CN101556262A - Method for detecting impurities in cefoxitin product - Google Patents
Method for detecting impurities in cefoxitin product Download PDFInfo
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- CN101556262A CN101556262A CNA2009101375691A CN200910137569A CN101556262A CN 101556262 A CN101556262 A CN 101556262A CN A2009101375691 A CNA2009101375691 A CN A2009101375691A CN 200910137569 A CN200910137569 A CN 200910137569A CN 101556262 A CN101556262 A CN 101556262A
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Abstract
The invention provides a method for detecting impurities in a cefoxitin product. The method adopts high performance liquid chromatography and comprises the steps that an inverted octadecylsilyl bonded phase silica gel chromatographic column is adopted; 0.7 percent (weight/volume) of dipotassium hydrogen phosphate aqueous solution with a pH of 3.5 adjusted by phosphoric acid serves as a mobile phase A and acetonitrile as a mobile phase B; the mobile phase A and the mobile phase B are combined into a mixed mobile phase which goes through gradient elution under the following conditions: during 0 to 5 minutes, the volume ratio of the mobile phase A and the mobile phase B is 95:5; during 5 to 15 minutes, the volume ratio of the mobile phase A and the mobile phase B is uniformly changed from 95:5 to 70:30; during 15 to 35 minutes, the volume ratio of the mobile phase A and the mobile phase B is uniformly changed from 70:30 to 30:70; during 35 to 45 minutes, the volume ratio of the mobile phase A and the mobile phase B is uniformly changed from 30:70 to 15:85; and during 45 to 60 minutes, the volume ratio of the mobile phase A and the mobile phase B is uniformly changed from 15:85 to 95:5. The method can be used for respectively conducting quantitative detection on four impurities in cefoxitin, which is simple and convenient and has strong specificity.
Description
Technical field
The present invention relates to a kind of method that detects impurity in the cefoxitin product, be specifically related to a kind of method that adopts high performance liquid chromatography to detect impurity in the cefoxitin product.
Background technology
Cefoxitin belongs to second generation cephalosporin class medicine, is a kind ofly to be derived and the semi-synthetic broad-spectrum sterilization medicine that comes through chemical modification by cephamycin C, and its bactericidal action comes from and can suppress the synthetic of bacteria cell wall.With respect to first generation cephalosporin, Cefoxitin obviously strengthens the effect of most gram-negative bacterias of first generation cephalosporin resistance, and anaerobion is had efficiently; More stable to multiple beta-lactamase; Toxicity to kidney also decreases.The chemical constitution uniqueness of Cefoxitin (seeing structure shown in the formula I); methoxyl in its structure is in " trans "; can hinder beta-lactamase near beta-lactam nucleus; the attenuating enzyme is affine to medicine; thereby the protection beta-lactam nucleus is not destroyed, and makes its stability to multiple beta-lactamase stronger than most cynnematins, has high stability; especially highly stable to the beta-lactamase of numerous plasmids or chromosome mediation, be difficult for by the beta-lactam enzyme hydrolysis.
Compare with other cynnematins, the Cefoxitin antimicrobial spectrum is wider, and is more balanced, all has strong active to Gram-positive and feminine gender, anaerobion or aerobic bacteria.Its antimicrobial spectrum further enlarges than first generation cephalosporin, and the gram-negative bacteria of many anti-first generation cephalosporins (as enterobacteria, the positive proteus of indoles etc.) is to the Cefoxitin sensitivity.This a pair of aerobic bacteria of Cefoxitin and anaerobion all have strong active characteristic, make it may become the promising a kind of selection that substitutes present drug combination in clinical treatment anaerobic infection or mixed infection.Has a broad antifungal spectrum, the antibacterial activity of Cefoxitin is strong, toxicity is low, be subjected to doctor and numerous patients' welcome deeply, has excellent clinical effectiveness, be successfully used to treat the microbial multiple infection of Gram-positive, negative aerobic bacteria and anaerobism, comprising last lower respiratory infection, urethral infection, infect in peritonitis and other intraperitoneal, the pelvic cavity, gynecological infection, bone, joint and soft tissue infection, septicemia etc.Because the Cefoxitin instant effect, dosage is little, spinoff is low, clinical efficacy is remarkable, is worth very much