CN114705769B - Method for detecting related substances in isopropyl tropine - Google Patents
Method for detecting related substances in isopropyl tropine Download PDFInfo
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- CN114705769B CN114705769B CN202210214754.1A CN202210214754A CN114705769B CN 114705769 B CN114705769 B CN 114705769B CN 202210214754 A CN202210214754 A CN 202210214754A CN 114705769 B CN114705769 B CN 114705769B
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- G—PHYSICS
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Abstract
The invention relates to the technical field of drug detection, and particularly discloses a method for detecting related substances in isopropyl tropine. The detection method comprises the following steps: preparing a test solution and a reference solution; detecting the test solution and the reference solution by adopting a gas chromatography, wherein the gas chromatography has the following chromatographic conditions: adopting a capillary column which takes nitroterephthalic acid modified polyethylene glycol as stationary liquid; the temperature of a sample inlet is 225-235 ℃; the temperature programming is as follows: the initial temperature is 78-82 ℃, the temperature is maintained for 1-5 min, the temperature is raised to 225-235 ℃ at the speed of 9-11 ℃/min, and the temperature is maintained for 3-8 min; a hydrogen flame ionization detector was used. The detection method provided by the invention has strong specificity and high accuracy, and can meet the detection requirements of 2,5-dimethoxy tetrahydrofuran and isopropyl tropinone in isopropyl tropine.
Description
Technical Field
The invention relates to the technical field of drug detection, in particular to a method for detecting related substances in ipratropium alcohol.
Background
Ipratropium Bromide (Ipratropium Bromide), its chemical name (1R, 3r,5S, 8r) -3- [ [ (2 RS) -3-hydroxy-2-phenylpropionyl group]Oxy radical]-8-methyl-8-isopropyl-8-azabicyclo [3.2.1]Octane bromide of formula C 20 H 30 BrNO 3 ·H 2 O, molecular weight 430.38. Ipratropium bromide is an M receptor blocker, belongs to the fourth generation derivatives of atropine, and is a powerful and highly selective anticholinergic drug.
Ipratropium bromide is an important starting material for synthesizing ipratropium bromide, and therefore, the quality control of ipratropium bromide has great influence on the synthesis of ipratropium bromide. In the process of synthesizing ipratropium alcohol, relevant substances 2,5-dimethoxy tetrahydrofuran and ipratropium ketone which are all likely to become impurities in the synthesis of ipratropium bromide inevitably occur, so that a detection method capable of effectively controlling the quality of ipratropium bromide needs to be developed, the quality of ipratropium bromide is further effectively controlled, and the industrial standard is perfected.
Disclosure of Invention
In view of the above, the invention provides a method for detecting related substances in ipratropium alcohol, which has the advantages of strong specificity, high sensitivity, excellent accuracy and linear relationship, and can meet the detection requirements of 2,5-dimethoxytetrahydrofuran and ipratropium ketone in ipratropium alcohol.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a method for detecting related substances in ipratropium alcohol comprises the following steps:
step one, preparing a test solution and a reference solution:
preparing a test solution: taking an isopropyl tropine sample, and preparing a test solution by using a solvent;
preparing a reference substance solution: preparing 2,5-dimethoxy tetrahydrofuran reference substance and isopropyl tropinone reference substance into reference substance solution with solvent;
step two, detecting the test solution and the reference solution by adopting a gas chromatography, wherein the chromatographic conditions of the gas chromatography are as follows:
adopting a capillary column which takes nitroterephthalic acid modified polyethylene glycol as stationary liquid; the temperature of a sample inlet is 225-235 ℃; the temperature programming is as follows: the initial temperature is 78-82 ℃, the temperature is maintained for 1-5 min, the temperature is raised to 225-235 ℃ at the speed of 9-11 ℃/min, and the temperature is maintained for 3-8 min; a hydrogen flame ionization detector is adopted, and the temperature of the detector is 245-255 ℃.
