CN111380992A - Method for detecting residual quantity of organic solvent in formoterol bulk drug - Google Patents
Method for detecting residual quantity of organic solvent in formoterol bulk drug Download PDFInfo
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- CN111380992A CN111380992A CN202010217829.2A CN202010217829A CN111380992A CN 111380992 A CN111380992 A CN 111380992A CN 202010217829 A CN202010217829 A CN 202010217829A CN 111380992 A CN111380992 A CN 111380992A
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Abstract
The invention relates to a method for detecting residual quantity of organic solvent in formoterol bulk drug, belonging to the technical field of drug analysis. The detection method comprises the following steps: firstly, preparing reference substance and test solution, and then detecting by using a gas chromatography external standard method, wherein the chromatographic conditions are as follows: adopting HP-5 capillary column, hydrogen flame ionization detector, nitrogen as carrier gas, and flow rate of 0.8-1.2 mL/min; the temperature of the sample inlet is 195-minus 205 ℃, and the split ratio is 1: 1; the temperature of the detector is 245-; the heating temperature of the headspace bottle is 100 ℃, the quantitative ring is 110 ℃, the transmission line is 120 ℃, the heating time of the headspace bottle is 30min, and the pressurizing time is 0.2 min. The method has the characteristics of simplicity, convenience, rapidness and accuracy, and can simultaneously detect the residual quantity of 7 organic solvents in formoterol tartrate.
Description
Technical Field
The invention relates to a method for detecting residual quantity of organic solvent in formoterol bulk drug, belonging to the technical field of drug analysis.
Background
Formoterol is a highly effective drug for chronic obstructive pulmonary disease, and can significantly improve the morbidity of asthmatic patients. Formoterol, which has 1000 times higher pharmacological activity in the (R, R) configuration than in the (S, S) configuration, showed less toxicity, and had twice the bronchorelaxing effect as the racemate when used alone. Therefore, the single use of the (R, R) -formoterol, namely the arformoterol can not only enhance the action activity and reduce the use dosage, but also reduce the occurrence of toxic and side effects. In the production process of the bulk drugs of formoterol tartrate and formoterol fumarate, organic solvents such as methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran, toluene and the like are used, and in order to effectively control the product quality and ensure the medication safety, whether the organic solvent residue in formoterol drugs meets the requirements of pharmacopoeia needs to be determined. In the prior art, no report exists on the aspect of simultaneously detecting the organic solvent residue of formoterol fumarate and formoterol tartrate bulk drugs.
Disclosure of Invention
The invention aims to provide a method for detecting the residual quantity of organic solvents in formoterol bulk drug, which has the characteristics of simplicity, rapidness and accuracy and can simultaneously detect the residual quantity of 7 organic solvents in formoterol tartrate.
Technical scheme
A method for detecting residual quantity of organic solvent in formoterol bulk drug, wherein the formoterol comprises formoterol tartrate and formoterol fumarate, and the detection method comprises the following steps:
(1) preparing a reference solution and a test solution:
accurately weighing methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene, placing into a measuring flask, adding a solvent to quantitatively dilute into mixed solution containing 120, 200, 26, 200, 30 and 36 mu g of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene in each 1mL of the mixed solution as a reference solution;
precisely weighing 200mg of formoterol bulk drug, placing the formoterol bulk drug in a 20mL headspace bottle, adding 5.0mL of DMF solvent, sealing and dissolving to obtain a test solution;
(2) and (3) detection:
detecting by using a gas chromatography external standard method, wherein the chromatographic conditions are as follows:
an HP-5 capillary column (30m × 0.32mm × 0.25.25 mu m) is adopted, a hydrogen flame ionization detector is adopted, carrier gas is nitrogen, the flow rate is 0.8-1.2mL/min, the temperature of a sample inlet is 195-plus, the flow split ratio is 1: 1, the temperature of the detector is 245-plus 255 ℃, the flow rate of hydrogen is 30mL/min, the air flow rate is 300mL/min, tail blowing is 25mL/min, the heating temperature of a headspace bottle is 100 ℃, a quantitative ring is 110 ℃, a transmission line is 120 ℃, the heating time of the headspace bottle is 30min, the pressurizing time is 0.2min, the quantitative ring filling time is 0.2min, and the quantitative ring balance time is 0.05 min;
precisely taking 1mL of each of the test solution and the reference solution, respectively injecting into a gas chromatograph, recording the chromatogram, and calculating the content of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene in the formoterol bulk drug by peak area according to an external standard method.
Further, in the step (1), DMF is used as a solvent for preparing the reference solution and the test solution, and the separation degree is good.
