CN110927279A - Method for separating imidapril hydrochloride related substances - Google Patents

Method for separating imidapril hydrochloride related substances Download PDF

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CN110927279A
CN110927279A CN201911248896.4A CN201911248896A CN110927279A CN 110927279 A CN110927279 A CN 110927279A CN 201911248896 A CN201911248896 A CN 201911248896A CN 110927279 A CN110927279 A CN 110927279A
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methanol
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雷文枚
张瑜
杨希
何莉
刘玉霞
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Hunan Jiudian Pharmaceutical Co Ltd
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Abstract

The application discloses a method for separating imidapril hydrochloride related substances, which consists of phosphate buffer solution with the pH value of 2.5-4.6 and methanol, and performs gradient elution. By using the separation method, related impurities in imidapril hydrochloride can be effectively separated, the analysis time is appropriate, and the system applicability solution can play a good positioning role.

Description

Method for separating imidapril hydrochloride related substances
Technical Field
The invention relates to a separation method and application of imidapril hydrochloride related substances.
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:
Figure 212576DEST_PATH_IMAGE001
。
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:
Figure 413751DEST_PATH_IMAGE002
Figure 325075DEST_PATH_IMAGE003
the prior art discloses a separation method in Japanese pharmacopoeia, wherein a chromatographic column is a C8 chromatographic column with the specification of 150 x 4.6mm and 5 μm, a mobile phase is phosphate buffer solution (1.36 g of monopotassium phosphate is taken and 1000ml of water is added for dissolving, the pH value is adjusted by phosphoric acid) -methanol (600: 400), the detection wavelength is 215nm, the flow rate is adjusted so that the retention time of imidapril hydrochloride is about 8min, and the collection time is about 2 times of the retention time of imidapril peak. However, although this method can separate the impurity C and the impurity F, the impurity J, and the impurity H cannot be separated efficiently. In addition, the detection method needs to prepare a reference substance solution of all impurities, but some impurities are not well obtained, and the problems of high detection cost and complex experimental operation steps exist.
The Chinese national drug Standard [ WS1- (X-270) -2003Z ] also provides a separation method, wherein a chromatographic column is a C8 chromatographic column, a mobile phase is phosphate buffer solution (1.36 g of monopotassium phosphate is taken, about 850ml of water is added, the phosphate buffer solution is dissolved, pH is adjusted to 2.7 +/-0.05 by phosphoric acid, water is added to 1000ml) -methanol (60: 40), a detection wavelength is 215nm, and a solvent is water-methanol 60: 40. In addition, the chromatographic column given in the registration standard of imported pharmaceutical products of crude drugs (JX 20000441) is C8, the mobile phase is phosphate buffer-methanol (60: 40), and the detection wavelength is 215nm, so that 3 impurities cannot be effectively separated by the method.
Therefore, in the situation of the above problems in the prior art, it is necessary to develop a method for effectively separating related substances from imidapril hydrochloride.
Disclosure of Invention
The main purpose of the application is to provide a method for separating imidapril hydrochloride related substances.
The technical scheme of the method is improved based on the problem that the impurity F, J, H cannot be effectively separated in the prior art, and the related scheme is optimized.
The following technical scheme is adopted in the application:
a method for separating imidapril hydrochloride related substances uses a C8 or C18 chromatographic column as a chromatographic column, a mobile phase consists of phosphate buffer solution with the pH value of 2.5-4.6 and methanol, and gradient elution is carried out. Wherein the pH value is 2.9, 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 40:60, mobile phase B: phosphate buffer solution and methanol in a volume ratio of 90: 10;
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 2.9 are used as a mobile phase A, the volume ratio of the phosphate buffer solution to the methanol is 40:60, 0.01mol/L phosphate buffer solution and methanol which are added for regulating the pH value to be 2.9 are used as a mobile phase B, the volume ratio of the phosphate buffer solution to the methanol is 90:10, and the procedure of gradient elution is as follows:
Figure 309211DEST_PATH_IMAGE004
。
the separation method comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride, an impurity F, an impurity H and an impurity J reference substance, adding a diluent to dissolve and quantitatively dilute the imidapril hydrochloride, the impurity F, the impurity H and the impurity J reference substance to prepare a mixed solution containing 0.5mg of imidapril hydrochloride and 2.5 micrograms of each impurity in every 1ml of the mixed solution as a system applicability solution, wherein the diluent is prepared from a phosphate buffer solution and methanol according to a volume ratio of 64: 36;
(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 0.5mg of imidapril hydrochloride in each 1ml, and taking the solution as a test solution;
(3) preparation of control solution: precisely measuring a proper amount of a test sample solution, and diluting the test sample solution with a diluent to prepare a solution containing 5 micrograms of imidapril hydrochloride in each 1ml of the test sample solution as a control solution;
(4) and (3) determination: according to the mobile phase proportion and the gradient elution program, 20 mul of the system applicability solution is taken and injected into a liquid chromatograph, 20 mul of the test solution and the reference solution are precisely measured and respectively injected into the liquid chromatograph, and the chromatogram is recorded.
The relevant substances to be separated are mainly impurity F, J, H, and the structures of the three are shown in the table of the background art.
Preferably, the analysis conditions of the liquid chromatography described above include one or more of the following (i) to (vii):
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 30. + -. 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 0.8 to 1.2ml/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 condition applied by the applicant, the separation degrees of the three impurities are higher than 1.5, the three impurities can be effectively separated, the separation time is appropriate, and the peak shape is good.
2. 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
