CN112924611A - Detection method of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one - Google Patents
Detection method of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one Download PDFInfo
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- DHRYDCOBLQUKRM-UHFFFAOYSA-N 4-chloro-4-methyl-5-methylidene-1,3-dioxolan-2-one Chemical compound CC1(Cl)OC(=O)OC1=C DHRYDCOBLQUKRM-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000001514 detection method Methods 0.000 title claims abstract description 25
- 239000012535 impurity Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 claims abstract description 16
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical group C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960001199 olmesartan medoxomil Drugs 0.000 claims abstract description 16
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- PWNMXPDKBYZCOO-UHFFFAOYSA-N Prulifloxacin Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N(CC1)CCN1CC=1OC(=O)OC=1C PWNMXPDKBYZCOO-UHFFFAOYSA-N 0.000 claims abstract description 6
- IHWFKDWIUSZLCJ-UHFFFAOYSA-M azilsartan kamedoxomil Chemical compound [K+].C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C=3[N-]C(=O)ON=3)C(OCC)=NC2=CC=CC=1C(=O)OCC=1OC(=O)OC=1C IHWFKDWIUSZLCJ-UHFFFAOYSA-M 0.000 claims abstract description 6
- -1 polysiloxane Polymers 0.000 claims abstract description 6
- 229960001224 prulifloxacin Drugs 0.000 claims abstract description 6
- 229920001296 polysiloxane Polymers 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 84
- 239000013558 reference substance Substances 0.000 claims description 37
- 238000012360 testing method Methods 0.000 claims description 28
- 230000035945 sensitivity Effects 0.000 claims description 25
- 239000012085 test solution Substances 0.000 claims description 25
- 239000012490 blank solution Substances 0.000 claims description 11
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 claims description 11
- 239000012088 reference solution Substances 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 229960001701 chloroform Drugs 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- QCLFSYYUWPUWQR-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1CCl QCLFSYYUWPUWQR-UHFFFAOYSA-N 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 2
- ZKUKMWMSYCIYRD-ZXFNITATSA-N lenampicillin Chemical compound O1C(=O)OC(COC(=O)[C@H]2C(S[C@H]3N2C([C@H]3NC(=O)[C@H](N)C=2C=CC=CC=2)=O)(C)C)=C1C ZKUKMWMSYCIYRD-ZXFNITATSA-N 0.000 claims 2
- 229950005831 lenampicillin Drugs 0.000 claims 2
- SERTYXGONOFYTI-UHFFFAOYSA-N ClC1(OCOC1=C)C Chemical compound ClC1(OCOC1=C)C SERTYXGONOFYTI-UHFFFAOYSA-N 0.000 claims 1
- 238000004949 mass spectrometry Methods 0.000 abstract description 4
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- 238000011084 recovery Methods 0.000 description 6
- 239000012488 sample solution Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 238000007865 diluting Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
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- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 description 1
- QYIOFABFKUOIBV-UHFFFAOYSA-N 4,5-dimethyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1C QYIOFABFKUOIBV-UHFFFAOYSA-N 0.000 description 1
- 241001562081 Ikeda Species 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000007075 allylic rearrangement reaction Methods 0.000 description 1
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- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
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Abstract
The invention provides a method for detecting the impurity content of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in a sample by adopting a gas phase-mass spectrometry method, wherein the sample is olmesartan medoxomil, azilsartan medoxomil potassium, lenamicillin and prulifloxacin, and the sample does not need to be specially treated and does not have matrix influence. The detection method adopts chromatographic conditions as follows: the chromatographic column is a capillary column taking (14% -cyanopropyl-phenyl) -methyl polysiloxane as stationary liquid, and adopts temperature programming; the temperature programming is that the initial temperature of the column temperature is 150 ℃ and is kept for 1 minute; heating to 200 deg.C at 35 deg.C per minute, and maintaining for 5 min; the temperature was raised to 250 ℃ at a rate of 30 ℃ per minute and held for 3 min.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a method for detecting impurity content of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in a sample by adopting a gas phase-mass spectrometry method, in particular to a method for detecting impurity content of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in a sample by adopting a gas phase-tandem mass spectrometry method.