Compared with the prior art, the method for detecting the related substances in the isopropyl tropine provided by the application has the following advantages:
the method for detecting related substances in isopropyl tropine provided by the application realizes quantitative and qualitative analysis of 2,5-dimethoxy tetrahydrofuran and isopropyl tropine which are impurities in isopropyl tropine raw material medicines, has strong specificity and high sensitivity, meets the detection requirements of 2,5-dimethoxy tetrahydrofuran and isopropyl tropine in the isopropyl tropine raw material medicines, and has good linear relation, high repeatability and more than 0.99 of correlation coefficient in the linear range of a standard curve; in addition, the detection method has the advantages of short analysis time, reliable and controllable whole operation process, suitability for practical application and popularization and wide application prospect.
Optionally, the programmed temperature rise is: the initial temperature is 80 deg.C, and is maintained for 3min, and the temperature is increased to 230 deg.C at a rate of 10 deg.C/min, and is maintained for 5min.
The temperature rise program is an important factor influencing the performance of the gas chromatographic column, and the initial temperature, the temperature rise rate and the final temperature determine the elution capacity of each component, so the initial temperature, the temperature rise rate and the final temperature are preferably selected in the application, the 2,5-dimethoxytetrahydrofuran and the isopropyl tropinone impurities can be rapidly separated from the isopropyl tropine bulk drug, and each component also has excellent separation degree.
Optionally, the injection inlet temperature is 230 ℃.
Optionally, the detector temperature is 250 ℃.
The preferable injection port temperature and the detector temperature are favorable for separating 2,5-dimethoxy tetrahydrofuran and isopropyl tropinone from the main components isopropyl tropine, and ensure that the peak shape is better and the separation degree is higher.
Optionally, the carrier gas is nitrogen, and the split ratio is 1-2:1.
Further optionally, the split ratio is 1:1.
The preferable split ratio ensures that the peak shape of the chromatographic peak is better, and avoids the occurrence of situations such as peak deformation and tailing.
Optionally, the flow rate is 4.9 ml/min-5.1 ml/min, and the sample injection volume is 0.5 μ L.
Further alternatively, the flow rate is 5ml/min.
Optionally, the capillary column is HP-FFAP in model number.
Optionally, the capillary column has a specification of 30m × 0.53mm × 1.0 μm.
Different chromatographic columns have larger difference on the retention performance of the compound, so the HP-FFAP capillary column with the specification of 30m multiplied by 0.53mm multiplied by 1.0 mu m is adopted in the method, the target can be quickly and effectively separated, and the peak shape is better.
Optionally, the solvent is N, N-dimethylformamide.
The preferable solvent has no interference to the detection of 2,5-dimethoxy tetrahydrofuran and isopropyl tropinone, and the accuracy of the detection result is ensured.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a gas chromatogram of a blank solution provided in example 1 of the present invention;
FIG. 2 is a gas chromatogram of a control solution provided in example 1 of the present invention;
FIG. 3 is a gas chromatogram of a test solution provided in example 1 of the present invention;
FIG. 4 is a gas chromatogram of a spiked solution provided in example 1 of the present invention;
FIG. 5 is a gas chromatogram of a control solution provided in comparative example 1 of the present invention;
FIG. 6 is a gas chromatogram of a control solution provided in comparative example 2 of the present invention;
FIG. 7 is a gas chromatogram of a test solution provided in comparative example 2 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The embodiment provides a method for detecting related substances in ipratropium alcohol, which comprises the following steps:
preparing a blank solution, a reference solution, a test solution and a standard solution:
blank solution: taking N, N-dimethylformamide as a blank solution;
preparing a test solution: taking a proper amount of an isopropyl tropine sample, precisely weighing, and preparing a test solution with the concentration of 30mg/ml by using N, N-dimethylformamide;
preparing a reference substance solution: taking 2,5-dimethoxy tetrahydrofuran reference substance and an appropriate amount of isopropyl tropinone reference substance, precisely weighing, and preparing reference substance solution by using N, N-dimethylformamide, wherein in the reference substance solution, the concentration of 2,5-dimethoxy tetrahydrofuran is 150 mu g/ml, and the concentration of isopropyl tropinone is 30 mu g/ml;
preparing a standard solution: taking an appropriate amount of an isopropyl tropine sample, 2,5-dimethoxy tetrahydrofuran and isopropyl tropinone, and preparing mixed solutions with the concentrations of 30mg/ml, 150 mu g/ml and 30 mu g/ml by using N, N-dimethylformamide.
