium phosphate soln-0.1mol/L (95: 5)] of pH8.0 as mobile phase A, take water as Mobile phase B, flow velocity is per minute 0.8ml, and column temperature is 40 ℃, and the detection wavelength is 254nm.Take mobile phase A, B as moving phase, get 0.1mg/ml blue dextran 2000 solution 200 μ l respectively, the injection liquid chromatography, number of theoretical plate all must not be lower than 700 with blue dextran 2000 peaks calculating.Tailing factor all should be less than 2.0.In two kinds of flow phase system, blue dextran 2000 peak retention time ratios should be between 0.93～1.07, and in reference substance solution main peak and need testing solution, in polymkeric substance peak and corresponding chromatographic system, the ratio of blue dextran 2000 peak retention time all should be between 0.93～1.07.Separately take Mobile phase B as moving phase, precision measures reference substance solution 200 μ l, continuous sample introduction 5 times, and the relative standard deviation of peak area should be not more than 5.0%.
Approximately 10mg of cefotiam hydrochloride reference substance is got in the preparation of reference substance solution, and is accurately weighed, is dissolved in water and quantitatively dilutes and make the solution that approximately contains cefotiam 20 μ g in every 1ml.
Assay method is got this product, and is accurately weighed, is dissolved in water to make the solution that every 1ml approximately contains cefotiam 4mg, and as need testing solution, precision measures 200 μ l injection liquid chromatographies immediately, measures as moving phase take mobile phase A, records color atlas.Another precision measures reference substance solution 200 μ l injection liquid chromatographies, take Mobile phase B as moving phase, measures with method, with calculated by peak area, contains the cefotiam polymkeric substance in cefotiam by external standard method, must not cross 0.5%.
Residual solvent is measured according to residual solvent assay method (2005 editions two appendix VIII P of Chinese Pharmacopoeia).
Ethanol, acetone, acetonitrile and methylene dichloride are take poly-6% cyanogen propylbenzene-94% dimethyl polysiloxane capillary column as chromatographic column, and 40 ℃ of column temperatures keep 6min, with 20 ℃/min temperature programming to 200 ℃, keep 3min; Detector is flame ionization ditector (FID), and detector temperature is 250 ℃; Injector temperature is 200 ℃; Headspace sampling, head space bottle equilibrium temperature is 90 ℃, starting time 30 minutes, sampling volume is 1ml.
The reference substance solution precision takes ethanol 250mg, acetone 250mg, acetonitrile 21mg and methylene dichloride 30mg, with putting in the 50ml measuring bottle, is diluted with water to scale, shakes up, and precision measures 5ml, puts in the 50ml measuring bottle, is diluted with water to scale, shakes up, and get final product.
Need testing solution takes this product 0.1g, and is accurately weighed, adds water 1ml and makes dissolving and get final product.
The assay method precision measures reference substance solution and each 1ml of sample solution, puts in an empty bottle, detects in accordance with the law, record color atlas,, contain ethanol and must not cross 0.5% with calculated by peak area by external standard method, acetone must not cross 0.5%, and acetonitrile must not cross 0.041%, and methylene dichloride must not cross 0.06%.
DMF is take poly-6% cyanogen propylbenzene-94% dimethyl polysiloxane capillary column as chromatographic column, and 80 ℃ of column temperatures keep 5min, with 20 ℃/min temperature programming to 200 ℃, keeps 4min; Detector is flame ionization ditector (FID), and detector temperature is 250 ℃; Injector temperature is 200 ℃; Sampling volume: 1 μ l.
It is appropriate that the reference substance solution precision takes DMF, adds that the 1mol/L sodium hydrogen carbonate solution dissolves and the solution that is diluted to 0.088mg/ml product solution in contrast;
Need testing solution takes this product 0.1g, adds 1mol/L sodium hydrogen carbonate solution 1ml and makes dissolving and get final product.
The assay method precision measures reference substance solution and each 1 μ l of sample solution, detects in accordance with the law, records color atlas,, contains DMF and must not cross 0.088% with calculated by peak area by external standard method.
Residue on ignition is got this product 1.0g, checks to leave over (2005 editions two appendix VIII N of Chinese Pharmacopoeia) residue and must not cross 0.2% in accordance with the law.
Heavy metal is got the residue of leaving under the residue on ignition item, checks to contain (2005 editions two appendix VIII H the second methods of Chinese Pharmacopoeia) heavy metal and must not cross 20/1000000ths in accordance with the law.
Arsenic salt sample thief 1.0g adds water 23ml and makes dissolving, after adding hydrochloric acid 5ml, checks (2005 editions two appendix VIII J first methods of Chinese Pharmacopoeia) in accordance with the law, should (0.0002%) up to specification.
