CN103760256A - Method for separating and measuring olmesartan medoxomil intermediate related substances by liquid chromatography - Google Patents
Method for separating and measuring olmesartan medoxomil intermediate related substances by liquid chromatography Download PDFInfo
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- CN103760256A CN103760256A CN201410004320.4A CN201410004320A CN103760256A CN 103760256 A CN103760256 A CN 103760256A CN 201410004320 A CN201410004320 A CN 201410004320A CN 103760256 A CN103760256 A CN 103760256A
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Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for separating and measuring olmesartan medoxomil intermediate 5-(1-hydroxy-1-methyl-ethyl)-2-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid ethyl ester related substances by liquid chromatography. By using a chromatographic column in which octadecyl 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 olmesartan medoxomil intermediate and related substances thereof, thereby effectively controlling the quality of the olmesartan medoxomil intermediate starting material and olmesartan medoxomil. 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 olmesartan medoxomil intermediate and related substance thereof.
Background technology
Olmesartan medoxomil is a kind of husky smooth class antihypertensive, within 1991, by Japanese Sankyo Co., Ltd, is succeeded in developing.It has overcome the shortcoming of angiotensin converting enzyme inhibitor (ACEI) and has preserved its advantage, it acts on similar but does not cause the effects such as the drug induced dry cough of ACEI class, fash and angioneurotic edema, bad reaction is less, patient's better tolerance, in light moderate hypertension treatment, curative effect is good, more welcome clinically.Olmesartan medoxomil intermediated chemistry is called 5-(1-Hydroxy-1-methyl-ethyl)-2-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid ethyl ester, molecular formula is C
45h
44n
6o
3.Olmesartan medoxomil intermediate structure 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, related substance for the synthetic major control of olmesartan medoxomil intermediate has 4, respectively related substance 1(2-Propyl-1H-imidazole-4, 5-dicarboxylic acid), related substance 2(2-Propyl-1H-imidazole-4, 5-dicarboxylic acid diethyl ester), related substance 3(5-(1-Hydroxy-1-methyl-ethyl)-2-propyl-3H-imidazole-4-carboxylic acid ethyl ester) and related substance 4(5-(4'-Bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole), structural formula is respectively:
For the impurity of introducing in synthetic olmesartan medoxomil intermediate, in bulk drug, need to carry out quality control, therefore, realize the separation of olmesartan medoxomil intermediate and related substance thereof, aspect the synthetic and quality control of olmesartan medoxomil, having important practical significance.
Summary of the invention
The object of the present invention is to provide and a kind ofly analyze olmesartan medoxomil intermediated chemistry purity and separate the method for its related substance, thereby realize the separation and mensuration of olmesartan medoxomil intermediate and its related substance, guarantee olmesartan medoxomil and the quality control containing Olmesartan ester formulation.
Of the present invention by liquid chromatography analysis olmesartan medoxomil intermediated chemistry purity and separate the method for its related substance, to adopt the chromatographic column that octadecylsilane chemically bonded silica is filler, take a certain proportion of inorganic salts buffer solution-organic phase as mobile phase.
Above-mentioned said chromatographic column, take octadecylsilane chemically bonded silica as filler, 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 methyl alcohol.
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.
The concentration of the inorganic salts that wherein comprise in inorganic salts buffer solution is 0.01～0.1mol/L, and preferred concentration is 0.03mol/L.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) get olmesartan medoxomil intermediate sample appropriate, by methyl alcohol or mobile phase dissolution sample, be mixed with the sample solution of every 1mL containing olmesartan medoxomil 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 210～280nm, and optimum detection wavelength is 254nm, 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 olmesartan medoxomil 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
18(5 μ m) for Kromasil, 250 × 4.6 mm
Mobile phase: A:0.03mol/L potassium dihydrogen phosphate buffer solution (take potassium dihydrogen phosphate 4.08g, be dissolved in water to 1000ml, with dilute phosphoric acid solution tune pH 3.0); B: methyl alcohol; Adopt gradient elution;
Flow velocity: 1.0 mL/min
Detect wavelength: 254 nm
Column temperature: 25 ℃
Sampling volume: 10 μ L
The present invention adopts C
18(5 μ m), can effectively separate olmesartan medoxomil intermediate and related substance thereof for Kromasil, 250 × 4.6 mm.The invention solves the separation determination problem of olmesartan medoxomil and related substance thereof, thereby guaranteed quality controllable (the results are shown in accompanying drawing 1～7) of olmesartan medoxomil intermediate feed medicine.
