Method for detecting menthol and propylene glycol in escitalopram oxalate oral liquid
The content of propylene glycol and menthol in the oral liquid of escitalopram oxalate was detected by gas chromatography, which solved the problem of lack of effective detection methods in the prior art, and achieved efficient separation and detection of the two auxiliary materials, with good reproducibility and sensitivity.
Patent Information
- Application Number
- CN202411991797.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-31
- Publication Date
- 2025-06-10
AI Technical Summary
The prior art lacks effective methods to simultaneously detect the content of propylene glycol and menthol in oral liquid escitalopram oxalate.
Gas chromatography was used to detect the content of menthol and propylene glycol in the oral liquid of escitalopram oxalate. By diluting the sample and using a polyethylene glycol elastic capillary column, combined with specific chromatographic conditions and heating procedures, effective separation and detection of the two auxiliary materials were achieved.
This method can effectively isolate and detect propylene glycol and menthol in escitalopram oxalate oral solution, and has the advantages of good reproducibility, strong specificity, high sensitivity and easy operation.
Smart Images
Figure CN120121770A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug detection, and particularly relates to a method for detecting menthol and propylene glycol in escitalopram oxalate oral solution. Background Art
[0002] Escitalopram oxalate oral solution is a drug mainly used for the acute and maintenance treatment of depression in adults and adolescents aged 12 to 17 years and the acute treatment of generalized anxiety disorder in adults. Propylene glycol and menthol are important excipients in escitalopram oxalate oral solution. Due to its special strong mint aroma and cool taste, menthol is widely used in personal care products, food, medicine and other industries, and has the effects of relieving itching, pain and cooling. It is one of the widely used spice types in the world and is widely used in medicines to improve the taste of medicines. Although propylene glycol has very low toxicity, as an excipient of oral solution, its dosage should be accurately controlled to ensure safety and effectiveness.
[0003] Escitalopram oxalate oral solution is not included in the pharmacopoeias of various countries. Only escitalopram oral solution is included in the USP 2023 edition, but there is no detection method for propylene glycol and menthol. There are few literature reports on the detection method for simultaneously detecting propylene glycol and menthol in pharmaceutical oral solutions. Han Shulei et al. developed a method for simultaneously determining the contents of 1,2 - propylene glycol, menthol, diethylene glycol, glycerol and triethylene glycol in e - cigarette liquid. The method uses organic solvent extraction of e - cigarettes to prepare test solutions, and the extraction method is complex. Salamat Tohti et al. used gas chromatography to quantitatively determine menthol, propylene glycol and glycerol in toothpaste. There is no literature report on the contents of propylene glycol and menthol in pharmaceutical oral solutions so far. Summary of the Invention
[0004] The main object of the present invention is to propose a method for detecting menthol and propylene glycol in escitalopram oxalate oral solution, aiming to solve the technical problem of simultaneously detecting the contents of propylene glycol and menthol in pharmaceutical oral solutions.
[0005] To achieve the above object, the present invention provides a gas chromatography method for determining menthol and propylene glycol in escitalopram oxalate oral solution, comprising the following steps: Dilute escitalopram oxalate oral solution, menthol and propylene glycol with a diluent respectively to obtain a test solution and a reference solution; Detect the test solution and the reference solution by gas chromatography; Among them, the chromatographic conditions are as follows: Chromatographic column: polyethylene glycol elastic capillary column; Injection port temperature: 240 - 260 °C; Detector temperature: 240 - 260 °C; Carrier gas: nitrogen; Split ratio: (20 - 30):1; Flow rate: 20 - 35 cm / s; Injection volume: 1 μL; Temperature programming: The initial temperature is 40 °C, maintained for 1 - 5 minutes, heated at a rate of 10 - 20 °C per minute to 80 - 100 °C, maintained for 5 minutes, heated at a rate of 5 °C per minute to 150 - 180 °C, maintained for 3 minutes, heated at a rate of 20 °C per minute to 220 - 240 °C, maintained for 5 minutes.
[0006] Optionally, the concentration of the test solution is 0.2 mg / mL; the concentration of propylene glycol in the reference solution is 2 mg / mL, and the concentration of menthol is 0.02 mg / mL.
[0007] Optionally, the diluent is methanol.
[0008] Optionally, the injection port temperature is 250 °C.