A method for separating imidapril hydrochloride related substances comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride, impurities F, impurities H and impurities J as reference substances, adding a diluent [ phosphate buffer solution (1.36 g of monopotassium phosphate is taken and dissolved to 1000ml by adding water, and the pH value is adjusted to 2.9 by phosphoric acid) -methanol (64: 36) ] for dissolving and quantitatively diluting to prepare a solution containing 0.5mg of imidapril hydrochloride and 2.5 mu g of each impurity in each 1 ml;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding a diluent for dissolving, and quantitatively preparing a solution containing 0.5mg of imidapril hydrochloride in every 1ml as a test solution;
(3) preparation of control solution: precisely measuring a proper amount of a test solution, and quantitatively diluting with a diluent to prepare a solution containing 5 mu g of imidapril hydrochloride 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 2.9 with phosphoric acid) -methanol (40: 60). Mobile phase B: phosphate buffer (taking 1.36g of monopotassium phosphate, adding water to dissolve and dilute to 1000ml, adjusting pH value to 2.9 with phosphoric acid) -methanol (90: 10), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.0 ml/min; column temperature: at 30 ℃.
The procedure for the gradient elution is as follows:
Figure 625311DEST_PATH_IMAGE004
according to the mobile phase proportion and the gradient elution program, 20 μ l of the system suitability solution is injected into a liquid chromatograph, and after detection and chromatogram as shown in figure 1, as can be seen from figure 1, the separation degree of the impurity J from the adjacent peak (solvent peak) is 5.868, and the separation degree of the impurity H from the adjacent peak (impurity F peak) is 3.203, so that effective separation can be achieved. This embodiment is the preferred embodiment.
Example 2
A method for separating imidapril hydrochloride related substances comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride, impurities F, impurities H and impurities J as reference substances, adding a diluent [ phosphate buffer solution (1.36 g of monopotassium phosphate is taken and dissolved to 1000ml by adding water, and the pH value is adjusted to 2.6 by using phosphoric acid) -methanol (64: 36) ] for dissolving and quantitatively diluting to prepare a solution containing 0.5mg of imidapril hydrochloride and 2.5 mu g of each impurity in each 1 ml;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding a diluent for dissolving, and quantitatively preparing a solution containing 0.5mg of imidapril hydrochloride in every 1ml as a test solution;
(3) preparation of control solution: precisely measuring a proper amount of a test solution, and quantitatively diluting with a diluent to prepare a solution containing 5 mu g of imidapril hydrochloride 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 (40: 60). 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 (90: 10), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.0 ml/min; column temperature: at 30 ℃.
The procedure for the gradient elution is as follows:
Figure 669490DEST_PATH_IMAGE004
according to the mobile phase proportion and the gradient elution program, 20 mu l of the system suitability solution is injected into a liquid chromatograph, and after detection and chromatogram as shown in figure 2, as can be seen from figure 2, the separation degree of the impurity J from the adjacent peak (solvent peak) is 5.274, and the separation degree of the impurity H from the adjacent peak (impurity F peak) is 1.902, all the effective separation can be achieved.
Example 3
A method for separating imidapril hydrochloride related substances comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride, impurities F, impurities H and impurities J as reference substances, adding a diluent [ phosphate buffer solution (1.36 g of monopotassium phosphate is taken and dissolved to 1000ml by adding water, and the pH value is adjusted to 4.5 by using phosphoric acid) -methanol (64: 36) ] for dissolving and quantitatively diluting to prepare a solution containing 0.5mg of imidapril hydrochloride and 2.5 mu g of each impurity in each 1 ml;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding a diluent for dissolving, and quantitatively preparing a solution containing 0.5mg of imidapril hydrochloride in every 1ml as a test solution;
(3) preparation of control solution: precisely measuring a proper amount of a test solution, and quantitatively diluting with a diluent to prepare a solution containing 5 mu g of imidapril hydrochloride 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 4.5 with phosphoric acid) -methanol (40: 60). Mobile phase B: phosphate buffer (taking 1.36g of monopotassium phosphate, adding water to dissolve and dilute to 1000ml, adjusting pH value to 4.5 with phosphoric acid) -methanol (90: 10), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.0 ml/min; column temperature: at 30 ℃.
The procedure for the gradient elution is as follows:
Figure 536952DEST_PATH_IMAGE004
according to the mobile phase proportion and the gradient elution program, 20 mu l of the system suitability solution is injected into a liquid chromatograph, and after detection and chromatogram as shown in figure 3, as can be seen from figure 3, the separation degree of the impurity J from the adjacent peak (solvent peak) is 1.679, and the separation degree of the impurity H from the adjacent peak (impurity F peak) is 20.298, so that effective separation can be achieved.
Example 4
A method for separating imidapril hydrochloride related substances comprises the following steps:
(1) preparation of system suitability solution: taking a proper amount of imidapril hydrochloride, impurities F, impurities H and impurities J as reference substances, adding a diluent [ phosphate buffer solution (1.36 g of monopotassium phosphate is taken and dissolved to 1000ml by adding water, and the pH value is adjusted to 2.6 by using phosphoric acid) -methanol (64: 36) ] for dissolving and quantitatively diluting to prepare a solution containing 0.5mg of imidapril hydrochloride and 2.5 mu g of each impurity in each 1 ml;
(2) preparation of a test solution: taking a proper amount of imidapril hydrochloride, adding a diluent for dissolving, and quantitatively preparing a solution containing 0.5mg of imidapril hydrochloride in every 1ml as a test solution;
(3) preparation of control solution: precisely measuring a proper amount of a test solution, and quantitatively diluting with a diluent to prepare a solution containing 5 mu g of imidapril hydrochloride 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 2.6 with phosphoric acid) -methanol (40: 60). 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 (90: 10), and eluting according to gradient; detection wavelength: 215 nm; flow rate: 1.0 ml/min; column temperature: at 30 ℃.
The procedure for the gradient elution is as follows:
Figure 855938DEST_PATH_IMAGE004
according to the mobile phase proportion and the gradient elution program, 20 mu l of the system suitability solution is injected into a liquid chromatograph, and after detection and chromatogram as shown in figure 4, as can be seen from figure 4, the separation degree of the impurity J from the adjacent peak (solvent peak) is 5.514, and the separation degree of the impurity H from the adjacent peak (impurity F peak) is 2.465, both the effective separation can be achieved.
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 (6)

