CN114414716A - Detection method and application of triethylamine and N, N-diethylaniline in ceftazidime - Google Patents
Detection method and application of triethylamine and N, N-diethylaniline in ceftazidime Download PDFInfo
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 title claims abstract description 213
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 title claims abstract description 138
- 229960000484 ceftazidime Drugs 0.000 title claims abstract description 42
- 238000001514 detection method Methods 0.000 title claims abstract description 24
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 title claims abstract 14
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000012085 test solution Substances 0.000 claims abstract description 18
- 238000002347 injection Methods 0.000 claims abstract description 7
- 239000007924 injection Substances 0.000 claims abstract description 7
- 238000010812 external standard method Methods 0.000 claims abstract description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 claims abstract description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 238000011002 quantification Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 65
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 58
- 239000011550 stock solution Substances 0.000 description 34
- 238000012360 testing method Methods 0.000 description 34
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 28
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 27
- 238000011084 recovery Methods 0.000 description 19
- 239000013557 residual solvent Substances 0.000 description 18
- 239000012467 final product Substances 0.000 description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 description 13
- 239000011259 mixed solution Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 239000007789 gas Substances 0.000 description 10
- 238000012795 verification Methods 0.000 description 10
- 238000007865 diluting Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000012088 reference solution Substances 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- -1 N-diethylaniline Chemical compound 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000007813 chromatographic assay Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
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Abstract
The invention discloses a detection method and application of triethylamine and N, N-diethylaniline in ceftazidime. The detection method disclosed by the invention comprises the following steps of: injecting a test solution containing ceftazidime into a gas chromatograph by adopting a direct sample injection mode, recording a chromatogram, and calculating the content according to an external standard method; wherein, the chromatographic detection conditions are as follows: a chromatographic column: a capillary column or a capillary chromatographic column with equivalent efficiency by taking the modified dimethyl polysiloxane as a stationary liquid; column temperature is programmed temperature rise: the initial temperature was 95-105 deg.C for 3 minutes, and the temperature was raised to 220 deg.C at a rate of 10 deg.C per minute for 10 minutes. The method has good specificity and system adaptability, extremely low detection limit and quantification limit, good linearity and good accuracy.
Description
Technical Field
The invention relates to a detection method and application of triethylamine and N, N-diethylaniline in ceftazidime.
Background
Ceftazidime is a semi-synthetic third-generation cephalosporin antibiotic, belongs to beta-lactam antibiotics, and has good antibacterial action on gram-negative bacteria and gram-positive bacteria.
The ceftazidime (containing sodium carbonate) raw material medicine is mixed powder of ceftazidime and anhydrous sodium carbonate, and an organic solvent is used during production. The content thereof should be controlled within a limited range during the production process in consideration of the harm of the organic solvent to human bodies and the possibility of the solvent used remaining in the product.
The united states pharmacopeia 43 edition, european pharmacopeia 10.0 edition, british pharmacopeia 2020 edition and chinese pharmacopeia 2020 only collect the quality standards of ceftazidime, but do not collect the detection methods and standards of residual solvents. In order to detect the residual solvent in ceftazidime more completely, a method for detecting the residual solvent in the ceftazidime (containing sodium carbonate) bulk drug needs to be established.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art that the types of residual solvents in ceftazidime are limited, and provides a detection method and application of triethylamine and N, N-diethylaniline in ceftazidime. The method has good specificity and system adaptability, extremely low detection limit and quantification limit, good linearity and good accuracy.
The invention provides a method for detecting triethylamine and N, N-diethylaniline in ceftazidime, which comprises the following steps: injecting a test solution containing ceftazidime into a gas chromatograph by adopting a direct sample injection mode, recording a chromatogram, and calculating the content according to an external standard method;
wherein, the chromatographic detection conditions are as follows:
a chromatographic column: a capillary column or a capillary chromatographic column with equivalent efficiency by taking the modified dimethyl polysiloxane as a stationary liquid;
column temperature is programmed temperature rise: the initial temperature was 95-105 deg.C for 3 minutes, and the temperature was raised to 220 deg.C at a rate of 10 deg.C per minute for 10 minutes.