advocating using.It is reported that use Cefoxitin and treat various infection, total effective rate is 74%.The efficient of respiratory tract infection such as medical patient's mesobronchus inflammation, pneumonia, pulmonary abscess are 72.6%; The efficient of acute and chronic urinary tract infections is respectively 99.5% and 77.8%.The efficient of suppurative osteoarthritis, osteomyelitis, subcutaneous abscess etc. is 66.7%.Pathogen is based on gram negative bacilli, and treatment back bacteria clearance is 71.6%; The clearance rate of Escherichia coli and pneumobacillus is respectively 89.6% and 65.7%.The removing effect of GPCs such as gold Portugal bacterium is also satisfied.Surgery, urological department and gynecologic and obstetric disease philtrum clinical effective rate are respectively 71.6%, 71.0% and 85.2%, total bacteria clearance of 3 groups of patients is 75.2%, wherein the clearance rate of Escherichia coli, pneumobacillus and Serratia is respectively 79.2%, 82.1% and 60.0%, and the bacteria clearance of Grain-positive and negative cocci is 83.3%.Documents and materials show that Cefoxitin is similar with Cefamandole to cephazoline to the curative effect that gram positive aerobic bacteria infects, and are better than cefoxitin to the curative effect of gram negative aerobic bacteria infection, anaerobic infection and anaerobism and aerobic mixed infection.The efficient of lower respiratory infection is 80%, comprising other antibiotic therapies nonresponder.Because Cefoxitin all has effect to aerobic and anaerobion (especially bacteroides fragilis), surpass 85% so be used for the treatment of the clinical effective rate of intraperitoneal and female genital tract infection.Use Cefoxitin treatment immunodeficiency person infection and also obtain good efficacy, and seldom bad reaction takes place.
Usually, be raw material with the cefoxitin, by methoxylation, deacetylation, the synthetic cefoxitin sodium of ammonia methoxy acidylate three-step reaction.Specifically, at first, at synthetic 7-α-methoxyl-7-[(2-thienyl) acetylamino]-process of 4-cephalosporanic acid cyclohexylamine salt in, be reflected at 7 of cefoxitin master nuclear by williamson and generate methoxyls; Secondly, in the process of synthetic 3-methylol-7-α-[(2-thienyl) acetylamino]-4-cephalosporanic acid acetic acid benzyl star salt, the hydrolysis of intermediate cephalosporanic acid cyclohexylamine salt generates goes formamido group west fourth, cause containing in the finished product several major impurities such as formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone like this, these impurity easily cause bad reactions such as allergy in the preparation use, the content of therefore controlling these four kinds of impurity in process of production is very important.Conventional detection adopts Self-control method to measure related substance more, only the content of single impurity or total impurities is measured, and can not be distinguished and carry out respectively quantitative examination simultaneously to four kinds of impurity in the product.
Summary of the invention
Therefore, the purpose of this invention is to provide four kinds of methods that impurity removes formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone in a kind of detection by quantitative cefoxitin product simultaneously effectively.
Be used to realize that the technical scheme of above-mentioned technical purpose of the present invention is as follows:
A kind of method that adopts high performance liquid chromatography to detect impurity in the cefoxitin product, this method comprises the anti-phase octadecyl bonding phase silica gel chromatographic column of employing, to regulate pH with phosphoric acid is that 0.7% (weight/volume) aqueous dibasic potassium phosphate solution of 3.5 is as mobile phase A, acetonitrile is formed the mixed flow phase as Mobile phase B, carries out gradient elution according to following condition:
0 to 5 minute: the volume ratio of mobile phase A and Mobile phase B was 95: 5;
5 to 15 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 70: 30 by 95: 5;
15 to 35 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 30: 70 by 70: 30;
35 to 45 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 15: 85 by 30: 70;
45 to 60 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 95: 5 by 15: 85.
In said method, high performance liquid chromatography preferably adopts UV-detector, and the detection wavelength is 254nm.Anti-phase octadecyl bonding phase silica gel chromatographic column is preferably the YWG-C12H25 chromatographic column.The flow velocity of mixed flow phase can be 0.8ml/min.
