CN111812234A - Method for detecting residual solvent in pantoprazole sodium sesquihydrate - Google Patents
Method for detecting residual solvent in pantoprazole sodium sesquihydrate Download PDFInfo
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- 229960005019 pantoprazole Drugs 0.000 title claims abstract description 36
- 239000013557 residual solvent Substances 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 33
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 title claims abstract description 21
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 6
- 238000011067 equilibration Methods 0.000 claims description 6
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 claims description 6
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- 238000011002 quantification Methods 0.000 abstract description 4
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- CGJRLPRCWSHOFU-UHFFFAOYSA-N sodium;5-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]benzimidazol-1-ide;hydrate Chemical compound O.[Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC CGJRLPRCWSHOFU-UHFFFAOYSA-N 0.000 description 21
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- 238000002474 experimental method Methods 0.000 description 7
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- YYRIKJFWBIEEDH-UHFFFAOYSA-N 2-(chloromethyl)-3,4-dimethoxypyridine;hydrochloride Chemical compound [Cl-].COC1=CC=[NH+]C(CCl)=C1OC YYRIKJFWBIEEDH-UHFFFAOYSA-N 0.000 description 1
- WHCXDEORRDVLKS-UHFFFAOYSA-N 6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole;sodium Chemical compound [Na].COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC WHCXDEORRDVLKS-UHFFFAOYSA-N 0.000 description 1
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- 108010052343 Gastrins Proteins 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
Abstract
The invention provides a method for detecting a residual solvent in pantoprazole sodium sesquihydrate, which comprises the following steps: (1) preparing a test solution, wherein the test solution comprises pantoprazole sodium sesquihydrate and a solvent; the solvent comprises dimethyl sulfoxide and/or water; (2) preparing a control solution comprising methanol, dichloromethane, ethanol, acetonitrile, and benzene; the solvent is the same as the solvent in the step (1); (3) carrying out headspace gas chromatography test by using a medium-polarity capillary column and adopting programmed temperature rise; wherein, the sequence of the steps (1) and (2) is not divided into sequences. The method can simultaneously detect the residual amounts of methanol, dichloromethane, ethanol, acetonitrile and benzene in the pantoprazole sodium sesquihydrate. The method has good specificity, system adaptability, extremely low detection limit and quantification limit, good linearity, good accuracy and durability.
Description
Technical Field
The invention relates to the technical field of drug analysis, in particular to a method for detecting residual solvent in pantoprazole sodium sesquihydrate.
Background
Pantoprazole sodium (pantoprazole sodium) with chemical name 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) -methyl]sulfinyl-1H-benzimidazole sodium salt, is H+，K+The ATP enzyme inhibitor can inhibit gastric acid secretion stimulated by various factors such as histamine, gastrin, acetylcholine and the like, is used for treating diseases related to gastric acid secretion disorder, and has the advantages of high cure rate, quick response, small adverse reaction and the like. Pantoprazole sodium is usually a monohydrate or an anhydrate.
The pantoprazole sodium sesquihydrate manufacturer is a Jiutai pharmaceutical industry, Inc. in Jinzhou, and belongs to the first manufacturer for developing sesquihydrate raw material medicines at home. According to a synthesis line for analyzing raw material medicines, in a process route for synthesizing pantoprazole starting material 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride (SM-1) by dimethyl sulfate, dichloromethane, methanol and ethanol are respectively used; in the process route for synthesizing pantoprazole sodium from SM-1, acetonitrile, methyl formate, ethanol, acetone and ethyl acetate are respectively used.
According to the corresponding recommendations of EMEA (european medicines agency), all projects using solvents such as acetone and toluene need to consider the risk of introducing benzene, and therefore benzene needs to be detected at the same time. The U.S. pharmacopoeia 41 edition, the European pharmacopoeia 9.6 edition and the British pharmacopoeia 2019 edition collect the quality standard of pantoprazole sodium sesquihydrate, but do not collect the standard and the detection method of residual solvent. The second part of the Chinese pharmacopoeia 2015 is loaded with mass standards of pantoprazole monohydrate, and a detection method and limits of acetone and toluene are loaded.
In order to detect the residual solvent in the pantoprazole sodium sesquihydrate more comprehensively, the variety of the residual solvent needs to be expanded and detected. Furthermore, the residual solvent benzene is difficult to detect because of the very low benzene limit.
Disclosure of Invention
The invention provides a method for detecting residual solvent in pantoprazole sodium sesquihydrate, aiming at solving the problem of limited types of residual solvent in pantoprazole sodium sesquihydrate in the prior art. The method can simultaneously detect the residual amounts of methanol, dichloromethane, ethanol, acetonitrile and benzene in the pantoprazole sodium sesquihydrate. The method has good specificity, system adaptability, extremely low detection limit and quantification limit, good linearity, good accuracy and durability.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a method for detecting residual solvent in pantoprazole sodium sesquihydrate, which is a method for detecting residual solvent according to a second method of 0861 in the four-part rule of the national pharmacopoeia 2015 edition and comprises the following steps of:
(1) preparing a test solution, wherein the test solution comprises pantoprazole sodium sesquihydrate and a solvent; the solvent comprises dimethyl sulfoxide and/or water;
(2) preparing a control solution comprising methanol, dichloromethane, ethanol, acetonitrile, and benzene; the solvent is the same as the solvent in the step (1);
(3) carrying out headspace gas chromatography test by using a medium-polarity capillary column and adopting programmed temperature rise;
wherein, the sequence of the steps (1) and (2) is not divided into sequences.