In the present invention, the method for preparing the test solution preferably comprises the following steps: taking 1.0g of ceftazidime (sodium carbonate-containing) raw material medicine (Qiluatan pharmacy Co., Ltd.; batch number: 801MJ81JD3), precisely weighing, placing in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute to scale, shaking uniformly, filtering, and taking a subsequent filtrate to obtain the ceftazidime.
In the method for detecting triethylamine and N, N-diethylaniline in ceftazidime, a reference substance solution and a blank solvent can be added in the chromatographic detection process. The preparation method of the control solution preferably comprises the following steps: taking a proper amount of triethylamine and N, N-diethylaniline, precisely weighing, adding dimethyl sulfoxide to dissolve and quantitatively dilute to prepare a mixed solution containing about 500 mu g of triethylamine and 5 mu g of N, N-diethylaniline in every lmL, and thus obtaining the product.
In the present invention, the blank solvent is typically dimethyl sulfoxide.
In one embodiment, the column is preferably a CP-Volamine or equivalent performance capillary column. The size of the chromatographic column is preferably 30m × 0.32mm, 5.0 μm.
In one embodiment, the starting temperature is preferably 100 ℃.
In one embodiment, the temperature of the sample inlet is preferably 225 ℃ to 235 ℃, for example, 230 ℃ in the detection conditions of the chromatography.
In one embodiment, the temperature of the detector in the detection condition of the chromatography is preferably 245-255 ℃, for example 250 ℃.
In one embodiment, the chromatographic assay conditions preferably comprise a column flow rate of 0.9 to 1.1mL/min, e.g., 1.0 mL/min.
In one embodiment, the gas chromatograph has model number Shimadzu GC-2014C.
In one aspect, the detectors are all hydrogen flame ionization detectors.
The external standard method calculates by peak area:
calculating the formula:
in the formula: at is the peak area of each residual solvent in the chromatogram of the test solution;
as is the peak area of each residual solvent in the chromatogram of the reference solution;
cs is the concentration of each residual solvent in the reference solution, mg/mL;
ct is the concentration of the test solution, mg/mL.
The invention also provides application of the detection method of triethylamine and N, N-diethylaniline in ceftazidime in detection of the content of triethylamine and N, N-diethylaniline in ceftazidime bulk drugs or preparations.
In the present invention, the term "external standard method" refers to a method of quantifying the amount of a component to be measured in a sample by comparing the response signals of the component to be measured with those of the control substance using a pure product of the component to be measured as the control substance.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
1) the method can be used for simply, rapidly and accurately detecting the residual quantity of triethylamine and N, N-diethylaniline in ceftazidime (sodium carbonate) simultaneously.
2) The invention has good specificity, and no interference peak is generated near the peak position of the target peak in the blank solution atlas.
3) The invention has good system adaptability, and the RSD and the tailing factor of the peak area both meet the requirements.
4) The invention has extremely low detection limit and quantification limit.
5) The invention has good linearity.
6) The method has good accuracy, the recovery rate of triethylamine is 103.02-107.80%, the average value is 106.37%, and the RSD value is 1.61%; the recovery rate of the N, N-diethylaniline is 88.67-117.34%, the average value is 101.46%, and the RSD value is 8.38%.
Drawings
FIG. 1 shows GC spectrums of blank solvents of triethylamine and N, N-diethylaniline in residual solvents of ceftazidime (containing sodium carbonate).
FIG. 2 is a GC spectrum of a control solution of ceftazidime (containing sodium carbonate) residual solvent triethylamine and N, N-diethylaniline
FIG. 3 is a GC spectrum of a test solution of ceftazidime (containing sodium carbonate) residual solvent triethylamine and N, N-diethylaniline.
FIG. 4 is a GC spectrum of a recovery rate solution of triethylamine and N, N-diethylaniline which are residual solvents of ceftazidime (containing sodium carbonate).