[0009] Optionally, the split ratio is 20:1.
[0010] Optionally, the flow rate is 35 cm / s.
[0011] Optionally, the detector temperature is 250 °C.
[0012] Optionally, the specifications of the chromatographic column are Agilent DB - WAX UI 30 m × 0.25 mm, 0.25 μm.
[0013] Optionally, in the temperature programming, the initial temperature is 40 °C, maintained for 1 minute, heated at a rate of 10 °C per minute to 80 °C, maintained for 5 minutes, heated at a rate of 5 °C per minute to 150 °C, maintained for 3 minutes, heated at a rate of 20 °C per minute to 220 °C, maintained for 5 minutes.
[0014] In the technical solution of the present invention, it can effectively separate the excipients propylene glycol and menthol in the oral liquid. At the same time, in gas chromatography, by using the method of gas chromatography temperature programming, it has good reproducibility, strong specificity, high sensitivity, and simple operation. Brief Description of the Drawings
[0015] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on the structures shown in these drawings.
[0016] Figure 1It is a schematic flowchart of an embodiment of the detection method for menthol and propylene glycol in escitalopram oxalate oral solution provided by the present invention; Figure 2 It is the liquid chromatogram of the blank solution in an embodiment of the detection method provided by the present invention; Figure 3 It is the liquid chromatogram of the reference solution in an embodiment of the detection method provided by the present invention; Figure 4 It is the liquid chromatogram of the test solution in an embodiment of the detection method provided by the present invention; Figure 5 It is the linear relationship diagram of propylene glycol in an embodiment of the linearity and range experiment provided by the present invention; Figure 6 It is the linear relationship diagram of menthol in an embodiment of the linearity and range experiment provided by the present invention.
[0017] The realization, functional characteristics and advantages of the object of the present invention will be further described with reference to the embodiments and the accompanying drawings. Detailed Embodiments
[0018] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.
[0019] It should be noted that for those conditions not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase. In addition, the meaning of "and / or" appearing throughout the text includes three parallel solutions. Taking "A and / or B" as an example, it includes solution A, or solution B, or the solution where A and B are satisfied simultaneously. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of those of ordinary skill in the art to implement. When the combination of technical solutions appears to be contradictory or unable to be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.
[0020] Escitalopram oxalate oral solution is not included in the pharmacopoeias of various countries. Only escitalopram oral solution is included in the USP 2023 edition, but there is no detection method for propylene glycol and menthol. There are few literature reports on the detection method for simultaneously detecting propylene glycol and menthol in pharmaceutical oral solutions.
[0021] In view of this, the present invention proposes a detection method for menthol and propylene glycol in escitalopram oxalate oral solution, combined withFigure 1 The flow schematic diagram of an embodiment of the detection method for menthol and propylene glycol in escitalopram oxalate oral solution provided, which includes the following steps: Step S10: Dilute escitalopram oxalate oral solution, menthol and propylene glycol with a diluent respectively to obtain a test solution and a reference solution.
[0022] In this embodiment, by screening a suitable solvent to obtain the test solution, diluting the oral solution with a methanol solution can well dissolve the sample without precipitation, and at the same time ensure that the solvent peak in the test solution does not affect the elution peaks of the target peaks of propylene glycol and menthol. If other organic phases such as ethanol or acetonitrile are used to dilute the sample, the sample solution will become turbid and precipitate. If other alcohols such as isopropanol are selected as the organic phase solvent, it is easy to introduce a solvent peak to affect the elution peaks of propylene glycol and menthol in the sample. It should be noted that the concentration of the test solution is set to 0.2 mg / mL; the concentration of propylene glycol in the reference solution is set to 2 mg / mL, and the concentration of menthol is set to 0.02 mg / mL.
[0023] Step S20: Detect the test solution and the reference solution by gas chromatography.
[0024] Among them, the chromatographic column uses a polyethylene glycol elastic capillary column, preferably Agilent DB-WAX UI 30m×0.25mm, 0.25μm specification; the inlet temperature is 240~260°C, preferably 250°C; the detector temperature is 240~260°C, preferably 250°C; the carrier gas is nitrogen; the split ratio is (20~30):1, preferably 20:1; the flow rate is 20~35 cm / s, preferably 35 cm / s; the injection volume is 1 μL.