Further, in the step (2), the temperature rise procedure of the HP-5 capillary column is as follows: the temperature is maintained at 40 ℃ for 8min, and then the temperature is raised to 120 ℃ at a rate of 8 ℃/min for 5 min.
The invention has the beneficial effects that: the method adopts the gas chromatography to detect the contents of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene in the formoterol bulk drugs (formoterol tartrate and formoterol fumarate), optimizes chromatographic conditions, and has the characteristics of high sensitivity, good repeatability, simplicity, convenience, rapidness and accuracy.
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FIG. 1 is a gas chromatogram of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran, toluene, and DMF.
Detailed Description
The technical solution of the present invention is further explained with reference to the accompanying drawings and specific embodiments.
In the following examples, the experimental instruments and experimental materials were: an Agilent 7890A gas chromatograph, an Agilent G1888 headspace sample injector; methanol, ethanol and isopropanol are chromatographic grade, and dichloromethane, ethyl acetate, tetrahydrofuran, toluene and N, N-Dimethylformamide (DMF) are analytically pure; in formoterol bulk drugs, formoterol tartrate bulk drugs are prepared (batch numbers 20101118, 20101119 and 20101120), and formoterol fumarate bulk drugs are prepared (batch numbers 20101201, 20101202 and 20101203).
Example 1
1.1 preparing reference solution and test solution:
precisely weighing methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene, placing the methanol, the ethanol, the isopropanol, the dichloromethane, the tetrahydrofuran and the toluene into a measuring flask, adding DMF (dimethyl formamide) for quantitative dilution to obtain mixed solution of which each 1mL contains 120, 200, 26, 200, 30 and 36 mu g of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene respectively, and taking the mixed solution as a reference solution;
precisely weighing 200mg of formoterol tartrate raw material medicine, putting the formoterol tartrate raw material medicine into a 20mL headspace bottle, adding 5.0mL of DMF, sealing and dissolving to obtain a test solution A;
precisely weighing 200mg of formoterol fumarate raw material medicine, placing the raw material medicine into a 20mL headspace bottle, adding 5.0mL of DMF solvent, sealing and dissolving to obtain a test solution B.
1.2 chromatographic conditions:
an HP-5 capillary column (30m × 0.32.32 mm × 0.25.25 mu m) is adopted, a hydrogen flame ionization detector is adopted, carrier gas is nitrogen, the flow rate is 1.0mL/min, the injection port temperature is 200 ℃, the split ratio is 1: 1, the detector temperature is 250 ℃, the hydrogen flow rate is 30mL/min, the air flow rate is 300mL/min, tail blowing is 25mL/min, the headspace bottle heating temperature is 100 ℃, the quantitative ring is 110 ℃, the transmission line is 120 ℃, the headspace bottle heating time is 30min, the pressurization time is 0.2min, the quantitative ring filling time is 0.2min, the quantitative ring equilibrium time is 0.05min, the injection time is 1.0min, and the temperature rise program of the HP-5 capillary column is that the temperature is kept for 8min at 40 ℃ and then is increased to 120 ℃ at the speed of 8 ℃/min and kept for 5 min.
2.1 System specificity test
Taking a proper amount of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran, toluene and DMF respectively, sampling 5mL under the condition that the signal-to-noise ratio is not less than 3, carrying out headspace sample injection analysis, and showing a gas chromatogram of 7 organic solvents in figure 1. The peak sequences were methanol (2.636), ethanol (2.756), isopropanol (2.877), dichloromethane (3.040), ethyl acetate (3.621), tetrahydrofuran (3.804), toluene (6.942), DMF (8.207). The separation degrees of the 7 organic solvents are all more than 2, the theoretical plate numbers are all more than 10000, and the symmetry is good.
2.2 linearity and Range
The control solutions were pipetted into 25mL flasks at 0.5mL, 1.0mL, 2.0mL, 2.5mL, 3.0mL, 4.0mL, and 5.0mL, respectively, and diluted to the appropriate volume with DMF to give 7 linear concentrations (1, 2, 3, 4, 5, 6, and 7). Respectively sucking 5.0mL of the solution under each line into a 20mL headspace bottle, sealing, and respectively carrying out sample injection analysis, wherein the determination results are shown in Table 1:
TABLE 1 measurement of Linear relationship
As can be seen from table 1: the content of ethanol, isopropanol and ethyl acetate is in the range of 40.00-400.00 mu g/mL; the methanol is in the range of 60.00-240.00 mu g/mL; the dichloromethane is in the range of 4.80-48.00 mu g/mL; tetrahydrofuran is in the range of 5.76-57.60 mu g/mL; the toluene content is in the range of 7.12-71.20 mu g/mL, and the linear relation is good.
