CN103760258A - Method for separating and measuring asenapine maleate related substances by liquid chromatography - Google Patents
Method for separating and measuring asenapine maleate related substances by liquid chromatography Download PDFInfo
- Publication number
- CN103760258A CN103760258A CN201410005829.0A CN201410005829A CN103760258A CN 103760258 A CN103760258 A CN 103760258A CN 201410005829 A CN201410005829 A CN 201410005829A CN 103760258 A CN103760258 A CN 103760258A
- Authority
- CN
- China
- Prior art keywords
- separating
- inorganic salts
- maleic acid
- assaying
- buffer solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Investigating Or Analysing Biological Materials (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for separating and measuring asenapine maleate 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 content of asenapine maleate and related substances thereof, thereby effectively controlling the quality of the asenapine maleate. 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 maleic acid asenapine and related substance 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.It is racemic mixture, and 52HT2 and D2 acceptor are had to dual antagonism.Maleic acid asenapine chemistry (3aRS, 12bRS)-5-Chloro-2-methyl-2 by name, 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:
In the process of synthetic this compound, there is the important intermediate of several steps may not exclusively affect due to removal purity and the quality of medicine, these intermediates are the related substance in Control of drug quality, related substance for the synthetic major control of maleic acid asenapine has 2, respectively intermediate 1(11-Chloro-2-methyl-2, 3-dihydro-8-oxa-2-aza-dibenzo[e, h] azulen-1-one), intermediate 2(11-Chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-8-oxa-2-aza-dibenzo[e, h] azulen-1-one), structural formula is respectively:
Intermediate 1 intermediate 2
For the related substance of introducing in synthetic maleic acid asenapine, in bulk drug, need to carry out quality control, therefore, realize the separation of maleic acid asenapine and related substance thereof, aspect the quality control of maleic acid asenapine building-up process, having important practical significance.
Summary of the invention
The object of the present invention is to provide and a kind ofly analyze the purity of maleic acid asenapine and separate the method for its related substance, thereby realize the separation and mensuration of maleic acid asenapine and its related substance, thereby the purity that guarantees maleic acid asenapine, realizes the quality control of its finished product bulk drug.
Purity with liquid chromatography analysis maleic acid asenapine of the present invention and separate the method for its related substance is to adopt the chromatographic column that octyl silane group silica gel is filler, take a certain proportion of inorganic salts buffer solution-organic phase as mobile phase.
Above-mentioned said chromatographic column, take octyl silane group silica gel as filler, is selected from Kromasil-C
8or Alltima-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 gradient 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 maleic acid asenapine sample appropriate, by methyl alcohol or mobile phase dissolution sample, be mixed with the sample solution of every 1mL containing maleic acid 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 210～250nm, and optimum detection wavelength is 210nm, 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 maleic acid asenapine 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(5 μ m) for ES, 250 × 4.6 mm
Mobile phase: A:0.02mol/L potassium dihydrogen phosphate buffer solution (take potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000mL, with phosphoric acid,diluted adjust pH be 3.0); B: acetonitrile; Adopt gradient elution;
Flow velocity: 1.0mL/min
Detect wavelength: 210nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
The present invention adopts C
8(5 μ m), can effectively separate maleic acid asenapine and related substance thereof for Kromasil, 250 × 4.6 mm.The invention solves the separation determination problem of maleic acid asenapine and related substance thereof, thereby guaranteed the quality controllable of maleic acid asenapine bulk drug.
Accompanying drawing explanation
Maleic acid asenapine when Fig. 1 is embodiment 1 and related substance HPLC figure thereof;
Maleic acid asenapine HPLC figure when Fig. 2 is embodiment 1;
Maleic acid asenapine when Fig. 3 is embodiment 2 and related substance HPLC figure thereof;
The HPLC figure of maleic acid asenapine when Fig. 4 is embodiment 2;
Solvent HPLC figure when Fig. 5 is embodiment 3;
Maleic acid asenapine when Fig. 6 is embodiment 3 and related substance HPLC figure thereof;
The HPLC figure of maleic acid asenapine 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(5 μ m) for Kromasil, 250 × 4.6 mm
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 (20:80)
Flow velocity: 1.0mL/min
Detect wavelength: 210nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
Experimental procedure
Get maleic acid asenapine and intermediate thereof appropriate, use respectively methyl alcohol dissolution sample, be mixed with the sample solution containing maleic acid asenapine and intermediate 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 9.995min is maleic acid asenapine, and all the other chromatographic peaks are the chromatographic peak of the each related substance of maleic acid asenapine; The chromatographic peak that in Fig. 2, retention time is 10.305min is maleic acid asenapine.