[0025] Temperature rising program: The initial temperature is 40°C, maintained for 1~5 minutes, heated at a rate of 10~20°C per minute to 80~100°C, maintained for 5 minutes, heated at a rate of 5°C per minute to 150~180°C, maintained for 3 minutes, and heated at a rate of 20°C per minute to 220~240°C, maintained for 5 minutes. Preferably, in the temperature rising program, the initial temperature is 40°C, maintained for 1 minute, heated at a rate of 10°C per minute to 80°C, maintained for 5 minutes, heated at a rate of 5°C per minute to 150°C, maintained for 3 minutes, and heated at a rate of 20°C per minute to 220°C, maintained for 5 minutes.
[0026] In the technical solution of the present invention, the GC-FID method for determining propylene glycol and menthol in escitalopram oxalate oral solution is provided for the first time, which can effectively separate the excipients propylene glycol and menthol in the oral solution. In gas chromatography, compared with the internal standard method, the external standard method has the characteristics of simple operation and convenient calculation. In addition, the dilution factor screened by this detection method is 10 times. If the dilution factor is too small, the water content in the test solution is relatively high, which causes obvious damage to the gas chromatography column. If the dilution factor is too large, the response of menthol in the test solution is small, making quantitative determination difficult.
[0027] The following further details the technical solution of the present invention in conjunction with specific embodiments and drawings. It should be understood that the following embodiments are only used to explain the present invention and are not used to limit the present invention.
[0028] In this embodiment, the various instruments and materials involved are described as follows:
[0029] Main instruments: Agilent 1260 gas chromatograph; FID (hydrogen flame ionization detector). Example 1 Detection of Propylene Glycol and Menthol in Escitalopram Oxalate Oral Solution
[0030] The gas chromatography conditions are as follows: Chromatographic column: Agilent DB-WAX UI (30m×0.25mm, 0.25μm) or polyethylene glycol elastic capillary column; Injection port temperature: 250°C; Detector temperature: 250°C; Carrier gas: nitrogen; Split ratio: 20:1; Flow rate: 35 cm / s; Temperature programming: The initial temperature is 40°C, maintained for 1 minute, heated at a rate of 10°C per minute to 80°C, maintained for 5 minutes, heated at a rate of 5°C per minute to 150°C, maintained for 3 minutes, and heated at a rate of 20°C per minute to 220°C, maintained for 5 minutes.
[0031] (1) Preparation of samples and solutions Diluent: methanol; Blank solution: diluent; Test solution: Take 2.0 mL of the sample into a 10 mL volumetric flask, dilute to the mark with the diluent, and shake well; Reference solution: Weigh an appropriate amount of propylene glycol and menthol precisely, and dilute with the solvent to contain 2 mg / mL of propylene glycol and 0.02 mg / mL of menthol; (2) Determination method Separate the blank solution, reference solution, and test solution, inject them using the above chromatographic conditions, record the chromatograms, and calculate by the external standard method.
[0032] Experimental results: The chromatogram of the blank solution is shown in Figure 2 , the chromatogram of the reference solution is shown in Figure 3 (the elution order is propylene glycol, menthol), and the liquid chromatogram of the test solution is shown in Figure 4 .
[0033] Table 1 Verification of Propylene Glycol and Menthol - System Suitability - Reference Solution
[0034] Please refer to Figure 2 - 4 , the experimental results show that the blank solution has no interference on the elution of propylene glycol and menthol. In the chromatogram of the reference solution, the resolution between each peak is greater than 1.2, and the theoretical plate number of each component elution is greater than 3000. Example 2: Methodology Verification 2.1 Specificity
[0035] The instrument and chromatographic conditions are the same as in Example 1.
[0036] Examine the elution of the blank solvent and blank excipient solution at the positions of propylene glycol and menthol; the resolution between propylene glycol and menthol; Separate 1 μL of the blank solvent and reference solution each, inject them into the gas chromatograph. The results show that the blank solvent has no interference on the elution of the reference solution. The resolution between the propylene glycol and menthol peaks in the reference solution is 4.5, meeting the requirements. 2.2 Linearity and Range
[0037] Reference stock solution: Take appropriate amounts of propylene glycol and menthol reference substances, and prepare a mixed solution containing 20 mg of propylene glycol and 0.5 mg of menthol in each 1 mL with methanol.
