CN103645252A - Detection method for residual solvent in tilmicosin phosphate - Google Patents
Detection method for residual solvent in tilmicosin phosphate Download PDFInfo
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- CN103645252A CN103645252A CN201310576354.6A CN201310576354A CN103645252A CN 103645252 A CN103645252 A CN 103645252A CN 201310576354 A CN201310576354 A CN 201310576354A CN 103645252 A CN103645252 A CN 103645252A
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Abstract
A detection method for a residual solvent in tilmicosin phosphate comprises: preparing a reference substance solution, preparing a to-be-detected sample solution, employing a gas chromatography method, injecting the reference substance solution and the to-be-detected sample solution into a gas chromatograph by a headspace sampling manner, and calculating the residual quantity according to an external standard method. Through optimization of chromatographic conditions and the tests on preparation methods of the to-be-detected sample and the reference substance, a gas chromatograph method is established for detecting residues such as butyl acetate and n-butanol possibly existing in tilmicosin phosphate; through optimization of the chromatographic separation system, the detection method for the residual solvent in the veterinary drug tilmicosin phosphate; methodological verification tests show that the established method is high in accuracy, strong in specificity and good in reproducibility; and by controlling the content of the residual solvent in the veterinary drug tilmicosin phosphate, the safety of the veterinary drug tilmicosin phosphate is guaranteed, and thus infectious diseases of animals such as cattle, goat, sheep, cow, pig, chicken and the like are relatively effectively controlled.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to the detection method of residual solvent in a kind of phosphoric acid Tilmicosin.
Background technology
Tilmicosin is a kind of novel macrolide antibiotic of animal specific, and the clinical infectious diseases such as ox, pig, chicken, sheep, goat, rabbit that are mainly used in, especially for livestock and birds respiratory disease, and obtain significant curative effect.This medical instrument has the features such as antibacterial activity is strong, Pharmacokinetic Characteristics is good, consumption is few, toxicity is little.Clinical practice shows: Tilmicosin is a kind of novel veterinary drug safely and effectively, has broad application prospects.
Tilmicosin has the similar broad spectrum antibiotic activity of same tylosin, gram-positive bacteria and some Gram-negative bacteria, Mycoplasma, conveyor screw etc. are all had to inhibiting effect, Actinobacillus pleuropneumoniae, Pasteurella and Mycoplasma are had to the antibacterial activity stronger than tylosin.The reports such as Inamoto, Tilmicosin (TMS), aureomycin (CTC), Thiamphenicol (TP) and tylosin (TS) between Japan 1980～1989 years from the antibacterial actions of the isolated 61 strain pasteurella multocida of pig pneumonia damaging part and 35 strain Actinobacillus pleuropneumoniaes, most of bacterial strains are responsive to TMS, CTC, TP.CTC and TP have inhibiting effect to 51 strains (83.6%) and 46 strains (75.4%) pasteurella multocida respectively when 3.13 μ g/ml and 0.78 μ g/ml.TS is lower to the antibacterial activity of almost all strains, MIC >=6.25 μ g/ml.MIC >=1.56 μ the g/ml of TMS to 23 strains (37.7%) pasteurella multocida, but when 3.13 μ g/ml, TP and TMS can suppress respectively 32 strains (91.4%) and 33 strains (94.3%) Actinobacillus, visible as same Macrocyclolactone lactone kind medicine, tylosin to the antibacterial activity of two kinds of bacteriums all not as good as Tilmicosin.The 515 strain pathogenic bacteria that the Salmon SADeng Yongcong U.S., Canada are separated to are measured the susceptibility of 9 kinds of medicines such as Ceftiofur, Enrofloxacin, erythromycin, sulfadimidine, spectinomycin, lincomycin, sulphadiazine/TMP, ampicillin and Tilmicosin.Found that, what antibacterial action was the strongest is Enrofloxacin and Ceftiofur, and Tilmicosin is medium to Pasteurella and Actinobacillus pleuropneumoniae activity.Tilmicosin shows stronger antibacterial activity in vitro to chicken Mycoplasma.Jordan etc. have reported Tilmicosin and the external MIC value of tylosin to poultry 6 strain mycoplasma gallisepticums and 3 strain synovia Mycoplasmas.Tilmicosin is respectively the MIC value of 6 strain mycoplasma gallisepticums: < 0.0125,0.0025,0.0025, > 12.5,0.004,0.1,0.0125,0.006 and 0.025 μ g/ml; The MIC value of tylosin is respectively: < 0.0125,0.02,0.02,3.2,0.016,0.8,0.0125,0.025 and 0.025 μ g/ml.The application Tilmicosins such as Ziv carry out MIC-90 mensuration to the 112 strain staphylococcus aureuses from mastitis for milk cows separation and other pathogenic bacteria.Result Tilmicosin is all very sensitive to mammitis staphylococcus aureus and streptococcus, wherein to micrococcus scarlatinae activity the strongest (MIC-90 is 0.04 μ g/ml).Tilmicosin can suppress other Gram-positive mammitis pathogenic bacteria of 90.8% when being less than 3.12 μ g/ml.
