CN104215697B - A kind of method detecting related substance in piperacillin sodium injection sulbactam - Google Patents
A kind of method detecting related substance in piperacillin sodium injection sulbactam Download PDFInfo
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Abstract
The invention provides a kind of method detecting related substance in piperacillin sodium injection sulbactam.The present invention adopts octadecylsilane chemically bonded silica chromatographic column to carry out gradient elution, achieves the mensuration of piperacillin-sulbactam sodium related substance fast and accurately.In gained chromatogram, mainly contain between related substance (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid and Piperacillin penicilloic acid, and other each related substance with reach good being separated (degree of separation is greater than 1.5) between Piperacillin and Sulbactam.By Study on degradation and the Method validation of piperacillin-sulbactam sodium, method of the present invention has stability indicative function, can by such detection method, realize carrying out limit handling to each impurity of piperacillin-sulbactam sodium, can be used for the quality control of piperacillin sodium injection sulbactam.This method is easy and simple to handle, with low cost, has good economic benefit and promotion prospect.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to the detection method of pharmaceutical preparation, particularly relate to a kind of method detecting related substance in piperacillin sodium injection sulbactam.
Background technology
Avocin is a kind of PCs, and it plays bactericidal action by disturbing synthesis of bacteria cell wall, is widely used in the prevention and therapy of the microbial various infectious diseases of Grain-negative.Due to containing beta-lactam nucleus, easily produced drug resistance by bacteriogenic beta-lactam enzyme hydrolysis.Sulbactam is beta-lactamase inhibitor, the beta-lactamase produced for staphylococcus aureus and most gram-negative bacteria has irreversible Reverse transcriptase, therefore the normal and penicillins of sulbactam or Cephalosporins coupling, have good antibacterial synergy.Avocin is penicillins broad-spectrum antibiotic, and molecular formula is C
23h
26n
5naO
7s, molecular weight is 539.54, its chemistry (2S by name, 5R, 6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine carboxamides base)-2-phenylacetyl amido]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid sodium salt, its structural formula is as follows:
The related substance of the avocin of having confirmed recorded in 2009 editions British Pharmacopoeias (BP2009) has 8 kinds (the Piperacillin related substance described in patent specification is the impurity occurred in compou nd synthesis production run), ampicillin respectively, Piperacillin penicilloic acid, Piperacillin penilloic acid, Piperacillin ampicillin dimer, 1-ethyl piperazidine-2, 3-diketone, the acid of Piperacillin acetamido penicillanate thiazole, piperazine formamido group phenylacetic acid and 6-amino-penicillanic acid, the limit of above all impurity all controls as <2.0% by BP2009.In American Pharmacopeia 32 editions (USP32), piperacillin for inj preparation and Piperacillin sodium raw materials are all explicitly called for and running water is carried out to related substance, USP32 has mainly carried out limiting the quantity describing to Piperacillin penicilloic acid and Piperacillin acetamido penicillanate thiazole acid two kinds of related substances, and limit is <3.5% and <1.0% respectively.2010 editions Chinese Pharmacopoeias (CP2010) are for the running water only describing a kind of related substance and Piperacillin penicilloic acid in Piperacillin sodium raw materials and piperacillin sodium injection preparation, and limit is <3.5%.
Sulbactam has another name called Sulbactam sodium, is semisynthetic beta-lactamase inhibitor, and its molecular formula is C
8h
10nNaO
5s, molecular weight is 255.23, chemistry (2S, 5R) by name-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium-4,4-dioxide, and its structure is as follows:
Specify that in BP2009 in sulbactam containing 7 kinds of related substances (the Sulbactam related substance described in patent specification occurs impurity in compou nd synthesis production run), (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid, 6-APA, 6-bromo Sulbactam, 6-penicillium bromo acid, 6 respectively, 6-bis-bromo Sulbactam, 6,6-bis-penicillium bromo acids and (2E)-3-[[(1S)-1-carboxyl-2-methyl-2-sulfinic acid base propyl group] is amino]-2-hexenoic acid.BP2009 has made regulation to kind of the limit of 6 wherein, be that (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid is no more than 0.5%, 6-APA, 6-penicillium bromo acid, 6,6-bis-penicillium bromo acid is all no more than 0.1%, 6-bromo Sulbactam, 6,6-bis-bromo Sulbactam is no more than 0.2%, other no special impurity contents be less than 0.1%, CP2010 define (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid must not more than 0.5%, 6-APA must not more than 0.1%.Be the main source of the bad reaction of medicine due to related substance, the running water that pharmacopoeia of each country has nearly all carried out related substance for the single preparations of ephedrine of beta-lactam antibiotic describes.Chinese Pharmacopoeia CP2010 version records four kinds of compound antibiotics containing beta-lactamase inhibitor, but pharmacopoeia of each country does not all record the standard of the related substance running water about piperacillin sodium injection sulbactam.
