CN113945647A - Method for detecting ethanol and isopropanol in valsartan hydrochlorothiazide - Google Patents
Method for detecting ethanol and isopropanol in valsartan hydrochlorothiazide Download PDFInfo
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- CN113945647A CN113945647A CN202010687909.4A CN202010687909A CN113945647A CN 113945647 A CN113945647 A CN 113945647A CN 202010687909 A CN202010687909 A CN 202010687909A CN 113945647 A CN113945647 A CN 113945647A
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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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
Abstract
The invention belongs to the field of pharmaceutical analysis, and relates to a method for simultaneously detecting ethanol and isopropanol in a valsartan hydrochlorothiazide preparation. The detection method can effectively detect the content of ethanol and isopropanol in the valsartan hydrochlorothiazide, and has the advantages of high sensitivity, high separation degree, good repeatability and durability, simple operation and stable and reliable result, thereby being used for controlling the ethanol and the isopropanol in the valsartan hydrochlorothiazide and providing effective guarantee for the quality of final finished products.
Description
Technical Field
The invention relates to a method for detecting solvent residues in a valsartan and hydrochlorothiazide raw material and a preparation, in particular to a method for detecting ethanol and isopropanol in the valsartan and hydrochlorothiazide raw material and the preparation by using a gas chromatography, belonging to the field of pharmaceutical analysis.
Background
Valsartan is an angiotensin II receptor antagonist antihypertensive drug, can be used for various types of hypertension, has a good protective effect on heart, brain and kidney, does not affect the bradykinin level in vivo after administration, stably reduces blood pressure, does not affect cardiac rhythm, has few side effects, has good safety and tolerance, and belongs to one of five classic antihypertensive drugs. The composition has the advantages of being capable of achieving more obvious curative effect when being used together with hydrochlorothiazide, reducing blood pressure of patients, being beneficial to preventing left ventricular remodeling and reducing proteinuria, being a very advantageous composition in clinic at present, being capable of avoiding hyperkalemia caused by valsartan and hypokalemia caused by hydrochlorothiazide, being capable of avoiding adverse reactions to a great extent, and being a first-line clinical medicine. In the production process, the valsartan and hydrochlorothiazide tablets/capsules/dispersion tablets use organic solvents of ethanol and isopropanol, the valsartan structure contains carboxyl, and after the valsartan and the isopropanol contact with the ethanol and the isopropanol, the valsartan and the hydrochlorothiazide tablets react to generate valsartan ethyl ester and valsartan isopropyl ester, so that the content of related substances in a valsartan raw material and a preparation of the valsartan raw material is increased. Therefore, the content of ethanol and isopropanol needs to be strictly controlled in the production process.
CN111060628A discloses a method for detecting residual solvent, which can continuously detect the residual amount of 7 mailing solvents of acetonitrile, toluene, methanol, ethanol, acetone, ethyl acetate, and isopropanol, but the method is only used for detecting tacrolimus drugs, and is not suitable for valsartan hydrochlorothiazide.
CN103698424B discloses a method for detecting ethanol and isopropanol residues, but is applicable to insoluble aluminum salt drugs and also not applicable to valsartan hydrochlorothiazide.
In view of the fact that excessive organic solvent residues are harmful to human bodies, and the international harmonization conference (ICH) guidelines are limited to ethanol and isopropanol in the national pharmacopoeia 2015 edition and the technical requirements for registration of human drugs, the residual amounts of ethanol and isopropanol in valsartan hydrochlorothiazide are not controlled in the current standard, and therefore a method for detecting the contents of ethanol and isopropanol must be established.
Disclosure of Invention
The method can simultaneously detect the ethanol and the isopropanol in the valsartan hydrochlorothiazide by adopting the gas chromatography, and can be used for quality control in production. The method has the characteristics of high sensitivity and good peak shape, the analysis method is stable, and the detection limit of ethanol and isopropanol is low.
In order to achieve the purpose of the invention, the inventor finally obtains the following technical scheme through a large number of experiments:
the method for detecting ethanol and isopropanol in valsartan hydrochlorothiazide by using gas chromatography comprises the following steps:
a chromatographic column: the stationary phase is a chromatographic column of polyethylene glycol;
initial column temperature: 35-55 ℃;
a detector: hydrogen flame ionization, the detector temperature is 180-280 ℃;
carrier gas: nitrogen, flow rate: 1-5 ml/min;
headspace sample introduction: the head space temperature is 60-120 ℃, and the head space time is 20-60 min;
the valsartan and hydrochlorothiazide preparation is valsartan and hydrochlorothiazide bulk drug, tablet, dispersible tablet or capsule.