Accompanying drawing explanation
Olmesartan medoxomil intermediate when Fig. 1 is embodiment 1 and related substance HPLC figure thereof;
Olmesartan medoxomil intermediate HPLC figure when Fig. 2 is embodiment 1;
Olmesartan medoxomil intermediate when Fig. 3 is embodiment 2 and related substance HPLC figure thereof;
The HPLC figure of olmesartan medoxomil intermediate when Fig. 4 is embodiment 2;
Solvent HPLC figure when Fig. 5 is embodiment 3;
Olmesartan medoxomil intermediate when Fig. 6 is embodiment 3 and related substance HPLC figure thereof;
The HPLC figure of olmesartan medoxomil 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
18(5 μ m) for Kromasil, 250 × 4.6 mm;
Mobile phase: A phase: 0.03 mol/L potassium dihydrogen phosphate buffer solution (take potassium dihydrogen phosphate 4.08 g, be dissolved in water to 1000ml, with dilute phosphoric acid solution tune pH 6.5), B phase: acetonitrile, adopts gradient elution;
| T(min) | 0 | 5 | 30 | 50 | 55 | 60 |
| B% | 40 | 40 | 85 | 85 | 40 | 40 |
Flow velocity: 1.0mL/min
Detect wavelength: 254 nm
Column temperature: 25 ℃
Sampling volume: 10 μ L.
Experimental procedure
Get olmesartan medoxomil intermediate and related substance thereof appropriate, use respectively methyl alcohol dissolution sample, be mixed with the sample solution containing olmesartan medoxomil 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 46.551min is olmesartan medoxomil intermediate, and all the other chromatographic peaks are the chromatographic peak of the each related substance of olmesartan medoxomil intermediate; The chromatographic peak that in Fig. 2, retention time is 46.613min is olmesartan medoxomil intermediate.
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
18(5 μ m) for Kromasil, 250 × 4.6 mm;
Mobile phase: A phase: 0.03 mol/L potassium dihydrogen phosphate buffer solution (take potassium dihydrogen phosphate 4.08 g, be dissolved in water to 1000ml, with dilute phosphoric acid solution tune pH 5.0), B phase: acetonitrile, adopts gradient elution;
| T(min) | 0 | 5 | 30 | 50 | 55 | 60 |
| B% | 40 | 40 | 90 | 90 | 40 | 40 |
Flow velocity: 1.0mL/min
Detect wavelength: 254 nm
Column temperature: 25 ℃
Sampling volume: 10 μ L.
Experimental procedure
Get olmesartan medoxomil intermediate and related substance thereof appropriate, use respectively methyl alcohol dissolution sample, be mixed with the sample solution containing olmesartan medoxomil 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 36.905min is olmesartan medoxomil intermediate, and all the other chromatographic peaks are the chromatographic peak of the each related substance of olmesartan medoxomil intermediate; The chromatographic peak that in Fig. 4, retention time is 36.645min is olmesartan medoxomil intermediate.
Embodiment 3
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
18(5 μ m) for Kromasil, 250 × 4.6 mm;
Mobile phase: A phase: 0.03 mol/L potassium dihydrogen phosphate buffer solution (take potassium dihydrogen phosphate 4.08 g, be dissolved in water to 1000ml, with dilute phosphoric acid solution tune pH 3.0), B phase: methyl alcohol, adopts gradient elution;
| T(min) | 0 | 3 | 30 | 50 | 60 | 70 |
| B% | 30 | 30 | 90 | 90 | 30 | 30 |
Flow velocity: 1.0mL/min
Detect wavelength: 254 nm
Column temperature: 25 ℃
Sampling volume: 10 μ L.