[0038] Linear solution 1 (50%): Accurately measure 1.0 mL of the reference stock solution, place it in a 20 mL volumetric flask, dilute it to the mark with methanol, and shake well. (Propylene glycol 1 mg / mL, menthol 0.01 mg / mL) Linear solution 1 (80%): Accurately measure 1.6 mL of the reference stock solution, place it in a 20 mL volumetric flask, dilute it to the mark with methanol, and shake well. (Propylene glycol 1.6 mg / mL, menthol 0.016 mg / mL) Linear solution 3 (100%): Accurately measure 1.0 mL of the reference stock solution, place it in a 10 mL volumetric flask, dilute it to the mark with methanol, and shake well. (Propylene glycol 2 mg / mL, menthol 0.02 mg / mL) Linear solution 4 (120%): Accurately measure 1.2 mL of the reference stock solution, transfer it to a 10 mL volumetric flask, dilute it to the mark with methanol, and mix well. (Propylene glycol 2.4 mg / mL, menthol 0.024 mg / mL) Linear solution 5 (150%): Accurately measure 1.5 mL of the reference stock solution, transfer it to a 10 mL volumetric flask, dilute it to the mark with methanol, and mix well. (Propylene glycol 3 mg / mL, menthol 0.03 mg / mL) Accurately measure 1 μL of each of the above linear solutions, inject them into the gas chromatograph, record the chromatogram, use the concentration as the abscissa and the peak area as the ordinate, and make a linear regression equation.
[0039] Table 2 Validation of propylene glycol and menthol - Linear results
[0040] Please refer to Figure 5 and Figure 6 , the results show that: within the range of 50% to 150% for propylene glycol and menthol, there is a good linear relationship between the peak area and the concentration, and the correlation coefficient r is greater than 0.9990. The relative standard deviation (RSD) of the response factor (A / C) is between 0.98% and 1.23%. The ratio of the Y-axis intercept to the 100% response value is less than 1.49%, meeting the acceptance criteria of ≤5.0%. 2.3 Precision 2.3.1 Repeatability
[0041] Blank solution (diluent): Methanol Reference solution: Take appropriate amounts of propylene glycol and menthol reference substances, and prepare a mixed solution containing 2 mg of propylene glycol and 0.02 mg of menthol per 1 mL with methanol.
[0042] Test solution: Accurately transfer 2.0 mL of escitalopram oxalate oral solution, place it in a 10 mL volumetric flask, dissolve it with the solvent and dilute it to the mark, and mix well.
[0043] Accurately measure 1 μL of each of the above reference solution and test solution, inject them into the gas chromatograph, record the chromatogram, and calculate the content and relative standard deviation (RSD) of propylene glycol and menthol in each test solution in 6 intermediate precision solutions by the external standard method.
[0044] Table 3 Validation of propylene glycol and menthol - Precision - Repeatability test results
[0045] The results show that: in the 6 test solutions, the RSDs of propylene glycol and menthol are 3.8% and 6.3% respectively, both meeting the acceptance criteria. 2.3.4 Accuracy
[0046] Reference stock solution: Weigh appropriate amounts of propylene glycol and menthol reference substances, and prepare a mixed solution with methanol containing approximately 20 mg of propylene glycol and 0.2 mg of menthol per 1 mL.
[0047] Recovery - 50%: Take 2.0 mL of blank excipients of escitalopram oxalate, place it in a 20 mL volumetric flask, add 1.0 mL of the reference stock solution, dissolve and dilute to the mark with the solvent, and shake well. (Prepare 3 parallel portions) (propylene glycol 1 mg / mL, menthol 0.01 mg / mL) Recovery - 100%: Take 2.0 mL of blank excipients of escitalopram oxalate, place it in a 20 mL volumetric flask, add 2.0 mL of the reference stock solution, dissolve and dilute to the mark with the solvent, and shake well. (Prepare 3 parallel portions) (propylene glycol 2 mg / mL, menthol 0.02 mg / mL) Recovery - 150%: Take 2.0 mL of blank excipients of escitalopram oxalate, place it in a 20 mL volumetric flask, add 3.0 mL of the reference stock solution, dissolve and dilute to the mark with the solvent, and shake well. (Prepare 3 parallel portions) (propylene glycol 3 mg / mL, menthol 0.03 mg / mL) Precisely measure 1 μL of the above solution, inject it into the gas chromatograph, record the chromatogram, calculate the measured amounts of the 3 recovery rate solutions at each concentration by the external standard method, calculate the recovery rate based on the added amount, original amount, and measured amount, and calculate the average value of the 3 recovery rates at the quantitation limit concentration, the average value of the 9 recovery rates at other concentrations, and the relative standard deviation (RSD).