It is appropriate that bacterial endotoxin is got this product, mixes by weight 5: 2 with sodium carbonate (170 ℃, heating more than 4 hours), and checking in accordance with the law that (2005 editions two appendix XI E of Chinese Pharmacopoeia), every 1mg contain the amount of bacterial endotoxin should be higher than 0.125EU.
The aseptic this product of getting is appropriate, all be transferred in appropriate pH7.0 sodium-chlor-peptone buffered soln, process (pH7.0 sodium-chlor-peptone buffered soln 2250ml gradation flushing filter membrane with membrane-filter procedure, each 50ml, remove with the washing fluid that contains β-lactamase (approximately 3,000,000 units) microbiotic that remains on filter cylinder and filter membrane at last), with the positive contrast of streptococcus aureus bacterium, check (2005 editions two appendix XI H of Chinese Pharmacopoeia) in accordance with the law, should be up to specification.
Visible foreign matters is got this product 2.0g, and totally 5 parts, after adding sterile water for injection and making dissolving, check (2005 editions two appendix IX H first methods of Chinese Pharmacopoeia) in accordance with the law, should be up to specification.
Particulate matter is got this product 2.0g, and totally 3 parts, after adding sterile water for injection and making dissolving, check (2005 editions two appendix IX C of Chinese Pharmacopoeia) in accordance with the law, should be up to specification.
[assay] measured according to high performance liquid chromatography (2005 editions two appendix VD of Chinese Pharmacopoeia).
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are weighting agent; (the 0.05mol/L disodium phosphate soln is transferred pH to 7.7 with the potassium dihydrogen phosphate of 0.05mol/L)-acetonitrile (88: 12) is moving phase with phosphate buffered saline buffer; Detect wavelength 254nm, 25 ℃ of column temperatures.Precision takes cefotiam hydrochloride reference substance and 3,5-orcin (orcinol) is appropriate, make approximately containing cefotiam hydrochloride 0.5mg and 3 of every 1ml with moving phase, the mixing solutions of 5-orcin 2mg, sample introduction 20 μ l, cefotiam peak and the peak-to-peak resolution of 3,5-orcin must not be less than 5.
It is appropriate that assay method is got this product, makes with moving phase the solution that every 1ml approximately contains cefotiam 0.5mg, and as need testing solution, precision measures 20 μ l injection liquid chromatographies, records color atlas; Separately get the cefotiam hydrochloride reference substance appropriate, measure with method.Press external standard method with cefotiam (C in the calculated by peak area trial-product
18H
23N
9O
4S
3) content.This product is pressed anhydride and is calculated, and contains cefotiam (C
18H
23N
9O
4S
3) should be 79.0%～92.5%.
Annotate: reference substance solution and sample solution all should face uses new system.
The full inspection result of table 1 cefotiam hydrochloride of the present invention
Above assay shows, the impurity of cefotiam hydrochloride produced according to the invention (related substance and polymkeric substance) content is low, can fully ensure the security of clinical application; The indexs such as aseptic, bacterial endotoxin are all up to specification, can be directly used in by the aseptic subpackaged cefotiam hydrochloridefor inj for preparing, and need not further sterilization or except thermal source.
The stability test of experimental example 2-cefotiam hydrochloride of the present invention
One, accelerated test
Get respectively the aseptic cefotiam hydrochloride of high purity of embodiment 1-4, adopt medicinal Aluminum Bottle packing, at 30 ± 2 ℃, placed 6 months under the condition of RH 65% ± 5%.Respectively at the 0th, 1,2,3, take a sample once June, detects every stability and examine the wiping index, the results are shown in Table 2.
The accelerated test result shows, cefotiam hydrochloride of the present invention is positioned under the simulation commercially available back, at 30 ± 2 ℃, and RH
Placed under 65% ± 5% condition 6 months, except related substance increased to some extent, all the other indices comprised that aseptic, bacterial endotoxin etc. has no significant change, all in acceptability limit.
Two, test of long duration
Get respectively the aseptic cefotiam hydrochloride of high purity of embodiment 1-4, adopt medicinal Aluminum Bottle packing, at 18 ± 2 ℃, place under the condition of RH 60% ± 10%, respectively at the 0th, 3,6,9,12,18,24 month every study on the stability index of taking a sample to check, the results are shown in Table 3.
Long-term test results shows, cefotiam hydrochloride of the present invention is positioned under the simulation commercially available back, at 18 ± 2 ℃, places 24 months under RH60% ± 10% condition, and except related substance slightly raise, bacterial endotoxin, other every inspections such as aseptic were all up to specification.