Said method comprises respectively the cefoxitin product with known quantity, and the potpourri that removes formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone of known quantity carries out high performance liquid chromatography and detects, and the high performance liquid chromatogram collection of illustrative plates of the cefoxitin product high performance liquid chromatogram collection of illustrative plates with the potpourri that removes formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone is compared.Specifically, said method comprises respectively the cefoxitin product with known quantity, and the potpourri that removes formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone of known quantity carries out high performance liquid chromatography and detects, and corresponding peak carries out peak area ratio in the high performance liquid chromatogram collection of illustrative plates with the high performance liquid chromatogram collection of illustrative plates of cefoxitin product and the potpourri that removes formamido group west fourth, the western fourth of δ-3-, thiophene lactone and western butyrolactone.Wherein, preferably, the ratio that goes formamido group west fourth, δ-3-west fourth, thiophene lactone or western butyrolactone and the quality of the cefoxitin product of known quantity of known quantity is all less than 0.25%.
This detection method is through the methodology checking, and sample is noiseless to impurity determination, and each impurity is good linear relationship in measurement range, and the recovery meets the requirement of assay, the results are shown in Table 1.
Table 1 methodology checking result
Beneficial effect of the present invention has been cefoxitin product perfect, and for example the method for detecting impurities of cefoxitin sodium for injection has carried out detection by quantitative simultaneously at four kinds of clear and definite impurity in the Cefoxitin.This method is easy, specificity is strong, can more effectively be used to control the quality of product, reduces the generation of bad reaction, guarantees the safety of human body medication.
Description of drawings
Below, describe embodiments of the invention in conjunction with the accompanying drawings in detail, wherein:
Fig. 1 is the high-efficient liquid phase chromatogram of need testing solution;
Fig. 2 is the high-efficient liquid phase chromatogram of reference substance solution.
Embodiment
The invention will be further described by the following examples.Should be understood that following examples only are used to illustrate the present invention, and be not used in the scope of the present invention that limits.
Embodiment 1
Adopt reversed-phased high performace liquid chromatographic, the mixed solvent by opposed polarity carries out gradient elution, in the absorption peak of ultraviolet 254nm place mensuration impurity, and utilizes known impurity reference substance, calculates the content of impurity.
(1) chromatographic condition:
Chromatographic column: YWG-C12H25 post (producer is Tianjin reagent two factories);
Instrument: Tianjin, island 10A high performance liquid chromatograph: LC-10AT solvent delivery pump, SPD-10AV UV-detector, Zhejiang University's 2010 chromatographic work stations;
Reagent: acetonitrile (chromatographically pure), potassium dihydrogen phosphate (A.R.), phosphoric acid (A.R.);
Mobile phase A: 0.7% (weight/volume) dipotassium hydrogen phosphate solution, regulating pH with phosphoric acid is 3.5;
Mobile phase B: acetonitrile;
Carry out wash-out according to the listed gradient of following table:
Table 2 gradient elution program
(2) determination method: precision takes by weighing an amount of cefoxitin product, adds initial mobile phase A and makes the solution that every 1ml contains Cefoxitin 5mg, as need testing solution; Precision is measured an amount of known contrast impurity formamide west fourth, δ-3-west fourth, thiophene lactone, western butyrolactone respectively, add that respectively initial mobile phase A makes the solution that every 1ml contains formamide west fourth, δ-3-west fourth, thiophene lactone, each 12.5 μ g of western butyrolactone, product solution in contrast.According to above-mentioned chromatographic condition operation, precision measures need testing solution and each 20 μ l of contrast solution inject liquid chromatograph respectively, operates respectively according to above-mentioned gradient elution.The chromatogram of need testing solution as shown in Figure 1, wherein each impurity peaks can separate fully, by retention time, be followed successively by the impurity peaks of formamide west fourth, δ-3-west fourth, thiophene lactone, western butyrolactone etc., for each impurity peak area of test agent must not greater than corresponding impurity peak area in the contrast solution (be each impurity quality must not greater than cefoxitin product weight 0.25%), referring to Fig. 2.
The lot number of getting Haikou Pharmaceutical Factory Co., Ltd.'s production respectively is 081101,081102,081103 cefoxitin sodium for injection, measures relative substance according to above-mentioned detection method, and measurement result is as shown in table 3.
