CN110927278A - Improved method for separating imidapril hydrochloride related substances - Google Patents
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Abstract
The application discloses an improved method for separating imidapril hydrochloride related substances, which consists of phosphate buffer solution with the pH value of 2.5-2.9 and methanol, and carries out gradient elution. By using the separation method, each component in imidapril hydrochloride can be effectively separated, the analysis time is appropriate, and the system applicability solution can play a good positioning role.
Description
Technical Field
The invention relates to an improved method for separating imidapril hydrochloride related substances and application thereof.
Background
Imidapril Hydrochloride (Imidapril Hydrochloride) with chemical name (-) - (4S) -3- [ (2S) -2- [ [ (1S) -1-ethoxycarbonyl-3-phenylpropyl]Amino group]Propionyl group]-1-methyl-2-oxoimidazoline-4-carboxylic acid hydrochloride with molecular formula C20H27N3O6HCl, molecular weight 441.97, structural formula shown below:
imidapril hydrochloride is a white crystal, odorless or slightly specific odor. It is easily soluble in methanol, soluble in water, slightly soluble in anhydrous ethanol, and hardly soluble in ethyl acetate, chloroform, diethyl ether or cyclohexane. The melting point is 208-213 deg.C (decomposition during melting).
Imidapril hydrochloride is an antihypertensive drug and is an Angiotensin Converting Enzyme Inhibitor (ACEIs). The mechanism of the voltage reduction may be: after oral administration, the active metabolite imidaprilat is converted in vivo, which can inhibit the activity of ACE, prevent angiotensin I from being converted into angiotensin II, relax peripheral blood vessels, reduce vascular resistance and generate the effect of reducing blood pressure.
During the production or preparation process of the raw material drug of imidapril hydrochloride, some impurities are generated, and the numbering of European pharmacopoeia is continued, and the main impurities known at present are shown in the following table:
the prior art discloses a separation method in the Japanese pharmacopoeia, wherein the chromatographic column is a C8 chromatographic column with the specification of 150 x 4.6mm and 5 μm, the mobile phase is phosphate buffer solution (1.36 g of monopotassium phosphate is taken and 1000ml of water is added for dissolution, the pH value is adjusted by phosphoric acid to 2.7) -methanol (60: 40), the detection wavelength is 215nm, the flow rate is adjusted so that the retention time of imidapril hydrochloride is about 8min, and the solvent is water-methanol (60: 40). However, although the raw material, the intermediate and each impurity can be detected under the condition, the analysis time of M-2 is long, the separation degree of the impurity F and the RSS isomer is not satisfactory, and in addition, a reference substance solution of all the impurities is required to be prepared in the detection method, but some impurities are not well obtained, the detection cost is high, and the experimental operation steps are complicated.
Therefore, in the situation of the prior art having the above problems, it would be very significant to develop an improved method for separating and detecting imidapril hydrochloride related substances, which is suitable for effectively separating related substances, and has low cost and simple operation. Disclosure of Invention
The main object of the present application is to provide an improved method for the isolation of imidapril hydrochloride related substances.
The technical scheme of the method is improved based on the problem that impurities F and RSS isomers cannot be effectively separated in the prior art. And self-prepared system applicability solution, and optimized related schemes.
The following technical scheme is adopted in the application:
the improved method for separating imidapril hydrochloride related substances adopts a C8 or C18 chromatographic column as a chromatographic column, a mobile phase consists of phosphate buffer solution with the pH value of 2.5-2.9 and methanol, and gradient elution is carried out. Wherein the pH value is 2.7, the mobile phase can be divided into A, B two phases, the two phases can be interchanged, and the mobile phases A and B are selected from one of the following solution combinations:
mobile phase A: phosphate buffer and methanol, in a volume ratio of 50:50, mobile phase B: phosphate buffer solution and methanol in a volume ratio of 70: 30;
mobile phase A: phosphate buffer, mobile phase B: methanol.