The temperature rising procedure is as follows:
specifically, the gas chromatography method of the invention comprises the following steps:
initial column temperature: 45 ℃;
the carrier gas is nitrogen;
the chromatographic column is a chromatographic column with a fixed phase of polyethylene glycol;
the temperature of the detector is 280 ℃;
the temperature of a sample inlet is 200 ℃;
the headspace temperature was 100 ℃ and the headspace time was 30 min;
the flow rate is 3.0 mL/min;
the temperature rising procedure is as follows:
the invention relates to a method for detecting ethanol and isopropanol in valsartan hydrochlorothiazide by using gas chromatography, which comprises the following specific operation steps:
a. dissolving appropriate amount of ethanol reference substance in water to obtain reference substance solution containing 0.5mg ethanol per 1ml, placing 2ml in 20ml headspace bottle, and sealing to obtain reference substance solution;
b. dissolving appropriate amount of isopropanol reference substance in water to obtain reference substance solution containing 0.5mg ethanol per 1ml, placing 2ml in 20ml headspace bottle, and sealing to obtain reference substance solution;
c. taking a proper amount of valsartan hydrochlorothiazide, placing the valsartan hydrochlorothiazide in a 20ml headspace bottle, adding 2ml of water, and sealing to obtain a test solution;
d. respectively taking headspace samples of a reference substance and a test solution, and completing analysis and detection of ethanol and isopropanol in the valsartan hydrochlorothiazide according to the following chromatographic conditions;
chromatographic conditions are as follows:
a chromatographic column: the stationary phase is a chromatographic column of polyethylene glycol;
initial column temperature: 35-55 ℃;
a detector: hydrogen flame ionization, the detector temperature is 180-280 ℃;
carrier gas: nitrogen, flow rate: 1-5 ml/min;
headspace sample introduction: the head space temperature is 60-120 ℃, and the head space time is 20-60 min;
the temperature rising procedure is as follows:
the analysis method provided by the invention can effectively detect the content of ethanol and isopropanol in the valsartan hydrochlorothiazide, and the method has the advantages of high separation degree, good repeatability and durability, low detection limit, simple operation and stable and reliable result, so that the method can be used for quality control of valsartan raw materials and preparations thereof, and provides effective guarantee for the quality of final finished products.
Drawings
FIG. 1 GC spectrum of blank solvent
FIG. 2 GC spectrum of blank auxiliary materials
FIG. 3 GC spectrum of ethanol peak location
FIG. 4 GC spectra of isopropanol peak localization
FIG. 5 GC-Spectroscopy of ethanol and isopropanol control solutions of example 1
FIG. 6 GC-map of valsartan raw material test sample solution in example 1
FIG. 7 GC spectrum of sample solution of example 1 hydrochlorothiazide
FIG. 8 GC spectrum of test solution of valsartan hydrochlorothiazide tablet in example 1
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
First, research and evaluation of ethanol and isopropanol checking methodology
1. Instruments and conditions: shimadzu chromatography system, hydrogen flame ionization detector, column: TRACE TR-WAX (30 m.times.0.32 mm, 0.25 μm); detector temperature: 280 ℃; sample inlet temperature: 200 ℃; taking nitrogen as carrier gas; the flow rate is 3 ml/min; introducing a sample in a headspace, wherein the headspace temperature is 100 ℃, and the headspace time is 30 min; initial column temperature: at 45 ℃.
The temperature programmed elution was set as:
2. the test steps are as follows:
2.1 specificity
1) Blank solvent interference test
Placing 2ml water in 20ml headspace bottle, sealing, determining according to the above chromatographic conditions, and recording chromatogram, wherein GC chromatogram is shown in figure 1.
As can be seen from the attached figure 1, the blank solvent has no interference with the impurity peaks detected by ethanol and isopropanol.
2) Interference test of auxiliary materials
Taking about 200mg of valsartan and hydrochlorothiazide tablet auxiliary materials, placing the valsartan and hydrochlorothiazide tablet auxiliary materials into a 20ml headspace bottle, adding 2ml of water, sealing, determining according to the chromatographic conditions, recording a chromatogram, wherein a GC (gas chromatography) spectrum is shown in an attached figure 2. As can be seen from the attached figure 2, the auxiliary materials do not interfere with the impurity peaks detected by ethanol and isopropanol.