In sum, Tilmicosin is as a kind of newer macrolide antibiotics, the antibacterial activity that it is stronger and superior pharmacokinetic characteristic, make to play an important role aspect the preventing and treating of diseases such as pneumonia, pasteurellosis and mammitis that it causes at livestock and poultry caused by sensitive bacteria.Therefore, set up the quality control system of phosphoric acid Tilmicosin, guarantee that its product quality just has very actual meaning.
In the building-up process of phosphoric acid Tilmicosin, use peracetic acid butyl ester and normal butyl alcohol, the residual quality that not only reduces product of these solvents, can bring impact to the security of medicine simultaneously, but primary standard is not measured these two solvents, we adopt vapor-phase chromatography to set up the detection method of butyl acetate, normal butyl alcohol by test for this reason, and stipulate rational limit, to guarantee the security of phosphoric acid Tilmicosin.
Summary of the invention
Object of the present invention is just to provide the detection method of residual solvent in a kind of phosphoric acid Tilmicosin.
The present invention adopts following technical proposals to realize:
A detection method for residual solvent in phosphoric acid Tilmicosin, is characterized in that adopting vapor-phase chromatography, in the mode of headspace sampling, detects.
Described vapor-phase chromatography testing process is:
1) preparation of reference substance solution: precision takes butyl acetate and normal butyl alcohol reference substance is appropriate, adds water and makes every 1ml respectively containing the solution of butyl acetate, each 50 μ g of normal butyl alcohol, gets in 10ml top set empty bottle, seals;
2) preparation of need testing solution: get phosphoric acid Tilmicosin sample 0.25g, accurately weighed, put in 25ml volumetric flask, be dissolved in water and be diluted to scale, shake up, precision measures in 10ml top set empty bottle, seals;
3) measure: in the mode of headspace sampling, by above-mentioned reference substance solution and need testing solution inject gas chromatograph, according to external standard method, calculate residual quantity,
Wherein chromatographic condition is: take polyglycol as the fixing Rtx-WAX capillary column of phase (column length 30m, internal diameter 0.53mm, thickness 1.0 μ m), column temperature is constant temperature: 30～60 ℃; With flame ionization ditector, detect 240～260 ℃ of detector temperatures; 200 ℃ of injector temperatures; Post flow 1.0～2.0ml/min; Carrier gas: high pure nitrogen;
Head space condition: 80 ℃ of heating 20～40min of vaporizer temperature, sample size 1ml.The detection method of residual solvent in phosphoric acid Tilmicosin of the present invention, process of the test is found: two kinds of solvents be take water as solvent, direct injected, cause water residual in chromatographic column, the test accuracy and the peak shape that affect the later stage adopt headspace sampling for this reason, have effectively solved the problems referred to above; Constant Temperature Detection is simple, easy to operate.The residue butyl acetate that may exist in phosphoric acid Tilmicosin, the gas chromatography analysis method of normal butyl alcohol after optimum detection method, have been set up; And newly-established detection method is verified.
The result shows: the average recovery rate of accuracy test is: 101.8%, 95.48%, and relative standard deviation RSD:2.20%, 1.25%; The RSD of precision test is respectively 1.69%, 1.24%; Linear relationship is good, related coefficient γ=0.9997,0.9998; Specificity test is investigated without negative and is disturbed.Method accuracy that evidence is set up is high, specificity is strong, reappearance is good, by the control to residual solvent amount in veterinary drug phosphoric acid Tilmicosin, guarantee its security, thus the animal infectious diseases such as more effective control ox, goat, sheep, milk cow, pig, chicken.
Accompanying drawing explanation
Fig. 1 is ethyl acetate canonical plotting;
Fig. 2 is normal butyl alcohol canonical plotting.
Embodiment
Sample title: phosphoric acid Tilmicosin, (source: Ningxia Tairui Pharmaceutical Co., Ltd.).
Instrument: Shimadzu GC-2014 gas chromatograph
Chromatographic condition: chromatographic column: take polyglycol (PEG) as the fixing Rtx-WAX capillary column of phase (column length 30m, internal diameter 0.53mm, thickness 1.0 μ m), column temperature is constant temperature: 30～60 ℃; With flame ionization ditector, detect 240～260 ℃ of detector temperatures; 200 ℃ of injector temperatures; Post flow 1.0～2.0ml/min; Carrier gas: high pure nitrogen; Head space condition: 80 ℃ of heating 20～40min of vaporizer temperature, sample size 1ml.
The preparation of reference substance solution: precision takes butyl acetate, normal butyl alcohol reference substance is appropriate, adds water and makes every 1ml respectively containing the solution of butyl acetate, each 50 μ g of normal butyl alcohol, gets in 10ml top set empty bottle, seals 80 ℃ of heating 20～40min, headspace sampling 1ml.