Background
4-chloromethyl-5-methyl-1, 3-dioxol-2-one (DMDO-Cl) is an important chemical intermediate, which can be used for synthesizing olmesartan medoxomil, azilsartan medoxomil potassium, lenamicillin, prulifloxacin and the like, and can improve the bioavailability and stability of the medicine. The literature (SHOJI IKEDA, YASUSHI TAKEBE, RYOICHI HIRAYAMA, FUMIO SAKAMOTO, KOJI IUCHI, GORO TSUKAMOTO. A Convenient and Practical Preparation of 4-Chloromethyl-5-methyl-1, 3-dioxol-2-one [ J ]. Chemical and Pharmaceutical Bulletin,1988,36 (1)) reports a process for the Preparation of DMDO-Cl, from 4, 5-dimethyl-1, 3-dioxol-2-one (DMDO) which is chlorinated with a chlorinating agent to give 4-chloro-4-methyl-5-methylene-1, 3-dioxolan-2-one (formula I) which is then subjected to allylic rearrangement to give DMDO-Cl, the compound of formula I (impurity A) which may remain in the DMDO-Cl and thus be transferred to the product of the final reaction, even in the next step.
The literature (Liu Yong Jun, bear schwarrior, nest yanfang, gold poplar, gas chromatography-mass spectrometry combined determination of genotoxic impurity 4-chloromethyl-5-methyl-1, 3-dioxole-2-ketone [ J ] in olmesartan medoxomil. aging and application of synthetic materials, 2017,46(03): 91-95.) reports that GC-MS is adopted to determine DMDO-Cl in olmesartan medoxomil, and in order to reduce the influence of matrix olmesartan medoxomil on impurity DMDO-Cl, special treatment needs to be carried out on a sample to be determined so as to reduce matrix effect, improve recovery rate and obtain good reproducibility.
The detection method of the impurity A is not reported, so that the development of the detection method aiming at the impurity A has important significance on the process development and quality control of related raw material medicaments.
Disclosure of Invention
The invention provides a method for detecting impurity content of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one, which is characterized in that the inventor obtains a condition that the recovery rate can meet the standard without special treatment on a sample to be detected through deep research on a gas chromatography condition. The detection method adopts a gas chromatography-mass spectrometry (GC-MS), has high sensitivity, high accuracy and good repeatability, and can be used for detecting the impurity A in the sample.
The invention provides a method for detecting impurity content of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one, which is characterized by adopting GC-MS/MS for detection and comprises the following steps:
solution preparation: respectively preparing a reference substance solution, a sensitivity solution and a test solution; the reference solution and the sensitivity solution are both solutions of impurity A;
wherein, the reference substance solution and the sensitivity solution are both prepared by dissolving impurity A in a diluent; the test sample solution is prepared by dissolving a test sample in a diluent;
the test sample contains or possibly contains impurity A; the chemical structural formula of the sample contains a fragment of a formula III,
the test sample is 4-chloromethyl-5-methyl-1, 3-dioxol-2-one, olmesartan medoxomil, azilsartan medoxomil potassium, prulifloxacin, lenamicillin or pharmaceutically acceptable salts of lenamicillin, wherein the pharmaceutically acceptable salts of lenamicillin are preferably lenamicillin hydrochloride;
sample introduction: after a GC-MS/MS instrument system is stabilized, feeding a blank solution 1 needle (if necessary, a plurality of needles are fed), a sensitivity solution 1 needle, a reference substance solution 6 needle and a test sample solution 1 needle, and recording spectrograms;
wherein the content of the first and second substances,
the detection method adopts chromatographic conditions as follows: the chromatographic column is a capillary column taking (14% -cyanopropyl-phenyl) -methyl polysiloxane as stationary liquid, and adopts temperature programming;
the mass spectrometry conditions for the examination method are shown in table 1:
the concentration of the impurity A in the reference substance solution is 150 ng/ml-350 ng/ml, preferably 200 ng/ml-250 ng/ml; the concentration of the impurity A in the sensitivity solution is 20 ng/ml-60 ng/ml, and preferably 40 ng/ml-50 ng/ml; the concentration of the test solution is 2 mg/ml-15 mg/ml, preferably 5 mg/ml-8 mg/ml.