[0048] Table 6 Validation of Propylene Glycol and Menthol - Accuracy Test Results
[0049] The results show that: the average spiked recovery rates of propylene glycol and menthol at 50%, 100%, and 150% concentrations are all between 95% and 105%, and the RSD of the 9 recovery rates is less than 5%, indicating good accuracy of the method. 2.3.5 Solution Stability
[0050] Place the reference solution and the test solution at room temperature respectively. At different times after preparation, precisely measure 1 μL respectively, inject it into the gas chromatograph, and record the chromatogram. Compare the percentages of the peak areas of propylene glycol and menthol in the reference solution and the test solution at each time point with the peak area at 0 h.
[0051] Precisely measure 1 μL of the above solution of the reference solution and the test solution, inject it into the gas chromatograph, and record the chromatogram.
[0052] Table 7 Validation of Propylene Glycol and Menthol - Robustness - Stability of Reference Solution
[0053] Table 8 Verification of Propylene Glycol and Menthol - Durability - Stability of Test Solution
[0054] The results show that: for the reference solution placed at room temperature for 24 hours, the ratios of the contents of propylene glycol and menthol to the peak areas of propylene glycol and menthol at 0 hour are all between 98.51% and 101.81%. Therefore, the test solution has good stability within 24 hours at room temperature; for the test solution placed at room temperature for 24 hours, the ratios of the contents of propylene glycol and menthol to the peak areas of propylene glycol and menthol at 0 hour are all between 98.76% and 101.80%. Therefore, the test solution has good stability within 24 hours at room temperature.
[0055] The technical features of the above embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.
[0056] The above embodiments only represent several implementation manners of this application, and the description is relatively specific and detailed. However, it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of this application, several modifications and improvements can still be made, and these all belong to the protection scope of this application. Therefore, the protection scope of the patent of this application shall be subject to the appended claims.
Claims
1. A method for detecting menthol and propylene glycol in escitalopram oxalate oral solution, characterized in that: The steps include: Dilute the escitalopram oxalate oral solution, menthol and propylene glycol with diluents to obtain a test solution and a reference solution; The test solution and the reference solution are tested by gas chromatography; The chromatographic conditions are as follows: Chromatographic column: polyethylene glycol elastic capillary column; Inlet temperature: 230~260℃; Detector temperature: 230~260℃; Carrier gas: nitrogen; Split ratio: (20~30):1; Flow rate: 20~35cm / s; Injection volume: 1 μL; Heating program: starting temperature is 40℃, maintain for 1~5 minutes, increase the temperature to 80~100℃ at a rate of 10~20℃ per minute, maintain for 5 minutes, increase the temperature to 150~180℃ at a rate of 5℃ per minute, maintain for 3 minutes, increase the temperature to 220~240℃ at a rate of 20℃ per minute, maintain for 5 minutes.
2. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The escitalopram concentration of the test solution was 0.2 mg / mL.
3. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The concentration of propylene glycol in the reference solution is 2 mg / mL, and the concentration of menthol is 0.02 mg / mL.
4. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The diluent is methanol.
5. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The injection port temperature is 250°C.
6. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The split ratio is 20:
1.
7. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The flow rate is 35 cm / s.
8. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The detector temperature was 250°C.
9. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: The specifications of the chromatographic column are Agilent DB-WAX UI 30m×0.25mm, 0.25μm.
10. The method for detecting menthol and propylene glycol in escitalopram oxalate oral solution according to claim 1, characterized in that: In the heating program, the starting temperature is 40°C, maintained for 1 minute, heated to 80°C at a rate of 10°C per minute, maintained for 5 minutes, heated to 150°C at a rate of 5°C per minute, maintained for 3 minutes, heated to 220°C at a rate of 20°C per minute, and maintained for 5 minutes.