CN103760280A - Method for separating and measuring asenapine intermediate related substances by liquid chromatography - Google Patents
Method for separating and measuring asenapine intermediate related substances by liquid chromatography Download PDFInfo
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- CN103760280A CN103760280A CN201410011662.9A CN201410011662A CN103760280A CN 103760280 A CN103760280 A CN 103760280A CN 201410011662 A CN201410011662 A CN 201410011662A CN 103760280 A CN103760280 A CN 103760280A
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Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for separating and measuring chemical purity of asenapine intermediate 1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one,11-chloro-2,3-dihydro-2-methyl related substances by liquid chromatography. By using a chromatographic column in which octyl-silane bonded silica gel is used as a filler and using inorganic acid salt buffer solution-organic phase in a certain ratio as a mobile phase, the method can be used for measuring the contents of the asenapine intermediate and related substances thereof, thereby effectively controlling the quality of the asenapine intermediate and asenapine. The method has the advantages of high specificity and high accuracy, and is simple to operate.
Description
Technical field
The invention belongs to analytical chemistry field, be specifically related to the method for liquid chromatography for separating and determining asenapine intermediate and related substance thereof.
Background technology
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.Asenapine intermediated chemistry is called 11-Chloro-2-methyl-2,3-dihydro-8-oxa-2-aza-dibenzo[e, h] azulen-1-one, molecular formula is C
17h
12clNO
2.Asenapine intermediate structure formula is:
In the process of synthetic this compound, there is the important intermediate of several steps not exclusively to affect purity and the quality of medicine due to removal, related substance for the synthetic major control of asenapine intermediate has 3, respectively related substance 1 (5-Chloro-2-phenoxy-phenyl)-acetic acid, related substance 2 { [2-(5-Chloro-2-phenoxy-phenyl)-acetyl]-methyl-amino}-acetic acid methyl ester and related substance 3(3-(5-Chloro-2-phenoxy-phenyl)-1-methyl-pyrrolidine-2, 4-dione, structural formula is respectively:
Related substance 1 related substance 2 related substances 3
For the impurity of introducing in synthetic asenapine intermediate, in bulk drug, need to carry out quality control, therefore, realize the separation of asenapine intermediate and related substance thereof, aspect the synthetic and quality control of asenapine, having important practical significance.
Summary of the invention
The object of the present invention is to provide a kind of method of analyzing asenapine intermediated chemistry purity and separated its related substance, thereby realize asenapine intermediate and the separated of its related substance and measure, guaranteeing asenapine and containing the quality control of asenapine preparation.
Method with liquid chromatography analysis asenapine intermediated chemistry purity and separated its related substance of the present invention, is to adopt the chromatographic column that octyl silane group silica gel is filler, and a certain proportion of inorganic salts buffer solution-organic phase of take is mobile phase.
It is filler that above-mentioned said chromatographic column be take octyl silane group silica gel, is selected from Kromasil-C
8or ES-C
8.
Above-mentioned said organic phase is selected from following compound: methyl alcohol, acetonitrile, propyl alcohol, isopropyl alcohol, be preferably acetonitrile.
Above-mentioned said method, its mobile phase inorganic salts buffer solution-organic phase adopts isocratic elution.
In above-mentioned said method, the inorganic salts that comprise in inorganic salts buffer solution are selected from phosphate, carbonate, citrate, are preferably phosphate, are specially potassium dihydrogen phosphate, ammonium dihydrogen phosphate (ADP).
The concentration of the inorganic salts that wherein comprise in inorganic salts buffer solution is 0.01～0.1mol/L, and preferred concentration is 0.02mol/L.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) get asenapine intermediate sample appropriate, by methyl alcohol or mobile phase sample dissolution, be mixed with every 1mL containing the sample solution of asenapine 0.1～1.5mg.
2) flow rate of mobile phase being set is 0.5～1.5mL/min, and flow rate of mobile phase is preferably 1.0mL/min, and detection wavelength is 200～250nm, and optimum detection wavelength is 205nm, and column oven temperature is 20～50 ℃, and column oven temperature the best is 25 ℃.