Experimental procedure
Get olmesartan medoxomil intermediate and related substance thereof appropriate, use respectively methyl alcohol dissolution sample, be mixed with the sample solution containing olmesartan medoxomil 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 42.173min is olmesartan medoxomil intermediate, all the other chromatographic peaks are the chromatographic peak of the each related substance of olmesartan medoxomil intermediate, as seen from the figure, olmesartan medoxomil intermediate and its related substance can reach baseline separation, meet the requirement of Chinese Pharmacopoeia; The chromatographic peak olmesartan medoxomil intermediate that in Fig. 7, retention time is 42.151min, can find out that olmesartan medoxomil intermediate can be completely separation with its related substance under this condition.
Claims (10)
1. a method for liquid chromatography for separating and determining olmesartan medoxomil intermediate related substance, is characterized in that: the chromatographic column that octadecylsilane chemically bonded silica 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, it is Kromasil, ES and ACCHROM 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 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. method of separating and assaying according to claim 1, in said inorganic salts buffer solution, the concentration of contained inorganic salts optimum is 0.03mol/L; The pH value of inorganic salts buffer solution is preferably 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 olmesartan medoxomil intermediate sample appropriate, respectively by methyl alcohol or mobile phase dissolution sample, be mixed with the sample solution of every 1mL containing olmesartan medoxomil 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 olmesartan medoxomil intermediate 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 1.0 mL/min, and said detection wavelength is 254 nm.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105158359A (en) * | 2015-08-19 | 2015-12-16 | 江苏中邦制药有限公司 | Olmesartan medoxomil and HPLC (high performance liquid chromatography) separation and analysis method for intermediate of olmesartan medoxomil |
| CN106568862A (en) * | 2016-11-04 | 2017-04-19 | 万全万特制药江苏有限公司 | Method for separation and determination of vortioxetine hydrobromide intermediate related substances by liquid chromatography |
| CN109400577A (en) * | 2019-01-07 | 2019-03-01 | 石药集团中奇制药技术（石家庄）有限公司 | Razaxaban has related compounds and its preparation method and application |
| CN110082449A (en) * | 2019-05-24 | 2019-08-02 | 珠海润都制药股份有限公司 | The detection method of triphenylchloromethane in a kind of olmesartan medoxomil |
| CN111505166A (en) * | 2020-05-29 | 2020-08-07 | 山东省食品药品检验研究院 | Method for determining azodiisoheptonitrile in olmesartan medoxomil |
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2014
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105158359A (en) * | 2015-08-19 | 2015-12-16 | 江苏中邦制药有限公司 | Olmesartan medoxomil and HPLC (high performance liquid chromatography) separation and analysis method for intermediate of olmesartan medoxomil |
| CN106568862A (en) * | 2016-11-04 | 2017-04-19 | 万全万特制药江苏有限公司 | Method for separation and determination of vortioxetine hydrobromide intermediate related substances by liquid chromatography |
| CN109400577A (en) * | 2019-01-07 | 2019-03-01 | 石药集团中奇制药技术（石家庄）有限公司 | Razaxaban has related compounds and its preparation method and application |
| CN109400577B (en) * | 2019-01-07 | 2021-01-19 | 石药集团中奇制药技术（石家庄）有限公司 | Rivaroxaban related compound and preparation method and application thereof |
| CN110082449A (en) * | 2019-05-24 | 2019-08-02 | 珠海润都制药股份有限公司 | The detection method of triphenylchloromethane in a kind of olmesartan medoxomil |
| CN110082449B (en) * | 2019-05-24 | 2020-05-19 | 珠海润都制药股份有限公司 | Method for detecting triphenylchloromethane in olmesartan medoxomil |
| CN111505166A (en) * | 2020-05-29 | 2020-08-07 | 山东省食品药品检验研究院 | Method for determining azodiisoheptonitrile in olmesartan medoxomil |
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