The preparation method of the reference substance solution comprises the following steps: precisely measuring a proper amount of the reference substance stock solution 2 in a measuring flask, adding a diluent to dilute to a scale, and shaking up;
sensitivity solution: precisely measuring a proper amount of the reference solution, placing in a measuring flask, adding the diluent to dilute to a scale, and shaking up.
The preparation method of the reference substance stock solution 2 comprises the following steps: precisely measuring a proper amount of the reference substance stock solution 1 in a measuring flask, adding a diluent to dilute to a scale, and shaking up;
the preparation method of the reference substance stock solution 1 comprises the following steps: taking a proper amount of reference substances, precisely weighing, placing in a proper amount of measuring flask, adding diluent to dilute to scale, and shaking up.
The test solution: taking a proper amount of a test sample, precisely weighing, placing into a measuring flask, adding a diluent, ultrasonically dissolving, and diluting to a scale.
The blank solution and the diluent are halogenated alkane, and the halogenated alkane is preferably trichloromethane.
Wherein the adopted halogenated alkane is AR or above, and the impurity A reference substance is purchased from outsourcing and is AR grade or above. The capillary column using (14% -cyanopropyl-phenyl) -methyl polysiloxane as a stationary liquid is an Agilent DB-1701, 30 m x 0.25 mm, 1 μm or a chromatographic column with equivalent efficiency.
The temperature programming is that the initial temperature of the column temperature is 150 ℃ and is kept for 1 minute; heating to 200 deg.C at 35 deg.C per minute, and maintaining for 5 min; heating to 250 deg.C at a rate of 30 deg.C per minute, and maintaining for 3 min; sample inlet temperature: 130 ℃; carrier gas: he; shunting mode: shunting; flow rate of carrier gas: 1 mL/min; the split ratio is as follows: 10: 1; GC run time: 12.095 min; sample introduction amount: 1 muL.
More preferably, the detection method of the present invention comprises the following steps:
(1) solution preparation:
diluting liquid: trichloromethane
Blank solution: diluent liquid
Comparison product stock solution (i): taking about 10mg of a reference substance, accurately weighing, placing in a 10mL measuring flask, adding a diluent to dilute to a scale, and shaking up. (concentration: 1000. mu.g/mL of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one)
Reference stock solution 2: precisely measuring 1.0mL of the reference stock solution, placing the reference stock solution into a 100mL measuring flask, adding the diluent to dilute to a scale, and shaking up. (concentration: 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one 10 μ g/mL)
Control solution: precisely measuring a reference substance stock solution (450 mu L), placing the reference substance stock solution into a 20mL measuring flask, adding a diluent to dilute the reference substance stock solution to a scale, and shaking the reference substance stock solution uniformly.
Sensitivity solution: precisely measuring 2.0mL of the reference solution, placing the reference solution in a 10mL measuring flask, adding the diluent to dilute to the scale, and shaking up.
Test solution: taking about 120mg of a test sample, precisely weighing, placing in a 20mL measuring flask, adding a diluent, ultrasonically dissolving, and diluting to a scale.
The test sample is 4-chloromethyl-5-methyl-1, 3-dioxol-2-one, olmesartan medoxomil, azilsartan medoxomil potassium, prulifloxacin, lenamicillin or pharmaceutically acceptable salts of lenamicillin, wherein the pharmaceutically acceptable salts of lenamicillin are preferably lenamicillin hydrochloride;
the reference substance is 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-ketone;
(2) sample introduction: after a GC-MS/MS instrument system is stabilized, feeding a blank solution 1 needle (if necessary, a plurality of needles are fed), a sensitivity solution 1 needle, a reference substance solution 6 needle and a test sample solution 1 needle, and recording spectrograms;
wherein the content of the first and second substances,
the detection method adopts chromatographic conditions as follows: the column was an Agilent DB-1701, 30 m x 0.25 mm, 1 μm, using temperature programming: the initial temperature was 150 ℃ and held for 1 minute; heating to 200 deg.C at 35 deg.C per minute, and maintaining for 5 min; heating to 250 deg.C at a rate of 30 deg.C per minute, and maintaining for 3 min; sample inlet temperature: 130 ℃; carrier gas: he; shunting mode: shunting; flow rate of carrier gas: 1 mL/min; the split ratio is as follows: 10: 1; GC run time: 12.095 min; sample introduction amount: 1 mu L;
the mass spectrometry conditions of the detection method are shown in table 1.
