CN109633021B - Method for detecting additive in sufentanil medicine - Google Patents
Method for detecting additive in sufentanil medicine Download PDFInfo
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- CN109633021B CN109633021B CN201811645643.6A CN201811645643A CN109633021B CN 109633021 B CN109633021 B CN 109633021B CN 201811645643 A CN201811645643 A CN 201811645643A CN 109633021 B CN109633021 B CN 109633021B
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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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
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Abstract
The invention relates to the technical field of sufentanil purity, in particular to a method for detecting an additive in a sufentanil medicine. The invention relates to a method for detecting an additive in a sufentanil medicament, which comprises the following steps: (1) sample treatment: s1, dissolving sufentanil citrate in water, adjusting the pH value, adding water to 1000mL to obtain a sample mother solution, S2, extracting the sample mother solution with an organic solvent, separating an organic phase, adding a dehydrating agent, and taking a supernatant to be tested; (2) preparing a standard solution; preparing a standard series solution of dibutyl phthalate; (3) GC-MS testing was performed. The method can accurately detect the content of the dibutyl phthalate in the sufentanil, and has low cost, simplicity, convenience and quickness.
Description
Technical Field
The invention relates to the technical field of sufentanil purity, in particular to a method for detecting an additive in a sufentanil medicine.
Background
Phthalate compounds (PAEs) are an important class of endocrine disruptors. Trace PAEs can be enriched in water, soil, animals and plants, are difficult to degrade in the environment, interfere endocrine systems of human bodies, directly influence the metabolism of the human bodies, and the toxicity of the plasticizer, namely di (2-ethylhexyl) phthalate (DEHP) is 20 times higher than that of melamine. Researches show that the plasticizer can increase the burden of liver and kidney, cause chronic damage to immune system and digestive system, and even cause liver cancer. In the wine wind wave of 2012, the highest detected value of dibutyl phthalate (DBP) in the sample reaches 1.04 mg/kg. With the use of a large number of plastic packaging products, the PAEs are increasingly polluted in the process of residue and migration in the environment, and part of water and soil are also polluted by the PAEs. The analysis, detection and control of phthalate compounds in the environment has been a new problem and challenge for environmental monitoring workers.
The U.S. environmental protection agency prioritizes dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), Butyl Benzyl Phthalate (BBP), di (2-ethylhexyl) phthalate (DEHP), and di-n-octyl phthalate (DNOP). Among them, DMP, DBP and DNOP have also been blacklisted as environmental priority pollutants in China.
At present, the instrument analysis method of the PAEs mainly adopts a Gas Chromatography (GC) method and a Liquid Chromatography (LC) method, and the pretreatment of a sample is the key for determining the detection sensitivity of the PAEs. The sample pretreatment method of PAEs varies with the sample matrix. Liquid-liquid extraction (LLE) is a common pretreatment method for PAEs in simple matrix liquid samples such as water, white spirit, beverages and the like, and normal hexane is usually adopted as an extraction solvent. The method has the advantages of simple operation, but also has the defects of large organic solvent consumption, secondary pollution to the environment, long time consumption, low recovery rate, serious emulsification phenomenon, difficult realization of automatic operation and the like.
Therefore, the establishment of an efficient qualitative and quantitative analysis method for dibutyl phthalate for detecting dibutyl phthalate in sufentanil citrate process liquid is of great significance.
Disclosure of Invention
In order to solve the technical problems, the first aspect of the invention provides a method for detecting an additive in a sufentanil drug, which comprises the following steps:
(1) sample treatment:
s1, dissolving sufentanil citrate in water, adjusting the pH value, adding water to 1000mL to obtain a sample mother solution,
s2, extracting the sampled mother liquor by using an organic solvent, separating an organic phase, adding a dehydrating agent, and taking a supernatant to be tested;
(2) preparing a standard solution; preparing a standard series solution of dibutyl phthalate;
(3) GC-MS testing was performed.
As a preferable technical scheme, in the step S1, sufentanil citrate is dissolved in water, then the pH is adjusted to be acidic, and water is added to 1000mL to obtain a sample mother solution.
As a preferable technical scheme, in the step S1, sufentanil citrate is dissolved in water, the pH value is adjusted to 3.7-4.2, and water is added to 1000mL to obtain a sample mother solution.
As a preferable technical scheme, the pH regulator is citric acid solution.
As a preferable technical solution, the organic solvent in step S2 is a mixed solvent of n-hexane, acetonitrile and ethyl acetate.
