CN110398541B - Method for separating and measuring maropiptan citrate and optical isomer thereof - Google Patents
Method for separating and measuring maropiptan citrate and optical isomer thereof Download PDFInfo
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- CN110398541B CN110398541B CN201810370276.7A CN201810370276A CN110398541B CN 110398541 B CN110398541 B CN 110398541B CN 201810370276 A CN201810370276 A CN 201810370276A CN 110398541 B CN110398541 B CN 110398541B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining maropiptan citrate and optical isomers thereof. The method is characterized in that a chiral chromatographic column using a polysaccharide derivative as a filler uses a mixed solution of n-hexane, isopropanol, methanol and diethylamine or a mixed solution of n-heptane, isopropanol, methanol and diethylamine as a mobile phase. The separation detection method can effectively separate the citric acid mallopitant and 3 optical isomers thereof, thereby accurately and effectively controlling the quality of the mallopitant. The method of the invention is simple and rapid, and the separation degree can reach 3.09-4.63.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a method for separating and determining citric acid maropritan and an optical isomer thereof by using liquid chromatography.
Background
Maropintan Citrate (Maropintant Citrate), a receptor antagonist of neurokinin type 1 (NK 1), acts on the central nervous system by inhibiting substance P (a key neurotransmitter causing emesis), and also inhibits peripheral and central emesis; the chemical structure is shown as formula (1):
the acid citrate malapidan is a chiral drug and has two chiral centers, namely 1 enantiomer and 2 diastereoisomers, and 3 optical isomers in total. The optical isomer as an impurity can affect the quality of a citric acid maropiptan raw material medicine and a preparation product thereof, and in order to ensure the safety of the medicine, strict quality control needs to be carried out on the citric acid maropiptan raw material medicine in the production process.
At present, the separation of enantiomers containing chiral carbon atoms is always a difficulty in the synthesis of chiral drugs and the quality control in the preparation process, and an analysis method of an enantiomer of mariopram citrate and an optical isomer thereof is not recorded in United States Pharmacopeia (USP), european Pharmacopeia (EP) and Chinese Pharmacopeia (Ch.P), and a relevant literature report on a separation detection method of the enantiomer of mariopram citrate and the optical isomer thereof is not retrieved.
Therefore, the invention is particularly important for the method for separating and determining the maririptan citrate and the optical isomer thereof.
Disclosure of Invention
Definition of terms
In the following or following text, all numbers disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. Each numerical value may vary by 1%, 2%, 5%, 7%, 8%, or 10%.
Detailed Description
In order to more accurately control the content of the optical isomer in the product and ensure the quality of the raw material medicine and the preparation product, the inventor develops an analysis method suitable for determining the content of the citric acid maropiptan and the optical isomer thereof through repeated experiments and researches. The method can simply, quickly and accurately separate and detect the citric acid malariptan and the optical isomer thereof, and the separation degree can reach 3.09-4.63.
The invention aims to provide a method for separating and determining the impurities of the maririptan citrate and the optical isomers thereof by using a liquid chromatography, which is suitable for the quality control in the synthesis and preparation processes of the maririptan citrate.
A method for separating and measuring malapidem citrate and optical isomers thereof by using a liquid chromatography is characterized in that a chiral chromatographic column with polysaccharide derivatives as fillers is adopted, and a mixed solution of n-hexane, isopropanol, methanol and diethylamine or a mixed solution of n-heptane, isopropanol, methanol and diethylamine is used as a mobile phase.
In some embodiments, the polysaccharide derivative filler of the chiral chromatography column is amylose-tris (3, 5-dichlorophenyl carbamate), cellulose-tris (3, 5-dichlorophenyl carbamate), amylose-tris (3, 5-xylyl carbamate), amylose-tris [ (S) - α -tolyl carbamate ], cellulose-tris (3, 5-xylyl carbamate), cellulose-tris [ 4-methylbenzoate ], or a combination thereof, and in some embodiments, the polysaccharide derivative filler is amylose-tris (3, 5-dichlorophenyl carbamate) or cellulose-tris (3, 5-dichlorophenyl carbamate).
In some embodiments, the CHIRAL chromatography column is CHIRALPAK IE or CHIRALPAK IC, marketed by xylonite CHIRAL technology (shanghai) LTD, british name DAICEL CHIRAL techlogies (CHINA) co.
