CN112540130A - Method for separating and measuring loratadine cyclic compound and related substances thereof by liquid chromatography - Google Patents

Method for separating and measuring loratadine cyclic compound and related substances thereof by liquid chromatography Download PDF

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CN112540130A
CN112540130A CN201910901708.7A CN201910901708A CN112540130A CN 112540130 A CN112540130 A CN 112540130A CN 201910901708 A CN201910901708 A CN 201910901708A CN 112540130 A CN112540130 A CN 112540130A
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loratadine
cyclic compound
related substances
separation
mobile phase
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张灵敏
刘秋叶
王宇杰
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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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
    • 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
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • 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
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
    • 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
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/74—Optical detectors

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Abstract

The invention belongs to the field of analytical chemistry, and discloses a method for separating and determining related substances of a loratadine cyclic compound by using a liquid chromatography. The method has the advantages of strong specificity, high accuracy and simple and convenient operation.

Description

Method for separating and measuring loratadine cyclic compound and related substances thereof by liquid chromatography
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and measuring loratadine cyclic compound and related substances thereof by using a liquid chromatography.
Background
Loratadine is a second generation antihistamine with high selectivity for peripheral nerve H1 receptor, competitively inhibits histamine H1 receptor, and is commonly used clinically for treating allergic symptoms, and its cyclic compound chemical name is 8-chloro-11- (1-methylpiperidin-4-ylidine) -6, 11-dihydo-5H-benzo[5,6]cyclohepta[1,2-b]pyridine of the formula C20H21N2And (4) Cl. The structural formula of the loratadine cyclic compound is as follows:
Figure 783483DEST_PATH_IMAGE001
in the process of producing loratadine cyclic compound, there are several important intermediates, namely related substances in controlling the quality of the drug, 5 related substances mainly controlling the production of loratadine cyclic compound, namely intermediate 13- (3-chlorophenylethyl) pyridine 1-oxide, intermediate 23- (3-chlorophenylethyl) picolinone, intermediate 3 (3- (3-chlorophenylethyl) pyridine-2-yl) (1-methylpiperidin-4-yl) methyl chloride, intermediate 48-chloro-5, 6-dihydo-11H-benzo [5,6] cyclohexa [1,2-b ] pyridine-11-one, intermediate 58-chloro-11- (1-chlorophenylethyl) -6-yl, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-ol, the structural formula is respectively as follows:
Figure 709851DEST_PATH_IMAGE002
the related substances introduced in the production process of the loratadine cyclic compound need to be subjected to quality control in the bulk drug, so that the separation of the loratadine cyclic compound and the related substances is realized, and the method has important practical significance in the aspect of quality control of the loratadine cyclic compound.
Disclosure of Invention
The invention aims to provide a method for analyzing the purity of a loratadine cyclic compound and separating related substances thereof, so that the separation and the determination of the loratadine cyclic compound and the related substances thereof are realized, and the quality control of the loratadine cyclic compound is ensured.
The method for analyzing the purity of the loratadine cyclic compound and separating related substances thereof by using the liquid chromatography adopts a chromatographic column with octadecylsilane chemically bonded silica as a filler, and takes a buffer salt solution-organic phase with a certain proportion as a mobile phase.
The chromatographic column takes octadecylsilane chemically bonded silica as a filler and is selected from Phenomenex, Alltima or Apollo.
The organic phase is selected from one or two of the following reagents: methanol, acetonitrile, propanol, isopropanol, tetrahydrofuran, etc., with acetonitrile or methanol and acetonitrile being preferred.
In the method, the mobile phase buffer salt solution-organic phase adopts concentration gradient elution.
In said method, said buffer salt is selected from one of the following salts: sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and the like.
In the method, the dosage of the buffer salt is 10-50 mmol/L, preferably 25 mmol/L. Wherein 0.02-0.1% of phosphoric acid is added into the buffer salt solution, and the preferred concentration is 0.05%.
The separation and measurement method of the present invention can be realized by the following method:
1) taking a proper amount of a loratadine cyclic compound sample, dissolving the sample by using acetonitrile or a solvent (mobile phase A: mobile phase B =40: 60), and preparing a sample solution containing 0.1-1.5 mg of the loratadine cyclic compound per 1 mL.
2) Setting the flow rate of the mobile phase to be 0.5-1.5 mL/min, preferably setting the flow rate of the mobile phase to be 1.0mL/min, the detection wavelength to be 200-280 nm, the detection wavelength to be 230nm, the temperature of the column incubator to be 10-40 ℃, and the temperature of the column incubator to be 30 ℃.
3) And (2) injecting 10-50 mu L of the sample solution of the step (1) into a liquid chromatograph, and completing the separation and measurement of the loratadine cyclic compound and related substances thereof under the method. Wherein:
the type of the high performance liquid chromatograph has no special requirements, and the chromatograph adopted by the invention is Shimadzu: LC-20AT pump, SPD-M20A detector, SIL-20AC autosampler, CBM-20A controller, CTO-10AS column oven, LC solution workstation
A chromatographic column: c18（250×4.6mm，5μm）
Mobile phase: a: 0.05% phosphoric acid-25 mmol/L potassium dihydrogen phosphate solution (1000 ml water added with 3.4g potassium dihydrogen phosphate, added with 0.5ml phosphoric acid); b: methanol-acetonitrile (1: 3); elution with concentration gradient
Flow rate: 1.0mL/min
Detection wavelength: 230nm
Sample introduction volume: 10 μ L