3) get 1) sample solution 10～50 μ L, injection liquid chromatography, completes the separation determination of asenapine intermediate and related substance.Wherein:
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph that the present invention adopts is Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp
Chromatographic column: C
8(Kromasil, 250 * 4.6 mm, 5 μ m)
Mobile phase: 0.02mol/L potassium dihydrogen phosphate buffer solution (take potassium dihydrogen phosphate 2.72g, be dissolved in water to 1000ml, adjust pH 3.0 with dilute phosphoric acid solution)-acetonitrile (60:40)
Flow velocity: 1.0 mL/min
Detect wavelength: 205 nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
The present invention adopts C
8(Kromasil, 250 * 4.6 mm, 5 μ m), can effective separated asenapine intermediate and related substance thereof.The invention solves the separation determination problem of asenapine and related substance thereof, thereby guaranteed quality controllable (the results are shown in accompanying drawing 1～7) of asenapine intermediate feed medicine.
Accompanying drawing explanation
Asenapine intermediate when Fig. 1 is embodiment 1 and related substance HPLC figure thereof;
Asenapine intermediate HPLC figure when Fig. 2 is embodiment 1;
Asenapine intermediate when Fig. 3 is embodiment 2 and related substance HPLC figure thereof;
The HPLC figure of asenapine intermediate when Fig. 4 is embodiment 2;
Solvent HPLC figure when Fig. 5 is embodiment 3;
Asenapine intermediate when Fig. 6 is embodiment 3 and related substance HPLC figure thereof;
The HPLC figure of asenapine intermediate when Fig. 7 is embodiment 3.
embodiment:
Following examples are used for further understanding the present invention, but are not limited to the scope of this enforcement.
Embodiment 1
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
8(Kromasil, 250 * 4.6 mm, 5 μ m)
Mobile phase: 0.02mol/L ammonium dihydrogen phosphate (ADP) buffer solution (claim ammonium dihydrogen phosphate (ADP) 2.3g, be dissolved in water and be settled to 1000mL)-methyl alcohol (40:60)
Flow velocity: 1.0mL/min
Detect wavelength: 205nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
Experimental procedure
Get asenapine intermediate and related substance thereof appropriate, use respectively methyl alcohol sample dissolution, be mixed with the sample solution containing asenapine intermediate and related substance approximately 0.5 mg/mL thereof.By above-mentioned condition, carry out efficient liquid phase chromatographic analysis, record chromatogram.The results are shown in accompanying drawing 1～2, the chromatographic peak that in Fig. 1, retention time is 37.166min is asenapine intermediate, and all the other chromatographic peaks are the chromatographic peak of each related substance of asenapine intermediate; The chromatographic peak that in Fig. 2, retention time is 37.161min is asenapine intermediate.
Embodiment 2
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
8(Kromasil, 250 * 4.6 mm, 5 μ m)
Mobile phase: 0.02mol/L phosphate buffer (take potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000ml, adjust pH to 3.0 with dilute phosphoric acid solution)-acetonitrile (50:50)
Flow velocity: 1.0mL/min
Detect wavelength: 205nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
Experimental procedure
Get asenapine intermediate and related substance thereof appropriate, use respectively methyl alcohol sample dissolution, be mixed with the sample solution containing asenapine intermediate and related substance approximately 0.5 mg/mL thereof.By above-mentioned condition, carry out efficient liquid phase chromatographic analysis, record chromatogram.The results are shown in accompanying drawing 3 ~ 4, the chromatographic peak that in Fig. 3, retention time is 33.685min is asenapine intermediate, and all the other chromatographic peaks are the chromatographic peak of each related substance of asenapine intermediate; The chromatographic peak that in Fig. 4, retention time is 33.687min is asenapine intermediate.
Embodiment 3
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
8(Kromasil, 250 * 4.6 mm, 5 μ m)
Mobile phase: 0.02mol/L phosphate buffer (take potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000ml, adjust pH to 3.0 with dilute phosphoric acid solution)-acetonitrile (60:40)
Flow velocity: 1.0mL/min
Detect wavelength: 205nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
Experimental procedure
Get asenapine intermediate and related substance thereof appropriate, use respectively methyl alcohol sample dissolution, be mixed with the sample solution containing asenapine intermediate and related substance approximately 0.5 mg/mL thereof; Separately get methyl alcohol in right amount as blank solvent.By above-mentioned condition, carry out efficient liquid phase chromatographic analysis, record chromatogram.The results are shown in accompanying drawing 5 ~ 7, Fig. 5 is solvent chromatogram; The chromatographic peak that in Fig. 6, retention time is 37.737min is asenapine intermediate, all the other chromatographic peaks are the chromatographic peak of each related substance of asenapine intermediate, as seen from the figure, asenapine intermediate and its related substance can reach baseline separation, meet the requirement of Chinese Pharmacopoeia; The chromatographic peak asenapine intermediate that in Fig. 7, retention time is 38.491min, can find out that asenapine intermediate can be completely separated with its related substance under this condition.