Step two, detecting the blank solution, the reference solution, the test solution and the standard solution by adopting gas chromatography, wherein chromatograms are shown in figures 1-4; wherein the chromatographic conditions of the gas chromatograph are as follows:
a capillary column with the model of HP-FFAP and the specification of 30m multiplied by 0.53mm multiplied by 1.0 mu m and taking nitroterephthalic acid modified polyethylene glycol as stationary liquid is adopted; the temperature of a sample inlet is 230 ℃; the temperature programming is as follows: the initial temperature is 80 ℃, the temperature is maintained for 3min, the temperature is increased to 230 ℃ at the speed of 10 ℃/min, and the temperature is maintained for 5min; adopting a hydrogen flame ionization detector, wherein the temperature of the detector is 250 ℃; nitrogen is used as carrier gas, the split ratio is 1:1, the flow rate is 5.0ml/min, and the sample injection volume is 0.5 mul.
As can be seen from the figures 1-4, the N, N-dimethylformamide solvent and the isopropyl tropine have no interference on the detection of the impurities 2,5-dimethoxytetrahydrofuran and isopropyl tropine, and the accuracy of the detection result is ensured.
As can be seen from FIG. 2, a peak of 2,5-dimethoxytetrahydrofuran isomer 1 occurred at retention time 4.579min, a peak of 2,5-dimethoxytetrahydrofuran isomer 2 occurred at retention time 5.348min, a peak of N, N-dimethylformamide occurred at retention time 7.255min, a peak of isopropyl tropinone occurred at retention time 12.723min, and the degrees of separation of the components were good.
As can be seen from FIG. 3, 2,5-dimethoxytetrahydrofuran was not detected, a chromatographic peak of N, N-dimethylformamide occurred at 7.237min, a chromatographic peak of isopropyltropinone occurred at 12.723min, a chromatographic peak of isopropyltropinone occurred at 13.969min, and the separation degree of each component was good.
As can be seen from FIG. 4, a chromatographic peak of 2,5-dimethoxytetrahydrofuran isomer 1 occurred at retention time 4.578min, a chromatographic peak of 2,5-dimethoxytetrahydrofuran isomer 2 occurred at retention time 5.348min, a chromatographic peak of N, N-dimethylformamide occurred at retention time 7.238min, a chromatographic peak of isopropyltropinone occurred at retention time 12.725min, a chromatographic peak of isopropyltropinone occurred at retention time 13.967min, and the chromatographic peaks were all well separated.
The results of the separation degree detection of each component in the above-mentioned labeled solution are shown in table 1 below, and it can be seen from table 1 that the separation degree between the components is good, thereby illustrating that the specificity of the detection method for related substances in ipratropium alcohol provided by the present application is good.
TABLE 1 results of resolution measurements
Example 2 detection and quantitation limits
Detection limit: the control solution prepared in example 1 was diluted quantitatively with N, N-dimethylformamide step by step, and then detected by gas chromatography under the conditions specified in example 1, and the spectrum was recorded with a signal-to-noise ratio of not less than 3:1 to obtain the detection limit, with the results shown in table 2.
And (4) quantitative limit: the control solution prepared in example 1 was diluted quantitatively with N, N-dimethylformamide step by step, and then detected by gas chromatography, the specific conditions of which were as described in example 1, and the spectrum was recorded with the signal-to-noise ratio of not less than 10 as the limit of quantitation.
TABLE 2 detection results of quantitation limit and detection limit
The quantitative limit solution is repeatedly measured for 6 times, the peak areas are respectively recorded, the results are shown in the following table 3, and the RSD of the peak area is 4.27% at most according to the results shown in the table 3, which indicates that the detection method provided by the scheme has good quantitative limit repeatability.
