CN115060824B - Liquid chromatography detection method for enantiomer impurities of ramiazepam intermediate - Google Patents
Liquid chromatography detection method for enantiomer impurities of ramiazepam intermediate Download PDFInfo
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- 238000001514 detection method Methods 0.000 title claims abstract description 50
- 239000012535 impurity Substances 0.000 title claims abstract description 36
- 238000004811 liquid chromatography Methods 0.000 title claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 110
- 239000000243 solution Substances 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 28
- ZZNXHQSAOHUNDA-SECBINFHSA-N (9r)-9-hydroxy-6,7,8,9-tetrahydrocyclohepta[b]pyridin-5-one Chemical compound O[C@@H]1CCCC(=O)C2=CC=CN=C12 ZZNXHQSAOHUNDA-SECBINFHSA-N 0.000 claims description 21
- 238000002347 injection Methods 0.000 claims description 17
- 239000007924 injection Substances 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 14
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 11
- 239000005695 Ammonium acetate Substances 0.000 claims description 11
- 229940043376 ammonium acetate Drugs 0.000 claims description 11
- 235000019257 ammonium acetate Nutrition 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 8
- 230000005526 G1 to G0 transition Effects 0.000 claims description 5
- KBRZBBOTZJFKFH-UHFFFAOYSA-N (3,5-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC(Cl)=CC(Cl)=C1 KBRZBBOTZJFKFH-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 5
- 239000000523 sample Substances 0.000 description 32
- ZZNXHQSAOHUNDA-VIFPVBQESA-N (9s)-9-hydroxy-6,7,8,9-tetrahydrocyclohepta[b]pyridin-5-one Chemical compound O[C@H]1CCCC(=O)C2=CC=CN=C12 ZZNXHQSAOHUNDA-VIFPVBQESA-N 0.000 description 31
- 230000003044 adaptive effect Effects 0.000 description 14
- 238000007865 diluting Methods 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
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- 239000000203 mixture Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
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- 230000000052 comparative effect Effects 0.000 description 7
- 238000011835 investigation Methods 0.000 description 7
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- 239000007853 buffer solution Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- -1 (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one hydrochloride Chemical compound 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
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- 206010027599 migraine Diseases 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 2
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
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- 238000011161 development Methods 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KRNAOFGYEFKHPB-ANJVHQHFSA-N [(5s,6s,9r)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl] 4-(2-oxo-3h-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate Chemical compound C1([C@H]2[C@@H](C3=CC=CN=C3[C@H](OC(=O)N3CCC(CC3)N3C(NC4=NC=CC=C43)=O)CC2)N)=CC=CC(F)=C1F KRNAOFGYEFKHPB-ANJVHQHFSA-N 0.000 description 1
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- 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 description 1
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- DNKYDHSONDSTNJ-XJVRLEFXSA-N chembl1910953 Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)N)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C1=CN=CN1 DNKYDHSONDSTNJ-XJVRLEFXSA-N 0.000 description 1
- 238000012733 comparative method Methods 0.000 description 1
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- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 229950004372 rimegepant Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
Classifications
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a liquid chromatography detection method for the content of enantiomer impurity (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone, which is quick and convenient, high in sensitivity, high in accuracy and good in durability.
Description
Technical Field
The invention belongs to the technical fields of pharmaceutical chemistry and analytical chemistry, and relates to a liquid chromatography detection method for an enantiomer of a migraine drug ramigempam intermediate. More particularly, the present invention relates to a liquid chromatographic detection method for (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one and any form of salt enantiomer impurity thereof.
Background
Rayleigh Mi Ji (English generic name: rimegepant, trade name: nurtec)) Is a small molecule oral Calcitonin Gene Related Peptide (CGRP) receptor antagonist developed by Biohaven company, and is approved for the first time in the United states in 2020 for the treatment and prevention of migraine in adults. The long half-life period, good oral bioavailability and high affinity to human CGRP receptor make the Rayleigh Mi Ji a potential best-in-class anti-acute migraine drug.
At present, only two original patents of WO2012050764 and WO2013130402 are queried, and the synthesis method of Rayleigh Mi Ji is reported. In the disclosed synthesis technical scheme of the ramigempam, the key chiral intermediate shown in the formula I, namely (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one, is involved. In the synthesis of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one, as shown in scheme one, the carbonyl reduction gives rise to a problem of stereoselectivity in the formation of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one, while at the same time producing the enantiomer shown in formula II, namely (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one.
