Detection method of levodropropizine oral solution related substances
The existing technology cannot effectively detect oral solution of levohydroxypropiprazine by using octane bonds and silica gel chromatography columns in oral solution of levohydroxypropiprazine, which is solved by the failure of the existing technology to effectively detect oral solution of levohydroxypropiprazine. The problems of related substances have achieved accurate detection of impurities and guaranteed product quality.
Patent Information
- Application Number
- CN202411506640.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-28
- Publication Date
- 2025-01-17
AI Technical Summary
The prior art cannot effectively detect related substances in oral solution of levohydroxypropiperazine, especially impurity B produced during storage, which makes it difficult to ensure quality and safety.
The high-performance liquid chromatography was used to detect the octane bond and silica gel chromatography column. The gradient elution technology was used to use 0.03mol/L potassium hexafluorophosphate solution and methanol as the mobile phase. The column temperature was controlled at 25-35℃, and the wavelength was determined. It is set at 252-254 nm, combined with specific chromatographic conditions and injection volume, the accurate detection of substances related to levohydroxypropiperazine oral solution is achieved.
This method can effectively isolate and detect impurities in oral solution of levohydroxypropiperazine, with high specificity and accuracy, ensuring the safety of product quality.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of drug analysis, and in particular relates to a method for detecting related substances of a levodropropizine oral solution. Background Art
[0002] Chlorpheniramine Maleate is an antitussive drug, its chemical name is S-(I)-3-(4-phenyl-1-piperazinyl)-1,2-propanediol, and its chemical structure is: .
[0003] Common dosage forms of levodropropizine include levodropropizine tablets, levodropropizine capsules, and levodropropizine oral solution. It is clinically mainly used for dry cough and persistent cough caused by acute upper respiratory tract infection and acute bronchitis.
[0004] Among them, levohydroxypropylpiperazine oral solution is suitable for children due to its flexible dosage, good taste and compliance, and has irreplaceable advantages in clinical practice.
[0005] The main impurity A (phenylpiperazine) of levuloproprazine is listed in the pharmacopoeias of various countries. The structural formula is shown in the attached Figure 1 .
[0006] During the storage of levodropropizine oral solution, levodropropizine degrades to produce impurity B, the structural formula of which is shown in the attached Figure 2 .
[0007] At present, the mainstream pharmacopoeias of various countries do not include levodropropizine oral solution, and there is no detection method for related substances of levodropropizine oral solution. Due to the large number of excipients and complex ingredients of oral solution, the detection method using the method for related substances of levodropropizine cannot effectively separate the components, and it is urgent to develop a detection method for related substances of levodropropizine oral solution. Summary of the invention
[0008] Purpose of the invention: The purpose of the present invention is to provide a detection method that can detect related substances of levodropropizine oral solution, which is beneficial to ensure the quality and safety of levodropropizine oral solution.
[0009] The objective of the present invention is achieved through the following technical scheme: a method for detecting related substances of levodropropizine oral solution, characterized in that an octyl bond and a silica gel chromatographic column are selected, mobile phase A and mobile phase B are used for gradient elution, the flow rate is 0.9-1.1 ml / min, the column temperature is 25-35°C, and the detection wavelength is 252-254 nm; the mobile phase A is 0.03 mol / L potassium hexafluorophosphate solution (containing 0.1% phosphoric acid); the mobile phase B is methanol; the mobile phase A and mobile phase B are used for gradient elution, time (min) / mobile phase B (v%): 0 / 14; 15 / 14; 30 / 45; 50 / 60; 50.1 / 14; 60 / 14.
[0010] The filler of the chromatographic column is octylsilane bonded silica gel.
[0011] The particle size of the filler of the octyl bond and silica gel chromatographic column is 2.7 μm, and the specification is 150 mm×4.6 mm.
[0012] Other chromatographic conditions of the high performance liquid chromatography method are: flow rate of 0.9-1.1 ml / min, column temperature of 25-35° C., and detection wavelength of 252-256 nm.