Record according to CP2010, the detection method of piperacillin sodium and tazobactam sodium for injection related substance adopts the mobile phase of avocin single preparations of ephedrine and elution requirement to single impurity and each impurity and detects, not correction up factor major component Self-control method is adopted to calculate its content, and accordingly according to carrying out limit regulation to related substance.Cefoperazone sodium and sulbactam sodium for injection have employed the mobile phase being different from folk prescription cefoperazone sodium and sulbactam, adopt isocratic condition, calculate the content of cefoperazone impurity A by external standard method, with not correction up factor major component Self-control method calculate other single impurity and other single impurity and content.Ampicillin Sodium For Injection sulbactam adopts the mobile phase and the condition of gradient elution that are different from two folk prescription ampicillin sodiums and sulbactam, adopt relative retention time to determine a kind of impurity ampicillin dimer of ampicillin, relative to the major component Self-control method of ampicillin, cubage has been carried out to it with it; And to other single impurity and other single impurity with adopt the major component Self-control method of the not correction up factor to carry out cubage, carry out limit regulation accordingly.And amoxicillin and clavulanate potassium adopts and is different from mobile phase and the elution requirement of Amoxicillin and potassium clavulanate, for single impurity and each impurity with carry out cubage by not correction up factor major component Self-control method.Therefore, above-mentioned four kinds of compound preparations are when controlling related substance, all adopt not correction up factor major component Self-control method, to single impurity, other single impurity and each impurity and carried out limit regulation, wherein cefoperazone sodium and sulbactam sodium for injection uses external standard method, control a kind of content from microbiotic major impurity, Ampicillin Sodium For Injection sulbactam uses relative retention time and major component Self-control method, from antibiotic major impurity, independent regulation has been carried out to one, but, four kinds of compound antibiotics all do not carry out independent limit handling to the major impurity of beta-lactamase inhibitor.Sulbactam impurity A i.e. (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid, and being the final catabolite that sulbactam destroys in acid-base solution, is also the major impurity in Sulbactam raw material.The limit of (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid that Japanese Pharmacopoeia 15 editions (JP15) specifies is 1.0%, higher than 0.5% of other States Pharmacopoeia specifications.Although pharmacopeia does not carry out limit handling to containing the impurity deriving from Sulbactam in the antibiotic compound preparation of Sulbactam, because the impurity contained in medicine is not only the main cause affecting purity, and Inhibiting enzyme activity reduction, the increase of clinical adverse toxic and side effect etc. can be affected.So set up the method that in compound, effective checked for impurities detects, the content controlling the major impurity in sulbactam is necessary.BP2009, USP32 and CP2010 detect avocin and all use HPLC method, wherein in mobile phase, the ratio of organic phase is minimum is 25%, but the polarity of (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid is very large, Sulbactam impurity and Sulbactam cannot be separated; Usually the method detecting sulbactam related substance in addition at present adopts gradient elution, elution time is only 13min, and high organic phase elution time only about 1min, found through experiments the detection that such chromatographic test strip part is not suitable for the related substance of avocin.But, adopt if simple the method detecting related substance in avocin and sulbactam two folk prescriptions, be also unsuitable for the detection of related substance in compound piperacillin-sulbactam sodium.Therefore, exploitation quick and precisely and to detect in piperacillin sodium injection sulbactam the method for the related substance in two kinds of sources, for ensureing the quality controllable of piperacillin sodium injection sulbactam, has positive effect simultaneously.
