CN115616122A - Method for separating and measuring related substances of loratadine starting material by liquid chromatography - Google Patents
Method for separating and measuring related substances of loratadine starting material by liquid chromatography Download PDFInfo
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- CN115616122A CN115616122A CN202110799250.6A CN202110799250A CN115616122A CN 115616122 A CN115616122 A CN 115616122A CN 202110799250 A CN202110799250 A CN 202110799250A CN 115616122 A CN115616122 A CN 115616122A
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- loratadine
- starting material
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- 229960003088 loratadine Drugs 0.000 title claims abstract description 51
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 239000007858 starting material Substances 0.000 title claims abstract description 50
- 239000000126 substance Substances 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000004811 liquid chromatography Methods 0.000 title claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000012071 phase Substances 0.000 claims description 19
- 238000000926 separation method Methods 0.000 claims description 14
- 239000012488 sample solution Substances 0.000 claims description 10
- ROBLTDOHDSGGDT-UHFFFAOYSA-M sodium;pentane-1-sulfonate Chemical compound [Na+].CCCCCS([O-])(=O)=O ROBLTDOHDSGGDT-UHFFFAOYSA-M 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000000523 sample Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 238000000691 measurement method Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 claims description 2
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000003556 assay Methods 0.000 claims 4
- 238000004587 chromatography analysis Methods 0.000 claims 2
- 238000002955 isolation Methods 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000003908 quality control method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- -1 2- (3-chlorophenylethyl) pyridine 1-oxide Chemical compound 0.000 description 2
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 2
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 2
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- JPCGKKFEDUHGDF-UHFFFAOYSA-N 3-[2-(3-chlorophenyl)ethyl]pyridine-2-carbonitrile Chemical compound ClC1=CC=CC(CCC=2C(=NC=CC=2)C#N)=C1 JPCGKKFEDUHGDF-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
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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
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for separating and determining related substances of a loratadine starting material by using a liquid chromatography. The method has the advantages of strong specificity, high accuracy and simple and convenient operation.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and measuring loratadine starting material 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 for treating anaphylaxis in clinic, and its cyclic compound chemical name is 8-chloro-11- (1-methylpiperdin-4-ylidine) -6,11-dihydo-5H-benzo[5,6]cyclohepta[1,2-b]pyridine of the formula C 20 H 21 N 2 And (4) Cl. The structural formula of the loratadine starting material is as follows:
in the process of producing loratadine starting material, several important intermediates, i.e., the intermediates involved in quality control of the drug, may affect the purity and quality of the drug due to incomplete removalThe main control related substances for the production of the loratadine starting material are 4, namely the related substances 1-chloro-5,6-dihydri-11H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-one, related substance 2- (3-chlorophenylethyl) pyridine 1-oxide, related substance 3- (3-chlorophenylethyl) picolinonitrile, related substance 4 (3- (3-chlorophenylethyl) pyridine-2-yl) (1-methylpiperidin-4-yl) methane hydrochloride, the structural formulas of which are respectively as follows:
the quality control is required to be carried out on related substances introduced in the production process of the loratadine starting material in the bulk drug, so that the separation of the loratadine starting material and the related substances is realized, and the method has important practical significance in the quality control of the loratadine starting material.
Disclosure of Invention
The invention aims to provide a method for analyzing the purity of a loratadine starting material and separating related substances thereof, so that the separation and the determination of the loratadine starting material and the related substances thereof are realized, and the quality control of the loratadine starting material is ensured.
The method for analyzing the purity of the loratadine starting material and separating related substances thereof by using the liquid chromatography is a chromatographic column adopting octadecylsilane chemically bonded silica as a filler, and an ion pair reagent-organic phase with a certain proportion is used as a mobile phase.
The chromatographic column takes octadecylsilane chemically bonded silica as a filler and is selected from Ultimate, 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 ion adopts gradient elution to the reagent-organic phase.
In said method, said ion-pairing reagent is selected from one of the following reagents: sodium pentane sulfonate, sodium heptane sulfonate, sodium octane sulfonate, and the like.
In the method, the dosage of the ion pair reagent is 0.1-20 mmol/L. Wherein phosphoric acid is added into the ion pair solution to adjust the pH value to be 2.8 to 3.0.