One scheme of the technical scheme of the method is that 0.01mol/L phosphate buffer solution and methanol which are added for regulating the pH value to be 2.7 are used as a mobile phase A, the volume ratio of the phosphate buffer solution to the methanol is 50:50, 0.01mol/L phosphate buffer solution and methanol which are added for regulating the pH value to be 2.7 are used as a mobile phase B, the volume ratio of the phosphate buffer solution to the methanol is 70:30, and the procedure of gradient elution is as follows:
the separation method comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride reference substance, adding phosphate buffer solution to dissolve the imidapril hydrochloride reference substance to prepare a solution containing 0.45-0.55 mg in each 1ml, heating the solution in a water bath at the temperature of 60-90 ℃ for 1-5 hours, and cooling the solution to obtain the imidapril hydrochloride reference substance;
(2) preparation of a test solution: taking a proper amount of the product, adding a diluent to dissolve the product to prepare a solution containing 0.45-0.55 mg of the product in each 1ml of the product as a test solution;
(3) preparation of control solution: measuring a test solution, and quantitatively diluting with a diluent to obtain a solution containing 5 μ g of the test solution per 1ml as a control solution;
(4) and (3) determination: according to the mobile phase proportion and the gradient elution program, 20 mu l of the system applicability solution is taken and injected into a liquid chromatograph, the flow rate is adjusted to ensure that the retention time of the imidapril hydrochloride peak is about 12min, 20 mu l of the test solution and 20 mu l of the reference solution are precisely measured and respectively injected into the liquid chromatograph, and the chromatogram is recorded.
Among them, the substances to be separated are mainly impurity F and RSS isomers, and the structures of both are shown in the table of the background art.
Preferably, the analysis conditions of the liquid chromatography include one or more of the following (i) to (viii):
the size of the column was 4.6 x 150mm, 5um,
(ii) the chromatographic column is of type Inertsil C8 or Ultimate XB-C18,
(iii) the column temperature is 35. + -. 5 ℃ C,
(iv) variation range of mobile phase ratio: plus or minus 2 percent of the total weight of the mixture,
(v) a flow rate of 1.2 to 2.0ml/min,
(vi) the sample injection amount is 10-30 mul,
(vii) a wavelength of 210 to 220 nm.
Preferably, the sample size is 20. mu.l.
The application also includes the application of the separation method in the separation of medicine impurities.
Due to the adoption of the technical scheme, the beneficial effects of the application are as follows:
1. under the conditions applied by the applicant, related substances in imidapril hydrochloride can be effectively separated, and the separation time is appropriate.
2. In the preparation process of the system applicability solution, the imidapril hydrochloride generates impurities C and F, and no additional preparation or addition of reference substances of the impurities C and F is needed, so that the cost is saved, and the separation process is simplified.
3. The system of the present application has good solution localization.
Drawings
FIG. 1 is the separation detection chromatogram of my example 1;
FIG. 2 is the separation detection chromatogram of my party example 2;
FIG. 3 is the separation detection chromatogram of my party example 3;
FIG. 4 is the separation detection chromatogram of my example 4.
Detailed Description
The present application is described in further detail below with reference to specific embodiments and the attached drawings. The following examples are intended to be illustrative of the present application only and should not be construed as limiting the present application.
Example 1
An improved method for separating related substances in imidapril hydrochloride comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride reference substance, adding phosphate buffer solution (taking 1.0g of monopotassium phosphate and 0.025g of dipotassium hydrogen phosphate, adding water to dissolve to 100 ml) to prepare 0.5mg solution in each 1ml, heating in a water bath at 90 ℃ for 2 hours, and cooling to obtain the imidapril hydrochloride reference substance;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding a diluent [ phosphate buffer (1.36 g of monopotassium phosphate is taken and dissolved to 1000ml by adding water), adjusting the pH value to 2.7 by using phosphoric acid) -methanol (64: 36) ] to dissolve to prepare a solution containing 0.50mg in each 1ml, and taking the solution as a test solution;
(3) preparation of control solution: measuring a test solution, and quantitatively diluting with a diluent to obtain a solution containing 5 μ g of the test solution per 1ml as a control solution;
(4) and (3) determination: a chromatographic column: inertsil C8; 4.6X 150mm X5 μm,
according to volume ratio, mobile phase A: phosphate buffer (1.36 g of monopotassium phosphate was taken, dissolved in water and diluted to 1000ml, and the pH was adjusted to 2.7 with phosphoric acid) -methanol (50: 50). Mobile phase B: phosphate buffer (taking 1.36g of monopotassium phosphate, adding water to dissolve and dilute to 1000ml, adjusting pH value to 2.7 with phosphoric acid) -methanol (70: 30), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.6 ml/min; column temperature: at 30 ℃.