In the invention, in the step (1), the weighing mass of the pantoprazole sodium sesquihydrate can be conventional in the art, and is preferably 0.1-1 g, more preferably 0.15-0.8 g, and most preferably 0.5g according to the general rule of the four kingdoms of pharmacopoeia 2015 edition.
In the present invention, in step (1), preferably, the solvent is a mixture of dimethyl sulfoxide and water, and more preferably, the volume ratio of dimethyl sulfoxide to water is 8: 2.
in the invention, in the step (1), the solvent can be used in an amount which is conventional in the art and is used for dissolving the pantoprazole sodium sesquihydrate.
The concentration of the pantoprazole sodium sesquihydrate in the test solution is preferably 0.02-0.5 g/mL, more preferably 0.05-0.2 g/mL, and most preferably 0.1 g/mL.
Preferably, the pantoprazole sodium sesquihydrate is 0.5g, and the solvent is 5 mL.
In a preferred embodiment of the present invention, the specific operation of step (1) is: taking 0.5g of pantoprazole sodium sesquihydrate, precisely weighing, placing in a headspace bottle, adding 5ml of solvent [ dimethyl sulfoxide-water (80-20) ] to dissolve, and sealing to obtain a test solution.
In the present invention, in the step (2), the concentrations of the methanol, the dichloromethane, the ethanol, the acetonitrile and the benzene in the control solution may be determined according to a conventional method in the art, and are generally the limits each of which is a residual solvent. Benzene is a first solvent (solvent which should be avoided) according to the classification of residual solvents in ICH (International conference on coordination of human drug registration technology) Q3C, and is carcinogenic, so that benzene should not be used in the production of bulk drugs, excipients and preparations, and the limit is 2 ppm; dichloromethane, methanol, acetonitrile are a second class of solvents, and due to their inherent toxicity, their use in pharmaceutical formulations should be limited, with limits established as calculated by ICH Q3C: c(ppm)1000 × PDE/dose, dichloromethane (CH)2Cl2) Limit of (2) is 0.06%, methanol (CH)3OH) limit of 0.3%, acetonitrile (CH)3CN) limit ofIs 0.041%; ethanol is a third solvent, and the third solvent has lower toxicity and less harm to human bodies; ethanol (CH)3CH2OH) limit of 0.5%. The percentage is the percentage of the mass of residual solvent relative to the mass of pantoprazole sodium sesquihydrate. Namely, the concentrations of the methanol, the dichloromethane, the ethanol, the acetonitrile and the benzene in the control solution are respectively 0.3%, 0.06%, 0.5%, 0.041% and 0.0002% of the concentration of the pantoprazole sodium sesquihydrate.
In the present invention, in the step (2), the control solution may be prepared by a method conventional in the art.
Preferably, the preparation method of the control solution comprises the following steps: preparing a reference stock solution containing methanol, dichloromethane, ethanol, acetonitrile and benzene; an amount of the control stock solution was diluted. Wherein the dilution multiple of the reference stock solution can be 5-20 times.
Preferably, the preparation method of the reference stock solution comprises the following steps: preparing a first stock solution containing methanol, dichloromethane, ethanol and acetonitrile and a second stock solution containing benzene respectively; and then mixing a certain amount of the first stock solution and the second stock solution to obtain the reference substance stock solution.
More preferably, the preparation method of the second stock solution comprises the following steps: preparing a benzene intermediate stock solution, and then diluting the benzene intermediate stock solution to obtain the second stock solution. The dilution factor of the benzene intermediate stock solution may be 100 to 300 times, preferably 200 times.
In a preferred embodiment of the present invention, the specific operation of step (2) is: accurately weighing 300mg of methanol, 60mg of dichloromethane, 500mg of ethanol and 41mg of acetonitrile, placing the weighed materials into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the materials to a scale, and shaking the materials uniformly to obtain a first stock solution; the preparation process of the benzene intermediate stock solution comprises the following steps: precisely weighing 40mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the benzene to a scale, and shaking up to obtain a benzene intermediate stock solution; precisely transferring 0.5ml of the benzene intermediate stock solution into a 100ml measuring flask with 2-5ml of solvent, adding the solvent to dilute to a scale, and shaking up to obtain a second stock solution; precisely transferring 10ml of the first stock solution and 10ml of the second stock solution into a 100ml measuring flask, and shaking up to obtain a reference stock solution; diluting with solvent to scale, precisely sucking 5ml into a headspace bottle, sealing, and shaking to obtain reference solution.
In the present invention, in the step (3), the medium polarity capillary column may be a capillary column conventional in the art.
Preferably, the moderately polar capillary column is one of (35%) diphenyl-dimethylpolysiloxane, (50%) diphenyl-dimethylpolysiloxane, (35%) diphenyl-dimethylarylene polysiloxane, (14%) cyanopropylphenyl-dimethylpolysiloxane, and (6%) cyanopropylphenyl-methylpolysiloxane.
More preferably, the moderately polar capillary column is (6%) cyanopropylphenyl-methylpolysiloxane.
In the present invention, in the step (3), the temperature raising procedure may be a temperature raising procedure conventional in the art.
Preferably, the temperature programming includes: the initial temperature is 34-36 ℃, the temperature is kept for 5 minutes, then the temperature is raised to 240 ℃ at the rate of 18 ℃ per minute, and the temperature is kept for 2 minutes; the injection port temperature is 180 ℃, the column flow rate is 1.1-1.3 ml/min, the detector temperature is 250 ℃, the headspace bottle equilibrium temperature is 85 ℃, the equilibrium time is 38-42 minutes, the quantitative loop temperature is 100 ℃, and the transmission line temperature is 150 ℃.