FIG. 5 is a GC spectrum of a reference solution for a ceftazidime (sodium carbonate-containing) residual solvent triethylamine and N, N-diethylaniline system applicability test
FIG. 6 is a GC spectrum of a mixed solution for a system applicability test of a ceftazidime (sodium carbonate-containing) residual solvent triethylamine and N, N-diethylaniline
Fig. 7 is a linear relationship diagram of residual solvent triethylamine of ceftazidime (containing sodium carbonate).
FIG. 8 is a linear relationship diagram of residual solvent N, N-diethylaniline of ceftazidime (containing sodium carbonate).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
And (3) testing the sample: ceftazidime (containing sodium carbonate) bulk drug (ziluatan pharmaceuticals ltd.; lot 801MJ81JD 3). The reagents in the invention are all analytically pure.
Example 1
(1) Chromatographic conditions are as follows:
the instrument comprises the following steps: a gas chromatograph (Shimadzu GC-2014C), the detector being a hydrogen Flame Ionization Detector (FID);
a chromatographic column: CP-Volamine, 30m × 0.32mm, 5.0 μm or equivalent performance capillary chromatography column;
column temperature: the initial temperature is 100 ℃, the temperature is maintained for 3 minutes, the temperature is raised to 220 ℃ at the rate of 10 ℃ per minute, and the temperature is maintained for 10 minutes;
the temperature of a sample inlet is 230 ℃; the temperature of the detector is 250 ℃;
the column flow rate was 1.0mL/min
Blank solvent: dimethyl sulfoxide (DMSO).
(2) Solution preparation: the solution formulation process is shown in table 1.
TABLE 1 preparation of triethylamine and N, N-diethylaniline solutions
The specific operation is as follows:
stock solution of N, N-diethylaniline: taking 50mg of N, N-diethylaniline, placing the N, N-diethylaniline into a 100mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute the N, N-diethylaniline to a scale, and shaking up the solution to obtain the compound preparation;
reference stock solution: taking 2mL of 100mg triethylamine and N, N-diethylaniline stock solution, placing the stock solution in a 100mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute the stock solution to a scale, and shaking up the solution to obtain the product;
control solution: taking 5mL of the reference stock solution, placing the reference stock solution in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute the reference stock solution to a scale, and shaking up the reference stock solution to obtain the reagent;
test solution: taking 1.0g of a sample, precisely weighing, placing in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute to a scale, shaking up, filtering, and taking a subsequent filtrate to obtain the final product;
100% recovery solution: taking 1.0g of a sample and 5mL of a reference stock solution, placing the samples and the reference stock solution into a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute the samples to a scale, and shaking up the samples to obtain the reagent;
(3) and (3) determination: the filtered solutions were measured in an amount of 1. mu.L each according to the above gas chromatography conditions, and injected into a gas chromatograph, and chromatograms were recorded (see FIGS. 1 to 4 for results).
Calculating the formula:
in the formula: at is the peak area of each residual solvent in the chromatogram of the test solution;
as is the peak area of each residual solvent in the chromatogram of the reference solution;
cs is the concentration of each residual solvent in the reference solution, mg/mL;
ct is the concentration of the test solution, mg/mL.
And (3) judging standard: calculated by peak area according to an external standard method, the residual quantity of triethylamine is not more than 0.5 percent, and the residual quantity of N, N-diethylaniline is not more than 0.005 percent.
The results of the chromatogram analysis are shown in table 2:
TABLE 2 chromatogram analysis results
| Composition (I) | Retention time (min) | Degree of separation | Tailing factor | Number of theoretical plates | Recovery (%) |
| Triethylamine | 6.899 | / | 1.03 | 49776 | 117.96、110.88 |
| N, N-diethylaniline | 18.160 | 78.49 | 0.98 | 196112 | 89.52、93.27 |
And (4) conclusion: dimethyl sulfoxide and ceftazidime do not interfere with the assay; the separation degrees of triethylamine and N, N-diethylaniline in the control solution are 78.49, the tailing factors are 1.03 and 0.98 respectively, and the number of theoretical plates is more than 5000. The recovery rate is 80-120%, and the accuracy is good.