The accelerated test result of table 2 cefotiam hydrochloride of the present invention
The long-term test results of table 3 cefotiam hydrochloride of the present invention
The check of experimental example 3-cefotiam hydrochloride medicament composition of the present invention
Get the cefotiam hydrochloride medicament composition of embodiment 5-8, press the check of cefotiam hydrochloridefor inj quality standard, the results are shown in Table 4.
The full inspection result of table 4 cefotiam hydrochloride composition of the present invention
Above assay shows, the indices such as aseptic, bacterial endotoxin of cefotiam hydrochloride medicament composition produced according to the invention is all up to specification.
The stability test of experimental example 4-cefotiam hydrochloride medicament composition of the present invention
One, accelerated test
Get respectively the cefotiam hydrochloride composition of embodiment 5-8, at 30 ± 2 ℃, placed 6 months under the condition of RH 65% ± 5%.Respectively at the 0th, 1,2,3, take a sample once June, detects every stability and examine the wiping index, the results are shown in Table 5.
The accelerated test result shows, cefotiam hydrochloride composition of the present invention is pressed commercially available back, at 30 ± 2 ℃, place after 6 months under the condition of RH65% ± 5%, compared with 0 month, except related substance increases to some extent, all the other indices, comprise that aseptic, bacterial endotoxin etc. has no significant change, all in acceptability limit.
Two, test of long duration
Get respectively the cefotiam hydrochloride composition of embodiment 5-8, at 18 ± 2 ℃, place under the condition of RH 60% ± 10%, respectively at the 0th, 3,6,9,12,18,24 month every study on the stability index of taking a sample to check, the results are shown in Table 6.
Long-term test results shows, cefotiam hydrochloride composition of the present invention is pressed commercially available back, at 18 ± 2 ℃, places 24 months under RH60% ± 10% condition, and except related substance slightly raise, bacterial endotoxin, other every inspections such as aseptic were all up to specification.
The accelerated test result of table 5 cefotiam hydrochloride composition of the present invention
The long-term test results of table 6 cefotiam hydrochloride composition of the present invention
Claims (12)
1. the preparation method of the aseptic cefotiam hydrochloride of high purity is characterized in that comprising the following steps:
(1) the cefotiam hydrochloride crude product is added in treatment tank, be dissolved in water for injection, add concentrated hydrochloric acid, sodium bisulfite, EDTA – Na under stirring
2And gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with water for injection, merging filtrate changed in crystallizer;
(2) add dehydrated alcohol and gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, is cooled to 18～22 ℃, adds the crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, solution changes in multi-functional bipyramid and filters, and gets the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection mixed solvent, is cooled to 5～10 ℃, with the cefotiam hydrochloride crystallizing and washing of step (3) gained 3 times;
(5) the described method of same step (2) is processed dehydrated alcohol, is cooled to 5～10 ℃, with the cefotiam hydrochloride crystallizing and washing of step (4) gained 3 times;
(6) be dried to moisture≤7.0%, and get final product.
2. the preparation method of the aseptic cefotiam hydrochloride of high purity is characterized in that comprising the following steps:
(1) cefotiam hydrochloride crude product 6-10kg is added in treatment tank, be dissolved in 20-24kg water for injection, add 1.5-2.5L concentrated hydrochloric acid, 20-40g sodium bisulfite, 10-20g EDTA – Na under stirring
2With the 600-800g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 1-3kg water for injection, merging filtrate changed in crystallizer;
(2) add 90-100kg dehydrated alcohol, 200-500g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stir after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 90-100kg dehydrated alcohol, slowly splash in the described crystallizer of step (1), approximately dropwised in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, solution changes in multi-functional bipyramid and filters, and gets the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (40-50kg/5-7kg) mixed solvent, is cooled to 5～10 ℃, with the cefotiam hydrochloride crystallizing and washing of step (3) gained 3 times;
(5) the described method of same step (2) is processed the 40-50kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
3. the preparation method of the aseptic cefotiam hydrochloride of high purity is characterized in that comprising the following steps:
(1) cefotiam hydrochloride crude product 6.5kg is added in treatment tank, be dissolved in 22kg water for injection, add 1.95L concentrated hydrochloric acid, 35g sodium bisulfite, 14g EDTA – Na under stirring
2With the 700g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 94.7kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 94.7kg dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (45kg/6kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed dehydrated alcohol 47.4kg, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