More preferably, the temperature programming includes: the initial temperature was 35 ℃ for 5 minutes, then the temperature was raised to 240 ℃ at a rate of 18 ℃ per minute for 2 minutes; the injection port temperature was 180 ℃, the column flow rate was 1.2 ml/min, the detector temperature was 250 ℃, the headspace bottle equilibration temperature was 85 ℃, the equilibration time was 40 minutes, the quantitative loop temperature was 100 ℃, and the transmission line temperature was 150 ℃.
In the present invention, in the step (3), the headspace gas chromatography test may be performed by a method conventional in the art.
Preferably, the headspace gas chromatography test employs a FID detector.
Preferably, the carrier gas used in the headspace gas chromatography test is nitrogen.
In a preferred embodiment of the present invention, the specific operation of step (3) is:
a capillary column (Agilent DB-62430 m.times.0.32 mm, 1.8 μm, or equivalent performance column) using (6% cyanopropylphenyl) -methylpolysiloxane as the stationary liquid; adopting temperature programming: the initial temperature was 35 ℃, held for 5 minutes, then raised to 240 ℃ at a rate of 18 ℃ per minute, held for 2 minutes, using a FID detector; the injection port temperature is 180 ℃, the carrier gas is nitrogen, the column flow rate is 1.2 ml/min, the detector temperature is 250 ℃, the headspace bottle equilibrium temperature is 85 ℃, the equilibrium time is 40 minutes, the quantitative loop temperature is 100 ℃, and the transmission line temperature is 150 ℃; sampling the reference solution and the sample solution, and recording the chromatogram.
In a best embodiment of the invention, the method for detecting the residual solvent in the pantoprazole sodium sesquihydrate specifically comprises the following operations:
(1) preparing a test solution: taking 0.5g of pantoprazole sodium sesquihydrate, precisely weighing, placing in a headspace bottle, adding 5ml of solvent [ dimethyl sulfoxide-water (80-20) ] to dissolve, and sealing to obtain a test solution;
(2) preparation of control solutions: accurately weighing 300mg of methanol, 60mg of dichloromethane, 500mg of ethanol and 41mg of acetonitrile, placing the weighed materials into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the materials to a scale, and shaking the materials uniformly to obtain a first stock solution; precisely weighing 40mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the benzene to a scale, and shaking up to obtain a benzene intermediate stock solution; precisely transferring 0.5ml of the benzene intermediate stock solution into a 100ml measuring flask with 2-5ml of solvent, adding the solvent to dilute to a scale, and shaking up to obtain a second stock solution; precisely transferring 10ml of the first stock solution and 10ml of the second stock solution into a 100ml measuring flask, and shaking up to obtain a reference stock solution; diluting with solvent to scale, precisely sucking 5ml into a headspace bottle, sealing, and shaking to obtain reference solution;
(3) and (3) carrying out headspace gas chromatography test by using a medium polarity capillary column and adopting temperature programming: a capillary column (Agilent DB-62430m × 0.32mm, 1.8 μm, or a comparable performance column) using (6% cyanopropylphenyl) -methylpolysiloxane as a stationary liquid, as determined by the residual solvent assay (second method 0861, fourth pharmacopoeia 2015 edition); adopting temperature programming: the initial temperature was 35 ℃, held for 5 minutes, then raised to 240 ℃ at a rate of 18 ℃ per minute, held for 2 minutes, using a FID detector; the injection port temperature is 180 ℃, the carrier gas is nitrogen, the column flow rate is 1.2 ml/min, the detector temperature is 250 ℃, the headspace bottle equilibrium temperature is 85 ℃, the equilibrium time is 40 minutes, the quantitative loop temperature is 100 ℃, and the transmission line temperature is 150 ℃; sampling the reference solution and the sample solution, and recording the chromatogram.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) the method can simultaneously detect the residual amounts of methanol, ethanol, acetonitrile, dichloromethane and benzene in the pantoprazole sodium sesquihydrate.
(2) The method has good specificity, no interference peak is generated near the peak position of a target peak in a blank solution map, and the separation degrees of methanol, ethanol, acetonitrile, dichloromethane and benzene are all more than 3.
(3) The invention has good system adaptability, and RSD of the peak-off time of methanol, ethanol, acetonitrile, dichloromethane and benzene is less than 0.06%; RSD of peak area is less than 3%; the tailing factors are all less than 1.5.
(4) The invention has extremely low detection limit and quantification limit.
(5) The invention has good linearity.
(6) The method has good precision, and the RSD of the solvent peak areas of methanol, ethanol, acetonitrile, dichloromethane and benzene are all less than 3%; RSD of f values were all less than 3%.
(7) The method has good accuracy, and the RSD of the solvent peak areas of methanol, ethanol, acetonitrile, dichloromethane and benzene is less than 2.2%; the recovery rates RSD are all less than 4.5%.
(8) The invention has better durability.
Drawings
FIG. 1 is a gas chromatogram of a sample solution in example 1 of the present invention.
Fig. 2 is a gas chromatogram of a blank solution of validation example 1 of the present invention.
Fig. 3 is a gas chromatogram of the separation solution of validation example 1 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
(1) Preparing a test solution: taking 0.5g of pantoprazole sodium sesquihydrate, precisely weighing, placing in a headspace bottle, adding 5ml of solvent [ dimethyl sulfoxide-water (80-20) ] to dissolve, and sealing to obtain a test solution.