TABLE 3 quantitative limit repeatability test results
Example 3 linearity
Respectively taking 2,5-dimethoxytetrahydrofuran, isopropyltropinone and isopropyltropine, dissolving with N, N-dimethylformamide, quantitatively diluting to prepare a series of concentration solutions, detecting by gas chromatography, specifically using the gas chromatography conditions as shown in example 1, recording a spectrogram, drawing a standard curve by using the concentration (mu g/ml) as a horizontal coordinate and the peak area as a vertical coordinate, and calculating a regression equation, wherein the results are shown in a table 4. As can be seen from Table 4, 2,5-dimethoxytetrahydrofuran isomer 1 has good linearity in the concentration range of 1.2341 μ g/ml to 123.4094g/ml, 2,5-dimethoxytetrahydrofuran isomer 2 has good linearity in the concentration range of 1.8511 μ g/ml to 185.1142 μ g/ml, isopropyltropinone has good linearity in the concentration range of 1.4800 μ g/ml to 59.2000 μ g/ml, and isopropyltropine has good linearity in the concentration range of 0.3628 μ g/ml to 120.9201 μ g/ml.
TABLE 4 results of the Linear test
Example 4 recovery
Respectively taking 2,5-dimethoxy tetrahydrofuran and isopropyl tropinone, precisely weighing, and preparing a mixed solution with 10 times of limit concentration by using N, N-dimethylformamide as a reference substance storage solution; taking about 300mg of an isopropyl tropine sample, accurately weighing, placing the sample in a 10ml measuring flask, preparing 9 parts in parallel, respectively and accurately adding 0.4ml, 0.8ml and 1.0ml of reference substance storage solutions, fixing the volume to the scale by using N, N-dimethylformamide, taking the volume of each concentration as 3 parts in parallel, taking the solution as a recovery rate sample solution, and detecting by adopting gas chromatography, wherein the conditions of the gas chromatography are specifically shown in example 1, and the results are shown in tables 5 to 7.
TABLE 5 recovery test results of 2, 5-dimethoxytetrahydrofuran isomer 1
TABLE 6 results of recovery test of 2, 5-dimethoxytetrahydrofuran isomer 2
TABLE 7 recovery test results for ipratropione
As can be seen from tables 5 to 7, the recovery rates of 2,5-dimethoxytetrahydrofuran and isopropyltropinone are between 99% and 108%, and the maximum value of RSD is 2.14%, so that the detection method provided by the application is good in accuracy.
Example 5 reproducibility
Taking the same batch of samples, preparing 6 parts of test solution according to the preparation method of the test solution in the example 1, and detecting by adopting gas chromatography, wherein the specific conditions of the gas chromatography are described in the example 1, and the results are shown in the table 8. As can be seen from Table 8, the test results of 6 test solutions are substantially consistent, indicating that the test method provided by the present application has good repeatability.
TABLE 8 results of repeated measurements
EXAMPLE 6 solution stability
The control solutions prepared in example 1 were allowed to stand for 0h, 2h, 4h, and 8h, respectively, and then detected by gas chromatography, the specific conditions of which were as described in example 1, the peak areas thereof were recorded, and RSD (%) thereof was calculated, and the test results are shown in table 9 below. As can be seen from Table 9, the RSD% of the control solution was less than 5% for 2,5-dimethoxytetrahydrofuran and isopropyltropinone when they were left at room temperature for 8 hours, indicating that the stability of the control solution was good.
TABLE 9 results of solution stability measurements
EXAMPLE 7 durability
The control solution prepared in example 1 was examined by gas chromatography, the conditions of which were as described in example 1, and the degree of separation was recorded.
Initial temperature was adjusted to 78 ℃ and 82 ℃ respectively, and the remaining test conditions were the same as in example 1, and the degrees of separation were recorded, and the results are shown in Table 10.
TABLE 10 degrees of separation at different initial temperatures
The flow rates were fine-tuned to 4.9ml/min and 5.1ml/min, respectively, and the remaining test conditions were identical to those of example 1, and the degrees of separation were recorded, and the results are shown in Table 11.