Wherein the S/N of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution should be not less than 3;
wherein the peak area RSD of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in 6-needle reference substance solution is not more than 10.0%.
The blank solution and the diluent are both trichloromethane and are in AR grade or above, and the impurity A reference substance is purchased from outsourcing and is in AR grade or above.
The instrument used was equipped with EI ion source, electron analytical balance for gas chromatograph, autosampler, Agilent GC \ MS QQQ 7000D.
The solution was controlled with the control solution as a limit, and the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution was compared with the average peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in 6-pin control solutions:
when the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution is not less than 6, the average peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the control solution, the measured value of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sample is reported to be not less than 37.5 ppm;
when the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution is less than 6, which is the average peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the control solution and is not less than the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution, the measured value of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sample is reported to be less than 37.5 ppm;
when the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution was not detected or was smaller than the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution, the measured value of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sample was reported to be smaller than LOD.
The limit of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one is less than or equal to 37.5ppm, and the LOD is 7.1 ppm.
The detection method adopts olmesartan medoxomil as a test sample to carry out methodology verification, and the verification result shows that the test method meets the relevant requirements and the test result is as follows:
the GC-MS is a gas chromatography-mass spectrum, and the GC-MS/MS is a gas chromatography-tandem mass spectrum.
The method for detecting the content of the impurity A in the test sample has high sensitivity and low quantitative limit, the content of the impurity A in the olmesartan medoxomil is strictly controlled according to related guiding principles, the limit of the impurity A in the olmesartan medoxomil is 37.5ppm, the detection method adopts the olmesartan medoxomil as the test sample, and the content of the impurity A in the olmesartan medoxomil meets related requirements after being verified by items such as system applicability, specificity, detection limit, durability and the like.
Drawings
FIG. 1 spectrum of sensitive solution in example 2
FIG. 2 spectrum of control solution of example 2
FIG. 3 spectrum of olmesartan medoxomil locating solution in example 3
FIG. 4 spectrum of control solution in example 3
FIG. 5 spectrum of selective solution in example 3
FIG. 6 LOD solution spectrum of the instrument in example 4
FIG. 7 LOD solution spectrum of the method in example 4
FIG. 8 3hr spectrogram of test solution in example 5
FIG. 9 spectrum of control solution 4hr in example 5
FIG. 10 spectrum of 3hr selective solution in example 5
Detailed Description
The invention is further illustrated by the following specific examples. It should be understood that: the examples of the present invention are provided for illustration only and not for limitation of the present invention. The technical scheme obtained by simply improving the invention or equivalently replacing the conventional means or components on the basis of the technical scheme of the invention belongs to the protection scope of the invention.
Information on instruments, chromatography columns, reagents, reference substances, test substances and the like used in the examples of the present invention are shown in tables 3, 4 and 5.
Example 1 detection method
Instrument conditions and reagents
The instrument comprises the following steps: gas chromatograph, autosampler, Agilent GC \ MS QQQ 7000D Equipped with EI ion source, electronic analytical balance
A chromatographic column: capillary column using (14% -cyanopropyl-phenyl) -methyl polysiloxane as stationary liquid (such as Agilent DB-1701, 30 m x 0.25 mm, 1 μm or equivalent performance chromatographic column)
Column temperature: the initial temperature was 150 ℃ and held for 1 minute; heating to 200 deg.C at 35 deg.C per minute, and maintaining for 5 min; the temperature was raised to 250 ℃ at a rate of 30 ℃ per minute and held for 3 min.