Claims (10)
1. a method for liquid chromatography for separating and determining asenapine intermediate related substance, is characterized in that: the chromatographic column that octyl silane group silica gel is filler, a certain proportion of inorganic salts buffer solution-organic phase of take is mobile phase.
2. method of separating and assaying according to claim 1, it is Kromasil, ES and Apollo chromatographic column that chromatographic column is selected from brand.
3. according to the method for separating and assaying described in claim 1, said organic phase is selected from a kind of in following compound: methyl alcohol, acetonitrile, propyl alcohol, isopropyl alcohol.
4. according to the method for separating and assaying described in claim 3, said organic phase is methyl alcohol or acetonitrile.
5. method of separating and assaying according to claim 1, in said inorganic salts buffer solution, inorganic salts are selected from following inorganic salts: phosphate, carbonate, citrate.
6. in method of separating and assaying according to claim 1, in said inorganic salts buffer solution, the concentration of contained inorganic salts optimum is 0.02mol/L, and the pH value of inorganic salts buffer solution is 3.0.
7. according to the method for separating and assaying described in claim 5, inorganic salts preferably phosphate in said inorganic salts buffer solution.
8. according to the method for separating and assaying described in claim 1, it is characterized in that, comprise following step:
1) get asenapine intermediate sample appropriate, respectively by methyl alcohol or mobile phase sample dissolution, be mixed with every 1mL containing the sample solution of asenapine intermediate and related substance 0.1～1.5mg thereof;
2) flow rate of mobile phase being set is 0.5～1.5mL/min, and detection wavelength is 205～280nm, and chromatographic column post case temperature is 20～40 ℃;
3) get 1) sample solution 10～50 μ L, injection liquid chromatography, completes the separation determination of asenapine intermediate and related substance thereof.
9. Analyze & separate method according to claim 5, inorganic salts preferably phosphoric acid potassium dihydrogen.
10. Analyze & separate method according to claim 8, step 2) said flow rate of mobile phase is preferably 1.0 mL/min, and said detection wavelength is 205nm.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104297366A (en) * | 2014-09-24 | 2015-01-21 | 万特制药(海南)有限公司 | Liquid phase analysis method of maleic acid asenapine and impurities thereof |
| 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 |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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| WO2007046554A1 (en) * | 2005-10-21 | 2007-04-26 | Sumitomo Chemical Company, Limited | Process for production of dibenzoxepinopyrrole compound, intermediate for production of the compound, and process for production of the intermediate |
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2014
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007046554A1 (en) * | 2005-10-21 | 2007-04-26 | Sumitomo Chemical Company, Limited | Process for production of dibenzoxepinopyrrole compound, intermediate for production of the compound, and process for production of the intermediate |
Non-Patent Citations (5)
| Title |
|---|
| KIRAN AARELLY ET AL.: "Method development and validation of asenapine in bulk by RP-HPLC method", 《JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARCH》 * |
| NAGARAJAN GOVINDARAJAN ET AL.: "Method development and validation of RP-HPLC method for determination of new antipsychotic agent asenapine maleate in bulk and in pharmaceutical formulation", 《DER PHARMACIA LETTRE,》 * |
| T.R.PARTHASARATHI ET AL.: "QUANTITATIVE DETERMINATION OF ASENAPINE MALEATE USING REVERSE PHASE-HIGH PERFORMANCE LIQUID CHROMATOGRAPHY", 《INT J PHARM BIO SCI》 * |
| THERMO SCIENTIFIC INC.: "HPLC-UV Method for the Determination of Asenapine Maleate Impurities Using a Solid Core C8 Column", 《APPLICATION NOTE 20739》 * |
| USMANGANI K. CHHALOTIYA ET AL.: "Stability-Indicating Liquid Chromatographic Method for the Quantification of the New Antipsychotic Agent Asenapine in Bulk and in Pharmaceutical Formulation", 《SCIENTIA PHARMACEUTICA》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104297366A (en) * | 2014-09-24 | 2015-01-21 | 万特制药(海南)有限公司 | Liquid phase analysis method of maleic acid asenapine and impurities thereof |
| 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 |
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