Summary of the invention
Technical matters to be solved by this invention is that research and design can detect the method for related substance in piperacillin sodium injection sulbactam simultaneously.
The invention provides a kind of method detecting related substance in piperacillin sodium injection sulbactam.Particularly, the present invention's high-efficient liquid phase determining method carries out.
A kind of method detecting related substance in piperacillin sodium injection sulbactam of the present invention, comprises the following steps:
(1) get piperacillin sodium injection sulbactam, with mixed solvent dissolve, make 30mg/ml as need testing solution;
Described mixed solvent is mobile phase A and Mobile phase B mixes in 5:95 ratio V/V;
Described mobile phase: A phase is methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=550:366:82:2V/V;
B phase is water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=447:100:3V/V;
The pH:4.5-6.5 of mobile phase A phase and B phase; The best is 5.5;
(2) adopt the reference substance solution of need testing solution, own control solution and impurity in HPLC difference determination step (1), chromatographic condition is as follows:
Chromatographic column: octadecylsilane chemically bonded silica is the chromatographic column of filling agent;
Mobile phase: A phase is methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=550:366:82:2,
B phase is water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=447:100:3
The pH:4.5-6.5 of mobile phase; The best is 5.5
Flow velocity: 0.5-1.5ml/min; The best is 1.0ml/min
Determined wavelength: 220-254nm; The best is 220nm
Column temperature: 20-35 DEG C, the best is 30 DEG C
Sample size: 10-20ul, the best is 10ul
Condition of gradient elution is as following table:
Optimum washing engaging condition is:
When the present inventor states method in design, consider in BP2009 that defining Piperacillin sodium impurity has 8 kinds, sulbactam impurity has 7 kinds, when carrying out methodological study, have chosen content in Piperacillin maximum, the Piperacillin impurity A controlled as major impurity and Piperacillin penicilloic acid, and the impurity that in Sulbactam, content is maximum (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid, as known impurities.
The present inventor is through screening chromatographic column, the equal condition that flows in efficient liquid phase chromatographic analysis, select suitable buffer solution system, on the proportion adjustment of mobile phase, fully take into account the separation requirement of tens kinds of impurity in avocin and sulbactam, finally establish the method for HPLC gradient elution, to control analysis time at 60min, achieve simultaneously to the compartment analysis of avocin, sulbactam and related substance thereof.
In the present invention the optimization of mobile phase be have studied measure avocin related substance mobile phase composition and ratio, in conjunction with needs of the present invention, be divided into two-phase, wherein mobile phase A is the mixed solution of organic solvent and buffer salt solution, Mobile phase B is buffer salt solution, then respectively by mobile phase A, B is adjusted to same pH, so just can when meeting condition of gradient elution, in guarantee detection system, mobile phase pH's is stable, avoid and mobile phase is divided into pure organic phase and pure water phase under normal circumstances, the pH of aqueous phase can only be regulated, organic solvent in sample introduction process is had an impact for overall flow phase pH, the drawback that in system, the pH of mobile phase can not be stable.
A kind of method detecting related substance in piperacillin sodium injection sulbactam of the present invention, is applicable to instrument automatically and hand sampling, is particularly suitable for instrument auto injection, can avoids the error of the improper introducing of manual operation, improve the degree of accuracy measured.
The present invention adopts octadecylsilane chemically bonded silica chromatographic column to carry out gradient elution, achieves the mensuration of piperacillin-sulbactam sodium related substance fast and accurately.In gained chromatogram, mainly contain between related substance (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid and Piperacillin penicilloic acid, and other each related substance with reach good being separated (degree of separation is greater than 1.5) between Piperacillin and Sulbactam.By Study on degradation and the Method validation of piperacillin-sulbactam sodium, method of the present invention has stability indicative function, can by such detection method, realize carrying out limit handling to each impurity of piperacillin-sulbactam sodium, can be used for the quality control of piperacillin sodium injection sulbactam.This method is easy and simple to handle, with low cost, has good economic benefit and promotion prospect.