In some embodiments, the volume ratio (V/V) of n-hexane, isopropanol, methanol, and diethylamine in the mobile phase is 94.5; or 95; or 93.
In some embodiments, the volume ratio (V/V) of n-heptane, isopropanol, methanol, and diethylamine in the mobile phase is 94.5; or 95; or 93.
The separation and determination method of the present invention comprises the following steps:
1) Taking a proper amount of citric acid malopram with any optical purity or a preparation sample containing citric acid malopram with any optical purity, and dissolving the sample by taking a certain amount of mixed solution or mobile phase solution with the volume ratio (V/V) of n-hexane to ethanol being 4;
2) Setting instrument parameters: the flow rate of the mobile phase, the detection wavelength and the temperature of a column box of the chromatographic column;
3) Injecting a certain amount of the solution obtained in the step 1) into a high performance liquid chromatograph to complete the separation and determination of the maririptan citrate and the optical isomer thereof.
The citric acid malopressin in the step 1) can be of any optical purity, and the citric acid malopressin used for detection can be prepared by adopting a method disclosed by CN 1048492C.
In some embodiments, the mobile phase solution in step 1) is a mixed solution of n-hexane, isopropanol, methanol and diethylamine; in some embodiments, the volume ratio (V/V) of n-hexane, isopropanol, methanol, and diethylamine is 94.5; or 95; or 93.
In some embodiments, the mobile phase solution in step 1) is a mixed solution of n-heptane, isopropanol, methanol and diethylamine; in some embodiments, the volume ratio (V/V) of n-heptane, isopropanol, methanol and diethylamine is 94.5; or 95; or 93.
In some embodiments, the diluent of step 1) contains 0.5mg to 5mg of hippeasant citrate per 1ml of the diluent; in other embodiments, the diluent of step 1) contains 1mg to 3mg of hippeasant citrate per 1ml of the diluent; in certain embodiments, the diluent of step 1) contains 2mg of a sample of maririptan citrate per 1ml of diluent; in certain embodiments, the diluent of step 1) contains 5mg of an maririptan citrate sample per 1ml of the diluent.
Step 2) the flow rate of the mobile phase is 0.3ml/min to 2ml/min; in some embodiments, the flow rate of the mobile phase is 0.8 to 1.1ml/min. The detection wavelength is 220nm to 300nm; in some embodiments, the detection wavelength is 230nm; the temperature of the chromatographic column box is 20-40 ℃; in some embodiments, the column box temperature is 35 ℃.
Step 3) the sample solution is injected into the sample container in an amount of 2 to 20 mu l; in some embodiments, the sample solution is introduced in an amount of 3 μ l.
In some embodiments, the separation assay method of the invention comprises the steps of:
1) Taking a proper amount of a mixture of the hippopotamus citrate and an optical body thereof or a sample of the hippopotamus citrate or a preparation containing the hippopotamus citrate, dissolving the sample by using a mobile phase solution or a mixed solvent of n-hexane and ethanol, and preparing a sample solution containing 0.5mg to 5mg of the hippopotamus citrate per 1 ml;
2) Setting the flow rate of a mobile phase to be 0.3ml/min to 2ml/min, the flow rate of the mobile phase is preferably 0.8 to 1.1ml/min, the detection wavelength is 220nm to 300nm, the detection wavelength is preferably 230nm, and the temperature of a chromatographic column box is 20 ℃ to 40 ℃, preferably 35 ℃;
3) And (2) taking 2 to 20 mul, preferably 3 mul of the sample solution obtained in the step 1), and injecting the sample solution into a high performance liquid chromatograph to complete the separation and determination of the citric acid mallopitan and the optical body thereof.
Wherein:
the adopted high performance liquid chromatograph is an Agilent 1260 type high performance liquid chromatograph system and a workstation in the United states,
the chiral chromatographic column is selected from CHIRALPAK IE or CHIRALPAK IC.