(2) Preparation of control solutions: accurately weighing 300mg of methanol, 60mg of dichloromethane, 500mg of ethanol and 41mg of acetonitrile, placing the weighed materials into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the materials to a scale, and shaking the materials uniformly to obtain a first stock solution; precisely weighing 40mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the benzene to a scale, and shaking up to obtain a benzene intermediate stock solution; precisely transferring 0.5ml of the benzene intermediate stock solution into a 100ml measuring flask with 2-5ml of solvent, adding the solvent to dilute to a scale, and shaking up to obtain a second stock solution; precisely transferring 10ml of the first stock solution and 10ml of the second stock solution into a 100ml measuring flask, and shaking up to obtain a reference stock solution; diluting to scale with solvent, precisely sucking 5ml into a headspace bottle, sealing, and shaking to obtain control solution.
(3) And (3) carrying out headspace gas chromatography test by using a medium polarity capillary column and adopting temperature programming: a capillary column (Agilent DB-62430m × 0.32mm, 1.8 μm, or a comparable performance column) using (6% cyanopropylphenyl) -methylpolysiloxane as a stationary liquid, as determined by the residual solvent assay (second method 0861, fourth pharmacopoeia 2015 edition); adopting temperature programming: the initial temperature was 35 ℃, held for 5 minutes, then raised to 240 ℃ at a rate of 18 ℃ per minute, held for 2 minutes, using a FID detector; the injection port temperature was 180 ℃, the carrier gas was nitrogen, the column flow rate was 1.2 ml/min, the detector temperature was 250 ℃, the headspace bottle equilibration temperature was 85 ℃, the equilibration time was 40 minutes, the quantitative loop temperature was 100 ℃, and the transmission line temperature was 150 ℃. Sampling the reference solution and the sample solution, and recording the chromatogram. The separation degree of each peak can realize effective separation, and the sample solvent has no interference. FIG. 1 is a gas chromatogram of a sample solution.
Verification example 1
Selective interference and system applicability: preparing blank solution, residual solvent positioning solution, reference solution, sample solution, separation degree solution and system applicability solution, and determining according to analysis method (GC-HS) of methanol, ethanol, acetonitrile, dichloromethane and benzene.
In the obtained map, the blank solution does not interfere with the inspection of each solvent peak; in the resolution solution, the resolution of each residual solvent peak and adjacent peaks is more than or equal to 1.5.
RSD of each residual solvent peak-out time of 6 needles of continuous sample injection of the system applicability solution is less than or equal to 1%, RSD of peak area is less than or equal to 10%, and tailing factor is less than or equal to 2.0.
Solution preparation
Blank solution: accurately transferring 5ml of diluent to a top empty bottle, and sealing to obtain the final product.
Test solution: precisely weighing 500.01mg pantoprazole sodium sample, placing in a 20ml headspace bottle, adding 5ml diluent for dissolving, and shaking up to obtain the final product.
Methanol positioning solution: accurately weighing 303.5mg of methanol, placing into a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute to scale, and shaking up to obtain the final product.
Dichloromethane positioning solution: accurately weighing 61.0mg of dichloromethane, placing the dichloromethane into a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute the dichloromethane to a scale, and shaking up to obtain the dichloromethane-free water-soluble film.
Ethanol positioning solution: accurately weighing 500.5mg of ethanol, placing into a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute to scale, and shaking up to obtain the final product.
Acetonitrile positioning solution: accurately weighing 42.4mg of acetonitrile, placing the acetonitrile in a 100ml measuring flask with 10ml of diluent, adding the diluent for quantitative dissolution, diluting to a scale, and shaking up to obtain the final product.
Benzene localization solution: precisely weighing 44.6mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of diluent, adding ultrapure water for dissolving, diluting to scale, and shaking up to obtain the benzene intermediate stock solution. Precisely transferring 0.5ml of benzene intermediate stock solution, placing into a measuring flask with 100ml of existing 2.5ml of diluent, diluting to scale with the diluent, and shaking up to obtain the final product.
Control stock solutions: accurately weighing 304.2mg and 303.8mg of methanol, 61.5mg and 63.8mg of dichloromethane, 500.3mg and 500.0mg of ethanol, 43.7mg of acetonitrile and 44.5mg of acetonitrile, placing the materials in a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute the materials to a scale, shaking up the materials to serve as reference stock solutions which are marked as reference stock solution #1 and reference stock solution # 2.
Benzene control stock solution: accurately weighing 43.9mg and 44.7mg of benzene, placing the weighed materials into a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute scales, and shaking up to obtain the benzene intermediate stock solution. Then accurately transferring 0.5ml of benzene intermediate stock solution, placing the intermediate stock solution in a 100ml measuring flask with 2.5ml of diluent, diluting the intermediate stock solution to a scale by using the diluent, shaking up, and taking the intermediate stock solution as benzene reference stock solution which is marked as benzene reference stock solution #1 and benzene reference stock solution # 2.
Control solution: accurately transferring 10ml of each of the reference substance stock solution #1 and the benzene reference substance stock solution #1, placing 10ml of each of the reference substance stock solution #2 and the benzene reference substance stock solution #2 in a 100ml measuring flask with 2.5ml of diluent, diluting the solution to a scale with the diluent, shaking up to obtain reference substance solutions, and marking the reference substance solutions as a reference substance solution #1 and a reference substance solution # 2.
Resolution solution: precisely weighing 500.55mg of pantoprazole sodium sample, placing the pantoprazole sodium sample in a 20ml headspace bottle, adding 5ml of reference solution #1, and shaking up to obtain the pantoprazole sodium sample.