The control of the enantiomer content in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone plays a vital role in the quality control of subsequent ramiazepam bulk drugs. Therefore, the development of a rapid, sensitive and effective analytical method for quantitatively detecting the content of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one is of great importance in order to develop a more effective asymmetric reduction or purification process based on the enantiomer detection results during the development and production of related products, and to effectively control the content of enantiomers.
The invention provides a liquid chromatography method with high sensitivity, high accuracy and good durability, which is used for quantitatively detecting the content of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone.
Disclosure of Invention
The invention provides a liquid chromatography detection method for the content of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone, which is quick and convenient, high in sensitivity, high in accuracy and good in durability.
The liquid chromatography detection method for the content of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone comprises the following steps:
a liquid chromatographic detection method of enantiomer impurity of compound (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one or any form of salt thereof is shown in formula I, which is characterized in that: the detection sample in the liquid chromatography detection is dissolved by ethanol and water mixed solvent, the stationary phase of the chromatographic column is silica gel with cellulose-tris (3, 5-dichlorophenyl carbamate) covalently bonded on the surface, the mobile phase is mixed solution of ammonium acetate aqueous solution and methanol, the liquid chromatography detector is an ultraviolet detector,
further, the liquid chromatography detection method of the present invention is characterized in that the content of water in the ethanol and water mixed solvent for dissolving the detection sample is not more than 10%.
The liquid chromatography detection method is characterized in that the concentration of the detection sample is 0.5 mg/mL-1.5 mg/mL.
The liquid chromatography detection method is characterized in that the stationary phase is a silica gel chromatographic column with the surface covalently bonded with cellulose-tris (3, 5-dichlorophenyl carbamate) and the specification is 4.6mm multiplied by 250mm multiplied by 5 mu m.
The liquid chromatography detection method is characterized in that the pH=5.0+/-0.5 of the aqueous ammonium acetate solution in the mobile phase of the liquid chromatography is 0.75 g/L-0.8 g/L.
The liquid chromatography detection method is characterized in that the mixing ratio of the ammonium acetate aqueous solution and the methanol in the mobile phase of the liquid chromatography is 550: 450-650: 350.
further, the liquid chromatography detection method according to the present invention is characterized in that the detection conditions of the liquid chromatography are as follows: the flow rate is 0.7-0.9 mL/min, the sample injection amount is 10-20 mu L, the column temperature is 25-35 ℃, the wavelength is 235nm, and the operation time is 40min.
The liquid chromatography detection method of the present invention is characterized in that the detection limit of the enantiomer impurity is 0.1 μg/mL-10 μg/mL.
The content of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one is difficult to detect: the (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone has serious peak front trailing in a conventional analysis method, and large matrix interference, so that the separation degree of a main peak and an enantiomer does not reach the requirement of 1.5, further the detection sensitivity of the enantiomer impurity is low, the detection limit is higher, and the impurity condition with lower content cannot be detected. According to the invention, after the sample is dissolved by ethanol, a small amount of water is added to solve the front tailing problem, and through reasonable selection of a chromatographic column stationary phase, the problems of peak shape and separation degree are effectively solved. The reasonable choice of the mobile phase further solves the problem of matrix interference, and effectively improves the sensitivity and durability of the method.
Drawings
FIG. 1 exemplary spectra of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one quantitative limits in the methods of the invention
FIG. 2 examination of typical spectra for the detection limits of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one in the method of the invention
FIG. 3 exemplary spectrogram of the method and system of the present invention for adaptability investigation
FIG. 4A typical spectrum of a durability investigation of the method according to the invention (buffer pH=5.0, concentration 0.77 g/L)
FIG. 5A typical spectrum of durability investigation of the method of the present invention (flow rate of mobile phase 0.7mL/min, column temperature 25 ℃ C.)
FIG. 6A standard curve of the linear equation of the method according to the present invention
FIG. 7 is a liquid phase diagram of comparative example 1 (sample dissolution solvent change)
FIG. 8 comparison example 2 liquid phase spectrogram (mobile phase Change)
FIG. 9 comparative example 3 liquid phase spectrogram (column change)
Detailed Description
The following specific examples are intended to provide a thorough understanding of the present invention to those skilled in the art and are not intended to limit the invention in any way.
In the following examples, all temperatures are degrees celsius unless otherwise indicated; unless otherwise indicated, the room temperature is 20-30 ℃; unless otherwise indicated, the various starting materials and reagents were all from commercial sources and were used without further purification; unless otherwise indicated, the various solvents used for chromatographic detection are chromatographic grade reagents and are used without further treatment; commercial manufacturers include, but are not limited to Honeywell, sigma, etc., unless otherwise indicated.