The separation and measurement method of the present invention can be realized by the following method:
1) Taking a proper amount of a sample of the loratadine starting material, dissolving the sample by using methanol or a solvent (mobile phase A: methanol = 1:4) to prepare a sample solution containing 0.1-3.0 mg of the loratadine starting material per 1 mL.
2) Setting the flow rate of the mobile phase at 0.5-1.5 mL/min, the flow rate of the mobile phase at 1.0mL/min preferably, the detection wavelength at 200-280 nm, the detection wavelength at 230nm preferably, the temperature of the column incubator at 10-40 ℃ and the temperature of the column incubator at 30 ℃.
3) Taking 10-50 mu L of the sample solution of 1), injecting into a liquid chromatograph, and completing the separation and measurement of the loratadine starting material 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
And (3) chromatographic column: c 18 （250×4.6mm，5μm）
Mobile phase: a: sodium pentane sulfonate solution (0.96 g sodium pentane sulfonate is taken, the pH is adjusted to 3.00 +/-0.05 by phosphoric acid, and 1000 mL is added with water); b: methanol-acetonitrile (1:1); elution with concentration gradient
Flow rate: 1.2mL/min
Detection wavelength: 254nm
Sample injection volume: 20 μ L
Column temperature: 30 deg.C
In the invention, C is used 18 The chromatographic column can effectively separate the loratadine starting material and related substances thereof. The invention solves the problem of separation and determination of the loratadine starting material and related substances thereof, thereby ensuring the controllable quality of the loratadine starting material.
Drawings
FIG. 1 is an HPLC chart of related substances of the starting material of loratadine of example 1;
FIG. 2 is an HPLC plot of the starting material of loratadine of example 1;
FIG. 3 is an HPLC chart of related substances of the starting material of loratadine in example 2;
FIG. 4 is an HPLC plot of the loratadine starting material of example 2;
FIG. 5 is an HPLC plot of the solvent at the time of example 3;
FIG. 6 is an HPLC chart of the loratadine starting material and related substances of example 3;
FIG. 7 is an HPLC plot of the loratadine starting material 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-10ASvp;
a chromatographic column: c 18 （Apollo，250×4.6mm，5μm）；
Mobile phase: a: sodium pentane sulfonate solution (0.96 g sodium pentane sulfonate, water 900ml, phosphoric acid to adjust pH to 3.00 + -0.05, water to 1000 mL); b: acetonitrile; elution was carried out with the following concentration gradient
| Time (min) | Mobile phase A% | Mobile phase B% |
| 0 | 75 | 25 |
| 20 | 50 | 50 |
| 30 | 40 | 60 |
| 35 | 30 | 70 |
| 45 | 30 | 70 |
| 50 | 75 | 25 |
| 55 | 75 | 25 |
Flow rate: 1.2mL/min
Detection wavelength: 254nm
Sample introduction volume: 20 μ L
Column temperature: 30 deg.C
Experimental procedure
Taking a proper amount of loratadine starting material and related substances thereof, and respectively dissolving samples by using solvents to prepare a sample solution containing the loratadine starting material and related substances thereof, wherein the sample solution is about 0.25 mg/mL. Performing high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The result is shown in figure 1~2, under which the chromatographic peak with the retention time of 13.241min in the sample solution of figure 2 is related to substance 2.
Example 2
Apparatus and conditions
High performance liquid chromatograph: shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
a chromatographic column: c 18 （Ultimate，250×4.6 mm，5μm）；
Mobile phase: a: sodium pentane sulfonate solution (0.96 g sodium pentane sulfonate, water 900ml, phosphoric acid to adjust pH to 3.00 + -0.05, water to 1000 mL); b: acetonitrile; elution was carried out with the following concentration gradient
| Time (min) | Mobile phase A% | Mobile phase B% |
| 0 | 80 | 20 |
| 10 | 65 | 35 |
| 20 | 65 | 35 |
| 30 | 50 | 50 |
| 40 | 30 | 70 |
| 50 | 30 | 70 |
| 50.1 | 80 | 20 |
| 60 | 80 | 20 |
Flow rate: 1.2mL/min
Detection wavelength: 254nm
Sample introduction volume: 20 μ L
Column temperature: 30 deg.C
Experimental procedure
Taking a proper amount of loratadine starting material and related substances, respectively dissolving samples by using solvents to prepare a sample solution containing the loratadine starting material and the related substances of about 0.25 mg/mL. Performing high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The result is shown in figure 3~4, and the chromatographic peak with the retention time of 15.865min in the sample solution in figure 4 is related substance 1, which is different from figure 2, therefore, under this system, unknown impurities exist in the sample solution to interfere with known impurities.