Sample inlet temperature: 130 ℃ carrier gas: he (He)
Shunting mode: flow rate of the divided carrier gas: 1mL/min
The split ratio is as follows: 10: 1 GC run time: 12.095min
Sample introduction amount: 1 mu L
Mass spectrum conditions:
reagent and reference substance
Trichloromethane: AR and above
4-chloro-4-methyl-5-methylene-1, 3-dioxolan-2-one: outsourcing
(1) Solution preparation:
diluting liquid: trichloromethane
Blank solution: diluent liquid
Comparison product stock solution (i): taking about 10mg of a reference substance, accurately weighing, placing in a 10mL measuring flask, adding a diluent to dilute to a scale, and shaking up.
Reference stock solution 2: precisely measuring 1.0mL of the reference stock solution, placing the reference stock solution into a 100mL measuring flask, adding the diluent to dilute to a scale, and shaking up.
Control solution: precisely measuring a reference substance stock solution (450 mu L), placing the reference substance stock solution into a 20mL measuring flask, adding a diluent to dilute the reference substance stock solution to a scale, and shaking the reference substance stock solution uniformly.
Sensitivity solution: precisely measuring 2.0mL of the reference solution, placing the reference solution in a 10mL measuring flask, adding the diluent to dilute to the scale, and shaking up.
Test solution: taking about 120mg of a test sample, precisely weighing, placing in a 20mL measuring flask, adding a diluent, ultrasonically dissolving, and diluting to a scale.
The test sample is 4-chloromethyl-5-methyl-1, 3-dioxol-2-one, olmesartan medoxomil, azilsartan medoxomil potassium, prulifloxacin, lenamicillin or pharmaceutically acceptable salts of lenamicillin, wherein the pharmaceutically acceptable salts of lenamicillin are preferably lenamicillin hydrochloride;
the reference substance is 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-ketone;
(2) sample introduction: after a GC-MS/MS instrument system is stabilized, feeding a blank solution 1 needle (if necessary, a plurality of needles are fed), a sensitivity solution 1 needle, a reference substance solution 6 needle and a test sample solution 1 needle, and recording spectrograms;
wherein the S/N of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution should be not less than 3;
wherein the peak area RSD of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in 6-needle reference substance solution is not more than 10.0%.
The solution was controlled with the control solution as a limit, and the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution was compared with the average peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in 6-pin control solutions:
when the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution is not less than 6, the average peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the control solution, the measured value of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sample is reported to be not less than 37.5 ppm;
when the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution is less than 6, which is the average peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the control solution and is not less than the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution, the measured value of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sample is reported to be less than 37.5 ppm;
when the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the test solution was not detected or was smaller than the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution, the measured value of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sample was reported to be smaller than LOD.
The limit of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one is less than or equal to 37.5ppm, and the LOD is 7.1 ppm.
Example 2 System applicability
The system applicability is realized by the S/N of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution and the RSD of the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in 6-needle comparison product solution, the S/N of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the sensitivity solution is required to be not less than 3, the RSD of the peak area of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in 6-needle comparison product solution is required to be not more than 10.0 percent, in order to confirm the system applicability in the sequence running process, in the verification process, a newly prepared reference substance solution is added every about 8 hours or at the end of the sequence, and the peak area RSD of the unit concentration of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in 6 continuous reference substance solutions is required to be not more than 10.0 percent; if the range is exceeded, an evaluation survey should be conducted.
The solution is prepared, sample injection is carried out according to the conditions of the embodiment 1, and the test results are shown in tables 6-8.
Example 3 specificity
The specificity is realized by measuring the separation degree of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one and adjacent peaks in a selective solution without interfering the detection of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one by a blank solution; the blank solution is required to have no interference on detection, the separation degree between the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one and adjacent impurity peaks in the selective solution is not less than 1.5, and the recovery rate of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one in the selective solution is 80.0% -120.0%.
The solution was prepared and injected under the conditions of example 1, and the test results are shown in tables 9 and 10.