The liquid chromatograph used in the invention is: agilent 1260 liquid chromatograph.
The liquid chromatography detection basic conditions used in the invention are: column CHIRALPAK IC 4.6.6mm×250mm×5μm; the flow rate is 0.8mL/min; the sample injection amount is 20 mu L; column temperature is 30 ℃; a wavelength of 235nm; running for 40min; the preparation method of the buffer solution comprises the following steps: 0.77g of ammonium acetate was weighed into 1000mL of purified water and pH adjusted to 5.00 with glacial acetic acid; the mobile phase composition is buffer: methanol=600: 400.
the (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one and the detection sample used in the present invention are all available from Zhejiang Hongyuan pharmaceutical industry Co., ltd.
The (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one impurity control used in the present invention is manufactured by Zhejiang macro-element pharmaceutical Co., ltd.
Example 1: quantitative limit and detection limit investigation method
(1) Quantitative Limit (LOQ) and detection Limit (LOD) profiles
The impurity content is calculated by an area normalization method, and the detection Limit (LOD) and the quantification Limit (LOQ) of the impurities are determined according to the detection Limit (LOD) and the quantification Limit (LOQ) of the self-control. The detection Limit (LOD) and the quantification Limit (LOQ) are determined according to the signal-to-noise ratio, solutions diluted into different concentrations are measured by a dilution method, the lowest detection limit concentration is obtained when the signal-to-noise ratio is 3, and the lowest quantification limit concentration is obtained when the signal-to-noise ratio is 10.
(2) Solution preparation
Preparing enantiomer impurity solution: weighing 50.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control, placing in a 50mL volumetric flask, dissolving with ethanol, diluting with ethanol+5 mL water to scale, and mixing well.
Preparing a system adaptive solution: 100.1mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed and placed in a 100mL volumetric flask, 1mL of enantiomer impurity solution is removed, dissolved with ethanol, diluted to scale with ethanol plus 6mL of water and mixed evenly.
Test solution a: weighing 50.0mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one sample, placing in a 50mL volumetric flask, dissolving with ethanol, diluting to scale with ethanol+5 mL water, and mixing well; accurately transferring into 1.00mL volumetric flask of 100mL, diluting with ethanol to scale, and mixing.
Quantitative Limit (LOQ) solution formulation: weighing 50.0mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one sample, placing in a 50mL volumetric flask, dissolving with ethanol, diluting with ethanol to a scale, and mixing well; precisely transferring 1.00mL into a 100mL volumetric flask, diluting with ethanol to scale, and mixing; then, the mixture was precisely transferred into a 50mL volumetric flask with 1.00mL, diluted to the scale with ethanol and 5mL of water, and mixed well.
Limit of detection (LOD) solution formulation: 3.0mL of quantitative limiting solution is precisely removed in a 10mL volumetric flask, diluted to a scale with ethanol and 5mL of water, and uniformly mixed.
(3) Sample injection program
System adaptability and LOD sampling procedure: sample injection blank (ethanol+5 mL water) 2 needles, system adaptive solution (6 needles), test solution a (1 needle), quantitative limiting solution (3 needles), detection limiting solution (3 needles) and system adaptive solution (1 needle).
Table 1: system adaptive solution measurement results
| Sample injection sequence | Peak area of the compound of formula I | Peak area of the compound of formula II |
| 1 | 31178.029 | 318.365 |
| 2 | 31136.311 | 316.247 |
| 3 | 31127.808 | 315.299 |
| 4 | 31083.720 | 313.390 |
| 5 | 31047.581 | 310.953 |
| 6 | 31021.386 | 309.719 |
| 7 (program control needle) | 30628.888 | 303.313 |
| Average peak area 1-6 | 31099.139 | 313.996 |
| RSD1-6 | 0.2％ | 1.0％ |
| Average peak area 1-7 | 31031.96043 | 312.4694286 |
| RSD1-7 | 0.6％ | 1.6％ |
Table 1 results of the system suitability test show that the blank solution showed no interference in the detection of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one, the peak purity index was 1.00, the peak area RSD of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one in the 6-needle system suitability solution was 0.2%, the peak area RSD of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one was 1.0%, and the maximum RSD of 1-7 needles (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one after the needle control was 0.6%, and the peak area RSD of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one was 0.6% of the maximum RSD.