As a preferable technical scheme, the volume ratio of n-hexane, acetonitrile and ethyl acetate in the step S2 is (20-35): (1-3): 1.
as a preferable technical scheme, the volume ratio of the n-hexane, the acetonitrile and the ethyl acetate is 30: 3: 1.
as a preferable technical solution, the volume ratio of the sample mother liquor to the organic solvent in the step S2 is (1-4): 1.
as a preferred technical solution, the volume ratio of the sample mother liquor to the organic solvent in the step S2 is 2: 1.
as a preferred technical scheme, the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; the carrier gas is high-purity helium; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the column flow rate was 1.0 ml/min.
Has the beneficial effects that: the method can accurately detect the content of dibutyl phthalate in sufentanil, and is low in cost, simple, convenient and quick.
Detailed Description
For purposes of the following detailed description, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Moreover, other than in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range from "1 to 10" should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10. Exemplary subranges of the range 1 to 10 include, but are not limited to, 1 to 6.1, 3.5 to 7.8, 5.5 to 10, and the like.
In order to solve the problems, the invention provides a method for detecting an additive in a sufentanil medicament, which comprises the following steps:
(1) sample treatment:
s1, dissolving sufentanil citrate in water, adjusting the pH value, adding water to 1000mL to obtain a sample mother solution,
s2, extracting the sampled mother liquor by using an organic solvent, separating an organic phase, adding a dehydrating agent, and taking a supernatant to be tested;
(2) preparing a standard solution; preparing a standard series solution of dibutyl phthalate;
(3) GC-MS testing was performed.
As a preferable technical scheme, the mass of the sufentanil citrate in the step S1 is 37-150 mg.
Preferably, the mass of the sufentanil citrate in the step S1 is 75 mg.
As a preferable technical scheme, in the step S1, sufentanil citrate is dissolved in water, then the pH is adjusted to be acidic, and water is added to 1000mL to obtain a sample mother solution.
As a preferable technical scheme, in the step S1, sufentanil citrate is dissolved in water, the pH value is adjusted to 3.7-4.2, and water is added to 1000mL to obtain a sample mother solution.
Preferably, in the step S1, sufentanil citrate is dissolved in water, then the pH is adjusted to 4.0, and water is added to 1000mL to obtain a sample mother solution.
As a preferable technical scheme, the pH regulator is citric acid solution.
As a preferable technical scheme, the concentration of the citric acid solution is 0.1-1 wt%.
Preferably, the citric acid solution has a concentration of 0.5 wt%.
The citric acid solution refers to a solution of citric acid dissolved in water.
The concentration of the citric acid solution refers to the ratio of the mass of the citric acid to the sum of the masses of the citric acid and the water.
The inventor determines dibutyl phthalate in the sufentanil drug, and finds that the test result is more accurate by adopting citric acid, so that the recovery rate and the recovery rate RSD are excellent, and the inventor speculates that the probable reason is that the citric acid is adopted to dissolve the sufentanil citrate, so that foreign impurities cannot be introduced, and the matrix effect is weakened; secondly, the citric acid solution is adopted to have good solubility to the medicine, and the medicine can be fully dissolved under the condition and is not easy to decompose or oxidize and deteriorate by adjusting the PH to be 3.7-4.2, so that the substance to be tested can be prevented from being stained, and the testing accuracy is improved.
As a preferable technical solution, the organic solvent in step S2 is a mixed solvent of n-hexane, acetonitrile and ethyl acetate.
As a preferable technical scheme, the volume ratio of n-hexane, acetonitrile and ethyl acetate in the step S2 is (20-35): (1-3): 1.
as a preferable technical solution, the volume ratio of n-hexane, acetonitrile and ethyl acetate in the step S2 is 30: 3: 1.
the applicant finds that the sample mother liquor is extracted by n-hexane singly, the test result is poor due to low extraction efficiency, and the loss of time, resources and a sample is easily caused by increasing the amount of a solvent or extracting for multiple times, so that the test time can be effectively shortened and the recovery rate can be improved by compounding acetonitrile and ethyl acetate with the n-hexane, and when the volume ratio of the n-hexane to the acetonitrile to the ethyl acetate is 30: 3: when 1, the dibutyl phthalate extraction efficiency is good, and the test result is most accurate.
As a preferable technical solution, the volume ratio of the sample mother liquor to the organic solvent in the step S2 is (1-4): 1.
as a preferred technical solution, the volume ratio of the sample mother liquor to the organic solvent in the step S2 is 2: 1.
the applicant finds that the ratio of the sample mother liquor to the organic solvent needs to be controlled to be (1-4): 1, if the proportion of the solvent is too high, partial volatilization of the solvent is easily caused, so that interference impurities in the mother liquor are separated out before detection, partial blockage of a detection passage is easily caused, and the test result is inaccurate; if the solvent ratio is too low, the substance to be detected in the mother liquor is not completely extracted, which easily results in a low detection result.
As a preferable technical solution, in the step S2, the dehydrating agent is at least one selected from anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium sulfate.