The preparation method of need testing solution: get the about 0.25g of this product, accurately weighed, put in 25ml volumetric flask, be dissolved in water and be diluted to scale, shake up, precision measures in 10ml top set empty bottle, seals 80 ℃ of heating 20～40min, headspace sampling 1ml.
Assay: adopt the mode of headspace sampling to be injected in gas chromatograph above-mentioned reference substance solution and need testing solution, adopt external standard method to calculate content by the typical curve of drawing.In the present invention, in Tilmicosin, containing butyl acetate, 5000ppm must not be greater than, containing normal butyl alcohol, 5000ppm must not be greater than.
The peak area that in formula, Ax is need testing solution;
Ar is the peak area of reference substance solution;
Cr is the concentration of reference substance solution;
Cx is the concentration of need testing solution.
Precision: get need testing solution under assay item, repeat sample introduction 5 times, the peak area RSD of result ethyl acetate and normal butyl alcohol is respectively 1.69%, 1.24%, repeatability good (in Table 1).
Table 1 ethyl acetate, Precision test result table
Linear test: precision takes ethyl acetate, normal butyl alcohol reference substance is appropriate, water is made every 1ml containing the stock solution of 60 μ g/ml, and precision measures above-mentioned storing solution 1.0,4.0,6.0,8.0,10.0ml respectively, put in 10ml measuring bottle, be diluted with water to scale, shake up, obtain.Sample introduction, take peak area as ordinate in accordance with the law, and solution concentration is horizontal ordinate, calculates regression equation and is respectively y=328491x-2E+06 r=0.9997, y=3E-05x+1.4492 r=0.9998.Test findings shows, ethyl acetate, normal butyl alcohol, within the scope of 6.0～60 μ g/ml, are good linear relationship.Measurement result is in Table 2, and linear relationship curve map is shown in Fig. 1.
Table 2 ethyl acetate, normal butyl alcohol are measured the range of linearity
Recovery test: phosphoric acid Tilmicosin test sample (our company's production of getting known content, lot number G811130705, ethyl acetate, normal butyl alcohol all do not detect) 9 parts, each 0.25g, accurately weighed, respectively according to established the limits 80%, 100%, 120% adds ethyl acetate (1) reference substance solution (50.25 μ g/ml), normal butyl alcohol (2) reference substance solution (51.8 μ g/ml) 0.8ml, 1.0ml, 1.2ml, according to the extracting method under determination method item and determination method, extract and measure, result average recovery rate is respectively: 101.80%, RSD:2.20%; 95.48%, RSD:1.25% (in Table 3).
Table 3: ethyl acetate accuracy test result
Claims (2)
1. a detection method for residual solvent in phosphoric acid Tilmicosin, is characterized in that adopting vapor-phase chromatography, in the mode of headspace sampling, detects.
2. according to the detection method of residual solvent in phosphoric acid Tilmicosin claimed in claim 1, it is characterized in that described vapor-phase chromatography testing process is:
1) preparation of reference substance solution: precision takes butyl acetate and normal butyl alcohol reference substance is appropriate, adds water and makes every 1ml respectively containing the solution of butyl acetate, each 50 g of normal butyl alcohol, gets in 10ml top set empty bottle, seals;
2) preparation of need testing solution: get phosphoric acid Tilmicosin sample 0.25g, accurately weighed, put in 25ml volumetric flask, be dissolved in water and be diluted to scale, shake up, precision measures in 10ml top set empty bottle, seals;
3) measure: in the mode of headspace sampling, by above-mentioned reference substance solution and need testing solution inject gas chromatograph, according to external standard method, calculate residual quantity,
Wherein chromatographic condition is: take polyglycol as the fixing Rtx-WAX capillary column of phase (column length 30m, internal diameter 0.53mm, thickness 1.0 m), column temperature is constant temperature: 30～60
oc; With flame ionization ditector, detect 240～260 ℃ of detector temperatures; 200 ℃ of injector temperatures; Post flow 1.0～2.0ml/min; Carrier gas: high pure nitrogen;
Head space condition: 80 ℃ of heating 20～40min of vaporizer temperature, sample size 1ml.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103926359A (en) * | 2014-03-24 | 2014-07-16 | 上海新华联制药有限公司 | Method for measuring residual solvent in bulk drug mifepristone |
| CN105806968A (en) * | 2014-12-31 | 2016-07-27 | 江苏万邦生化医药股份有限公司 | Gas chromatography method for simultaneously detecting n-heptane, isooctane, ethyl acetate and isopropanol and use thereof |
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| CN102998380A (en) * | 2012-10-15 | 2013-03-27 | 上海谱尼测试技术有限公司 | Method for detecting 21 volatile organic compounds (VOC) in tobacco packing box |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103926359A (en) * | 2014-03-24 | 2014-07-16 | 上海新华联制药有限公司 | Method for measuring residual solvent in bulk drug mifepristone |
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| CN105806968A (en) * | 2014-12-31 | 2016-07-27 | 江苏万邦生化医药股份有限公司 | Gas chromatography method for simultaneously detecting n-heptane, isooctane, ethyl acetate and isopropanol and use thereof |
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