Table 2: quantitative limit measurement results
The quantitative limit test results shown in Table 2 indicate that the concentration of the (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one sample is 0.2 mug/ml, the minimum signal to noise ratio is 11.3, and the RSD value is 7.5%, which meet the relevant regulatory requirements of the pharmacopoeia for analytical methods.
Table 3: detection limit measurement result
The quantitative limit test results shown in Table 3 indicate that the concentration of the (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one sample is 0.06 mug/ml, and the minimum signal to noise ratio is 4.0, which meets the relevant regulatory requirements of the pharmacopoeia for analytical methods.
Typical spectrograms of the related detection in the embodiment are shown in the accompanying drawings 1-3 of the specification.
Example 2: method durability investigation
(1) Brief description of method durability
Preparing 1 sample solution, and respectively heating to 25deg.C, 30deg.C and 35deg.C; the flow rate is 0.7mL/min, 0.8mL/min and 0.9mL/min; buffer salt pH is 4.5, 5.0, 5.5; the buffer salt concentration is 0.75g/L, 0.77g/L and 0.8g/L respectively; buffered saline solution and methanol ratio 550:450. 600:400. 650:350; the analysis was performed on the samples of 10. Mu.L, 15. Mu.L and 20. Mu.L, and the main peak was examined for peak formation and impurity separation.
(2) Solution preparation
Preparing enantiomer impurity solution: weighing 50.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control, placing in a 50mL volumetric flask, dissolving with ethanol, diluting to scale with ethanol+1 mL of water, and mixing well.
Preparing a system adaptive solution: 100.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed and placed in a 100mL volumetric flask, 1mL of enantiomer impurity solution is removed, dissolved with ethanol, diluted to scale with ethanol plus 1mL of water and mixed evenly.
(3) Sample injection program
Solution 1 needle was advanced under different methods for single needle system applicability.
Table 4: method durability measurement results
The durability investigation results of the above methods show that in the method for changing the conditions, the separation degree of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one and enantiomer impurities (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one are all larger than 1.5, and the requirements of pharmacopoeia on the separation degree of impurities are met.
Typical spectrograms for the correlation detection of the embodiment are shown in the accompanying figures 4-5 of the specification.
Example 3: square law linear range investigation
(1) Brief description of the test
And 6 concentration points which are relatively uniform in the concentration range of LOQ-200%, drawing a curve by taking the concentration as an abscissa and the peak area as an ordinate, and calculating the numerical value of a linear regression coefficient R2 of the curve.
(2) Solution preparation
Preparation of linear (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one solution: taking 50mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one, precisely weighing and placing the mixture into a 50mL volumetric flask, dissolving the mixture with ethanol, diluting the solution with ethanol to a scale, and uniformly mixing the solution; precisely transferring into 10.0mL volumetric flask of 100mL, diluting with ethanol to scale, and mixing; then precisely transferring 1.00mL, 2.0mL, 5.0mL, 8.0mL and 10.0mL, respectively placing into 5 volumetric flasks of 100mL, diluting to scale with ethanol and 2mL of water, and mixing well; 1, 2, 5, 8, 10 mug/mL linear solution is obtained; and drawing a linear equation standard curve by taking the concentration of the linear solution as an abscissa and the peak area as an ordinate.
Preparing quantitative limiting solution: 1.00mL of the 2 mug/mL linear solution is precisely removed in a 10mL volumetric flask, diluted to scale with ethanol+2 mL of water, and mixed well.
(3) Sample injection program
Blank (ethanol+2 mL water) 2 needles, 3 needles per linear solution and blank (1 needle) were injected.
Table 4: linear measurement result of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one
The above linear test results show that the blank solution does not interfere with the detection of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one; (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one linear regression coefficient r2= 0.9988; the recovery rate of the (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridine-5-ketone test solution is 85.7-102.2%; the maximum RSD value of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one was 2.3% and the recovery precision RSD of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one was 6.7% for each of the three-needle mass spectrum peak areas at the same concentration.
The linear equation standard curve of the method of the embodiment is shown in figure 6 of the specification.
Example 4: detection of enantiomeric impurities in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one hydrochloride samples
Chromatographic conditions: column CHIRALPAK IC 4.6.6mm×250mm×5μm; the flow rate is 0.8mL/min; the sample injection amount is 20 mu L; column temperature is 30 ℃; a wavelength of 235nm; running for 40min; the preparation method of the buffer solution comprises the following steps: 0.77g of ammonium acetate was weighed into 100mL of purified water and pH was adjusted to 5.0 with glacial acetic acid; the mobile phase composition is buffer: methanol=600: 400.
preparing enantiomer impurity solution: weighing 50.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control, placing in a 50mL volumetric flask, dissolving with ethanol, diluting with ethanol+5 mL water to scale, and mixing well.
