Method for determining content of N, N-dimethylethylenediamine (impurity E) in metoclopramide hydrochloride

Abstract

The invention discloses a method for determining the content of N, N-dimethylethylenediamine in metoclopramide hydrochloride. The method has the advantages that the problem of low recovery rate during determination of the N, N-dimethylethylenediamine is solved, and specific headspace equilibrium conditions are obtained, so that the content of the N, N-dimethylethylenediamine in the metoclopramide hydrochloride can be effectively detected, and the safety of clinical medication of the metoclopramide hydrochloride is ensured.

Description

Technical Field

[0001] The invention relates to a method for determining residual N,N-dimethylethylenediamine in metoclopramide hydrochloride, in particular to a method for detecting N,N-dimethylethylenediamine in metoclopramide hydrochloride by utilizing gas chromatography, and belongs to the technical field of analytical chemistry. Background Art

[0002] Metoclopramide hydrochloride is a dopamine 2 (D2) receptor antagonist. It also has a 5-hydroxytryptamine 4 (5-HT4) receptor agonist effect and a mild inhibitory effect on 5-HT3 receptors. It acts on dopamine receptors in the medullary chemo-emetic zone (CTZ), raising the CTZ threshold and exerting a potent central antiemetic effect. It also blocks hypothalamic dopamine receptors, inhibiting prolactin inhibitory factor and promoting prolactin secretion, thus exerting a mild galactagogue effect. Its inhibitory effect on other parts of the central nervous system is minimal, resulting in a weak sedative effect and a lesser hypnotic effect.

[0003] The chemical name of esmolol hydrochloride is N-[(2-diethylamino)ethyl]-4-amino-2-methoxy-5-chloro-benzamide hydrochloride monohydrate, and the structural formula is as follows.

[0004] .

[0005] Amide drugs are easily hydrolyzed and unstable in aqueous solution. Theoretical analysis shows that the degradation products are N-[(2-diethylamino)ethyl]-4-amino-2-methoxy-5-chloro-benzoic acid and N,N-dimethylethylenediamine, etc. The specific structural formulas are as follows.

[0006] .

[0007] The process impurity N,N-dimethylethylenediamine was detected under the relevant substance conditions.

[0008] N,N-dimethylethylenediamine is a related substance in Part IV of the 2025 edition of the Chinese Pharmacopoeia and must be controlled below 0.2%.

[0009] N,N-dimethylethylenediamine is a strong irritant to the skin, eyes, and respiratory tract. Contact may cause burns, redness, swelling, or pain. Inhalation of its vapors may cause coughing, sore throat, or difficulty breathing, and in severe cases, chemical pneumonia. High concentrations or prolonged exposure may corrode mucous membranes and tissues. Absorption through the skin or accidental ingestion may affect the central nervous system (such as headaches and dizziness) and even damage organs such as the liver and kidneys. Some people may experience allergic reactions, manifesting as eczema or asthma.

[0010] In order to strictly control the quality of drugs and ensure the safety of clinical drug use, it is necessary to control N,N-dimethylethylenediamine in metoclopramide hydrochloride.

[0011] Due to matrix effects, the recovery rate of N,N-dimethylethylenediamine in esmolol hydrochloride raw materials is relatively low. Therefore, it is necessary to develop a determination method to improve the recovery rate of N,N-dimethylethylenediamine, which is an urgent technical problem to be solved. Summary of the Invention

[0012] The present invention aims to establish a method for determining N,N-dimethylethylenediamine in metoclopramide hydrochloride. The method can accurately detect N,N-dimethylethylenediamine in metoclopramide hydrochloride, thereby ensuring the quality and safety of metoclopramide hydrochloride.

[0013] The present invention discloses a method for detecting N,N-dimethylethylenediamine in metoclopramide hydrochloride, comprising a capillary column using dimethylpolysiloxane (or a compound with similar polarity) treated with MPD (multifunctional deactivation) technology as a stationary phase as a chromatographic column, nitrogen as a carrier gas, an initial column temperature of 120°C, maintained for 2 minutes, then raised to 200°C at a rate of 10°C per minute, and maintained for 15 minutes; and headspace injection is used for sample analysis, with an injection port temperature of 180°C and a detector temperature of 250°C.

[0014] The headspace equilibrium temperature is 60-90° C. and the equilibrium time is 20-40 minutes; more preferably, the equilibrium temperature is 90° C. and the equilibrium time is 30 minutes.