Verification example 1: specificity test
(1) The test process comprises the following steps: the solution preparation process is shown in Table 3 (preparation of specific solution), precisely measuring 1 μ L, injecting into gas chromatograph, and recording chromatogram (the result is shown in FIG. 5 and FIG. 6).
TABLE 3 preparation of the specialty solutions
(2) Results and conclusions: the control solution profile data are shown in Table 4 and the mixed solution profile data are shown in Table 5.
TABLE 4 control solution profile data
Table 5 mixed solution profile data
TABLE 6 specificity results
Note: the specificity results were derived from the mixed solution chromatogram (see fig. 6).
And (4) conclusion: the blank solvent and other solvents have no interference to the determination of triethylamine and N, N-diethylaniline, and the triethylamine peak, the N, N-diethylaniline peak and the adjacent peak are well separated, and the specificity is good.
Verification example 2: linearity and range
(1) The test process comprises the following steps:
the preparation process of the linear solution is shown in table 7 (preparation process of linear solution of triethylamine and N, N-diethylaniline), 1. mu.L of each linear solution is precisely measured and respectively injected into a gas chromatograph, and a chromatogram is recorded. The 30% linear solution was used as the limit of quantitation and as the starting point of linearity, linear regression was performed with the concentration of each solution as the abscissa and the peak area of each solvent as the ordinate (see results in fig. 7 and 8).
TABLE 7 Triethylamine and N, N-diethylaniline Linear solution preparation procedure
| Linear solution | Concentration of triethylamine (. mu.g/mL) | Concentration of N, N-diethylaniline (. mu.g/mL) | Preparation of |
| 30％ | 150.00 | 1.50 | Linear stock solution 3mL → 20mL |
| 40％ | 200.00 | 2.00 | Linear stock solution 2mL → 10mL |
| 60％ | 300.00 | 3.00 | Linear stock solution 3mL → 10mL |
| 80％ | 400.00 | 4.00 | Linear stock solution 4mL → 10mL |
| 100％ | 500.00 | 5.00 | Linear stock solution 5mL → 10mL |
| 160％ | 800.00 | 8.00 | Linear stock solution 8mL → 10mL |
| 200％ | 1000.00 | 10.00 | Linear stock solution |
The specific operation is as follows:
linear stock solutions: taking a proper amount of triethylamine and N, N-diethylaniline, adding dimethyl sulfoxide to dilute into a mixed solution containing 1mg of triethylamine and 0.01mg of N, N-diethylaniline in every 1mL, and shaking up to obtain the compound;
30% linear solution: precisely measuring 3.0mL of linear stock solution, placing in a 20mL measuring flask, diluting to scale with dimethyl sulfoxide, and shaking up to obtain the final product;
40% linear solution: precisely measuring 2.0mL of linear stock solution, placing in a 10mL measuring flask, diluting to scale with dimethyl sulfoxide, and shaking up to obtain the final product;
60% linear solution: precisely measuring 3.0mL of linear stock solution, placing into a 10mL measuring flask, diluting to scale with dimethyl sulfoxide, and shaking up to obtain the final product;
80% linear solution: precisely measuring 4.0mL of linear stock solution, placing in a 10mL measuring flask, diluting to scale with dimethyl sulfoxide, and shaking up to obtain the final product;
100% linear solution: precisely measuring 5.0mL of linear stock solution, placing in a 10mL measuring flask, diluting to scale with dimethyl sulfoxide, and shaking up to obtain the final product;
160% linear solution: precisely measuring 8.0mL of linear stock solution, placing the linear stock solution in a 10mL measuring flask, diluting the linear stock solution to a scale with dimethyl sulfoxide, and shaking up to obtain the product;
200% linear solution: precisely measuring 10.0mL of linear stock solution, and placing in a 10mL measuring flask.
(2) Results and conclusions:
TABLE 8 Triethylamine Linear relationship test results
TABLE 9 Linear relationship test results for N, N-diethylaniline
And (4) conclusion: the concentration of triethylamine is 149.88 mu g/mL-999.20 mu g/mL (30% -200%), the concentration of N, N-diethylaniline is 1.50 mu g/mL-9.99 mu g/mL (30% -200%), and the peak area and the concentration have good linear relation.