3) Peak location test for ethanol
Dissolving appropriate amount of ethanol reference substance in water to obtain reference substance solution containing 0.5mg ethanol per 1ml, placing 2ml in 20ml headspace bottle, sealing, measuring according to the above chromatographic conditions, recording chromatogram, and showing HPLC chromatogram in figure 3. As can be seen from FIG. 3, the retention time of ethanol was 5.153 min.
4) Isopropanol peak location test
Dissolving appropriate amount of isopropanol reference substance in water to obtain reference substance solution containing isopropanol 0.5mg per 1ml, placing 2ml in 20ml headspace bottle, sealing, measuring according to the above chromatographic conditions, and recording chromatogram, wherein HPLC chromatogram is shown in figure 4. As can be seen from FIG. 4, the retention time of isopropanol is 6.355 min.
2.2 limit of quantitation and detection
1) And (4) quantitative limit: taking a proper amount of ethanol reference substance, preparing a solution of 3.11 μ g/ml with water as a limit solution, and determining according to the method, wherein the retention time of ethanol is 5.100min and the S/N is 12 according to the chromatogram map.
Taking a proper amount of isopropanol as a reference substance, preparing a solution of 2.98. mu.g/ml with water, and determining according to the method, wherein the retention time of ethanol is 6.350min and the S/N is 13 according to the chromatogram map.
2) Detection limit: taking appropriate amount of ethanol control, preparing 1.50 μ g/ml solution with water, and determining according to the method, wherein the retention time of ethanol is 5.113min and S/N is 4.
Taking a proper amount of isopropanol as a reference substance, preparing a solution with the concentration of 1.47 mu g/ml with water, and determining according to the method by using the detection limit solution, wherein the retention time of the isopropanol is 6.333min and the S/N is 3 according to a chromatogram map.
2.3 Linearity and Range
Taking a proper amount of ethanol reference substances, preparing solutions with the series concentrations of 47.7 mu g/ml, 95.4 mu g/ml, 190.9 mu g/ml, 286.3 mu g/ml, 477.2 mu g/ml, 763.5 mu g/ml and 954.3 mu g/ml by using water, injecting the solutions respectively, measuring according to the chromatographic conditions, recording a chromatogram map, and obtaining a linear equation.
TABLE 1 ethanol Peak area and concentration Curve Table
As is clear from Table 1, the linear relationship between the concentration and the peak area was good in the range of 47.7 to 954.3. mu.g/ml for ethanol.
Taking a proper amount of isopropanol reference substances, preparing solutions with series concentrations of 49.8 mu g/ml, 99.7 mu g/ml, 199.4 mu g/ml, 299.1 mu g/ml, 498.5 mu g/ml, 797.6 mu g/ml and 997.0 mu g/ml by using water, injecting samples respectively, measuring according to the chromatographic conditions, and recording a chromatogram map to obtain a linear equation.
TABLE 2 isopropyl alcohol peak area versus concentration curve table
As can be seen from Table 2, the isopropanol concentration was in the range of 49.8 to 997.0. mu.g/ml, and the linear relationship between the concentration and the peak area was good.
2.4 durability test
1) Instruments and conditions: shimadzu chromatography system, hydrogen flame ionization detector, column: TRACE TR-WAX (30 m.times.0.32 mm, 0.25 μm); detector temperature: 280 ℃; sample inlet temperature: 200 ℃; taking nitrogen as carrier gas; the flow rate is 3 ml/min; introducing a sample in a headspace, wherein the headspace temperature is 100 ℃, and the headspace time is 30 min; initial column temperature: at 45 ℃.
The temperature programmed elution was set as:
and (3) determination: respectively taking appropriate amount of ethanol and isopropanol as reference substances, dissolving in water to obtain reference substance solution containing ethanol and isopropanol 0.5mg each per 1ml, placing 2ml in 20ml headspace bottle, sealing, determining according to the above chromatographic conditions, and recording chromatogram.
Under the condition, the retention time of the ethanol is 5.117min, the retention time of the isopropanol is 6.341min, and impurity peaks of the ethanol and the isopropanol are not interfered.
2) Instruments and conditions: shimadzu chromatography system, hydrogen flame ionization detector, column: TRACE TR-WAX (30 m.times.0.32 mm, 0.25 μm); detector temperature: 280 ℃; sample inlet temperature: 200 ℃; taking nitrogen as carrier gas; the flow rate is 3 ml/min; introducing a sample in a headspace, wherein the headspace temperature is 100 ℃, and the headspace time is 30 min; initial column temperature: at 55 ℃.