System applicability solution: precisely measuring 15ml of the reference solution, placing in a headspace bottle, and sealing.
Specificity and System applicability results
TABLE 1 results of specialization
TABLE 2 System suitability results
Fig. 2 is a gas chromatogram of a blank solution, and fig. 3 is a gas chromatogram of a separation solution.
And (4) conclusion: blank interference: the blank solution does not interfere with the detection of each solvent; separation degree: the separation degree between every two adjacent peaks is not less than 1.5, and the separation degree is good; the system precision is that the peak time RSD of each residual solvent of 6 needles for continuous sampling is less than or equal to 1 percent, the RSD of the peak area is less than or equal to 10 percent, the tailing factors are less than or equal to 2.0 percent, and the system precision is good.
Verification example 2
Detection limit and quantification limit: the limit of detection (LOD) and limit of quantitation (LOQ) are determined by a signal-to-noise ratio method, and the lowest concentration or percentage that can be reliably detected is calculated by comparing the measured signal to the baseline noise. Diluting each residual solvent stock solution with known concentration to low concentration, and determining according to a method, wherein the S/N ratio of the detection limit signal to noise is required to be more than or equal to 3; the quantitative limit signal-to-noise ratio S/N is more than or equal to 10, and the RSD of the peak area of the LOQ solution of 6 needles is less than or equal to 15 percent.
Solution preparation
Blank solution: precisely transferring 5ml of diluent into a top empty bottle, and sealing to obtain the final product.
Quantitative limiting solution: precisely transferring 0.2ml of methanol positioning solution, 0.2ml of dichloromethane positioning solution, 0.125ml of ethanol positioning solution, 0.5ml of acetonitrile positioning solution and 2.5ml of benzene positioning solution, putting the mixture into a 100ml measuring flask with 2.5ml of diluent, adding the diluent to a constant volume, and shaking up to obtain the product.
Detection limiting solution: accurately transferring 2.5ml of the quantitative limiting solution, placing the quantitative limiting solution into a 10ml measuring flask with 2.5ml of diluent, adding the diluent to a constant volume, and shaking up to obtain the final product.
TABLE 3 detection Limit results
TABLE 4 quantitative limit results
And (4) conclusion: (1) the signal-to-noise ratios of the detection limit solutions of methanol, ethanol, acetonitrile, dichloromethane and benzene are respectively 19.8, 11.3, 11.2 and 15.0, and all the detection limit solutions meet the acceptance standard (the signal-to-noise ratio S/N of the detection limit of each residual solvent is more than or equal to 3); the signal-to-noise ratios of the quantitative limiting solution methanol, ethanol, acetonitrile, dichloromethane and benzene are respectively 32.7, 26.8, 23.8, 48.0 and 12.7; the peak area RSD of each residual solvent of 6 quantitive limiting solutions is less than or equal to 15 percent and meets the acceptance standard.
Verification example 3
Linearity: uniformly selecting 6 concentration levels from the quantitative limit to the 150% concentration of each residual solvent limit to prepare a solution, determining according to a method, fitting a curve by taking the main peak concentration as an abscissa and the peak area as an ordinate, and performing linear regression by taking Y as aX + b and requiring that the correlation coefficient r is more than or equal to 0.99; the peak area of Y-axis intercept/limit concentration should be less than or equal to 25%.
Solution preparation
Blank solution: accurately transferring 5ml of diluent to a top empty bottle, and sealing to obtain the final product.
Methanol positioning solution: accurately weighing 304.0mg of methanol, placing into a 100ml measuring flask with 10ml of diluent, adding the diluent to a constant volume to scale, and shaking up to obtain the final product, which is marked as ID-MeOH.
Dichloromethane positioning solution: accurately weighing 62.1mg of dichloromethane, placing the dichloromethane into a 100ml measuring flask with 10ml of diluent, adding the diluent to a constant volume to scale, and shaking up to obtain the product marked as ID-DCM.
Ethanol positioning solution: accurately weighing 501.6mg of ethanol, placing into a 100ml measuring flask with 10ml of diluent, adding the diluent to a constant volume to scale, and shaking up to obtain the label ID-EtOH.
Acetonitrile positioning solution: accurately weighing 44.3mg of acetonitrile, placing the acetonitrile in a 100ml measuring flask with 10ml of diluent, adding the diluent to a constant volume to scale, and shaking up to obtain the mark ID-ACN.
Control stock solutions: accurately weighing 304.0mg and 303.1mg of methanol, 60.1mg and 61.9mg of dichloromethane, 501.8mg and 501.6mg of ethanol, 42.3mg and 41.7mg of acetonitrile, respectively placing in a 100ml measuring flask with 10ml of diluent, adding the diluent to a constant volume scale, shaking up, and taking the solution as a reference stock solution which is marked as a reference stock solution 1 and a reference stock solution 2.
Benzene control stock solution: precisely weighing 44.1mg and 44.0mg of benzene, respectively placing into a 100ml measuring flask with 10ml of diluent, adding the diluent to a constant volume scale, and shaking up to obtain an intermediate benzene stock solution. And accurately transferring 0.5ml of Benzene intermediate Stock solution, placing the Benzene intermediate Stock solution into a 100ml measuring flask with 2.5ml of diluent, adding the diluent to a constant volume scale, shaking up, and taking the mixture as a Benzene reference Stock solution which is marked as Benzene Stock #1 and Benzene Stock # 2.