4. the preparation method of the aseptic cefotiam hydrochloride of high purity is characterized in that comprising the following steps:
(1) cefotiam hydrochloride crude product 8.5kg is added in treatment tank, be dissolved in 23kg water for injection, add 2L concentrated hydrochloric acid, 35g sodium bisulfite, 14g EDTA – Na under stirring
2With the 800g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 105kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 105kg dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (mixed solvent of 50kg/7kg) is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed the 50kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
5. the preparation method of the aseptic cefotiam hydrochloride of high purity is characterized in that comprising the following steps:
(1) cefotiam hydrochloride crude product 10kg is added in treatment tank, be dissolved in 24kg water for injection, add 2.2L concentrated hydrochloric acid, 40g sodium bisulfite, 16g EDTA – Na under stirring
2With the 850g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake was used 2kg water for injection detergent active charcoal, merging filtrate changed in crystallizer;
(2) add 115kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 110kg dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (53kg/7.5kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) the described method of same step (2) is processed the 53kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
6. the preparation method of the aseptic cefotiam hydrochloride of high purity is characterized in that comprising the following steps:
(1) cefotiam hydrochloride crude product 6kg is added in treatment tank, be dissolved in 20kg water for injection, add 1.95L concentrated hydrochloric acid, 34g sodium bisulfite, 14g EDTA – Na under stirring
2With the 700g gac, stirred 1 hour under 20～25 ℃, through 0.45 μ m and 0.22 μ m filter element filtering, after the charcoal cake washed with 2kg water for injection, merging filtrate changed in crystallizer;
(2) add 90kg dehydrated alcohol, 350g gac in treatment tank, stir 0.5 hour by 0.45 μ m and 0.22 μ m filter element filtering, filtrate changes in the described crystallizer of step (1), stirs after 10 minutes, be cooled to 18～22 ℃, add hydrochloric acid cefotiam crystal seed crystallization 3 hours;
(3) the described method of same step (2) is processed the 90kg dehydrated alcohol, slowly splashes in the described crystallizer of step (1), approximately dropwises in 2.5 hours, drip 10 ± 3 ℃ of the interior temperature of complete crystallization control tank, continue to stir 2 hours, change in multi-functional bipyramid and filter, get the cefotiam hydrochloride crystallization;
(4) the described method of same step (2) is processed dehydrated alcohol/water for injection (44kg/5.5kg) mixed solvent, is cooled to 5～10 ℃, with step (3) gained cefotiam hydrochloride crystallizing and washing 3 times;
(5) same step (2) method is processed the 45kg dehydrated alcohol, is cooled to 5～10 ℃, with step (4) gained cefotiam hydrochloride crystallizing and washing 3 times;
(6) be dried to moisture≤7.0%, and get final product.
7. according to claim 1-6 described preparation methods of any one, the concentration expressed in percentage by weight that it is characterized in that described concentrated hydrochloric acid is 33-37%.
8. according to claim 1-6 described preparation methods of any one, is characterized in that described dilute hydrochloric acid use concentrated hydrochloric acid and water are according to the volume ratio preparation of concentrated hydrochloric acid/water=1.18/10.
9. according to claim 1-6 described preparation methods of any one is characterized in that step (1) carries out at 100,000 grades of clean areas, and carry out at ten thousand grades of clean areas step (2) ~ (6).
10. the aseptic cefotiam hydrochloride of high purity for preparing of the described method of claim 1-6 any one.
11. comprise the pharmaceutical composition of cefotiam hydrochloride claimed in claim 10, described pharmaceutical composition comprises described cefotiam hydrochloride and anhydrous sodium carbonate, described cefotiam hydrochloride is take the weight ratio of cefotiam and anhydrous sodium carbonate as 500 ︰ 121.
12. the preparation method of the pharmaceutical composition of a claim 11, it comprises cefotiam hydrochloride (in cefotiam) and the anhydrous sodium carbonate weight ratio with 500 ︰ 121 is mixed; Empty cillin bottle fills nitrogen, packing, gland; After the assay was approved, packing.
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| CN103446047A (en) * | 2013-09-11 | 2013-12-18 | 杭州通盛医药科技有限公司 | Cefotiam hydrochloride pharmaceutical composition for injection and preparation method thereof |
| CN105085548A (en) * | 2015-09-10 | 2015-11-25 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical cefotiam composition for treating infectious diseases |
| CN107383063A (en) * | 2017-07-14 | 2017-11-24 | 浙江永宁药业股份有限公司 | The novel crystal forms and preparation method of cefotiam chloride |
| CN107383065A (en) * | 2017-07-14 | 2017-11-24 | 浙江永宁药业股份有限公司 | A kind of cefotiam chloride crystalline compounds and preparation method thereof |
| CN112986471A (en) * | 2019-12-18 | 2021-06-18 | 重庆圣华曦药业股份有限公司 | Detection method of cefotiam hydrochloride related substance for injection |
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Application publication date: 20130619 |