As a preferable technical solution, in the step S2, the dehydrating agent is anhydrous magnesium sulfate.
As a preferred technical scheme, at least 5 standard series solutions of dibutyl phthalate with gradient are prepared in the step (2).
As a preferred technical scheme, 6 standard series solutions of graded dibutyl phthalate are prepared in the step (2).
Preferably, the concentration of the 6 graded dibutyl phthalate series solution in the step (2) is 5, 20, 40, 60, 80 and 100 mu g/L respectively.
As a preferred technical scheme, 7 standard series solutions of graded dibutyl phthalate are prepared in the step (2).
Preferably, the concentration of the 7 graded dibutyl phthalate standard series solution in the step (2) is 2, 5, 20, 40, 60, 80 and 100 mu g/L respectively.
As a preferred technical scheme, 5 standard series solutions of graded dibutyl phthalate are prepared in the step (2).
Preferably, the concentration of the 5 graded dibutyl phthalate standard series solution in the step (2) is 20, 40, 60, 80 and 100 mu g/L respectively.
Preferably, the solvent of the standard series of solutions of dibutyl phthalate in step (2) is the same as the organic solvent in step S2.
As a preferred technical scheme, the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; the carrier gas is high-purity helium; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the column flow rate was 1.0 ml/min.
As a preferred technical scheme, the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min.
As a preferred technical scheme, the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min.
As a preferred technical scheme, the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ions: 104. 149, 223 m/z.
The present invention will be specifically described below by way of examples. It should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and that the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above disclosure are still within the scope of the present invention.
In addition, the starting materials used are all commercially available, unless otherwise specified.
Examples
Example 1
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg sufentanil citrate in 900mL of water, adjusting the pH to 3.7 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a sample, putting the mother liquor into an analysis bottle, adding 10mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ion: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 20: 1: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 2
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg sufentanil citrate in 900mL of water, adjusting the pH value to 4.2 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a product into an analysis bottle, adding 10mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: raising the temperature of 130 ℃ to 250 ℃ at every 20 ℃/min, and keeping the temperature for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ion: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 20: 1: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 3
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg sufentanil citrate in 900mL of water, adjusting the pH to 4.0 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a product into an analysis bottle, adding 10mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ion: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 20: 1: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 4
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg of sufentanil citrate in 900mL of water, adjusting the pH to 4.0 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a sample, putting the mother liquor into an analysis bottle, adding 10mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ions: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 35: 1: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 5
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg sufentanil citrate in 900mL of water, adjusting the pH to 4.0 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a product into an analysis bottle, adding 10mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: raising the temperature of 130 ℃ to 250 ℃ at every 20 ℃/min, and keeping the temperature for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ion: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 20: 3: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 6
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg of sufentanil citrate in 900mL of water, adjusting the pH to 4.0 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a product into an analysis bottle, adding 10mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ions: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are mixed solvents of n-hexane, acetonitrile and ethyl acetate respectively, and the volume ratio of the n-hexane to the acetonitrile to the ethyl acetate is 35: 3: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 7
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg sufentanil citrate in 900mL of water, adjusting the pH to 4.0 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a product into an analysis bottle, adding 10mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ions: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 30: 3: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 8
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg sufentanil citrate in 900mL of water, adjusting the pH to 4.0 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, sampling 10mL of mother liquor of a sample, putting the mother liquor into an analysis bottle, adding 2.5mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing;
(2) preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations are respectively 20, 40, 60, 80 and 100 mug/L;
(3) performing GC-MS tests, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ion: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 30: 3: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Example 9
A method for detecting an additive in a sufentanil drug comprises the following steps:
(1) sample treatment:
s1, dissolving 75mg sufentanil citrate in 900mL of water, adjusting the pH to 4.0 by using a citric acid solution, and adding water to 1000mL to obtain a sample mother solution;
s2, taking 10mL of sample mother liquor, putting the sample mother liquor into an analysis bottle, adding 5mL of organic solvent for extraction, separating an organic phase, adding anhydrous magnesium sulfate for dehydration, and then testing.
(2) Preparing a standard solution; preparing 5 standard series solutions of gradient dibutyl phthalate; the concentrations were 20, 40, 60, 80, 100. mu.g/L, respectively.
(3) And performing GC-MS test, wherein the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; specification: 30m 0.25mm 0.25 μm; the carrier gas is high-purity helium with the purity more than or equal to 99.999 percent; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the temperature of the transmission line is 300 ℃; the column flow rate was 1.0 ml/min; temperature rising procedure: heating to 250 deg.C at a temperature of 20 deg.C/min at 130 deg.C, and maintaining for 1 min; then the temperature is increased to 300 ℃ at the speed of 25 ℃/min and kept for 4 min. Mass spectrum conditions: the ion source temperature is 230 ℃; the temperature of the four-level bar is 150 ℃; solvent retardation: 4 min; scanning mode: SIM, select ion: 104. 149, 223 m/z.