TABLE 11 degrees of separation at different flow rates
The temperature rise rates were finely adjusted to 9 ℃/min and 11 ℃/min, respectively, and the remaining test conditions were the same as in example 1, and the degrees of separation were recorded, and the results are shown in table 12.
TABLE 12 degrees of separation at different ramp rates
The sample inlet temperature was adjusted to 225 ℃ and 235 ℃ respectively, the remaining test conditions were the same as in example 1, and the degree of separation was recorded, and the results are shown in Table 13.
TABLE 13 degrees of separation at different injection port temperatures
The detector temperature was adjusted to 245 ℃ and 255 ℃ respectively, and the remaining detection conditions were the same as in example 1, and the degrees of separation were recorded, and the results are shown in table 14.
TABLE 14 temperature resolution of different detectors
As can be seen from tables 10 to 14, the fine-tuning chromatographic conditions have no influence on the detection of 2,5-dimethoxytetrahydrofuran and isopropyltropinone, and the separation degrees of all components meet the requirements, which indicates that the detection method provided by the invention has good durability.
In order to better illustrate the technical solution of the present invention, further comparison is made below by means of a comparative example and an example of the present invention.
Comparative example 1
The comparative example provides a method for detecting related substances in isopropyl tropine, which comprises the following steps:
step one, preparing a reference substance solution:
the preparation method of the reference solution is as described in example 1, and is not repeated;
step two, detecting the reference solution by adopting gas chromatography, wherein a chromatogram is shown in figure 5; wherein the chromatographic conditions of the gas chromatograph are as follows:
a capillary column with the model of HP-FFAP and the specification of 30m multiplied by 0.53mm multiplied by 1.0 mu m and taking nitroterephthalic acid modified polyethylene glycol as stationary liquid is adopted; the temperature of a sample inlet is 160 ℃; the temperature programming is as follows: the initial temperature is 80 ℃, the temperature is maintained for 3min, the temperature is increased to 160 ℃ at the speed of 10 ℃/min, and the temperature is maintained for 5min; adopting a hydrogen flame ionization detector, wherein the temperature of the detector is 180 ℃; nitrogen is used as carrier gas, the split ratio is 1:1, the flow rate is 5.0ml/min, and the sample injection volume is 0.5 mul.
As can be seen from fig. 5, only 2,5- dimethoxytetrahydrofuran isomer 1 and 2,5-dimethoxytetrahydrofuran isomer 2 and isopropyl tropinone are detected by using the inlet temperature and the detection temperature, which shows that the temperature rising procedure is a key factor affecting the performance of the gas chromatography column, and the initial temperature, the final temperature and the detector temperature determine the elution capability of each component, so that the initial temperature, the final temperature and the detector temperature which are preferred in the present application can rapidly separate 2,5-dimethoxytetrahydrofuran and isopropyl tropinone from isopropyl tropine bulk drug, and each component also has an excellent separation degree.
Comparative example 2
The comparative example provides a method for detecting related substances in ipratropium alcohol, which comprises the following steps:
step one, preparing a reference substance solution and a test substance solution:
the preparation methods of the reference solution and the test solution are as described in example 1, and are not described again;
step two, detecting the reference solution and the test solution by adopting gas chromatography, wherein chromatograms are shown in fig. 6 and fig. 7; wherein the chromatographic conditions of the gas chromatograph are as follows:
adopting a capillary column with the model of HP-INNOWAX, the specification of 30m multiplied by 0.53mm multiplied by 1.0 mu m and cross-linked bonded polyethylene glycol as stationary liquid; the temperature of a sample inlet is 230 ℃; the temperature programming is as follows: the initial temperature is 80 ℃, the temperature is maintained for 3min, the temperature is increased to 230 ℃ at the speed of 10 ℃/min, and the temperature is maintained for 5min; adopting a hydrogen flame ionization detector, wherein the temperature of the detector is 250 ℃; nitrogen is used as carrier gas, the split ratio is 1:1, the flow rate is 5.0ml/min, and the sample injection volume is 0.5 mul.