The method adopts the chiral chromatographic column which takes polysaccharide derivatives as the filler, takes the mixed solution of normal hexane, isopropanol, methanol and diethylamine or the mixed solution of normal heptane, isopropanol, methanol and diethylamine as the mobile phase, and can effectively separate the citric acid mallopitan from the optical isomer thereof, thereby accurately and effectively controlling the quality of the citric acid mallopitan. The separation method can be used for separating and detecting the citric acid mallopitan and the optical isomer thereof simply, quickly and accurately, and the separation degree can reach 3.09-4.63.
Drawings
FIG. 1 shows a high performance liquid chromatogram of the separation assay of example 1;
FIG. 2 shows a high performance liquid chromatogram of the separation assay of example 2;
FIG. 3 shows a high performance liquid chromatogram of the separation assay of example 3;
FIG. 4 shows a high performance liquid chromatogram of a blank solution for the separation assay of example 4;
FIG. 5 shows a high performance liquid chromatogram of the test solution of the separation assay of example 4.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, g means g, and ml means ml.
The specifications of the instrument and the chromatographic column used in the invention are as follows:
an Agilent 1260 type high performance liquid chromatography system and workstation;
example 1-example 4: a method for separating and detecting Marupitant citrate and its optical isomer by using CHIRALPAK IE chiral chromatographic column is provided.
The acid citrate, malariptan, has two chiral centers, 1 enantiomer and 2 diastereoisomers, and has 3 optical isomers in total. In the examples, marupitan citrate is abbreviated as (S, S) -MRPT, its enantiomer is abbreviated as (R, R) -MRPT, and the two diastereomers are abbreviated as (S, R) -MRPT and (R, S) -MRPT, respectively.
Example 1
Condition parameter
Ultraviolet detection wavelength: 230nm; mobile phase: n-hexane: isopropyl alcohol: methanol solution: diethylamine (95ml; column temperature: 35 ℃; the injection volume was 3. Mu.l.
Experimental procedure
Diluent agent: n-hexane, ethanol = 80ml; taking about 20mg of the mixture of the mapitan and the diastereoisomer, putting the mixture into a 10ml volumetric flask, diluting the mixture to the mark by using a diluent, and shaking up the mixture to be used as a test solution.
Taking the test solution, performing high performance liquid chromatography analysis under the above conditions, and recording chromatogram, the result is shown in figure 1. Locating chromatographic peaks using (S, S) -MRPT, (R, R) -MRPT, (S, R) -MRPT and (R, S) -MRPT reference samples, respectively, the chromatographic peak with retention time of 9.69 minutes in FIG. 1 is the chromatographic peak of (S, S) -MRPT; the chromatographic peak at 8.63 minutes is the chromatographic peak of enantiomer (R, R) -MRPT of maririptan; the chromatographic peaks at 11.34 minutes and 12.99 minutes are those of diastereoisomers (S, R) -MRPT and (R, S) -MRPT of mariopritan respectively.
Example 2
Condition parameter
Ultraviolet detection wavelength: 230nm; mobile phase: n-hexane: isopropyl alcohol: methanol solution: diethylamine (94ml; column temperature: 35 ℃; the injection volume was 3. Mu.l.
Experimental procedure
Diluent agent: n-hexane, ethanol = 80ml; taking about 20mg of the mixture of the macriptan and the diastereoisomer, putting the mixture into a 10ml volumetric flask, diluting the mixture to a scale with a diluent, and shaking up to be used as a test solution.
Taking the test solution, performing high performance liquid chromatography analysis under the above conditions, and recording chromatogram, the result is shown in FIG. 2. The chromatographic peak with retention time of 8.47 minutes in FIG. 2 is that of (S, S) -MRPT; the chromatographic peak at 7.66 minutes is that of enantiomer (R, R) -MRPT of maripidan; the chromatographic peaks at 9.70 min and 10.99 min gave separate chromatographic peaks for the diastereoisomers of maropiptan (S, R) -MRPT and (R, S) -MRPT.
Example 3
Condition parameter
Ultraviolet detection wavelength: 230nm; mobile phase: n-hexane: isopropyl alcohol: methanol solution: diethylamine (93ml; column temperature: 35 ℃; the injection volume was 3. Mu.l.
Experimental procedure
Diluent agent: n-hexane, ethanol = 80ml; taking about 20mg of the mixture of the mapitan and the diastereoisomer, putting the mixture into a 10ml volumetric flask, diluting the mixture to the mark by using a diluent, and shaking up the mixture to be used as a test solution.