Control solution: precisely transferring 10ml of the reference substance stock solution 1 and the benzene reference substance stock solution 1, respectively placing the reference substance stock solution 2 and the benzene reference substance stock solution 2 into 100ml measuring bottles with 2.5ml of diluent, adding the diluent to a constant volume, shaking up to obtain reference substance solutions, and marking as the reference substance solution 1 and the reference substance solution 2.
TABLE 5 Linear solution formulation
Results and conclusions of the experiment
TABLE 6 results of methanol linearity experiment
TABLE 7 Linear ethanol test results
TABLE 8 acetonitrile Linear Experimental results
TABLE 9 Linear test results for methylene chloride
TABLE 10 results of benzene linearity experiment
And (4) conclusion: the methanol concentration is in the range of 6.08-456.00 mug/ml, the linearity is good, and the correlation coefficient (r) is more than or equal to 0.99; the peak area of the absolute value/limit concentration of the Y-axis intercept is less than or equal to 25 percent and meets the acceptance standard. The ethanol concentration is in the range of 6.27-752.70 mug/ml, the linearity is good, and the correlation coefficient (r) is more than or equal to 0.99; the peak area of the absolute value/limit concentration of the Y-axis intercept is less than or equal to 25 percent and meets the acceptance standard. The concentration of the acetonitrile is within the range of 2.22-63.45 mu g/ml, the linearity is good, and the correlation coefficient (r) is more than or equal to 0.99; the peak area of the absolute value/limit concentration of the Y-axis intercept is less than or equal to 25 percent and meets the acceptance standard). The concentration of the dichloromethane is in the range of 1.24-90.15 mu g/ml, the linearity is good, and the correlation coefficient (r) is more than or equal to 0.99; the peak area of the absolute value/limit concentration of the Y-axis intercept is less than or equal to 25 percent and meets the acceptance standard. The benzene concentration is in the range of 0.06-0.33 mu g/ml, the linearity is good, and the correlation coefficient (r) is more than or equal to 0.99; the peak area of the absolute value/limit concentration of the Y-axis intercept is less than or equal to 25 percent and meets the acceptance standard.
Verification example 4
Accuracy is achieved by measuring the test solution at three different concentration levels and calculating the recovery between the measured and theoretical values. Selecting concentration levels of 50%, 100% and 150% of the limit of residual solvent, preparing 3 parts of sample solution in parallel at each concentration level, and determining according to the method that the recovery rates of methanol and ethanol are required to be 90-108%; the recovery rates of acetonitrile and dichloromethane are both 85-110%; the recovery rate of benzene is 75-120%; the recovery rate RSD is less than or equal to 15 percent.
Blank solution: DMSO-H2O(80：20)
Control stock # 1: accurately transferring 300.0mg of methanol, 60.9mg of dichloromethane, 500.9mg of ethanol and 41.3mg of acetonitrile, placing the mixture into a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute the mixture to a scale, and shaking up the mixture to obtain the methanol-dichloromethane-acetonitrile mixed measuring flask.
Control stock # 2: precisely transferring 301.7mg of methanol, 61.0mg of dichloromethane, 501.8mg of ethanol and 41.6mg of acetonitrile into a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute to a scale, and shaking up to obtain the product.
Benzene control stock # 1: accurately weighing 43.8mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of diluent, adding the diluent to dissolve and dilute the benzene to a scale, and shaking up to obtain the benzene intermediate stock solution. Precisely measuring 0.5ml of benzene intermediate stock solution, placing into a 100ml measuring flask with 2.5ml of diluent, diluting to scale with diluent, and shaking.
Benzene control stock # 2: precisely weighing 43.6mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of diluent, adding ultrapure water for dissolving, diluting to scale, and shaking up to obtain the benzene intermediate stock solution. Precisely measuring 0.5ml of benzene intermediate stock solution, placing into a 100ml measuring flask with 2.5ml of diluent, diluting to scale with diluent, and shaking.
Control solution # 1: accurately weighing 10ml of each of the reference substance stock solution #1 and the benzene reference substance stock solution #2, placing the reference substance stock solution #1 and the benzene reference substance stock solution #2 into a 100ml measuring flask with 2.5ml of diluent, diluting the reference substance stock solution # with the diluent to a scale, and shaking up to obtain the product.
Control solution # 2: accurately transferring 10ml of each of the reference substance stock solution #2 and the benzene reference substance stock solution #2 into a 100ml measuring flask with 2.5ml of diluent, diluting to scale with the diluent, and shaking up to obtain the final product.
50% limiting concentration: precisely measuring the reference substance stock solution #1 and the benzene reference substance stock solution #1 by 1.25ml respectively, placing into a 25ml measuring flask with 2.5ml of diluent, diluting to scale with the diluent, and shaking up to obtain the final product.
100% limit concentration: precisely measuring the reference substance stock solution #1 and the benzene reference substance stock solution #1 by 2.5ml respectively, placing into a 25ml measuring flask with 2.5ml of diluent, diluting to scale with the diluent, and shaking up to obtain the final product.
150% limit concentration: precisely measuring 3.75ml of each of the reference substance stock solution #1 and the benzene reference substance stock solution #1, placing the reference substance stock solution #1 and the benzene reference substance stock solution #1 into a 25ml measuring flask with 2.5ml of diluent, diluting the reference substance stock solution #1 and the benzene reference substance stock solution # to scales by using the diluent, and shaking up to obtain the product.