Example 3
Apparatus and conditions
High performance liquid chromatograph: shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
a chromatographic column: c 18 （Ultimate，250×4.6 mm，5μm）；
Mobile phase: a: sodium pentane sulfonate solution (0.96 g sodium pentane sulfonate is taken, the pH is adjusted to 3.00 +/-0.05 by phosphoric acid, and 1000 mL is added with water); b: methanol-acetonitrile (1: 1); elution was carried out with the following concentration gradient
| Time (min) | Mobile phase A% | Mobile |
| 0 | 65 | 35 |
| 30 | 50 | 50 |
| 40 | 30 | 70 |
| 50 | 30 | 70 |
| 50.1 | 65 | 35 |
| 60 | 65 | 35 |
Flow rate: 1.2mL/min
Detection wavelength: 254nm
Sample injection volume: 20 μ L
Column temperature: 30 deg.C
Experimental procedure
Taking a proper amount of loratadine starting material and related substances thereof, respectively dissolving samples by using solvents to prepare a solution containing the loratadine starting material of about 2mg/mL and a mixed solution containing the loratadine starting material and the related substances of 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 result is shown in FIG. 5~7, FIG. 5 is a solvent chromatogram; in fig. 6, the chromatographic peak with the retention time of 17.600min is the loratadine starting material, and the rest chromatographic peaks are chromatographic peaks of various related substances of the loratadine starting material, and as can be seen from the chart, the loratadine starting material and the related substances can achieve baseline separation and meet the requirements of the Chinese pharmacopoeia; the chromatographic peak with retention time 15.826min in fig. 7 is the loratadine starting material, and it can be seen that the loratadine starting material and its related substances can be completely separated under this condition.
Specificity test
Taking appropriate amount of loratadine starting material and intermediate thereof, respectively dissolving samples with solvents to prepare a solution containing loratadine starting material and related substances of 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 5~7, under the condition, the chromatographic peak shapes of the loratadine starting material and the intermediate thereof are good, the separation degree meets the requirement, and the solvent has no interference on the determination of the loratadine starting material and the intermediate thereof.
The method can effectively separate the loratadine starting material 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 starting material, thereby effectively controlling the product quality of the loratadine starting material.
Claims (8)
1. A method for separating and measuring related substances of loratadine starting materials by liquid chromatography is characterized by comprising the following steps: using octadecylsilane chemically bonded silica as a chromatographic column of a filler, taking an ion pair reagent-organic phase with a certain proportion as a mobile phase, and carrying out gradient elution, wherein related substances of a loratadine starting material mainly comprise:
2. the separation assay of claim 1, wherein the chromatography column is selected from chromatography columns sold under the brand Ultimate, alltima or 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 separation assay method of claim 1, wherein the ion-pair reagent is selected from one of the following reagents: sodium pentane sulfonate, sodium heptane sulfonate, sodium octane sulfonate, and the like.
6. The separation and analysis method according to claim 1, wherein the amount of the ion pair is 0.1 to 20 mmol/L.
7. The isolation measurement method according to claim 1, wherein the pH of the ion pair solution is 2.8 to 3.0.
8. The separation assay method of claim 1, comprising the steps of:
1) Taking a proper amount of a sample of the loratadine starting material, dissolving the sample by using methanol or a solvent (a mobile phase A: methanol = 1:4) to prepare a sample solution containing 0.1-3.0 mg of the loratadine starting material and related substances thereof per 1 mL;
2) Setting the flow rate of the 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) Taking 10-50 μ L of the sample solution of 1), injecting into a liquid chromatograph, and completing the separation and determination of the loratadine starting material and related substances under the chromatographic conditions of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110799250.6A CN115616122A (en) | 2021-07-15 | 2021-07-15 | Method for separating and measuring related substances of loratadine starting material by liquid chromatography |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110799250.6A CN115616122A (en) | 2021-07-15 | 2021-07-15 | Method for separating and measuring related substances of loratadine starting material by liquid chromatography |
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| Publication Number | Publication Date |
|---|---|
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|---|---|---|---|
| CN202110799250.6A Pending CN115616122A (en) | 2021-07-15 | 2021-07-15 | Method for separating and measuring related substances of loratadine starting material by liquid chromatography |
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