Wherein, the area of the test sample carrying peak = test sample solution peak area ÷ test sample solution sample volume × selective solution sample volume; the average peak area of the control solution quoted in example 2 is the average peak area of the 6-phase control solution; measuring the concentration = (selective solution peak area-sample carried peak area)/reference solution average peak area x reference solution concentration; recovery (%) = measured concentration/theoretical concentration × 100%.
Example 4 detection Limit
The detection limit is determined by detecting that the ratio of the response signal to the noise is not less than 3: 1, and (b). It is required that the LOD should be not more than 11.25ppm and the signal-to-noise ratio of 4-chloro-4-methyl-5-methylene-1, 3-dioxolan-2-one in the LOD solution should be not less than 3 in the resulting chromatogram.
The solution was prepared and injected under the conditions of example 1, and the test results are shown in Table 11.
EXAMPLE 5 durability (solution stability)
And observing the rule that the reference substance solution, the test solution and the selective solution are placed in the dark at room temperature for a period of time and then injected, wherein the rule that the detection result changes along with time provides reference basis for the placing time of the reference substance solution and the test solution during detection. The method comprises the following steps:
the reference substance solution is placed in a dark place at room temperature for a period of time, the recovery rate is 80.0-120.0%, and the test period is stable;
if the test solution detects 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one within 0h, the test solution is placed in a dark place at room temperature for a period of time, and the change value of the measurement result is within 20 percent of the limit of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one, the test solution is stable during the investigation at room temperature; if the test solution does not detect 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one within 0h, the test solution is placed in a dark place at room temperature for a period of time, and no 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one is detected, the test solution is stable during the investigation at room temperature;
the selective solution is placed in a dark place at room temperature for a period of time, the recovery rate of the 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-ketone is 80.0% -120.0%, and the selective solution is stable in the investigation period.
The solution was prepared and injected under the conditions of example 1, and the test results are shown in tables 12 to 14.
Claims (6)
1. The method for detecting the impurity content of 4-chloro-4-methyl-5-methylene-1, 3-dioxolane-2-one is characterized by adopting GC-MS/MS for detection, wherein the chromatographic conditions adopted by the detection method are as follows: the chromatographic column is a capillary column taking (14% -cyanopropyl-phenyl) -methyl polysiloxane as stationary liquid, and adopts temperature programming;
the temperature programming is that the initial temperature of the column temperature is 150 ℃ and is kept for 1 minute; heating to 200 deg.C at 35 deg.C per minute, and maintaining for 5 min; the temperature was raised to 250 ℃ at a rate of 30 ℃ per minute and held for 3 min.
2. The detection method according to claim 1, which is used for detecting 4-chloro-4-methyl-5-methylene-1, 3-dioxolane in a test sample having a chemical structure containing a fragment of the formula IIIThe detection of the cyclic-2-one impurity,
。
3. the method of claim 2, wherein said test sample is selected from the group consisting of 4-chloromethyl-5-methyl-1, 3-dioxol-2-one, olmesartan medoxomil, azilsartan medoxomil potassium, prulifloxacin, lenampicillin, and a pharmaceutically acceptable salt of lenampicillin.
4. The method of claim 3, wherein the test sample is olmesartan medoxomil.
5. The method according to any one of claims 1-4, said method comprising the steps of: 1) respectively preparing a reference substance solution, a sensitivity solution and a test solution; the reference solution and the sensitivity solution are both solutions of impurity A; 2) sample introduction: after a GC-MS/MS instrument system is stabilized, feeding a blank solution 1 needle, a sensitivity solution 1 needle, a reference substance solution 6 needle and a test solution 1 needle, and recording spectrograms; the blank solution is trichloromethane, and the reference solution and the sensitivity solution are both prepared by dissolving impurity A in trichloromethane.
6. The method of claim 5, wherein the concentration of impurity A in the control solution is 150 ng/ml to 350 ng/ml; the concentration of the impurity A in the sensitivity solution is 20 ng/ml-60 ng/ml; the concentration of the test solution is 2 mg/ml-15 mg/ml.
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