Taking the sample solution, performing high performance liquid chromatography analysis according to the above conditions, and recording chromatogram, the result is shown in FIG. 3. The chromatographic peak with retention time of 8.21 minutes in FIG. 3 is that of (S, S) -MRPT; the chromatographic column for 7.46 minutes is the chromatographic peak of enantiomer (R, R) -MRPT of maririptan; the chromatographic peaks at 9.28 min and 10.43 min gave separate chromatographic peaks for the diastereoisomers of maropiptan (S, R) -MRPT and (R, S) -MRPT.
Example 4
Condition parameter
Ultraviolet detection wavelength: 230nm; mobile phase: n-hexane: isopropyl alcohol: methanol solution: diethylamine (94ml; column temperature: 35 ℃; the injection volume was 2. Mu.l. A sample of an maririptan citrate containing formulation, such as the general tablet of maririptan citrate, was purchased from zoetis.
Experimental procedure
Diluent (b): methanol; taking 0.5ml of the citric acid maropiptan reference preparation, putting the maropiptan citrate reference preparation into a 2ml volumetric flask, diluting the maropiptan reference preparation to a scale by using a diluent, preparing a 5mg/ml solution, and shaking up to be used as a test solution.
Taking the sample solution, performing high performance liquid chromatography analysis according to the above conditions, and recording chromatogram, the result is shown in FIG. 4 and FIG. 5. FIG. 4 is a spectrum of a blank solution, and a chromatographic peak of (S, S) -MRPT is a chromatographic peak of the solution with a retention time of 7.39 minutes in FIG. 5; the chromatographic peaks at 9.93 minutes are respectively chromatographic peaks of diastereoisomer (R, S) -MRPT of the maropiptan citrate.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (3)
1. A method for separating and measuring citric acid malapidem and 3 optical isomers thereof by using a liquid chromatography is characterized in that a chiral chromatographic column taking a polysaccharide derivative as a filler is adopted, and the polysaccharide derivative filler is amylose-tri (3, 5-dichlorophenyl carbamate); taking a mixed solution of n-hexane, isopropanol, methanol and diethylamine as a mobile phase; the volume ratio of n-hexane, isopropanol, methanol and diethylamine in the mobile phase is 94.5; or 95; or 93.
2. The method of claim 1, comprising the steps of:
1) Taking a proper amount of a sample containing the citric acid malariptan with any optical purity, and dissolving the sample by using a certain amount of mixed solution or mobile phase solution with the volume ratio of n-hexane to ethanol being 4;
2) Setting instrument parameters: the flow rate of the mobile phase, the detection wavelength and the temperature of a column box of the chromatographic column;
3) Injecting the solution obtained in the step 1) into a high performance liquid chromatograph to complete the separation and determination of the maririptan citrate and the optical isomer thereof.
3. The method of claim 2, the flow rate of the mobile phase in step 2) is from 0.3ml/min to 2ml/min; the detection wavelength is 220nm to 300nm; the temperature of the chromatographic column box is 20 ℃ to 40 ℃.
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| CN1902175A (en) * | 2003-12-30 | 2007-01-24 | 什诺波特有限公司 | Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof |
| CN106456620A (en) * | 2014-05-16 | 2017-02-22 | 拉夸里亚创药株式会社 | 5-ht4 receptor agonist for gastroparesis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1902175A (en) * | 2003-12-30 | 2007-01-24 | 什诺波特有限公司 | Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof |
| CN106456620A (en) * | 2014-05-16 | 2017-02-22 | 拉夸里亚创药株式会社 | 5-ht4 receptor agonist for gastroparesis |
Non-Patent Citations (3)
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| LC-QTOF MS screening of more than 1000 licit and illicit drugs and their metabolites in wastewater and surface waters from the area of Bogota,Colombia;Hernandez, Felix 等;《Analytical and Bioanalytical Chemistry》;20151231;第407卷(第21期);第6405-6416页 * |
| The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days;S. P. LESMAN 等;《J. vet. Pharmacol. Therap》;20121231;第462–470页 * |
| 磺丁基醚 -β- 环糊精的增溶机制及在难溶性药物制剂中的应用;胡裕迪 等;《中国医药工业杂志》;20180331;第49卷(第3期);第292-300页 * |
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