embodiment 2
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp;
Chromatographic column: C
8(5 μ m) for Kromasil, 250 × 4.6 mm
Mobile phase: 0.02mol/L potassium phosphate buffer (take potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000ml, with phosphoric acid,diluted tune pH to 3.0)-acetonitrile (60:40)
Flow velocity: 1.0mL/min
Detect wavelength: 210nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
Experimental procedure
Get maleic acid asenapine and intermediate thereof appropriate, use respectively methyl alcohol dissolution sample, be mixed with the sample solution containing maleic acid asenapine and intermediate 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 3 ~ 4, the chromatographic peak that in Fig. 3, retention time is 7.073min is maleic acid asenapine, and all the other chromatographic peaks are the chromatographic peak of the each related substance of maleic acid asenapine; The chromatographic peak that in Fig. 4, retention time is 7.004min is maleic acid asenapine.
Instrument and condition
Chromatographic column: C
8(5 μ m) for Kromasil, 250 × 4.6 mm
Mobile phase: A phase: 0.02mol/L potassium dihydrogen phosphate buffer solution (claim potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000mL, with phosphoric acid,diluted adjust pH be 3.0), B phase: acetonitrile, employing gradient elution;
| T(min) | 0 | 10 | 15 | 35 | 40 | 50 |
| B% | 35 | 35 | 50 | 50 | 35 | 35 |
Flow velocity: 1.0mL/min
Detect wavelength: 210nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
Experimental procedure
Get maleic acid asenapine and intermediate thereof appropriate, use respectively methyl alcohol dissolution sample, be mixed with the sample solution containing maleic acid asenapine approximately 0.5 mg/mL; 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 10.761min is maleic acid asenapine, all the other chromatographic peaks are the chromatographic peak of the each related substance of maleic acid asenapine, as seen from the figure, maleic acid asenapine and its related substance can reach baseline separation, meet the requirement of Chinese Pharmacopoeia; The chromatographic peak that in Fig. 7, retention time is 10.372min is maleic acid asenapine, can find out that maleic acid asenapine can be completely separation with its related substance under this condition.
From Fig. 1-Fig. 7, show: method of the present invention, can be clearly that maleic acid asenapine is separation with its intermediate, and can accurately detect quantitatively, to calculate the content of maleic acid asenapine, thereby effectively control the product quality of maleic acid asenapine.
Claims (10)
1. a method for liquid chromatography for separating and determining maleic acid asenapine related substance, is characterized in that: the chromatographic column that octyl silane group silica gel is filler, and take a certain proportion of inorganic salts buffer solution-organic phase as mobile phase.
2. method of separating and assaying according to claim 1, chromatographic column is selected from the chromatographic column that brand is Kromasil, ES and Alltima.
3. according to the method for separating and assaying described in claim 1, said organic phase is selected from the one 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 maleic acid asenapine sample appropriate, respectively by methyl alcohol or mobile phase dissolution sample, be mixed with the sample solution of every 1mL containing maleic acid asenapine and intermediate 0.1～1.5mg thereof;
2) flow rate of mobile phase being set is 0.5～1.5mL/min, and detection wavelength is 205～250nm, 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 maleic acid asenapine and related substance thereof.