TABLE 11 accuracy solution preparation
Results and conclusions of the experiment
TABLE 12 test results of control solutions
And (4) conclusion: meets the acceptance standard (the RSD of each residual solvent peak area is less than or equal to 10 percent, and the RSD of the f value of 6 parts of reference solution I and 1 part of reference solution II is less than or equal to 10 percent.
Table 13 accuracy experimental results:
and (4) conclusion: the recovery rate and the average recovery rate of 9 parts of methanol are both between 90 and 108 percent; RSD of the recovery rate of each concentration level and RSD of 9 parts of recovery rate data are both less than or equal to 15 percent; the recovery rate and the average recovery rate of 9 parts of ethanol are both between 90 and 108 percent; RSD of the recovery rate of each concentration level and RSD of 9 parts of recovery rate data are both less than or equal to 15 percent; the recovery rate and the average recovery rate of 9 parts of acetonitrile are both 85-110 percent; RSD of the recovery rate of each concentration level and RSD of 9 parts of recovery rate data are both less than or equal to 15 percent; the recovery rate and the average recovery rate of 9 parts of dichloromethane are both 85-110 percent; RSD of the recovery rate of each concentration level and RSD of 9 parts of recovery rate data are both less than or equal to 15 percent; the recovery rate and the average recovery rate of 9 parts of benzene are both 75-120 percent; RSD of the recovery rate of each concentration level and RSD of 9 parts of recovery rate data are both less than or equal to 15 percent; all meet the requirements.
Verification example 5
Durability the influence of fine adjustment of the chromatographic conditions on the amount of each residual solvent detected was examined. Preparing a reference substance solution and a test solution, and respectively measuring according to a method under different chromatographic conditions, wherein the separation degree of each residual solvent peak and adjacent impurity peaks in the separation degree solution is more than or equal to 1.5 under different chromatographic conditions; the tailing factor is less than or equal to 2.0; the difference between the residual solvent in the test solution under each condition and the residual solvent under the normal condition is less than or equal to 20 percent of the limit value. The experiment was carried out using the following condition parameters.
TABLE 14 durability test conditions
Solution preparation
TABLE 15 durability solution formulations
Results and conclusions of the experiment
Summary of durability test results
And (4) conclusion: adding the sample solution into different chromatographic conditions including carrier gas flow rate, initial column temperature and headspace bottle balance time, wherein the separation degree of each residual solvent peak and adjacent impurity peaks is not less than 1.5; the tailing factor is less than or equal to 2.0; the ratio of the response factor of the reference solution 2 to the response factor of the reference solution 1 is between 90 and 108 percent; under different chromatographic conditions, the difference value between the residual detection amount of each solvent and the difference value under normal conditions is less than or equal to 20 percent of the limit, and the difference values all accord with the acceptance standard, which indicates that the analysis method has good durability.
Table 16 summary of the verification examples
Claims (10)
1. A method for detecting a residual solvent in pantoprazole sodium sesquihydrate is characterized by comprising the following steps:
(1) preparing a test solution, wherein the test solution comprises pantoprazole sodium sesquihydrate and a solvent; the solvent comprises dimethyl sulfoxide and/or water;
(2) preparing a control solution comprising methanol, dichloromethane, ethanol, acetonitrile, and benzene; the solvent is the same as the solvent in the step (1);
(3) carrying out headspace gas chromatography test by using a medium-polarity capillary column and adopting programmed temperature rise;
wherein, the sequence of the steps (1) and (2) is not divided into sequences.
2. The detection method according to claim 1, wherein the solvent is a mixture of dimethyl sulfoxide and water; preferably, the volume ratio of the dimethyl sulfoxide to the water is 8: 2.
3. the detection method according to claim 1, wherein the pantoprazole sodium sesquihydrate is weighed in an amount of 0.1 to 1g, preferably 0.15 to 0.8g, more preferably 0.5 g;
and/or the concentration of the pantoprazole sodium sesquihydrate in the test solution is 0.02-0.5 g/mL, preferably 0.05-0.2 g/mL, and more preferably 0.1 g/mL;
preferably, the pantoprazole sodium sesquihydrate is 0.5g, and the solvent is 5 mL;
more preferably, the specific operation of step (1) comprises: taking 0.5g of pantoprazole sodium sesquihydrate, precisely weighing, placing in a headspace bottle, adding 5ml of solvent [ dimethyl sulfoxide-water (80-20) ] to dissolve, and sealing to obtain a test solution.
4. The assay of claim 1 wherein the concentrations of said methanol, dichloromethane, ethanol, acetonitrile and benzene in said control solution are 0.3%, 0.06%, 0.5%, 0.041% and 0.0002% of the concentration of pantoprazole sodium sesquihydrate, respectively.
5. The assay of claim 1, wherein the control solution is prepared by a method comprising: preparing a reference stock solution containing methanol, dichloromethane, ethanol, acetonitrile and benzene; diluting the reference stock solution; the dilution multiple of the reference substance stock solution can be 5-20 times;
preferably, the preparation method of the reference stock solution comprises the following steps: preparing a first stock solution containing methanol, dichloromethane, ethanol and acetonitrile and a second stock solution containing benzene respectively; then mixing a certain amount of the first stock solution and the second stock solution to obtain a reference substance stock solution;
more preferably, the preparation method of the second stock solution comprises the following steps: preparing a benzene intermediate stock solution, and then diluting the benzene intermediate stock solution to obtain a second stock solution; the dilution factor of the benzene intermediate stock solution may be 100 to 300 times, preferably 200 times.