The impurity testing result of table 3 different batches
Claims (7)
1. method that adopts high performance liquid chromatography to detect impurity in the cefoxitin product, this method comprises the anti-phase octadecyl bonding phase silica gel chromatographic column of employing, to regulate pH with phosphoric acid is that 0.7% (weight/volume) aqueous dibasic potassium phosphate solution of 3.5 is as mobile phase A, acetonitrile is formed the mixed flow phase as Mobile phase B, carries out gradient elution according to following condition:
0 to 5 minute: the volume ratio of mobile phase A and Mobile phase B was 95: 5;
5 to 15 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 70: 30 by 95: 5;
15 to 35 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 30: 70 by 70: 30;
35 to 45 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 15: 85 by 30: 70;
45 to 60 minutes: the volume ratio of mobile phase A and Mobile phase B at the uniform velocity was changed to 95: 5 by 15: 85.
2. method according to claim 1 is characterized in that, described high performance liquid chromatography adopts UV-detector, and the detection wavelength is 254nm.
3. method according to claim 1 and 2 is characterized in that, described anti-phase octadecyl bonding phase silica gel chromatographic column is the YWG-C12H25 chromatographic column.
4. according to each described method in the claim 1 to 3, it is characterized in that the flow velocity of described mixed flow phase is 0.8ml/min.
5. according to each described method in the claim 1 to 4, it is characterized in that, described method comprises respectively the cefoxitin product with known quantity, and the potpourri that removes formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone of known quantity carries out high performance liquid chromatography and detects, and the high performance liquid chromatogram collection of illustrative plates of the cefoxitin product high performance liquid chromatogram collection of illustrative plates with the potpourri that removes formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone is compared.
6. according to each described method in the claim 1 to 5, it is characterized in that, described method comprises respectively the cefoxitin product with known quantity, and the potpourri that removes formamido group west fourth, δ-3-west fourth, thiophene lactone and western butyrolactone of known quantity carries out high performance liquid chromatography and detects, and corresponding peak carries out peak area ratio in the high performance liquid chromatogram collection of illustrative plates with the high performance liquid chromatogram collection of illustrative plates of cefoxitin product and the potpourri that removes formamido group west fourth, the western fourth of δ-3-, thiophene lactone and western butyrolactone.
7. according to claim 5 or 6 described methods, it is characterized in that the ratio that goes formamido group west fourth, δ-3-west fourth, thiophene lactone or western butyrolactone and the quality of the cefoxitin product of known quantity of described known quantity is all less than 0.25%.
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| CN103421025A (en) * | 2012-05-21 | 2013-12-04 | 上海医药工业研究院 | Method for preparing 7alpha-methoxyl cephalosporin C |
| CN106568853A (en) * | 2016-12-30 | 2017-04-19 | 山东康美乐医药科技有限公司 | A method of detecting impurities in a lapatinib intermediate |
| CN110396105A (en) * | 2018-09-10 | 2019-11-01 | 广东金城金素制药有限公司 | Mei Fu elder generation cefoxitin sodium pharmaceutical preparation prevents infection application in gastrointestinal surgery |
| CN110396102A (en) * | 2019-01-15 | 2019-11-01 | 广东金城金素制药有限公司 | Cefoxitin sodium pharmaceutical preparation is in vaginal hysterectomy, abdominal cavity uterectomy, the preoperative prevention infection application of (palace) production of cutting open the belly |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101226174B (en) * | 2008-01-31 | 2012-02-29 | 广州白云山天心制药股份有限公司 | Hydrochloric acid cefepime raw material and method for measuring content of N-methyl pyrrolidine in preparation thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103421025A (en) * | 2012-05-21 | 2013-12-04 | 上海医药工业研究院 | Method for preparing 7alpha-methoxyl cephalosporin C |
| CN103421025B (en) * | 2012-05-21 | 2016-05-11 | 上海医药工业研究院 | Prepare the method for 7 α-methoxy cephalosporin C |
| CN106568853A (en) * | 2016-12-30 | 2017-04-19 | 山东康美乐医药科技有限公司 | A method of detecting impurities in a lapatinib intermediate |
| CN110396105A (en) * | 2018-09-10 | 2019-11-01 | 广东金城金素制药有限公司 | Mei Fu elder generation cefoxitin sodium pharmaceutical preparation prevents infection application in gastrointestinal surgery |
| CN110396102A (en) * | 2019-01-15 | 2019-11-01 | 广东金城金素制药有限公司 | Cefoxitin sodium pharmaceutical preparation is in vaginal hysterectomy, abdominal cavity uterectomy, the preoperative prevention infection application of (palace) production of cutting open the belly |
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