2.3 precision test
Preparing a reference substance solution, sucking 5mL of the reference substance solution into a 20mL headspace bottle, sealing the headspace bottle, and continuously injecting samples for 6 times, wherein the determination results are shown in a table 2:
TABLE 2 results of precision test
As can be seen from table 2: the Relative Standard Deviation (RSD) of peak areas of 6 times of sample injection of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene is respectively 1.55%, 1.76%, 2.05%, 3.66%, 1.85%, 1.98% and 1.57%. The data show better precision.
2.4 recovery test
Precisely weighing 2 parts of formoterol tartrate raw material medicine to be tested, wherein each part is 200mg, respectively placing the 2 parts in a 20mL headspace bottle, adding 5.0mL of DMF, and sealing to dissolve the DMF to obtain a blank. In addition, 9 parts of formoterol tartrate to be tested, each part is 200mg, each part is 3 parts, 5.0mL of linear 3, 4 and 5 solutions are respectively added into each group, and the solution is sealed and dissolved. And (4) sequentially measuring, and calculating the recovery rate after blank is deducted from the measurement result.
The results are shown in Table 3:
TABLE 3 determination of recovery%
Precisely weighing 2 parts of formoterol fumarate raw material medicine to be tested, wherein each part is 200mg, respectively placing the 2 parts in a 20mL headspace bottle, adding 5.0mL of DMF, and sealing to dissolve the DMF to obtain a blank. In addition, 9 parts of formoterol fumarate to be tested, 200mg of the formoterol fumarate is precisely weighed, 3 parts of the formoterol fumarate are added into one group, 5.0mL of linear 3, 4 and 5 solutions are respectively added into each group, and the solution is sealed and dissolved. And (4) sequentially measuring, and calculating the recovery rate after blank is deducted from the measurement result.
The results are shown in Table 4:
TABLE 4 determination of recovery%
2.5 determination of quantitation Limit and detection Limit
Separately preparing 7 organic solvent solutions to be detected, properly diluting the organic solvent solutions to be detected by using DMF until the peak height of the chromatographic peak of the organic solvent to be detected is 10 times of the baseline noise, using the organic solvent solutions to serve as the quantitative limit, and further diluting the solutions reaching the quantitative limit until the peak height of the chromatographic peak of the organic solvent to be detected is 3 times of the baseline noise, and using the solutions to serve as the detection limit. The results show that when the signal-to-noise ratio is about 10, the concentrations of the 7 organic solutions are: 55.73 μ g/mL of methanol, 33.98 μ g/mL of ethanol, 20.50 μ g/mL of isopropanol, 2.41 μ g/mL of dichloromethane, 35.59 μ g/mL of ethyl acetate, 2.92 μ g/mL of tetrahydrofuran, and 6.58 μ g/mL of toluene. When the signal-to-noise ratio is about 3, the concentrations of the 7 organic solutions are respectively: methanol 15.22. mu.g/mL, ethanol 10.14. mu.g/mL, isopropanol 7.29. mu.g/mL, dichloromethane 0.72. mu.g/mL, ethyl acetate 10.64. mu.g/mL, tetrahydrofuran 0.88. mu.g/mL, toluene 1.98. mu.g/mL.
2.6 investigation of stability
Precisely weighing 200mg of formoterol tartrate to be tested, putting the formoterol tartrate into a 20mL headspace bottle, adding 5.0mL of DMF, sealing, dissolving, respectively standing for 0, 1, 2, 4 and 6 hours at room temperature, and determining according to chromatographic conditions, wherein 7 organic solvent residues are not detected. The test sample formoterol fumarate of 200mg was weighed precisely, and the stability was examined by the same method, and no 7 organic solvent residues were detected. The result shows that the method is used for measuring the residual organic solution in the formoterol raw material, and the data is reliable.
2.7 examination of durability
The RSD values were examined to be 1.3%, 1.9%, and 1.0%, respectively, under different conditions, not more than 2.0%, at carrier gas flow rates (0.8mL/min, 1.0mL/min, 1.2mL/min), at sample inlet temperatures (195 ℃, 200 ℃, 205 ℃), and at detector temperatures (245 ℃, 250 ℃, 255 ℃), and were all good in durability.
2.8 determination of organic solvent residue in formoterol tartrate or formoterol fumarate
Test solutions of 3 batches of formoterol tartrate samples (batches 20101118, 20101119, 20101120) were prepared according to the method 1.1 and measured by chromatography, and the results are shown in table 5:
TABLE 5 residual solvent assay results%
Test solutions of 3 formoterol fumarate samples (lot numbers 20101201, 20101202, 20101203) were prepared according to the method 1.1 and measured by chromatography, and the results are shown in table 6:
TABLE 6 residual solvent assay results%
The results show that: no 7 residual organic solvents are detected in 3 batches of formoterol tartrate samples and formoterol fumarate samples, and the standards of the organic solvent residual quantity research guiding principles of International harmonization Institute (ICH) which is the technical requirement of human drug registration are met.