Accompanying drawing explanation
Fig. 1 embodiment 1 detects the HPLC collection of illustrative plates of piperacillin sodium injection sulbactam related substance
Fig. 2 embodiment 2 detects the HPLC collection of illustrative plates of piperacillin sodium injection sulbactam related substance
Fig. 3 embodiment 3 detects the HPLC collection of illustrative plates of piperacillin sodium injection sulbactam related substance
Fig. 4 comparative example 1CP2010/USP32 measures the HPLC collection of illustrative plates that avocin related substance method measures piperacillin sodium injection sulbactam related substance
Fig. 5 comparative example 2CP2010/BP2009 measures the HPLC collection of illustrative plates that sulbactam related substance method measures piperacillin sodium injection sulbactam related substance
Embodiment
Below by way of each embodiment, the invention will be further described, but these embodiments do not limit the scope of the invention.
Embodiment 1: detect piperacillin sodium injection sulbactam related substance
1. instrument and condition
High performance liquid chromatograph: Agilent1200
Chromatographic column: AgilentXDB-C18 (250mm*4.6mm, 5um)
Mobile phase: A phase is methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=550:366:82:2V/V
B phase is water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=447:100:3V/V
The pH:5.5 of mobile phase
Flow velocity: 1.0ml/min
Determined wavelength: 220nm
Column temperature: 30 DEG C
Sampling volume: 10ul
Condition of gradient elution is as following table:
2. solution preparation
Mixed solvent: mobile phase A and Mobile phase B mix in 5:95V/V ratio;
Need testing solution: get piperacillin sodium injection sulbactam (manufacturing enterprise: Xiangbei Welman Pharmaceutical Co., Ltd., specification 2:1) 30mg and be placed in 10ml volumetric flask, dissolve with above-mentioned mixed solvent, be diluted to scale, shake up, as need testing solution;
3. get above-mentioned need testing solution sample introduction, obtain collection of illustrative plates as Fig. 1 and table 1
Table 1. piperacillin sodium injection sulbactam related substance testing result:
Conclusion: from Fig. 1 and table 1 draw the degree of separation of (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid, sulbactam, Piperacillin penicilloic acid and Piperacillin minimum be 9.53, be greater than that pharmacopeia (CP2010) requires 1.5, theoretical cam curve is minimum is 4598; Therefore this experiment condition can meet the requirement detecting piperacillin sodium injection sulbactam related substance, detects the impurity in avocin and sulbactam two kinds source simultaneously.
Embodiment 2: detect piperacillin sodium injection sulbactam related substance
1. instrument and condition
High performance liquid chromatograph: Agilent1200
Chromatographic column: AgilentXDB-C18 (250mm*4.6mm, 5um)
Mobile phase: A phase is methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=550:366:82:2, V/V
B phase is water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=447:100:3V/V
The pH:4.5 of mobile phase
Flow velocity: 1.5ml/min
Determined wavelength: 225nm
Column temperature: 20 DEG C
Sampling volume: 10ul
Condition of gradient elution is as following table:
2. solution preparation
Mixed solvent: mobile phase A and Mobile phase B mix in 5:95V/V ratio;
Need testing solution: get piperacillin sodium injection sulbactam (manufacturing enterprise: Xiangbei Welman Pharmaceutical Co., Ltd., specification 2:1) 30mg and be placed in 10ml volumetric flask, dissolve with above-mentioned mixed solvent, be diluted to scale, shake up, as need testing solution;
3. get above-mentioned need testing solution sample introduction, obtain collection of illustrative plates as Fig. 2 and table 2.
Table 2. piperacillin sodium injection sulbactam related substance testing result:
Conclusion: from Fig. 2 and table 2 draw the degree of separation of (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid, sulbactam, Piperacillin penicilloic acid and Piperacillin minimum be 9.31, be greater than 1.5 of CP2010 requirement,, theoretical cam curve is minimum is 4572; Therefore this experiment condition can meet the requirement detecting piperacillin sodium injection sulbactam related substance, detects the impurity in avocin and sulbactam two kinds source simultaneously.