The procedure for the gradient elution is as follows:
according to the mobile phase proportion and the gradient elution program, 20 mu l of the system applicability solution is taken and injected into a liquid chromatograph, the flow rate is adjusted to ensure that the retention time of the imidapril hydrochloride peak is about 12min, 20 mu l of the test solution and 20 mu l of the reference solution are precisely measured and respectively injected into the liquid chromatograph, and the chromatogram is recorded. The chromatogram is shown in figure 1 after detection, and as can be seen from figure 1, the impurity C and the impurity F can be effectively detected, and the separation degree of the impurity F and the imidapril hydrochloride is more than 3.0. This example is the best example, and the experiment repeatability is good for 6 times of experiments under the same conditions.
Example 2
An improved method for separating related substances in imidapril hydrochloride comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride reference substance, adding phosphate buffer solution (taking 1.0g of monopotassium phosphate and 0.025g of dipotassium hydrogen phosphate, adding water to dissolve to 100 ml) to prepare 0.5mg solution in each 1ml, heating in a water bath at 90 ℃ for 2 hours, and cooling to obtain the imidapril hydrochloride reference substance;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding the diluent to dissolve the imidapril hydrochloride into a solution containing 0.50mg of imidapril in each 1ml, and taking the solution as a test solution;
(3) preparation of control solution: measuring a test solution, and quantitatively diluting with a diluent to obtain a solution containing 5 μ g of the test solution per 1ml as a control solution;
(4) and (3) determination: a chromatographic column: inertsil C8; 4.6X 150mm X5 μm,
according to volume ratio, mobile phase A: phosphate buffer (1.36 g of monopotassium phosphate was taken, dissolved in water and diluted to 1000ml, and the pH was adjusted to 2.8 with phosphoric acid) -methanol (50: 50). Mobile phase B: phosphate buffer (taking 1.36g of monopotassium phosphate, adding water to dissolve and dilute to 1000ml, adjusting pH value to 2.8 with phosphoric acid) -methanol (70: 30), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.6 ml/min; column temperature: at 30 ℃.
The procedure for the gradient elution is as follows:
according to the mobile phase proportion and the gradient elution program, 20 mu l of the system applicability solution is taken and injected into a liquid chromatograph, the flow rate is adjusted to ensure that the retention time of the imidapril hydrochloride peak is about 12min, 20 mu l of the test solution and 20 mu l of the reference solution are precisely measured and respectively injected into the liquid chromatograph, and the chromatogram is recorded. The chromatogram is shown in figure 2 after detection, and as can be seen from figure 2, the impurity C and the impurity F can be effectively detected, and the separation degree of the impurity F and the imidapril hydrochloride is more than 3.0.
Example 3
An improved method for separating related substances in imidapril hydrochloride comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride reference substance, adding phosphate buffer solution (taking 1.0g of monopotassium phosphate and 0.025g of dipotassium hydrogen phosphate, adding water to dissolve to 100 ml) to prepare 0.5mg solution in each 1ml, heating in a water bath at 90 ℃ for 2 hours, and cooling to obtain the imidapril hydrochloride reference substance;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding the diluent to dissolve the imidapril hydrochloride into a solution containing 0.50mg of imidapril in each 1ml, and taking the solution as a test solution;
(3) preparation of control solution: measuring a test solution, and quantitatively diluting with a diluent to obtain a solution containing 5 μ g of the test solution per 1ml as a control solution;
(4) and (3) determination: a chromatographic column: inertsil C8; 4.6X 150mm X5 μm,
according to volume ratio, mobile phase A: phosphate buffer (1.36 g of monopotassium phosphate was taken, dissolved in water and diluted to 1000ml, and the pH was adjusted to 2.6 with phosphoric acid) -methanol (50: 50). Mobile phase B: phosphate buffer (taking 1.36g of monopotassium phosphate, adding water to dissolve and dilute to 1000ml, adjusting pH value to 2.6 with phosphoric acid) -methanol (70: 30), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.6 ml/min; column temperature: at 30 ℃.