The temperature programmed elution was set as:
and (3) determination: respectively taking appropriate amount of ethanol and isopropanol as reference substances, dissolving in water to obtain reference substance solution containing ethanol and isopropanol 0.5mg each per 1ml, placing 2ml in 20ml headspace bottle, sealing, determining according to the above chromatographic conditions, and recording chromatogram.
Under the condition, the retention time of the ethanol is 4.537min, the retention time of the isopropanol is 5.842min, and impurity peaks of the ethanol and the isopropanol are not interfered.
3) Instruments and conditions: shimadzu chromatography system, hydrogen flame ionization detector, column: TRACE TR-WAX (30 m.times.0.32 mm, 0.25 μm); detector temperature: 280 ℃; sample inlet temperature: 200 ℃; taking nitrogen as carrier gas; the flow rate is 3 ml/min; introducing a sample in a headspace, wherein the headspace temperature is 100 ℃, and the headspace time is 30 min; initial column temperature: 35 ℃ is carried out.
The temperature programmed elution was set as:
and (3) determination: respectively taking appropriate amount of ethanol and isopropanol as reference substances, dissolving in water to obtain reference substance solution containing ethanol and isopropanol 0.5mg each per 1ml, placing 2ml in 20ml headspace bottle, sealing, determining according to the above chromatographic conditions, and recording chromatogram.
Under the condition, the retention time of the ethanol is 6.432min, the retention time of the isopropanol is 7.366min, and impurity peaks of the ethanol and the isopropanol are not interfered.
4) Instruments and conditions: shimadzu chromatography system, hydrogen flame ionization detector, column: TRACE TR-WAX (30 m.times.0.32 mm, 0.25 μm); detector temperature: 280 ℃; sample inlet temperature: 200 ℃; taking nitrogen as carrier gas; the flow rate is 1 ml/min; introducing a sample in a headspace, wherein the headspace temperature is 100 ℃, and the headspace time is 30 min; initial column temperature: at 45 ℃.
The temperature programmed elution was set as:
and (3) determination: respectively taking appropriate amount of ethanol and isopropanol as reference substances, dissolving in water to obtain reference substance solution containing ethanol and isopropanol 0.5mg each per 1ml, placing 2ml in 20ml headspace bottle, sealing, determining according to the above chromatographic conditions, and recording chromatogram.
Under the condition, the retention time of the ethanol is 6.177min, the retention time of the isopropanol is 7.140min, and impurity peaks of the ethanol and the isopropanol are not interfered.
5) Instruments and conditions: shimadzu chromatography system, hydrogen flame ionization detector, column: TRACE TR-WAX (30 m.times.0.32 mm, 0.25 μm); detector temperature: 280 ℃; sample inlet temperature: 200 ℃; taking nitrogen as carrier gas; the flow rate is 5 ml/min; introducing a sample in a headspace, wherein the headspace temperature is 100 ℃, and the headspace time is 30 min; initial column temperature: at 45 ℃.
The temperature programmed elution was set as:
and (3) determination: respectively taking appropriate amount of ethanol and isopropanol as reference substances, dissolving in water to obtain reference substance solution containing ethanol and isopropanol 0.5mg each per 1ml, placing 2ml in 20ml headspace bottle, sealing, determining according to the above chromatographic conditions, and recording chromatogram.
Under the condition, the retention time of the ethanol is 4.260min, the retention time of the isopropanol is 5.107min, and impurity peaks of the ethanol and the isopropanol are not interfered.
Example 1
Instruments and conditions: shimadzu chromatography system, hydrogen flame ionization detector, column: TRACE TR-WAX (30 m.times.0.32 mm, 0.25 μm); detector temperature: 280 ℃; sample inlet temperature: 200 ℃; taking nitrogen as carrier gas; the flow rate is 3 ml/min; introducing a sample in a headspace, wherein the headspace temperature is 100 ℃, and the headspace time is 30 min; initial column temperature: at 45 ℃.
The temperature programmed elution was set as:
and (3) determination: respectively taking appropriate amount of ethanol and isopropanol as reference substances, dissolving in water to obtain reference substance solution containing ethanol and isopropanol 0.5mg each per 1ml, placing 2ml in 20ml headspace bottle, sealing, determining according to the above chromatographic conditions, and recording chromatogram. The GC spectrum is shown in FIG. 5.