Embodiment 3: the assay method of piperacillin sodium injection sulbactam related substance
Detect piperacillin sodium injection sulbactam related substance
1. instrument and condition
High performance liquid chromatograph: Agilent1200
Chromatographic column: WaterssymmetryC18 (250mm*4.6mm, 5um)
Mobile phase: A phase is methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=550:366:82:2,
B phase is water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=447:100:3
The pH:6.5 of mobile phase
Flow velocity: 0.5ml/min
Determined wavelength: 254nm
Column temperature: 35 DEG C
Sampling volume: 20ul
Condition of gradient elution is as following table:
2. solution preparation
Mixed solvent: mobile phase A and Mobile phase B mix in 5:95 ratio;
Need testing solution: get piperacillin sodium injection sulbactam (manufacturing enterprise: Xiangbei Welman Pharmaceutical Co., Ltd., specification 2:1) 100mg is placed in 10ml volumetric flask, and dissolve with above-mentioned mixed solvent, be diluted to scale, shake up, as need testing solution;
3. get above-mentioned need testing solution sample introduction, obtain collection of illustrative plates as Fig. 3 and table 3;
Table 3. piperacillin sodium injection sulbactam related substance testing result:
Conclusion: from Fig. 3 and table 3 draw the degree of separation of (2S)-2-amino-3-methyl-3-sulfinic acid base butyric acid, sulbactam, Piperacillin penicilloic acid and Piperacillin minimum be 9.39, be greater than 1.5 of pharmacopeia CP2010 requirement,, theoretical cam curve is minimum is 10893; Therefore this experiment condition can meet the requirement detecting piperacillin sodium injection sulbactam related substance, detects the impurity in avocin and sulbactam two kinds source simultaneously.
Embodiment 4(comparative example 1): CP2010/USP32 measures avocin related substance method and measures piperacillin sodium injection sulbactam related substance
1. instrument and condition
High performance liquid chromatograph: Agilent1200
Chromatographic column: AgilentXDB-C18 (250mm*4.6mm, 5um)
Mobile phase: methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=450:447:100:3,
The pH:5.5 of mobile phase
Flow velocity: 1.0ml/min
Determined wavelength: 220nm
Column temperature: room temperature
Sampling volume: 10ul
Isocratic elution
2. solution preparation
Need testing solution: get piperacillin sodium injection sulbactam (manufacturing enterprise: Xiangbei Welman Pharmaceutical Co., Ltd., specification 2:1) 100mg and be placed in 10ml volumetric flask, dissolves with mobile phase, is diluted to scale, shakes up, as need testing solution;
3. get above-mentioned need testing solution sample introduction, obtain collection of illustrative plates as Fig. 4; This kind of method is used to detect piperacillin sodium injection sulbactam, in isocratic condition, organic phase proportion is very large, but sulbactam and related substance polarity larger, at 2-4min, several material do not had wash-out with a grain of salt substantially, each material effectively can not be separated, fail to reach the object of this experiment, be not suitable for the detection of compound piperacillin-sulbactam sodium related substance.
Embodiment 5(comparative example 2): CP2010/BP2009 measures sulbactam related substance method and measures piperacillin sodium injection sulbactam related substance
1. instrument and condition
High performance liquid chromatograph: Agilent1200
Chromatographic column: AgilentXDB-C18 (250mm*4.6mm, 5um)
Mobile phase: A phase: 5.44g/l potassium dihydrogen phosphate (with 1mol/l phosphoric acid adjust pH to 4.0); B phase: acetonitrile
Flow velocity: 1.0ml/min
Determined wavelength: 215nm
Column temperature: room temperature
Sampling volume: 10ul
Condition of gradient elution is as following table:
2. solution preparation
Need testing solution: get piperacillin sodium injection sulbactam (manufacturing enterprise: Xiangbei Welman Pharmaceutical Co., Ltd., specification 2:1) 100mg and be placed in 10ml volumetric flask, dissolves with mobile phase, is diluted to scale, shakes up, as need testing solution;
3. get above-mentioned need testing solution sample introduction, obtain collection of illustrative plates as Fig. 5; The gradient elution time that this detection method uses is 13min, high organic phase elution time only about 1min, due to avocin and related substance polarity less, retention time is longer, and the material that this experiment will detect is more, avocin and impurity peaks thereof do not detected, fail to reach analysis purpose, be unsuitable for detecting related substance in piperacillin sodium injection sulbactam.