[0013] Other chromatographic conditions of the HPLC method are as follows: the flow rate is preferably 1.0 ml / min, the column temperature is preferably 30° C., and the detection wavelength is preferably 254 nm.
[0014] Other chromatographic conditions of the high performance liquid chromatography method: the preparation concentration of the test solution is 0.6 mg / ml.
[0015] 20 μl of the test solution was measured and automatically injected for determination, and the content of related substances in the levodropropizine oral solution was calculated by the self-control method.
[0016] The present invention has the positive effects that the detection method of the present invention can effectively detect the related substances of the levodropropizine oral solution, has the advantages of strong specificity and good accuracy, and effectively guarantees the quality of the levodropropizine oral solution. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 It is the structural formula of impurity A.
[0018] Figure 2 It is the structural formula of impurity B.
[0019] Figure 3 It is the chromatogram of blank auxiliary material solution of Example 1.
[0020] Figure 4 This is the solution chromatogram of the system suitability of Example 1.
[0021] Figure 5This is the chromatogram of the test solution (reference preparation 0 day) of Example 1.
[0022] Figure 6 It is the chromatogram of blank auxiliary material solution of Example 2.
[0023] Figure 7 This is the solution chromatogram of the system suitability of Example 2.
[0024] Figure 8 This is the chromatogram of the test solution of Example 2 (self-made agent influence factor 60℃30 days).
[0025] Fig. 9 Overlay chromatogram of Example 3 and Comparative Example 1 (25°C).
[0026] Fig.10 Overlay chromatogram of Example 3 and Comparative Example 2 (30°C).
[0027] Fig.11 Overlay chromatogram of Example 3 and Comparative Example 3 (35°C). DETAILED DESCRIPTION
[0028] The present invention is further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto. Example
[0029] A method for detecting related substances of levodropropizine oral solution (reference preparation 0 day), wherein the chromatographic conditions are shown in Table 1.
[0030] Table 1 Chromatographic conditions of Example 1 Chromatographic columns Horizon Aurashell C8, 150×4.6mm, 2.7μm Mobile phase A 0.03mol / L potassium hexafluorophosphate solution (containing 0.1% phosphoric acid) Mobile phase B Methanol Elution gradient Time (min) Mobile phase A (%) Mobile phase B (%) 0861415861430554550406050.18614608614 Flow rate 1.0ml / min Column temperature 30℃ Injection volume 20μl Detection wavelength 254nm Blank excipient solution Take 1 ml of blank excipient solution prepared according to the prescription of this product, place it in a 10 ml volumetric flask, dilute to the scale with water, and shake well. System Suitability Solutions Take appropriate amounts of levodropropizine and impurity A and impurity B reference substances, weigh accurately, dissolve and dilute with water to prepare a solution containing approximately 0.6 mg of levodropropizine and 6 μg each of impurity A and impurity B per 1 ml. Test solution Accurately measure 1 ml of this product, place it in a 10 ml volumetric flask, dilute to the scale with water, and shake well. .
[0031] The experimental results of Example 1 are shown in Table 2.
[0032] Table 2 Experimental results of Example 1 Experimental solution Experimental Results Attached photos Blank excipient solution Blank excipients do not interfere with impurity detection Figure 3 System Suitability Solutions In the system suitability solution, levophyline, impurity A and impurity B eluted in sequence, wherein the separation degree between impurity A and levophyline was 4.1, and the separation degree between impurity B and impurity A was 23.3. Figure 4 Test solution The detected amount of related substances in levodropropizine oral solution is: Impurity A: Not detected Impurity B: 0.19% Other impurities: 0.28% Total impurities: 0.82% Figure 5 . Example
[0033] A method for detecting related substances of levodropropizine oral solution (self-made formulation, influence factor 60°C for 30 days), the chromatographic conditions of which are shown in Table 3.