Preparing a system adaptive solution: 100.1mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed and placed in a 100mL volumetric flask, 1mL of enantiomer impurity solution is removed, dissolved with ethanol, diluted to scale with ethanol plus 5mL of water and mixed evenly.
Preparing a test solution: accurately weighing 50mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one hydrochloride test sample, dissolving in ethanol in a 50mL volumetric flask, and adding ethanol plus 5mL of water to a fixed volume to scale, and shaking uniformly.
Preparing a blank solution: in a 50mL volumetric flask, 5mL of water was added, the volume was fixed to the scale mark with ethanol, and shaking was performed.
Sample injection procedure: the sample injection is performed by a blank 2-needle, a system adaptive solution (6-needle), a sample solution (2-needle) and a system adaptive solution (1-needle).
The content of enantiomer impurity (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one was calculated from the area normalization result and found to be 0.09%.
Example 5: detection of enantiomeric impurities in (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one sulfate samples
Chromatographic conditions: column CHIRALPAK IC 4.6.6mm×250mm×5μm; the flow rate is 0.8mL/min; the sample injection amount is 20 mu L; column temperature 25 ℃; a wavelength of 235nm; running for 40min; the preparation method of the buffer solution comprises the following steps: 0.8g of ammonium acetate was weighed into 1000mL of purified water and pH adjusted to 4.5 with glacial acetic acid; the mobile phase composition is buffer: methanol=550: 450.
preparing enantiomer impurity solution: 50.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed into a 50mL volumetric flask, dissolved with ethanol, diluted to a scale with ethanol+3 mL of water and mixed evenly.
Preparing a system adaptive solution: 100.1mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed and placed in a 100mL volumetric flask, 1mL of enantiomer impurity solution is removed, dissolved with ethanol, diluted to scale with ethanol plus 3mL of water and mixed evenly.
Preparing a test solution: accurately weighing 50mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one sulfate test sample, dissolving in ethanol in a 50mL volumetric flask, and fixing the volume to a scale with ethanol+3 mL of water, and shaking uniformly.
Preparing a blank solution: in a 50mL volumetric flask, ethanol+3 mL of water is used for fixing the volume to the scale mark, and shaking is carried out uniformly.
Sample injection procedure: the sample injection is performed by a blank 2-needle, a system adaptive solution (6-needle), a sample solution (2-needle) and a system adaptive solution (1-needle).
The content of enantiomer impurity (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one was calculated from the area normalization result and found to be 0.11%.
Example 6: method comparative example 1 (front tailing severe, recovery only 50%)
Chromatographic conditions: column CHIRALPAK IC 4.6.6mm×250mm×5μm; the flow rate is 0.8mL/min; the sample injection amount is 20 mu L; column temperature is 30 ℃; a wavelength of 235nm; running for 40min; the preparation method of the buffer solution comprises the following steps: 0.77g of ammonium acetate was weighed into 100mL of purified water and pH was adjusted to 5.0 with glacial acetic acid; the mobile phase composition is buffer: methanol=600: 400.
preparing enantiomer impurity solution: weighing 50.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control, placing in a 50mL volumetric flask, dissolving with ethanol, diluting with ethanol to scale, and mixing well.
Preparing a system adaptive solution: 100.1mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed and placed in a 100mL volumetric flask, 1mL of enantiomer impurity solution is removed, dissolved and diluted to scale by an ethanol diluent, and uniformly mixed.
Preparing a blank solution: in a 50mL volumetric flask, ethanol is used for fixing the volume to the scale mark, and shaking is carried out uniformly.
Sample injection procedure: blank solution (1 needle), system applicability solution (1 needle).
Test results: when the sample is dissolved by pure ethanol, the unknown peak at about 7min moves to 16min, so that the unknown peak has an overlapping sign with the peak of RG5, the half-peak width, the peak area and the peak height are reduced, the peak has a front edge phenomenon, the front tailing of the main peak of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one is serious, and the recovery rate test result shows that the recovery rate of the main peak is only 50%. The related spectrogram of comparative example 1 is shown in figure 7 of the specification.