From the comparative descriptions of above-described embodiment and comparative example, detection method is accurate, easy and simple to handle, favorable reproducibility, highly sensitive, fully can meet the testing requirement of related substance in piperacillin sodium injection sulbactam, detect the impurity in avocin and sulbactam two kinds source simultaneously, ensure product quality.
Claims (3)
1. detect a method for related substance in piperacillin sodium injection sulbactam, it is characterized in that, the method comprises the following steps:
(1) get piperacillin sodium injection sulbactam, dissolve with mixed solvent, make 30mg/ml, as need testing solution;
Described mixed solvent is mobile phase A and Mobile phase B mixes in 5:95 ratio V/V;
Described mobile phase: A phase is methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=550:366:82:2V/V;
B phase is water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=447:100:3V/V;
The pH:4.5-6.5 of mobile phase A phase and B phase;
(2) adopt the reference substance solution of need testing solution, own control solution and impurity in HPLC difference determination step (1), chromatographic condition is as follows:
Chromatographic column: octadecylsilane chemically bonded silica is the chromatographic column of filling agent;
Mobile phase: A phase is methyl alcohol: water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=550:366:82:2;
B phase is water: 0.2mol/l sodium dihydrogen phosphate: 10% tetrabutylammonium solution=447:100:3;
The pH:4.5-6.5 of mobile phase;
Flow velocity: 0.5-1.5ml/min;
Determined wavelength: 220-254nm;
Column temperature: 20-35 DEG C;
Sample size: 10-20ul; Condition of gradient elution is as follows:
Time minA%B%
0.00595
5.00-10.0035-5565-45
15.00-30.0035-5565-45
40.00-45.0090-1000-10
46.00-50.0090-1000-10
51.00-56.00595
60.00595
。
2. detect the method for related substance in piperacillin sodium injection sulbactam according to claim 1, it is characterized in that, the pH of described step (1) mobile phase A phase and B phase is 5.5.
3. detect the method for related substance in piperacillin sodium injection sulbactam according to claim 1, it is characterized in that, described step (2); The pH of mobile phase is 5.5; The flow velocity of mobile phase is 1.0ml/min; Determined wavelength is 220nm; Column temperature is 30 DEG C; Sample size is 10ul;
Elution requirement is:
Time minA%B%
0.00595
10.004555
20.004555
45.001000
50.001000
51.00595
60.00595
。
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| CN104530039B (en) * | 2014-12-26 | 2017-01-18 | 江西富祥药业股份有限公司 | Method for preparing piperacillin impurity C |
| CN105067719B (en) * | 2015-07-20 | 2017-11-14 | 陈汝红 | The HPLC determination methods of three components in the triple mycins of injection |
| CN105911193B (en) * | 2016-06-17 | 2018-08-07 | 苏州二叶制药有限公司 | A kind of related substance detecting method of piperacillin sodium injection sulbactam |
| CN108107120B (en) * | 2017-12-12 | 2020-12-01 | 山东鑫泉医药有限公司 | Method for measuring intermediate product 6, 6-dibromo penicillanic acid by adopting high performance liquid chromatography |
| CN111060621B (en) * | 2019-12-20 | 2022-05-03 | 北京悦康科创医药科技股份有限公司 | Method for detecting cefoperazone sodium and sulbactam sodium related substances for injection |
| CN112611822B (en) * | 2020-12-31 | 2022-09-02 | 武汉九州钰民医药科技有限公司 | Detection method and application of cefoperazone sodium and sulbactam sodium related substances |
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| RP-HPLC法测定注射用哌拉西林钠/舒巴坦钠的含量;宋喆 等;《中国药科大学学报》;20031231;第34卷(第1期);第32页右栏，第34页左栏 * |
| 哌拉西林钠舒巴坦钠粉针剂的质量标准研究;吴继平 等;《广州化工》;20091231;第37卷(第5期);全文 * |
| 注射用哌拉西林钠舒巴坦钠HPLC法含量测定;裴宜军 等;《中国医学工程杂志》;20031231;第11卷(第6期);全文 * |
| 注射用哌拉西林钠舒巴坦钠含量测定方法探讨;汤艳群 等;《今日药学》;20130831;第23卷(第8期);全文 * |
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