CN104133012A - Method for determining asenapine maleate racemate by using HPLC - Google Patents
Method for determining asenapine maleate racemate by using HPLC Download PDFInfo
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- CN104133012A CN104133012A CN201410310045.9A CN201410310045A CN104133012A CN 104133012 A CN104133012 A CN 104133012A CN 201410310045 A CN201410310045 A CN 201410310045A CN 104133012 A CN104133012 A CN 104133012A
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- maleic acid
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Abstract
The invention belongs to the field of analytic chemistry, and discloses a method for separating and analyzing asenapine maleate and racemate thereof by using HPLC. The method employs a chiral chromatographic column taking amylose-tris(3,5-dimethyphenylcarbamate) as a filling material, employs a hexane-low alcohol solution as mobile phase, and is capable of quantitatively determining the content of optical isomers in asenapine maleate racemate and indicating the stability of the asenapine maleate racemate. The method is high in specificity, high in accuracy and simple to operate.
Description
Technical field
The invention discloses a kind of HPLC method, be specifically related to a kind of Analyze & separate method of maleic acid asenapine and raceme thereof.
Background technology
Maleic acid asenapine for acute manic disorder or with/without the two-way disturbance of emotion of I type of mental illness.Asenapine, by Merck & Co., Inc. and Ou Jianong biotech company joint development, is by Fourth Ring class antidepressants Mianserin (mianserin) is carried out to the novel atypical antipsychotic agents that structure of modification is found.When it is racemic mixture, 52HT2 and D2 acceptor are had to dual antagonism.The English chemistry of maleic acid asenapine (3aRS by name, 12bRS)-5-Chloro-2-methyl-2,3,3a, 12b-tetrahydro-1Hdibenzo[2,3:6,7] oxepino[4,5-c] pyrrole (2Z)-2-butenedioate (1:1), molecular formula is C
21h
20clNO
5.Maleic acid asenapine structural formula is:
The raceme structural formula of this compound is:
A kind of Analyze & separate method that creates maleic acid asenapine and raceme thereof is for synthetic maleic acid asenapine bulk drug and the quality control of optics impurity in maleic acid asenapine bulk drug is all had important practical significance.
Summary of the invention
The object of the present invention is to provide a kind of high efficiency liquid phase method of Analyze & separate maleic acid asenapine and raceme thereof, thereby ensure the accuracy of maleic acid asenapine purity detecting, realize the quality control of its finished product bulk drug.
The purity with high-efficient liquid phase chromatogram technique analysis maleic acid asenapine described in this method and separate the method for its raceme, to adopt with amylose-tri--(3,5-xylyl carbamate) be the chiral chromatographic column of filler, taking normal hexane-low-alcohol solution as mobile phase.
The chiral chromatographic column that the present invention adopts is CHIRALPAK AD or CHIRALPAK AD-H.
The low-alcohol solution that the present invention adopts is selected from methyl alcohol, absolute ethyl alcohol, propyl alcohol, isopropyl alcohol, is preferably absolute ethyl alcohol, isopropyl alcohol.
In the present invention, the volume ratio of mobile phase lower alcohol and normal hexane system is 40:60～0:100, and preferred proportion is 10:90～0:100.
The present invention adds 0.1% diethylamine in mobile phase.
Analyze & separate method of the present invention, can realize in accordance with the following methods:
(1) get maleic acid asenapine and raceme thereof each appropriate, use respectively anhydrous alcohol solution sample, be mixed with containing maleic acid asenapine and raceme 0.05～1mg/mL thereof, preferably the sample solution of 0.5mg/mL;
(2) flow rate of mobile phase being set is 0.4～1.0mL/min, preferably 0.5mL/min, and detection wavelength is 200～230nm, preferably 210nm, column temperature is room temperature;
(3) get sample solution 10～50 μ L of (1), preferably 10 μ L injection liquid chromatographies, complete the separation and analysis of maleic acid asenapine and raceme thereof.
Instrument and optimum chromatographic condition that the present invention uses are:
High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp
Chromatographic column: AD-H (CHIRALPAK 250mm*4.6mm)
Mobile phase: normal hexane-isopropyl alcohol=93:7, adds 0.1% diethylamine
Flow velocity: 0.5 mL/min
Detect wavelength: 210 nm
Column temperature: room temperature
Sampling volume: 10 μ L.