Example 7: comparative example 2 (matrix interference severe)
Chromatographic conditions: column CHIRALPAK IC 4.6.6mm×250mm×5μm; the flow rate is 0.8mL/min; the sample injection amount is 20 mu L; column temperature is 30 ℃; a wavelength of 235nm; running for 40min; water: methanol=600: 400.
preparing enantiomer impurity solution: 50.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed into a 50mL volumetric flask, dissolved with ethanol and diluted to scale with ethanol+5 mL water, and mixed well.
Preparing a system adaptive solution: 100.1mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed and placed in a 100mL volumetric flask, 1mL of enantiomer impurity solution is removed, dissolved by an ethanol diluent and diluted to scale by ethanol plus 5mL of water, and uniformly mixed.
Preparing a blank solution: in a 50mL volumetric flask, ethanol+5 mL of water is used for fixing the volume to the scale mark, and shaking is carried out uniformly.
Sample injection procedure: blank solution (1 needle), system applicability solution (1 needle).
Test results: when the flow phase changes to water: methanol=600: 400, a half-width of 0.798 to 1.521, a peak height of 528.1 to 302, and a peak area of 30759 to 209022. It can be seen that the matrix effect is evident. The related spectrogram of comparative example 2 is shown in figure 8 of the specification.
Example 8: comparative method 3 (impurity resolution does not meet the requirement)
Chromatographic conditions: the chromatographic column CHIRALCEL OJ-RH 4.6mm.times.150mm.times.5μm; the flow rate is 0.8mL/min; the sample injection amount is 20 mu L; column temperature is 30 ℃; a wavelength of 235nm; running for 40min; the preparation method of the buffer solution comprises the following steps: 0.77g of ammonium acetate was weighed into 100mL of purified water and pH was adjusted to 5.0 with glacial acetic acid; the mobile phase composition is buffer: methanol=600: 400.
preparing enantiomer impurity solution: weighing 50.1mg of (S) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control, placing in a 50mL volumetric flask, dissolving with ethanol+3 mL of water, diluting to scale, and mixing well.
Preparing a system adaptive solution: 100.1mg of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one working control is weighed and placed in a 100mL volumetric flask, 1mL of enantiomer impurity solution is removed, dissolved and diluted to scale with ethanol+3 mL of water diluent, and uniformly mixed.
Preparing a blank solution: in a 50mL volumetric flask, 3mL of water was added, the volume was fixed to the scale mark with ethanol, and shaking was performed.
Sample injection procedure: blank solution (1 needle), system applicability solution (1 needle).
Test results: the main peak of (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one did not achieve separation from its enantiomeric impurities. The related spectrogram of comparative example 3 is shown in figure 9 of the specification.
While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the method and application described herein can be modified, altered, and combined as appropriate and within the scope and spirit of the invention to make and use the invention. Those skilled in the art can also refer to the present disclosure by appropriately modifying the process parameters. It is expressly intended that all such modifications and adaptations as would be apparent to those skilled in the art are intended to be within the scope of the present invention.
Claims (2)
1. A liquid chromatographic detection method of enantiomer impurity of compound (R) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-one or hydrochloride and sulfate thereof is characterized in that: the detection sample in the liquid chromatography detection is dissolved by using a mixed solvent of ethanol and water, a stationary phase of a chromatographic column is silica gel with cellulose-tris (3, 5-dichlorophenyl carbamate) covalently bonded on the surface, a mobile phase is a mixed solution of ammonium acetate aqueous solution and methanol, and a liquid chromatography detector is an ultraviolet detector;
the method is characterized in that the content of water in the ethanol and water mixed solvent for dissolving the detection sample is not more than 10%; the concentration range of the detection sample is 0.5 mg/mL-1.5 mg/mL; the specification of the silica gel chromatographic column with the stationary phase of which the surface is covalently bonded with cellulose-tris (3, 5-dichlorophenyl carbamate) is 4.6mm multiplied by 250mm multiplied by 5 mu m; the pH=5.0+/-0.5 of the aqueous ammonium acetate solution in the mobile phase of the liquid chromatograph, and the concentration is 0.75g/L to 0.8g/L; the mixing ratio of the aqueous ammonium acetate solution and methanol in the mobile phase of the liquid chromatograph is 550: 450-650: 350; the detection conditions of the liquid chromatography are as follows: the flow rate is 0.7-0.9 mL/min, the sample injection amount is 10-20 mu L, the column temperature is 25-35 ℃, the wavelength is 235nm, and the operation time is 40min.
2. The method for detecting a liquid chromatograph according to claim 1, wherein the detection limit of the enantiomeric impurity is 0.1. Mu.g/mL to 10. Mu.g/mL.
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