As can be seen in FIG. 6, a chromatographic peak for 2,5-dimethoxytetrahydrofuran isomer 1 occurs at retention time 8.883 min; a chromatographic peak of 2,5-dimethoxytetrahydrofuran isomer 2 appeared at a retention time of 9.237 min; the chromatographic peak of the isopropyl tropinone appears at the retention time of 15.243min, and the peak shape of the chromatographic peak is poor and does not meet the detection requirement. As can be seen in FIG. 7, the chromatographic peak for ipratropium alcohol at 16.636min and the chromatographic peak for ipratropium ketone at 16.867min are not separated. It can be seen that the detection method provided in comparative example 2 does not separate the impurities 2,5-dimethoxytetrahydrofuran and ipratropione from the ipratropiol drug substance.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (7)
1. A method for detecting related substances in isopropyl tropine is characterized by comprising the following steps: the detection method comprises the following steps:
step one, preparing a test solution and a reference solution:
preparing a test solution: preparing an isopropyl tropine sample into a test solution by using a solvent;
preparing a reference substance solution: preparing 2,5-dimethoxy tetrahydrofuran reference substance and isopropyl tropinone reference substance into reference substance solution with solvent;
the solvent is N, N-dimethylformamide;
step two, detecting the test solution and the reference solution by adopting a gas chromatography, wherein the chromatographic conditions of the gas chromatography are as follows:
adopting a capillary column which takes nitroterephthalic acid modified polyethylene glycol as stationary liquid; the temperature of a sample inlet is 225-235 ℃; the temperature programming is as follows: the initial temperature is 80 ℃, the temperature is maintained for 3min, the temperature is increased to 230 ℃ at the speed of 10 ℃/min, and the temperature is maintained for 5min; a hydrogen flame ionization detector is adopted, and the temperature of the detector is 245-255 ℃.
2. The method for detecting a substance of interest in ipratropium alcohol according to claim 1, wherein: the injection port temperature is 230 ℃.
3. The method for detecting a substance of interest in ipratropium alcohol according to claim 1, wherein: the detector temperature was 250 ℃.
4. The method for detecting a substance of interest in ipratropium alcohol according to claim 1, wherein: the carrier gas is nitrogen, and the split ratio is 1-2:1.
5. The method for detecting a substance of interest in ipratropium alcohol according to claim 1, wherein: the flow rate is 4.9 ml/min-5.1 ml/min, and the sample injection volume is 0.5 mu L.
6. The method for detecting a substance of interest in ipratropium alcohol according to claim 1, wherein: the capillary column is HP-FFAP.
7. The method for detecting a substance of interest in ipratropium alcohol according to claim 6, wherein: the capillary column specification is 30m × 0.53mm × 1.0 μm.
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| US5154738A (en) * | 1989-09-12 | 1992-10-13 | Advanced Separation Technologies, Inc. | Chiral separation media |
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| CN112461953A (en) * | 2020-11-09 | 2021-03-09 | 山东鲁抗医药股份有限公司 | Detection method of methyl bromide in 7-azoniabicyclo [2.2.1] heptane derivative |
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| EP3230269A1 (en) * | 2014-11-20 | 2017-10-18 | Nederlandse Organisatie voor toegepast- natuurwetenschappelijk onderzoek TNO | Production of furans |
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|---|---|---|---|---|
| US5154738A (en) * | 1989-09-12 | 1992-10-13 | Advanced Separation Technologies, Inc. | Chiral separation media |
| US6379552B1 (en) * | 1998-07-06 | 2002-04-30 | Toray Industries, Inc. | Method for resolving optical isomers |
| CN112461953A (en) * | 2020-11-09 | 2021-03-09 | 山东鲁抗医药股份有限公司 | Detection method of methyl bromide in 7-azoniabicyclo [2.2.1] heptane derivative |
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| use of gas chromatography to study the thermodynamic parameters of solutions of isomers of 2,5-dimethoxytetrahydrofuran and 2,3-dichlorobutane;T.M. Shcherbina等;《Bulletin of the Academy of Sciences of the USSR, Division of chemical science》;19700430;第19卷;第907-908页 * |
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