The present invention adopts AD-H (CHIRALPAK, 250mm*4.6mm), can effectively separate maleic acid asenapine and raceme thereof, the purity of Accurate Determining maleic acid asenapine and raceme thereof; The invention solves the compartment analysis problem of maleic acid asenapine and raceme thereof, thereby guaranteed quality controllable (the results are shown in accompanying drawing 1～7) of maleic acid asenapine intermediate feed medicine.
Brief description of the drawings
Maleic acid asenapine raceme HPLC chromatogram when Fig. 1 is embodiment 1;
Maleic acid asenapine HPLC chromatogram when Fig. 2 is embodiment 1;
Maleic acid asenapine raceme HPLC chromatogram when Fig. 3 is embodiment 2;
The HPLC chromatogram of maleic acid asenapine when Fig. 4 is embodiment 2;
Solvent HPLC chromatogram when Fig. 5 is embodiment 3;
Maleic acid asenapine raceme HPLC chromatogram when Fig. 6 is embodiment 3;
The HPLC chromatogram of maleic acid asenapine when Fig. 7 is embodiment 3.
Embodiment
Embodiment 1
Instrument and condition:
High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp;
Chromatographic column: AD-H (CHIRALPAK, 250mm*4.6mm);
Mobile phase: normal hexane-isopropyl alcohol=90:10
Flow velocity: 0.5 mL/min;
Detect wavelength: 220nm;
Column temperature: room temperature;
Sampling volume: 10 μ L.
Experimental procedure
Get maleic acid asenapine and raceme thereof each appropriate, use respectively anhydrous alcohol solution sample, be mixed with the sample solution containing maleic acid asenapine and the about 0.5mg/mL of raceme thereof; Separately get absolute ethyl alcohol in right amount as blank solvent.Carry out efficient liquid phase chromatographic analysis by above-mentioned condition, record chromatogram.The results are shown in accompanying drawing 1 ~ 2, Fig. 1 is the HPLC chromatogram of maleic acid asenapine raceme; Fig. 2 is the HPLC chromatogram of maleic acid asenapine, can find out that maleic acid asenapine cannot separate completely with its optical isomer under this condition, and maleic acid asenapine appearance time is 14.550min.
Embodiment 2
Instrument and condition:
High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp
Chromatographic column: AD-H (CHIRALPAK, 250mm*4.6mm)
Mobile phase: normal hexane-isopropyl alcohol=95:5, adds 0.005% diethylamine
Flow velocity: 0.5 mL/min
Detect wavelength: 210 nm
Column temperature: room temperature
Sampling volume: 10 μ L.
Experimental procedure
Get maleic acid asenapine and raceme thereof appropriate, use respectively anhydrous alcohol solution sample, be mixed with the sample solution containing maleic acid asenapine and the about 0.5mg/mL of raceme thereof.Carry out efficient liquid phase chromatographic analysis by above-mentioned condition, record chromatogram.The results are shown in accompanying drawing 3 ~ 4, Fig. 3 is the HPLC chromatogram of maleic acid asenapine raceme; Fig. 4 is the HPLC chromatogram of maleic acid asenapine, can find out that maleic acid asenapine and its optical isomer cannot reach baseline separation under this condition, and chromatographic peak hangover is serious, and maleic acid asenapine appearance time is 19.550min.
Embodiment 3
Instrument and condition:
High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp
Chromatographic column: AD-H (CHIRALPAK 250mm*4.6mm)
Mobile phase: normal hexane-isopropyl alcohol=93:7, adds 0.1% diethylamine
Flow velocity: 0.5 mL/min
Detect wavelength: 210 nm
Column temperature: room temperature
Sampling volume: 10 μ L.
Experimental procedure
Get maleic acid asenapine and raceme thereof each appropriate, use respectively anhydrous alcohol solution sample, be mixed with the sample solution containing maleic acid asenapine and the about 0.5mg/mL of raceme thereof.Carry out efficient liquid phase chromatographic analysis by above-mentioned condition, record chromatogram.The results are shown in accompanying drawing 5 ~ 7, is the HPLC chromatogram of solvent absolute ethyl alcohol in Fig. 5; Fig. 6 is the HPLC chromatogram of maleic acid asenapine raceme; Fig. 7 is the HPLC chromatogram of maleic acid asenapine, can find out that maleic acid asenapine can separate completely with its optical isomer under this condition, and maleic acid asenapine appearance time is 15.614min.