The procedure for the gradient elution is as follows:
according to the mobile phase proportion and the gradient elution program, 20 mu l of the system applicability solution is taken and injected into a liquid chromatograph, the flow rate is adjusted to ensure that the retention time of the imidapril hydrochloride peak is about 12min, 20 mu l of the test solution and 20 mu l of the reference solution are precisely measured and respectively injected into the liquid chromatograph, and the chromatogram is recorded. The chromatogram is shown in figure 3 after detection, and as can be seen from figure 3, the impurity C and the impurity F can be effectively detected, and the separation degree of the impurity F and the imidapril hydrochloride is more than 3.0.
Example 4
An improved method for separating related substances in imidapril hydrochloride comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride reference substance, adding phosphate buffer solution (taking 1.0g of monopotassium phosphate and 0.025g of dipotassium hydrogen phosphate, adding water to dissolve to 100 ml) to prepare 0.5mg solution in each 1ml, heating in a water bath at 90 ℃ for 2 hours, and cooling to obtain the imidapril hydrochloride reference substance;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding the diluent to dissolve the imidapril hydrochloride into a solution containing 0.50mg of imidapril in each 1ml, and taking the solution as a test solution;
(3) preparation of control solution: measuring a test solution, and quantitatively diluting with a diluent to obtain a solution containing 5 μ g of the test solution per 1ml as a control solution;
(4) and (3) determination: a chromatographic column: ultimate XB-C18; 4.6X 150mm X5 μm,
according to volume ratio, mobile phase A: phosphate buffer (1.36 g of monopotassium phosphate was taken, dissolved in water and diluted to 1000ml, and the pH was adjusted to 2.7 with phosphoric acid) -methanol (50: 50). Mobile phase B: phosphate buffer (taking 1.36g of monopotassium phosphate, adding water to dissolve and dilute to 1000ml, adjusting pH value to 2.7 with phosphoric acid) -methanol (70: 30), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.7 ml/min; column temperature: 35 ℃ is carried out.
The procedure for the gradient elution is as follows:
according to the mobile phase proportion and the gradient elution program, 20 mu l of the system applicability solution is taken and injected into a liquid chromatograph, the flow rate is adjusted to ensure that the retention time of the imidapril hydrochloride peak is about 12min, 20 mu l of the test solution and 20 mu l of the reference solution are precisely measured and respectively injected into the liquid chromatograph, and the chromatogram is recorded. The chromatogram is shown in figure 4 after detection, and as can be seen from figure 4, the impurity C and the impurity F can be effectively detected, and the separation degree of the impurity F and the imidapril hydrochloride is more than 3.0.
The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. For those skilled in the art to which the present application pertains, several simple deductions or substitutions may be made without departing from the concept of the present application, and all should be considered as belonging to the protection scope of the present application.
Claims (7)
1. The improved method for separating imidapril hydrochloride related substances is characterized in that a used chromatographic column is a C8 or C18 chromatographic column, a mobile phase consists of phosphate buffer solution with the pH value of 2.5-2.9 and methanol, gradient elution is carried out, and the method further comprises the step of carrying out pretreatment on system applicability solution, wherein the related substances comprise F, RSS isomers, and the structure of impurity F is shown as the following formula
The structure of the RSS isomers is shown in the following formula
2. The separation method of claim 1, wherein the pH is 2.7.
3. The separation method according to claim 1, wherein the pretreatment of the system compatible solution is heating in a water bath at 60 to 90 ℃ for 1 to 5 hours.
4. The separation process of claim 1, wherein the mobile phase is divided into two phases a and B, the mobile phases a and B being selected from one of the following combinations of solutions:
mobile phase A: phosphate buffer and methanol, in a volume ratio of 50:50, mobile phase B: phosphate buffer solution and methanol in a volume ratio of 70: 30;
mobile phase A: phosphate buffer, mobile phase B: methanol.