In the invention, C is used18A chromatographic column is arranged on the top of the chromatographic column,can effectively separate loratadine cyclic compound and related substances. The invention solves the problem of separation and determination of the loratadine cyclic compound and related substances thereof, thereby ensuring the controllable quality of the loratadine cyclic compound.
Drawings
FIG. 1 is an HPLC chart of the loratadine cyclic compound and related substances in example 1;
FIG. 2 is a HPLC chart of loratadine cyclic compound of example 1;
FIG. 3 is an HPLC chart of the loratadine cyclic compound and related substances in example 2;
FIG. 4 is an HPLC chart of a loratadine cyclic compound of example 2;
FIG. 5 is a solvent HPLC plot for example 3;
FIG. 6 is an HPLC chart of the loratadine cyclic compound and related substances of example 3;
FIG. 7 is an HPLC chart of a loratadine cyclic compound at the time of example 3.
The specific implementation mode is as follows:
the following examples are presented to further understand the present invention, but are not intended to limit the scope of the practice.
Example 1
Apparatus and conditions
High performance liquid chromatograph: shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10 ASvp;
a chromatographic column: c18（Apollo，250×4.6mm，5μm）；
Mobile phase: a: 0.02% phosphoric acid-25 mmol/L potassium dihydrogen phosphate solution (1000 ml water added with 3.4g potassium dihydrogen phosphate, added with 0.2ml phosphoric acid); b: methanol-acetonitrile (4: 1); elution was carried out with the following concentration gradient
T(min) 0 20 30 35 40 45 45.01 55
B% 42 52 52 60 70 70 42 42
Flow rate: 1.0mL/min
Detection wavelength: 230nm
Sample introduction volume: 10 μ L
Experimental procedure
Taking a proper amount of the loratadine cyclic compound and the intermediate thereof, respectively dissolving the samples by using solvents to prepare a sample solution containing the loratadine cyclic compound and the intermediate thereof at about 0.25 mg/mL. Performing high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The result is shown in attached figures 1-2, the chromatographic peak with the retention time of 12.871min in the figure 1 is a loratadine cyclic compound, and the rest chromatographic peaks are chromatographic peaks of various related substances of the loratadine cyclic compound; the chromatographic peak with retention time of 12.591min in FIG. 2 is loratadine cyclide.
Example 2
Apparatus and conditions
High performance liquid chromatograph: shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10 ASvp;
a chromatographic column: c18（Apollo，250×4.6 mm，5μm）；
Mobile phase: a: 0.05% phosphoric acid-25 mmol/L potassium dihydrogen phosphate solution (1000 ml water added with 3.4g potassium dihydrogen phosphate, added with 0.5ml phosphoric acid); b: methanol-acetonitrile (4: 1); elution was carried out with the following concentration gradient
T(min) 0 20 30 35 40 50 50.01 60
B% 45 55 55 60 70 70 45 45
Flow rate: 1.0mL/min
Detection wavelength: 230nm
Sample introduction volume: 10 μ L
Experimental procedure
Taking a proper amount of the loratadine cyclic compound and the intermediate thereof, respectively dissolving the samples by using solvents to prepare a sample solution containing the loratadine cyclic compound and the intermediate thereof at about 0.25 mg/mL. Performing high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The result is shown in attached figures 3-4, the chromatographic peak with the retention time of 14.477min in the figure 3 is a loratadine cyclic compound, and the rest chromatographic peaks are chromatographic peaks of various related substances of the loratadine cyclic compound; the chromatographic peak with retention time of 14.185min in FIG. 4 is loratadine cyclide.
Example 3
Apparatus and conditions
High performance liquid chromatograph: shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10 ASvp;
a chromatographic column: c18（Phenomenex，250×4.6 mm，5μm）；
Mobile phase: a: 0.05% phosphoric acid-25 mmol/L potassium dihydrogen phosphate solution (1000 ml water added with 3.4g potassium dihydrogen phosphate, added with 0.5ml phosphoric acid); b: methanol-acetonitrile (3: 1); elution was carried out with the following concentration gradient
T(min) 0 20 30 40 50 50.01 60
B% 45 52 52 70 70 45 45
Flow rate: 1.0mL/min
Detection wavelength: 230nm
Sample introduction volume: 10 μ L
Experimental procedure
Taking a proper amount of the loratadine cyclic compound and the intermediate thereof, and respectively dissolving samples by using solvents to prepare a sample solution containing the loratadine cyclic compound and the intermediate thereof at about 0.25 mg/mL; and taking a proper amount of mobile phase as a blank solvent. Performing high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The results are shown in the attached figures 5-7, and figure 5 is a solvent chromatogram; in fig. 6, the chromatographic peak with the retention time of 11.174min is the loratadine cyclide, and the other chromatographic peaks are chromatographic peaks of various related substances of the loratadine cyclide, so that the loratadine cyclide and the related substances thereof can achieve baseline separation and meet the requirements of the Chinese pharmacopoeia; the chromatographic peak with retention time of 10.877min in FIG. 7 is loratadine cyclate, and it can be seen that the loratadine cyclate and its related substances can be completely separated under the condition.
Specificity test
Taking a proper amount of the loratadine cycliccompound and the intermediate thereof, respectively dissolving the samples by using solvents to prepare a solution containing the loratadine cycliccompound and the intermediate thereof about 0.1 mg/mL as a test solution. The separation measurement was carried out under the chromatographic conditions of example 3, and the chromatogram was recorded. As can be seen from FIGS. 5 to 7, under the condition, the chromatographic peak shape of the loratadine cyclic compound and the intermediate thereof is good, the separation degree meets the requirement, and the solvent has no interference on the determination of the loratadine cyclic compound and the intermediate thereof.
The method can effectively separate the loratadine cyclic compound from the intermediate thereof when the brands or organic phases of the chromatographic columns are different, has strong specificity and good durability of chromatographic conditions, and can accurately detect and quantify to calculate the content of the loratadine cyclic compound, thereby effectively controlling the product quality of the loratadine cyclic compound.