[0034] Table 3 Chromatographic conditions of Example 2 Chromatographic columns Horizon Aurashell C8, 150×4.6mm, 2.7μm Mobile phase A 0.03mol / L potassium hexafluorophosphate solution (containing 0.1% phosphoric acid) Mobile phase B Methanol Elution gradient Time (min) Mobile phase A (%) Mobile phase B (%) 0861415861430554550406050.18614608614 Flow rate 1.0ml / min Column temperature 30℃ Injection volume 20μl Detection wavelength 254nm Blank excipient solution Take 1 ml of blank excipient solution prepared according to the prescription of this product, place it in a 10 ml volumetric flask, dilute to the scale with water, and shake well. System Suitability Solutions Take appropriate amounts of levodropropizine and impurity A and impurity B reference substances, weigh accurately, dissolve and dilute with water to prepare a solution containing approximately 0.6 mg of levodropropizine and 6 μg each of impurity A and impurity B per 1 ml. Test solution Accurately measure 1 ml of this product, place it in a 10 ml volumetric flask, dilute to the scale with water, and shake well. .
[0035] The experimental results of Example 2 are shown in Table 4.
[0036] Table 4 Experimental results of Example 2 Experimental solution Experimental Results Attached photos Blank excipient solution Blank excipients do not interfere with impurity detection Figure 6 System Suitability Solutions In the system suitability solution, levophyline, impurity A and impurity B eluted in sequence, wherein the separation degree between impurity A and levophyline was 4.1, and the separation degree between impurity B and impurity A was 23.3. Figure 7 Test solution The detected amount of related substances in levodropropizine oral solution is: Impurity A: 0.02% Impurity B: 0.78% Other impurities: 0.17% Total impurities: 1.24% Figure 8 . Example
[0037] Comparative Example 1-3: Other chromatographic conditions are basically the same as those in Example 1, except for the column temperature, which is as follows.
[0038] The column temperature of Comparative Example 1 was 25°C.
[0039] The column temperature of Comparative Example 2 was 30°C.
[0040] The column temperature of Comparative Example 3 was 35°C.
[0041] Depend on Fig.10 It can be seen that under various column temperature conditions, blank auxiliary materials do not interfere with the detection of impurities. The column temperature will affect the separation degree of impurity B and auxiliary materials. The lower the column temperature, the lower the separation degree between the two, and the greater the interference with the detection of impurities. At the same time, in order to extend the service life of the chromatographic column and ensure the separation of impurities, the column temperature is controlled within the range of 25-35℃.
Claims
1. A method for detecting related substances in levodropropizine oral solution, using high performance liquid chromatography, characterized in that: Octyl bond and silica gel chromatographic column are selected, mobile phase A and mobile phase B are used for gradient elution, the flow rate is 0.9-1.1 ml / min, the column temperature is 25-35°C, and the detection wavelength is 252-256 nm; the mobile phase A is 0.03 mol / L potassium hexafluorophosphate solution (containing 0.1% phosphoric acid); the mobile phase B is methanol; the mobile phase A and mobile phase B are used for gradient elution, time (min) / mobile phase B (v%): 0 / 14; 15 / 14; 30 / 45; 50 / 60; 50.1 / 14; 60 / 14.
2. The method according to claim 1, characterized in that: The filler of the chromatographic column is octylsilane bonded silica gel.
3. The method according to claim 2, characterized in that The particle size of the filler of the octyl bond and silica gel chromatographic column is 2.7 μm, and the specification is 150 mm×4.6 mm.
4. The method according to claim 1, characterized in that: Other chromatographic conditions of the high performance liquid chromatography method are: flow rate of 0.9-1.1 ml / min, column temperature of 25-35° C., and detection wavelength of 252-256 nm.
5. The method according to claim 4, characterized in that Other chromatographic conditions of the HPLC method are as follows: flow rate of 1.0 ml / min, column temperature of 30° C., and detection wavelength of 254 nm.
6. The method according to claim 1, characterized in that Other chromatographic conditions of the high performance liquid chromatography method: the preparation concentration of the test solution is 0.6 mg / ml.
7. The method according to claim 6, characterized in that 20 μl of the test solution was measured and automatically injected for determination, and the content of related substances in the levodropropizine oral solution was calculated by the self-control method.