Verification example 3: detection limit and quantification limit
(1) The test process comprises the following steps:
precision measurement "verification example 2: linear and Range "linear solutions (limit 30%) with signal to noise ratio (S/N) greater than 10:1 can be used as a limit for quantitation. The quantitative limit is diluted and can be used as a detection limit according to the signal-to-noise ratio (S/N) of more than 3: 1. And continuously injecting samples for 6 times in a quantitative limit, recording peak areas, and calculating an average value and an RSD value.
(2) Results and conclusions:
TABLE 10 results of quantitative limit and detection limit of triethylamine and N, N-diethylaniline
TABLE 11 Triethylamine, N-diethylaniline quantitative limiting System precision results
| Composition (I) | 1 | 2 | 3 | 4 | 5 | 6 | Mean value | RSD(％) |
| Triethylamine | 203956 | 204855 | 199872 | 200868 | 198898 | 198591 | 201173 | 1.32 |
| N, N-diethylaniline | 2417 | 2460 | 2610 | 2439 | 2590 | 2533 | 2508 | 3.25 |
TABLE 12 Triethylamine quantitative limit recovery test results
TABLE 13 quantitative limit recovery test results for N, N-diethylaniline
Note: the quantitative limit recovery rate is prepared under the accuracy term.
And (4) conclusion: the method can effectively measure triethylamine and N, N-diethylaniline, and has extremely low detection limit and quantitative limit.
Verification example 4: precision of the system
(1) The test process comprises the following steps:
a suitable amount of each of triethylamine and N, N-diethylaniline was quantitatively diluted with dimethyl sulfoxide to prepare a solution containing 0.5mg of triethylamine and 5. mu.g of N, N-diethylaniline per 1mL, as a precise solution.
And (4) taking 1 mu L of the precision solution, injecting the precision solution into a gas chromatograph, and recording a chromatogram. And continuously feeding samples for six times, recording peak areas, and calculating an average value and an RSD value.
(2) Test results and conclusions:
TABLE 14 precision results of Triethylamine, N-diethylaniline systems
And (4) conclusion: RSD values of the peak areas of triethylamine and N, N-diethylaniline are 1.00 percent and 3.23 percent respectively, and the system precision is good.
Verification example 5: repeatability of
(1) The test process comprises the following steps:
the solution formulations are shown in table 17 (formulations of accuracy solutions) and the reproducibility was evaluated in terms of "accuracy" for 6 sets of 100% concentration recovery solution measurements.
(2) Test results and conclusions:
TABLE 15 repeatability results for triethylamine, N-diethylaniline
And (4) conclusion: the determination is repeated for 6 times, the RSD values of the results of the triethylamine and the N, N-diethylaniline are respectively 1.55 percent and 8.24 percent, and the repeatability is good.
Verification example 6: reproducibility of
Different laboratories and instruments are used by different experimenters on different dates to prepare solutions according to a repeatability method and evaluate the repeatability by combining the repeatability with the solutions.
TABLE 16 reproducibility of triethylamine, N-diethylaniline results
And (4) conclusion: different laboratories and instruments are used by different experimenters on different dates, and the RSD values of triethylamine and N, N-diethylaniline are respectively 3.80% and 6.14% (N is 12), so that the repeatability is good.
Verification example 7: accuracy of
(1) The test process comprises the following steps:
the preparation process of the accuracy solution is shown in table 17 (preparation of accuracy solution), 1 μ L of the accuracy solution is measured and injected into a gas chromatograph, and the chromatogram is recorded.
TABLE 17 preparation of accuracy solutions
Note: the results of the recovery rate in the quantitative limit are detailed in the quantitative limit and the detection limit.