Claims (8)

1. A method for separating and measuring related substances of loratadine cyclics by liquid chromatography is characterized by comprising the following steps: the chromatographic column using octadecylsilane chemically bonded silica as filler takes a buffer salt solution-organic phase with a certain proportion as a mobile phase.
2. The separation assay of claim 1, wherein the column is selected from the group consisting of columns sold under the names Phenomenex, alttima, and Apollo.
3. The separation assay method of claim 1, wherein the organic phase is selected from one or two of the following reagents: methanol, acetonitrile, propanol, isopropanol, tetrahydrofuran, and the like.
4. The organic phase according to claim 3, preferably methanol and acetonitrile.
5. The isolation assay of claim 1, wherein the buffer salt is selected from one of the following salts: sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and the like.
6. The separation and analysis method according to claim 1, wherein the amount of the buffer salt is 10 to 50 mmol/L.
7. The separation assay method according to claim 1, wherein 0.01 to 0.1% phosphoric acid is added to said buffered salt solution.
8. The separation assay method of claim 1, comprising the steps of:
1) taking a proper amount of a loratadine cyclic compound sample, dissolving the sample by using methanol or a solvent (mobile phase A: mobile phase B =40: 60) to prepare a sample solution containing 0.1-1.5 mg of loratadine cyclic compound and related substances thereof per 1 mL;
2) setting the flow velocity of a mobile phase to be 0.5-1.5 mL/min, the detection wavelength to be 200-280 nm, and the temperature of a column incubator to be 10-40 ℃;
3) and (2) injecting 10-50 mu L of the sample solution obtained in the step (1) into a liquid chromatograph, and completing the separation and measurement of the loratadine cyclic compound and related substances thereof under the chromatographic conditions of the claim 1.
CN201910901708.7A 2019-09-23 2019-09-23 Method for separating and measuring loratadine cyclic compound and related substances thereof by liquid chromatography Pending CN112540130A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114624358A (en) * 2022-03-11 2022-06-14 哈尔滨圣泰生物制药有限公司 Quality detection method of desloratadine oral liquid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114624358A (en) * 2022-03-11 2022-06-14 哈尔滨圣泰生物制药有限公司 Quality detection method of desloratadine oral liquid

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