6. The detection method according to claim 5, wherein the specific operation of the step (2) is:
accurately weighing 300mg of methanol, 60mg of dichloromethane, 500mg of ethanol and 41mg of acetonitrile, placing the weighed materials into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the materials to a scale, and shaking the materials uniformly to obtain a first stock solution; the preparation process of the benzene intermediate stock solution comprises the following steps: precisely weighing 40mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the benzene to a scale, and shaking up to obtain a benzene intermediate stock solution; precisely transferring 0.5ml of the benzene intermediate stock solution into a 100ml measuring flask with 2-5ml of solvent, adding the solvent to dilute to a scale, and shaking up to obtain a second stock solution; precisely transferring 10ml of the first stock solution and 10ml of the second stock solution into a 100ml measuring flask, and shaking up to obtain a reference stock solution; diluting with solvent to scale, precisely sucking 5ml into a headspace bottle, sealing, and shaking to obtain reference solution.
7. The detection method of claim 1, wherein the moderately polar capillary column is one of (35%) diphenyl-dimethylpolysiloxane, (50%) diphenyl-dimethylpolysiloxane, (35%) diphenyl-dimethylarylene-polysiloxane, (14%) cyanopropylphenyl-dimethylpolysiloxane, and (6%) cyanopropylphenyl-methylpolysiloxane; preferably, the medium polarity capillary column is (6%) cyanopropylphenyl-methylpolysiloxane;
and/or, the headspace gas chromatography test employs a FID detector;
and/or the carrier gas adopted by the headspace gas chromatography test is nitrogen.
8. The detection method of claim 1, wherein the programmed temperature rise comprises: the initial temperature is 34-36 ℃, the temperature is kept for 5 minutes, then the temperature is raised to 240 ℃ at the rate of 18 ℃ per minute, and the temperature is kept for 2 minutes; the injection port temperature is 180 ℃, the column flow rate is 1.1-1.3 ml/min, the detector temperature is 250 ℃, the headspace bottle equilibrium temperature is 85 ℃, the equilibrium time is 38-42 minutes, the quantitative loop temperature is 100 ℃, and the transmission line temperature is 150 ℃;
preferably, the temperature programming includes: the initial temperature was 35 ℃ for 5 minutes, then the temperature was raised to 240 ℃ at a rate of 18 ℃ per minute for 2 minutes; the injection port temperature was 180 ℃, the column flow rate was 1.2 ml/min, the detector temperature was 250 ℃, the headspace bottle equilibration temperature was 85 ℃, the equilibration time was 40 minutes, the quantitative loop temperature was 100 ℃, and the transmission line temperature was 150 ℃.
9. The detection method according to claim 8, wherein the specific operation of the step (3) is:
a capillary column using (6% cyanopropylphenyl) -methylpolysiloxane as a stationary liquid; adopting temperature programming: the initial temperature was 35 ℃, held for 5 minutes, then raised to 240 ℃ at a rate of 18 ℃ per minute, held for 2 minutes, using a FID detector; the injection port temperature is 180 ℃, the carrier gas is nitrogen, the column flow rate is 1.2 ml/min, the detector temperature is 250 ℃, the headspace bottle equilibrium temperature is 85 ℃, the equilibrium time is 40 minutes, the quantitative loop temperature is 100 ℃, and the transmission line temperature is 150 ℃; sampling the reference solution and the sample solution, and recording the chromatogram.
10. The detection method according to any one of claims 1 to 9, wherein the detection method of the residual solvent in the pantoprazole sodium sesquihydrate is implemented by the following specific operations:
(1) preparing a test solution: taking 0.5g of pantoprazole sodium sesquihydrate, precisely weighing, placing in a headspace bottle, adding 5ml of solvent [ dimethyl sulfoxide-water (80-20) ] to dissolve, and sealing to obtain a test solution;
(2) preparation of control solutions: accurately weighing 300mg of methanol, 60mg of dichloromethane, 500mg of ethanol and 41mg of acetonitrile, placing the weighed materials into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the materials to a scale, and shaking the materials uniformly to obtain a first stock solution; precisely weighing 40mg of benzene, placing the benzene into a 100ml measuring flask with 10ml of solvent, adding the solvent to dilute the benzene to a scale, and shaking up to obtain a benzene intermediate stock solution; precisely transferring 0.5ml of the benzene intermediate stock solution into a 100ml measuring flask with 2-5ml of solvent, adding the solvent to dilute to a scale, and shaking up to obtain a second stock solution; precisely transferring 10ml of the first stock solution and 10ml of the second stock solution into a 100ml measuring flask, and shaking up to obtain a reference stock solution; diluting with solvent to scale, precisely sucking 5ml into a headspace bottle, sealing, and shaking to obtain reference solution;
(3) and (3) carrying out headspace gas chromatography test by using a medium polarity capillary column and adopting temperature programming: a capillary column using (6% cyanopropylphenyl) -methylpolysiloxane as a stationary liquid, as determined by the residual solvent assay (second method 0861, fourth pharmacopoeia 2015 edition); adopting temperature programming: the initial temperature was 35 ℃, held for 5 minutes, then raised to 240 ℃ at a rate of 18 ℃ per minute, held for 2 minutes, using a FID detector; the injection port temperature is 180 ℃, the carrier gas is nitrogen, the column flow rate is 1.2 ml/min, the detector temperature is 250 ℃, the headspace bottle equilibrium temperature is 85 ℃, the equilibrium time is 40 minutes, the quantitative loop temperature is 100 ℃, and the transmission line temperature is 150 ℃; sampling the reference solution and the sample solution, and recording the chromatogram.
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Application publication date: 20201023 |