The specific operation is as follows:
reference stock solution: taking a proper amount of triethylamine and N, N-diethylaniline, precisely weighing, diluting with dimethyl sulfoxide to prepare a mixed solution containing 1mg of triethylamine and 0.01mg of N, N-diethylaniline in 1mL, and shaking up to obtain the compound;
control solution: precisely measuring 5mL of reference stock solution, placing in a 10mL measuring flask, diluting with dimethyl sulfoxide to scale, and shaking;
test solution: taking 1.0g of a sample, precisely weighing, placing in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute to a scale, shaking up, filtering, and taking a subsequent filtrate to obtain the final product;
50% recovery solution: taking 1.0g of a sample and 2.5mL of a reference stock solution, placing in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute to a scale, shaking up, filtering, and taking a subsequent filtrate to obtain the final product; preparing 3 parts in parallel;
100% recovery solution: taking 1.0g of a sample and 5mL of a reference stock solution, placing in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute to a scale, shaking up, filtering, and taking a subsequent filtrate to obtain the final product; preparing 6 parts in parallel;
120% recovery solution: taking 1.0g of a sample and 6mL of a reference stock solution, placing in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute to a scale, shaking up, filtering, and taking a subsequent filtrate to obtain the final product; preparing 3 parts in parallel;
quantitative limit recovery rate solution: taking 1.0g of a sample and 1.5mL of a reference stock solution, placing in a 10mL measuring flask, adding dimethyl sulfoxide to dissolve and dilute to a scale, shaking up, filtering, and taking a subsequent filtrate to obtain the final product; 3 parts are prepared in parallel.
(2) Test results and conclusions:
TABLE 18 Triethylamine recovery test results
TABLE 19 test results for recovery of N, N-diethylaniline
And (4) conclusion: the recovery rate of triethylamine is 103.02% -107.80%, the average value is 106.37%, the RSD value is 1.61%, and the accuracy is good; the recovery rate of the N, N-diethylaniline is 88.67-117.34%, the average value is 101.46%, the RSD value is 8.38%, and the accuracy is good.
Verification example 8: stability of solution
(1) The test process comprises the following steps:
control solution: weighing a proper amount of triethylamine and N, N-diethylaniline, precisely weighing, diluting with dimethyl sulfoxide to obtain a mixed solution containing 0.5mg of triethylamine and 0.005mg of N, N-diethylaniline in each 1mL, and shaking up to obtain the final product.
Test solution: taking 1.0g of a test sample, placing the test sample in a 10mL measuring flask, adding a reference substance solution to dissolve and dilute the test sample to a scale, shaking up, and filtering to obtain the test sample.
Measuring 1 μ L of the above solution, injecting into gas chromatograph, and recording chromatogram. And (4) injecting the reference substance solution and the test solution at intervals, and inspecting the stability of the reference substance solution and the test solution for 56 h.
(2) Test results and conclusions
TABLE 20 control solution stability test results
TABLE 21 test results of stability of test solutions
And (4) conclusion: after the sample is placed at room temperature for 56 hours, the RSD values of the peak areas of triethylamine and N, N-diethylaniline in the reference solution are respectively 2.40 percent and 7.66 percent, the RSD values of the peak areas of triethylamine and N, N-diethylaniline in the test solution are respectively 2.71 percent and 9.94 percent, and the solution stability is good.
Verification example 9: durability of the system
(1) The test process comprises the following steps:
the system durability solution preparation process is shown in table 22 (system durability solution preparation process), 1 μ L was precisely measured and injected into a gas chromatograph, respectively, and the chromatogram was recorded. The factors such as the injection port temperature, the detector temperature, the column flow rate, the column temperature and the like are respectively adjusted, and the variables of the same method test and the investigation are shown in a table 23 (the test conditions and the range of the system durability investigation).