Wherein the concentration of the citric acid solution is 0.5 wt%.
The organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are respectively a mixed solvent of n-hexane, acetonitrile and ethyl acetate, and the volume ratio of the n-hexane, the acetonitrile to the ethyl acetate is 30: 3: 1.
and (3) carrying out sample injection analysis on the standard substance solution in the step (2), and automatically calculating a regression equation by using an instrument by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate to obtain a linear correlation coefficient R larger than 0.999.
Comparative example 1
The specific steps of the method for detecting the additive in the sufentanil drug are the same as those in example 9, and the difference is that the pH value is adjusted to 3.0 by using a citric acid solution in the step S1.
Comparative example 2
The specific steps of the method for detecting the additive in the sufentanil drug are the same as those in example 9, and the difference is that the pH value is adjusted to 5.5 by using a citric acid solution in the step S1.
Comparative example 3
The specific steps of the method for detecting the additive in the sufentanil drug are the same as those in example 9, and the difference is that the organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are mixed solvents of n-hexane and acetonitrile, and the volume ratio of the n-hexane to the acetonitrile is 30: 4.
comparative example 4
The specific steps of the method for detecting the additive in the sufentanil drug are the same as those in example 9, and the difference is that the organic solvent in the step S2 and the solvent of the standard series solution of dibutyl phthalate in the step (2) are mixed solvents of n-hexane and ethyl acetate respectively, and the volume ratio of the n-hexane to the ethyl acetate is 30: 4.
GC-MS methodology investigation
The detection methods described in examples 1 to 9 and comparative examples 1 to 4 were verified, and the verification items and results are shown in table 1 below.
And (3) testing accuracy: taking 10mL of the mother liquor of the samples of the examples, adding a dibutyl phthalate reference substance into the analysis bottle, adding the organic solvent obtained in the step S2 of the examples, separating the organic phase, adding anhydrous magnesium sulfate, dehydrating and then testing. Wherein, the DBP adding concentration is 60 mug/L, and the proportion of the sample mother liquor and the organic solvent is the same as that of each embodiment. A total of 6 accurate solutions were prepared in parallel in the same way.
Precision-repeatability test: solution preparation the same accuracy solution preparation.
Detection of quantitative limit: taking 10mL of the mother liquor of the samples of the examples, adding a dibutyl phthalate reference substance into the analysis bottle, adding the organic solvent obtained in the step S2 of the examples, separating the organic phase, adding anhydrous magnesium sulfate, dehydrating and then testing. Wherein, the DBP adding concentration is 20 mug/L, and the proportion of the sample mother liquor and the organic solvent is the same as that of each embodiment. A total of 3 quantitation limit solutions were prepared in parallel in the same manner.
Table 1 verification results
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in other forms, and any person skilled in the art may modify or change the technical content of the above disclosure into equivalent embodiments with equivalent changes, but all those simple modifications, equivalent changes and modifications made to the above embodiments according to the technical spirit of the present invention still belong to the protection scope of the present invention.
Claims (1)
1. A method for detecting dibutyl phthalate in sufentanil is characterized by comprising the following steps:
(1) sample treatment:
s1, dissolving sufentanil citrate in water, adjusting the pH value, adding water to 1000mL to obtain a sample mother solution,
s2, extracting the sampled mother liquor by using an organic solvent, separating an organic phase, adding a dehydrating agent, and taking a supernatant to be tested;
(2) preparing a standard solution; preparing a standard series solution of dibutyl phthalate;
(3) performing GC-MS test;
in the step S1, sufentanil citrate is dissolved in water, the pH value is adjusted to 3.7-4.2 by using a citric acid solution, and water is added to 1000mL to obtain a sample mother solution;
the concentration of the citric acid solution is 0.5 wt%;
the organic solvent in the step S2 is a mixed solvent of n-hexane, acetonitrile and ethyl acetate, wherein the volume ratio of n-hexane, acetonitrile and ethyl acetate is 30: 3: 1;
the dehydrating agent in the step S2 is at least one selected from anhydrous magnesium sulfate, anhydrous sodium sulfate and anhydrous calcium sulfate;
the volume ratio of the sample mother liquor to the organic solvent in the step S2 is 2: 1;
the chromatographic conditions of the GC-MS are as follows: the chromatographic column is HP-5 MS; the carrier gas is high-purity helium; the temperature of a sample inlet is 300 ℃; the sample injection amount is 1 mu L; the sample feeding mode does not split; the column flow rate was 1.0 ml/min.
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