Claims (8)
1. the method for a high performance liquid chromatography compartment analysis maleic acid asenapine and raceme thereof, it is characterized in that: adopt with amylose-tri--(3,5-xylyl carbamate) be the chiral chromatographic column of filler, taking normal hexane-low-alcohol solution as mobile phase.
2. Analyze & separate method according to claim 1, chiral chromatographic column is selected from CHIRALPAK AD or CHIRALPAK AD-H.
3. according to the Analyze & separate method described in claim 1, said lower alcohol is selected from the one in following compound: methyl alcohol, absolute ethyl alcohol, propyl alcohol, isopropyl alcohol.
4. according to the choosing of the lower alcohol described in claim 3, preferably absolute ethyl alcohol, isopropyl alcohol.
5. according to the Analyze & separate method described in right 1, the volume ratio of mobile phase lower alcohol-normal hexane is 40:60～0:100.
6. according to the choosing of the mobile phase normal hexane-low-alcohol solution volume ratio described in claim 5, preferably 10:90～0:100.
7. according to the Analyze & separate method described in right 1, in said mobile phase, add 0.1% diethylamine.
8. according to the Analyze & separate method described in right 1, it is characterized in that comprising following step:
(1) get maleic acid asenapine and raceme sample is appropriate, use anhydrous alcohol solution sample, be mixed with every 1mL containing maleic acid asenapine and raceme 0.05～1mg thereof, preferably the sample solution of 0.5mg/mL;
(2) flow rate of mobile phase being set is 0.4～1.0mL/min, is preferably 0.5 mL/min; Detection wavelength is 200～230nm, is preferably 210nm; Column temperature is room temperature;
(3) get sample solution 10～50 μ L of (1), be preferably 10 μ L injection liquid chromatographies, the analysis that completes maleic acid asenapine and optical isomer thereof with separate.
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| CN201410310045.9A CN104133012B (en) | 2014-07-02 | 2014-07-02 | Method for measuring asenapine maleate racemate by high performance liquid chromatography |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| CN115494174A (en) * | 2022-09-23 | 2022-12-20 | 南京瑞孚医药科技有限公司 | Method for detecting thiourea in meloxicam by high performance liquid chromatography |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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| US3992547A (en) * | 1974-11-20 | 1976-11-16 | Merck & Co., Inc. | 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine-N-oxide isomer |
| US20090082572A1 (en) * | 2005-11-14 | 2009-03-26 | Hetero Drugs Limited | Process for amorphous esomeprazole |
| US20110263853A1 (en) * | 2008-11-03 | 2011-10-27 | Mylan India Private Limited | Hplc method for the analysis of bosetan and related substances and use of these substances as reference standards and markers |
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2014
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Patent Citations (3)
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| US3992547A (en) * | 1974-11-20 | 1976-11-16 | Merck & Co., Inc. | 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine-N-oxide isomer |
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| ANEESH T.P等: "STRESS DEGRADATION STUDIES AND DEVELOPMENT AND VALIDATION OF RP-HPLC METHOD FOR THE ESTIMATION OF ASENAPINE MALEATE", 《INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES》 * |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US10980753B2 (en) | 2016-12-20 | 2021-04-20 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| CN115494174A (en) * | 2022-09-23 | 2022-12-20 | 南京瑞孚医药科技有限公司 | Method for detecting thiourea in meloxicam by high performance liquid chromatography |
| CN115494174B (en) * | 2022-09-23 | 2024-03-29 | 南京瑞孚医药科技有限公司 | Method for detecting thiourea in meloxicam by high performance liquid chromatography |
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| CN104133012B (en) | 2020-01-07 |
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Address after: 102206 south building, Boda building, Life Science Park, Changping District, Beijing (Wanquan) Patentee after: BEIJING VENTUREPHARM BIOTECH Corp. Address before: 102206 Beijing City, Changping District Zhongguancun Life Science Park building, Boda Wanquan (Beijing) innovation base Patentee before: BEIJING VENTUREPHARM BIOTECH Corp. |
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