TABLE 22 System durability solution formulation procedure
The specific operation is as follows:
mixing the solution: taking a proper amount of absolute methanol, absolute ethanol, acetone, triethylamine, benzene, N-dimethylformamide, N-diethylaniline, dichloromethane and pyridine, adding dimethyl sulfoxide to dissolve and dilute the mixture to prepare a mixed solution containing 0.3mg of methanol, 0.5mg of ethanol, 0.5mg of acetone, 0.50mg of triethylamine, 0.2 mu g of benzene, 0.088mg of N, N-dimethylformamide, 5 mu g of N, N-diethylaniline, 0.06mg of dichloromethane and 0.02mg of pyridine in each 1mL of the mixture;
system applicability solution: taking 1.0g of a sample, placing the sample in a 10mL measuring flask, adding the mixed solution to dissolve and dilute the sample to a scale, shaking up the sample, and filtering the sample to obtain the test solution;
control solution: taking a proper amount of triethylamine and proper amount of N, N-diethylaniline, adding dimethyl sulfoxide to dissolve and dilute to prepare a mixed solution containing 0.5mg of triethylamine and 5 mu g of N, N-diethylaniline in each 1 mL;
test solution: placing 1.0g of test sample in a 10mL measuring flask, adding the reference solution to dissolve and dilute to scale, shaking up, and filtering to obtain the final product.
TABLE 23 System durability test conditions and ranges
| Factors for investigation | Defined test conditions | Range of durability |
| Initial temperature | 100℃ | 95-105℃ |
| Temperature of detector | 250℃ | 245-255℃ |
| Temperature at sample inlet | 230℃ | 225-235℃ |
| Flow rate of column | 1.0mL/min | 0.9-1.1mL/min |
(2) Test results and conclusions:
TABLE 24 System durability test results
And (4) conclusion: in the range of 225-235 ℃ of the injection port temperature, 245-255 ℃ of the detector temperature, 95-105 ℃ of the column temperature and 0.9-1.1mL/min of the column flow, the solvent is not interfered; the separation degrees of triethylamine peaks, N-diethylaniline peaks and adjacent impurity peaks are all between 6.08 and 10.25; the results of the RSD values of triethylamine and N, N-diethylaniline were 4.87% and 8.59%, respectively, and the durability was good.
Claims (10)
1. A detection method of triethylamine and N, N-diethylaniline in ceftazidime is characterized by comprising the following steps: injecting a test solution containing ceftazidime into a gas chromatograph by adopting a direct sample injection mode, recording a chromatogram, and calculating the content according to an external standard method;
wherein, the chromatographic detection conditions are as follows:
a chromatographic column: a capillary column or a capillary chromatographic column with equivalent efficiency by taking the modified dimethyl polysiloxane as a stationary liquid;
column temperature is programmed temperature rise: the initial temperature was 95-105 deg.C for 3 minutes, and the temperature was raised to 220 deg.C at a rate of 10 deg.C per minute for 10 minutes.
2. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime according to claim 1, wherein the chromatographic column is a CP-Volamine or equivalent performance capillary chromatographic column;
and/or the specification of the chromatographic column is 30m multiplied by 0.32mm and 5.0 mu m.
3. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime according to claim 1 wherein the initial temperature is 100 ℃.
4. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime as claimed in claim 1, wherein the variation range of the injection port temperature is between 225 ℃ and 235 ℃.
5. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime according to claim 4, wherein the injection port temperature is 230 ℃.
6. The method as claimed in claim 1, wherein the temperature of the detector is varied between 245 ℃ and 255 ℃.
7. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime as claimed in claim 6 wherein the detector temperature is 250 ℃.
8. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime according to claim 1 wherein the column flow rate varies from 0.9 to 1.1 mL/min.
9. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime according to claim 8, wherein the column flow rate is 1.0 mL/min.