As can be seen from fig. 5: the retention time of the ethanol is 5.165min, the retention time of the isopropanol is 6.357min, and impurity peaks of the ethanol and the isopropanol are not interfered.
2. Valsartan starting material
Taking about 200mg of valsartan raw material, placing the valsartan raw material in a 20ml headspace bottle, adding 2ml of water, sealing, determining according to the chromatographic conditions, and recording a chromatogram, wherein a GC (gas chromatography) spectrum is shown in figure 6.
As can be seen from figure 6, the valsartan starting material does not interfere with the impurity peaks detected by ethanol and isopropanol.
3. Hydrochlorothiazide feedstock
Taking about 200mg of hydrochlorothiazide as a raw material, placing the hydrochlorothiazide into a 20ml headspace bottle, adding 2ml of water, sealing, measuring according to the chromatographic conditions, and recording a chromatogram, wherein a GC (gas chromatography) spectrum is shown in figure 7.
As can be seen from fig. 7, the hydrochlorothiazide feed material has impurity peaks that interfere with the detection of ethanol and isopropanol.
4. Valsartan hydrochlorothiazide tablet
Taking about 200mg of valsartan and hydrochlorothiazide tablets, putting the valsartan and hydrochlorothiazide tablets into a 20ml headspace bottle, adding 2ml of water, sealing, determining according to the chromatographic conditions, recording a chromatogram, wherein the GC spectrum is shown in figure 8.
As shown in the attached figure 8, the valsartan hydrochlorothiazide tablet contains trace ethanol and isopropanol, the retention time is 5.152min and 6.346min respectively, and impurity peaks detected by the ethanol and the isopropanol are not interfered.
From the above test results, it can be seen that: the detection method can effectively detect the content of ethanol in the valsartan raw material and the preparation thereof, and the blank auxiliary materials and the blank solvent have no interference on the ethanol in the valsartan raw material and the preparation thereof, so the method can be used for quality control of the valsartan raw material and the preparation thereof.
Claims (9)
1. A method for simultaneously detecting ethanol and isopropanol in valsartan hydrochlorothiazide is characterized in that: the method is gas chromatography detection, adopts a headspace sample injection mode, adopts nitrogen as carrier gas, adopts a chromatographic column with a fixed phase of polyethylene glycol, adopts a hydrogen flame ionization detector as the type of the detector, and performs temperature programming.
2. The method of claim 1, wherein the valsartan hydrochlorothiazide formulation is a valsartan hydrochlorothiazide drug substance, tablet, dispersible tablet or capsule.
3. The method of claim 1, wherein the temperature ramp program is:
4. the method according to claim 1, wherein the headspace sampling temperature is 60 ℃ to 120 ℃ and the headspace time is 20min to 60min, preferably the headspace temperature is 100 ℃ and the headspace time is 30 min.
5. The method of claim 1, wherein the carrier gas is nitrogen at a flow rate of 1 to 5ml/min, preferably at a flow rate of 3 ml/min.
6. The method of claim 1, wherein the detector is a hydrogen flame ionization detector and the detector temperature is 180 ℃ to 280 ℃, preferably 280 ℃.
7. The method of claim 1, wherein the chromatographic column has a stationary phase of polyethylene glycol, the initial column temperature: 35-55 ℃.
8. The method according to claim 1, wherein the injection port temperature is 150 ℃ to 280 ℃, preferably 200 ℃.
9. The method of any one of claims 1-8, wherein the gas chromatography is:
initial column temperature: 45 ℃;
the carrier gas is nitrogen;
the chromatographic column is a chromatographic column with a fixed phase of polyethylene glycol;
the temperature of the detector is 280 ℃;
the temperature of a sample inlet is 200 ℃;
the headspace temperature was 100 ℃ and the headspace time was 30 min;
the flow rate is 3.0 mL/min;
the temperature rising procedure is as follows:
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| US20130316388A1 (en) * | 2012-05-25 | 2013-11-28 | Health Diagnostic Laboratory, Inc. | Process and apparatus for rapid, high-throughput analysis of fatty acids |
| CN108445110A (en) * | 2018-05-03 | 2018-08-24 | 四川科伦药业股份有限公司 | The detection method of residual solvent in a kind of semi-synthetic fish oil bulk pharmaceutical chemicals |
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| 李会轻等: "顶空气相色谱法测定盐酸拉贝洛尔中有机溶剂残留量", 《中国药事》 * |
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