5. The separation method according to claim 1, wherein a phosphate buffer solution and methanol of 0.01mol/L added with phosphoric acid to adjust the pH value to 2.7 are used as the mobile phase A, the volume ratio of the phosphate buffer solution to the methanol is 50:50, a phosphate buffer solution and methanol of 0.01mol/L added with phosphoric acid to adjust the pH value to 2.7 are used as the mobile phase B, the volume ratio of the phosphate buffer solution to the methanol is 70:30, and the procedure of the gradient elution is as follows:
6. the improved method for separating related substances in imidapril hydrochloride is characterized by comprising the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride reference substance, adding phosphate buffer solution to dissolve the imidapril hydrochloride reference substance to prepare a solution containing 0.45-0.55 mg in each 1ml, heating the solution in a water bath at the temperature of 60-90 ℃ for 1-5 hours, and cooling the solution to obtain the imidapril hydrochloride reference substance;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride raw material, adding a diluent to dissolve the imidapril hydrochloride raw material to prepare a solution containing 0.45-0.55 mg in each 1ml as a test solution;
(3) preparation of control solution: measuring a test solution, and quantitatively diluting with a diluent to obtain a solution containing 5 μ g of the test solution per 1ml as a control solution;
(4) and (3) determination: the procedure of gradient elution is as follows, using a C8 or C18 reversed phase chromatographic column, with 0.01mol/L phosphate buffer solution and methanol added with phosphoric acid to adjust the pH value to 2.7 as a mobile phase A, the volume ratio of the phosphate buffer solution to the methanol being 50:50, and 0.01mol/L phosphate buffer solution added with phosphoric acid to adjust the pH value to 2.7 and the methanol as a mobile phase B, the volume ratio of the phosphate buffer solution to the methanol being 70: 30:
injecting 20 mul of the system applicability solution into a liquid chromatograph, precisely measuring 20 mul of each of the test solution and the reference solution, respectively injecting into the liquid chromatograph, and recording the chromatogram;
the related substances to be separated comprise an impurity F, RSS isomer, wherein the structure of the impurity F is shown as the following formula
The structure of the RSS isomers is shown in the following formula
7. The separation process of claim 6, wherein the liquid chromatography is performed under one or more of the following conditions (i) to (vi):
the size of the column was 4.6 x 150mm, 5um,
(ii) the chromatographic column is of type Inertsil C8 or Ultimate XB-C18,
(iii) the column temperature is 35. + -. 5 ℃ C,
(iv) variation range of mobile phase ratio: plus or minus 2 percent of the total weight of the mixture,
(v) a flow rate of 1.2 to 2.0ml/min,
(vi) the sample injection amount is 10-30 mu l.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111253315A (en) * | 2020-03-10 | 2020-06-09 | 北京阳光诺和药物研究有限公司 | Imidapril hydrochloride organic impurity and preparation method thereof |
| CN115963217A (en) * | 2021-10-11 | 2023-04-14 | 北京阳光诺和药物研究股份有限公司 | Method for detecting imidapril intermediate and impurities |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101462947A (en) * | 2009-01-05 | 2009-06-24 | 上海柏鼎医药技术有限公司 | Preparation of (R) -4-phenyl-2-hydroxybutyrate |
| US20130101578A1 (en) * | 2010-04-12 | 2013-04-25 | National University Of Singapore | Biomarker for renal function in patients with type 2 diabetes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101462947A (en) * | 2009-01-05 | 2009-06-24 | 上海柏鼎医药技术有限公司 | Preparation of (R) -4-phenyl-2-hydroxybutyrate |
| US20130101578A1 (en) * | 2010-04-12 | 2013-04-25 | National University Of Singapore | Biomarker for renal function in patients with type 2 diabetes |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253315A (en) * | 2020-03-10 | 2020-06-09 | 北京阳光诺和药物研究有限公司 | Imidapril hydrochloride organic impurity and preparation method thereof |
| CN115963217A (en) * | 2021-10-11 | 2023-04-14 | 北京阳光诺和药物研究股份有限公司 | Method for detecting imidapril intermediate and impurities |
| CN115963217B (en) * | 2021-10-11 | 2023-09-22 | 北京阳光诺和药物研究股份有限公司 | Detection method of imidapril intermediate and impurity |
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