10. The method for detecting triethylamine and N, N-diethylaniline in ceftazidime according to any one of claims 1-9, for use in detecting the content of triethylamine and N, N-diethylaniline in a ceftazidime drug substance or preparation.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0584797A2 (en) * | 1992-08-24 | 1994-03-02 | Lucky Ltd. | Novel cephalosporin compounds and processes for the preparation thereof |
| JP2007007443A (en) * | 2006-09-12 | 2007-01-18 | Yuyama Manufacturing Co Ltd | Medicament put-out device |
| CN107966506A (en) * | 2017-11-20 | 2018-04-27 | 福州大学 | The detection method of N-ethylaniline content in a kind of Rubber ＆ Rubber Products |
| CN109633046A (en) * | 2019-02-22 | 2019-04-16 | 成都倍特药业有限公司 | A method of detecting dimethylamine from duloxetine hydrochloride |
| CN109725065A (en) * | 2017-10-31 | 2019-05-07 | 中国石油化工股份有限公司 | The analysis method of sulfur alcohol compound in a kind of light oil |
| CN111077259A (en) * | 2018-10-19 | 2020-04-28 | 中国石油化工股份有限公司 | Solid-phase extraction, derivatization, separation and determination method of aniline compounds in gasoline |
| CN111289676A (en) * | 2020-01-20 | 2020-06-16 | 南京林业大学 | Method for detecting residual tert-butylamine in terbutaline sulfate bulk drug |
| WO2020164598A1 (en) * | 2019-02-14 | 2020-08-20 | Dairen Chemical Corporation | Tricyclodecane dimethanol compositions and uses thereof |
| CN111735884A (en) * | 2020-08-04 | 2020-10-02 | 精晶药业股份有限公司 | High performance gas chromatography detection method for triethylamine content in feed liquid |
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0584797A2 (en) * | 1992-08-24 | 1994-03-02 | Lucky Ltd. | Novel cephalosporin compounds and processes for the preparation thereof |
| JP2007007443A (en) * | 2006-09-12 | 2007-01-18 | Yuyama Manufacturing Co Ltd | Medicament put-out device |
| CN109725065A (en) * | 2017-10-31 | 2019-05-07 | 中国石油化工股份有限公司 | The analysis method of sulfur alcohol compound in a kind of light oil |
| CN107966506A (en) * | 2017-11-20 | 2018-04-27 | 福州大学 | The detection method of N-ethylaniline content in a kind of Rubber ＆ Rubber Products |
| CN111077259A (en) * | 2018-10-19 | 2020-04-28 | 中国石油化工股份有限公司 | Solid-phase extraction, derivatization, separation and determination method of aniline compounds in gasoline |
| WO2020164598A1 (en) * | 2019-02-14 | 2020-08-20 | Dairen Chemical Corporation | Tricyclodecane dimethanol compositions and uses thereof |
| CN109633046A (en) * | 2019-02-22 | 2019-04-16 | 成都倍特药业有限公司 | A method of detecting dimethylamine from duloxetine hydrochloride |
| CN111289676A (en) * | 2020-01-20 | 2020-06-16 | 南京林业大学 | Method for detecting residual tert-butylamine in terbutaline sulfate bulk drug |
| CN111735884A (en) * | 2020-08-04 | 2020-10-02 | 精晶药业股份有限公司 | High performance gas chromatography detection method for triethylamine content in feed liquid |
Non-Patent Citations (7)
| Title |
|---|
| DJAVANSHIR DJOZAN: "Application of On-Line Sorbentless Cryogenic Needle Trap Extraction Coupled with GC-FID for Analysis of Some Organic Volatile Impurities in Solid Pharmaceuticals", JOURNAL OF CHROMATOGRAPHIC SCIENCE, vol. 60, no. 4, 23 June 2021 (2021-06-23) * |
| 周志刚;胡高云;刘文;黄本东;: "气相色谱法测定盐酸阿考替胺原料药中的残留溶剂", 中南药学, no. 03 * |
| 周永生;王文昌;顾浩;: "液液萃取-气相色谱-质谱联用技术测定废水中N-甲基甲酰苯胺、N-甲基苯胺和甲酰苯胺", 分析科学学报, no. 06 * |
| 张晓景;王英瑛;李俊;: "毛细管气相色谱法测定螺内酯中8种有机溶剂的残留量", 中国药师, no. 12 * |
| 朱伊婷;陈英杰;夏媛媛;杨沮勤;万丽;: "顶空气相色谱法测定甲磺酸普依司他中三乙胺的残留量", 广东化工, no. 09 * |
| 章为;李文波;李晓燕;王伟姣;谭桂山;: "毛细管气相色谱法测定盐酸莫西沙星中有机溶剂的残留量", 海峡药学, vol. 29, no. 04, pages 61 - 62 * |
| 罗国生: "气相色谱法测定阿莫西林钠中的N, N-二甲基苯胺", 医药导报, vol. 29, no. 8, pages 1084 - 1085 * |
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