9. Analyze & separate method according to claim 7, 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 1.0mL/min, and said detection wavelength is 210 nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410005829.0A CN103760258A (en) | 2014-01-07 | 2014-01-07 | Method for separating and measuring asenapine maleate related substances by liquid chromatography |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410005829.0A CN103760258A (en) | 2014-01-07 | 2014-01-07 | Method for separating and measuring asenapine maleate related substances by liquid chromatography |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103760258A true CN103760258A (en) | 2014-04-30 |
Family
ID=50527531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410005829.0A Pending CN103760258A (en) | 2014-01-07 | 2014-01-07 | Method for separating and measuring asenapine maleate related substances by liquid chromatography |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103760258A (en) |
Cited By (4)
| 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 |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008078482A1 (en) * | 2006-12-22 | 2008-07-03 | Sumitomo Chemical Company, Limited | Process for producing intermediate of asenapine synthesis |
| CN102657635A (en) * | 2012-05-04 | 2012-09-12 | 上海现代药物制剂工程研究中心有限公司 | Spongy asenapine sublingual film agent with micropores and preparation method thereof |
-
2014
- 2014-01-07 CN CN201410005829.0A patent/CN103760258A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008078482A1 (en) * | 2006-12-22 | 2008-07-03 | Sumitomo Chemical Company, Limited | Process for producing intermediate of asenapine synthesis |
| CN102657635A (en) * | 2012-05-04 | 2012-09-12 | 上海现代药物制剂工程研究中心有限公司 | Spongy asenapine sublingual film agent with micropores and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| 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》, vol. 4, no. 4, 31 December 2012 (2012-12-31), pages 448 - 451 * |
| T.R.PARTHASARATHI等: "QUANTITATIVE DETERMINATION OF ASENAPINE MALEATE USING REVERSE PHASE-HIGH PERFORMANCE LIQUID CHROMATOGRAPHY", 《INTERNATIONAL JOURNAL OF PHARMA AND BIO SCIENCES》, vol. 3, no. 4, 31 October 2012 (2012-10-31), pages 360 - 366 * |
| USMANGANI K. CHHALOTIYA等: "Stability-Indicating Liquid Chromatographic Method for the Quantification of the New Antipsychotic Agent Asenapine in Bulk and in Pharmaceutical Formulation", 《SCI PHARM》, vol. 80, 1 April 2012 (2012-04-01), pages 411 - 414 * |
| 王鹏等: "HPLC法测定人血浆中阿塞那平的含量", 《中国药师》, vol. 16, no. 6, 31 December 2013 (2013-12-31), pages 830 - 832 * |
Cited By (4)
| 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 |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103760257A (en) | Method for separating and measuring aprepitant related substances by liquid chromatography | |
| CN104316606B (en) | Method for separating and measuring vildagliptin related substances by liquid chromatography | |
| Materazzo et al. | Effect of the water content on the retention and enantioselectivity of albendazole and fenbendazole sulfoxides using amylose-based chiral stationary phases in organic–aqueous conditions | |
| CN103760280A (en) | Method for separating and measuring asenapine intermediate related substances by liquid chromatography | |
| CN103760258A (en) | Method for separating and measuring asenapine maleate related substances by liquid chromatography | |
| CN104965041A (en) | High performance liquid chromatography detection method for parecoxib sodium isomer | |
| CN104215697B (en) | A kind of method detecting related substance in piperacillin sodium injection sulbactam | |
| CN105259282A (en) | Method for separating and determining rivaroxaban related substances through liquid chromatography | |
| CN104133012A (en) | Method for determining asenapine maleate racemate by using HPLC | |
| CN104297366A (en) | Liquid phase analysis method of maleic acid asenapine and impurities thereof | |
| CN103353492A (en) | Method of separating and measuring solifenacin succinate raw material and preparation thereof by using liquid chromatography | |
| CN103760282A (en) | Method for separating and measuring ezetimibe intermediate related substances by liquid chromatography | |
| CN104535673B (en) | A kind of method of HPLC separation determination rosuvastain calcium enantiomter | |
| CN104133008A (en) | Method using liquid chromatographic method for analysis of paliperidone intermediate and related substances | |
| CN106680386A (en) | Method for separating and testing related substance of carbocisteine raw material medicine and preparation by using liquid chromatography | |
| CN102384946B (en) | By the method for high efficiency liquid chromatography for separating and determining Entecavir and diastereo-isomerism thereof | |
| CN103728392A (en) | Method for separating and measuring prucalopride succinate related substances by liquid chromatography | |
| CN103760286A (en) | Method for measuring optical purity of solifenacin succinate intermediate by high-performance liquid chromatography | |
| CN102305837A (en) | Detection method for controlling content of entecavir, and related intermediate substance and isomer thereof | |
| CN104483400A (en) | Method for separating and determining oxiracetam and midbody of oxiracetam by utilizing liquid chromatography | |
| CN103487532A (en) | Method for separating and determining vilazodone hydrochloride raw materials and preparations thereof by liquid chromatography | |
| CN104502466A (en) | Liquid chromatography separation method for determining paliperidone raw material and preparation thereof | |
| CN104133011A (en) | Method for separating and analyzing solifenacin succinate intermediate and correlated substances | |
| CN103207247A (en) | Method of separating and determining aliskiren intermediate and optical isomers thereof by using liquid chromatography | |
| CN102854273A (en) | Method for separation determination of duloxetine raw material and preparation thereof by using liquid chromatography method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140430 |
|
| WD01 | Invention patent application deemed withdrawn after publication |