1. A 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 2.5-4.6 and methanol, and gradient elution is carried out, wherein the related substances comprise impurities F, impurities J and impurities H, wherein the structure of the impurities F is shown as the following formula
Figure 535502DEST_PATH_IMAGE001
，
The structure of impurity J is shown in the following formula
Figure 734402DEST_PATH_IMAGE002
，
The structure of the impurity H is shown as the following formula
Figure 340964DEST_PATH_IMAGE003
。
2. The separation method of claim 1, wherein the pH is 2.9.
3. 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 40:60, mobile phase B: phosphate buffer solution and methanol in a volume ratio of 90: 10;
mobile phase A: phosphate buffer, mobile phase B: methanol.
4. The separation method according to claim 1, wherein a phosphate buffer solution and methanol of 0.01mol/L added with phosphoric acid to adjust pH to 2.9 are used as a mobile phase A, the volume ratio of the phosphate buffer solution to the methanol is 40:60, a phosphate buffer solution and methanol of 0.01mol/L added with phosphoric acid to adjust pH to 2.9 are used as a mobile phase B, the volume ratio of the phosphate buffer solution to the methanol is 90:10, and the procedure of the gradient elution is as follows:
Figure 334328DEST_PATH_IMAGE004
。
5. a 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, an impurity F, an impurity H and an impurity J reference substance, adding a diluent to dissolve and quantitatively dilute the imidapril hydrochloride, the impurity F, the impurity H and the impurity J reference substance to prepare a mixed solution containing 0.5mg of imidapril hydrochloride and 2.5 micrograms of each impurity in every 1ml of the mixed solution as a system applicability solution, wherein the diluent is prepared from a phosphate buffer solution and methanol according to a volume ratio of 64: 36;
(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 0.5mg of imidapril hydrochloride in each 1ml, and taking the solution as a test solution;
(3) preparation of control solution: precisely measuring a proper amount of a test sample solution, and diluting the test sample solution with a diluent to prepare a solution containing 5 micrograms of imidapril hydrochloride in each 1ml of the test sample solution 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 2.9 as a mobile phase A, the volume ratio of the phosphate buffer solution to the methanol being 40:60, and 0.01mol/L phosphate buffer solution added with phosphoric acid to adjust the pH value to 2.9 and the methanol being a mobile phase B, the volume ratio of the phosphate buffer solution to the methanol being 90: 10:
Figure 26340DEST_PATH_IMAGE004
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 impurities F, impurities J and impurities H, wherein the structure of the impurities F is shown as the following formula
Figure 763352DEST_PATH_IMAGE001
，
The structure of impurity J is shown in the following formula
Figure 224420DEST_PATH_IMAGE002
，
The structure of the impurity H is shown as the following formula
Figure 654265DEST_PATH_IMAGE003
。
6. The separation method according to claim 5, wherein the analysis conditions of the liquid chromatography are 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 30. + -. 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 0.8 to 1.2ml/min,
(vi) the sample injection amount is 10-30 mu l.
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