The invention establishes a method for determining the residual quantity of organic solvent in formoterol tartrate and formoterol fumarate by headspace capillary gas chromatography, and respectively determines the residual quantity of organic solvent in three batches of samples. The method is sensitive, accurate and rapid, the specificity, the detection limit, the linearity and range, the precision, the recovery rate and the like of the method meet the methodological requirements of the quality control of the medicament, and the established method can effectively measure the residual quantity of the organic solvent in the formoterol tartrate and the formoterol fumarate. The method can provide good reference for subsequent research and development of formoterol products and the like, and can be used as a quality control method to provide reference for detection of organic solvent residues of other drugs.
Claims (3)
1. A method for detecting residual quantity of organic solvent in formoterol bulk drug is characterized in that the formoterol comprises formoterol tartrate and formoterol fumarate, and the method comprises the following steps:
(1) preparing a reference solution and a test solution:
accurately weighing methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene, placing into a measuring flask, adding a solvent to quantitatively dilute into mixed solution containing 120, 200, 26, 200, 30 and 36 mu g of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene in each 1mL of the mixed solution as a reference solution;
precisely weighing 200mg of formoterol bulk drug, placing the formoterol bulk drug in a 20mL headspace bottle, adding 5.0mL of solvent, sealing and dissolving to obtain a test solution;
(2) and (3) detection:
detecting by using a gas chromatography external standard method, wherein the chromatographic conditions are as follows:
an HP-5 capillary column (30m × 0.32mm × 0.25.25 mu m) is adopted, a hydrogen flame ionization detector is adopted, carrier gas is nitrogen, the flow rate is 0.8-1.2mL/min, the temperature of a sample inlet is 195-plus, the flow split ratio is 1: 1, the temperature of the detector is 245-plus 255 ℃, the flow rate of hydrogen is 30mL/min, the air flow rate is 300mL/min, tail blowing is 25mL/min, the heating temperature of a headspace bottle is 100 ℃, a quantitative ring is 110 ℃, a transmission line is 120 ℃, the heating time of the headspace bottle is 30min, the pressurizing time is 0.2min, the quantitative ring filling time is 0.2min, and the quantitative ring balance time is 0.05 min;
precisely taking 1mL of each of the test solution and the reference solution, respectively injecting into a gas chromatograph, recording a chromatogram, and calculating the content of methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, tetrahydrofuran and toluene in the bulk drugs of formoterol tartrate and formoterol fumarate by peak area according to an external standard method.
2. The method for detecting the residual amount of organic solvent in formoterol as set forth in claim 1, wherein in the step (1), the solvent used in the preparation of the reference solution and the test solution is DMF.
3. The method for detecting the residual amount of organic solvent in formoterol as set forth in claim 1 or 2, wherein in the step (2), the temperature rise procedure of the HP-5 capillary column is: the temperature is maintained at 40 ℃ for 8min, and then the temperature is raised to 120 ℃ at a rate of 8 ℃/min for 5 min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115032313A (en) * | 2022-08-11 | 2022-09-09 | 精华制药集团南通有限公司 | Method for detecting methanol and ethanol in primidone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017172612A1 (en) * | 2016-03-28 | 2017-10-05 | Warsaw Orthopedic, Inc. | Methods for the separation and detection of an oxysterol |
| CN108614058A (en) * | 2018-06-19 | 2018-10-02 | 广西壮族自治区食品药品检验所 | Measure the headspace gas chromatography of glycine organic solvent residual in raw medicine amount |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017172612A1 (en) * | 2016-03-28 | 2017-10-05 | Warsaw Orthopedic, Inc. | Methods for the separation and detection of an oxysterol |
| CN108614058A (en) * | 2018-06-19 | 2018-10-02 | 广西壮族自治区食品药品检验所 | Measure the headspace gas chromatography of glycine organic solvent residual in raw medicine amount |
Non-Patent Citations (3)
| Title |
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| N.BARBARIN等: "Role of residual solvents in the formation of volatile compounds after radiosterilisation of cefotaxime", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| 欧嘉娜: "顶空气相色谱法测定富马酸福莫特罗中有机溶剂残留量", 《今日药学》 * |
| 郭俐麟: "顶空毛细管气相色谱法测定(R,R)-酒石酸福莫特罗中有机溶剂残留量", 《安徽医药》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115032313A (en) * | 2022-08-11 | 2022-09-09 | 精华制药集团南通有限公司 | Method for detecting methanol and ethanol in primidone |
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