[0015] The injection volume is 0.5 ml to 2.0 ml, more preferably 1.0 ml.

[0016] The chromatographic column is a capillary column treated with MPD (multifunctional deactivation) technology and using dimethylpolysiloxane (or dimethylpolysiloxane with similar polarity) as the stationary phase; more preferably, it is CP-Volamine (30m*0.32μm).

[0017] The diluent used in the injection solution can be one of N,N-dimethylformamide and N,N-dimethylsulfoxide, preferably N,N-dimethylformamide.

[0018] The concentration of the test sample is 10 mg / ml to 50 mg / ml, preferably 20 mg / ml.

[0019] The present invention has the positive effects of: the method adopts a headspace sampling mode, uses an organic solvent as a diluent, and adds a certain amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), thereby reducing the influence of the matrix effect and obtaining a higher recovery rate; at the same time, the method has a high sensitivity, thereby ensuring the safety and effectiveness of the quality of metoclopramide hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The chromatogram is of blank solvent.

[0021] Figure 2 This is the chromatogram of N,N-dimethylethylenediamine reference solution.

[0022] Figure 3 is the chromatogram of the test solution. DETAILED DESCRIPTION

[0023] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, the embodiments are merely exemplary and do not constitute any limitation to the scope of the present invention.

[0024] Example 1

[0025] A method for detecting N,N-dimethylethylenediamine in metoclopramide hydrochloride comprises the following steps.

[0026] Solvent: 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-dimethylformamide (3:97).

[0027] Solution preparation.

[0028] Step 1: Reference solution: Accurately weigh 0.04 g of N,N-dimethylethylenediamine, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well; accurately measure 1 ml, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well to use as the reference stock solution.

[0029] Step 2: Accurately measure 2 ml of the reference stock solution, place it in a 20 ml volumetric flask, shake, and mix well as the reference solution.

[0030] Step 3: Accurately weigh 40 mg of the test sample (metoclopramide hydrochloride) and place it in a 20 ml headspace bottle. Add 2 ml of solvent, shake, and mix to prepare the test solution.

[0031] Prepare 3 solutions in parallel in step 3.

[0032] Step 4: Accurately measure 40 mg of the test sample (metoclopramide hydrochloride) and place it in a 20 ml headspace bottle. Add 2 ml of the reference solution, shake, and mix to prepare the spiked test solution.

[0033] Prepare 6 portions of the solution in step 4 above in parallel.

[0034] Chromatographic conditions.

[0035] Agilent gas chromatograph.

[0036] The chromatographic column is CP-Volamine (30m*0.32μm).

[0037] Heating program: starting temperature 120 °C, maintain for 2 minutes, increase the temperature to 200 °C at a rate of 10 °C per minute, and maintain for 15 minutes.

[0038] The injection port temperature was 180 °C.

[0039] The detector temperature was 250°C.

[0040] The equilibrium temperature of the headspace bottle was 90°C.

[0041] The equilibration time was 30 minutes.

[0042] The injection volume was 1 ml.

[0043] result: N,N-Dimethylethylenediamine A (reference solution) A (test solution) A (spiked test solution) Recovery rate / % Measurement results 9473 Not detected 7927 83.68 .

[0044] Example 2

[0045] A method for detecting N,N-dimethylethylenediamine in metoclopramide hydrochloride comprises the following steps.

[0046] Solvent: 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-dimethylformamide (3.5:96.5).

[0047] Solution preparation.

[0048] Step 1: Reference solution: Accurately weigh 0.04 g of N,N-dimethylethylenediamine, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well; accurately measure 1 ml, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well to use as the reference stock solution.

[0049] Step 2: Accurately measure 2 ml of the reference stock solution, place it in a 20 ml volumetric flask, shake, and mix well as the reference solution.

[0050] Step 3: Accurately weigh 40 mg of the test sample (metoclopramide hydrochloride) and place it in a 20 ml headspace bottle. Add 2 ml of solvent, shake, and mix to prepare the test solution.

[0051] Prepare 3 solutions in parallel in step 3.

[0052] Step 4: Accurately measure 40 mg of the test sample (metoclopramide hydrochloride) and place it in a 20 ml headspace bottle. Add 2 ml of the reference solution, shake, and mix to prepare the spiked test solution.

[0053] Prepare 6 portions of the solution in step 4 above in parallel.

[0054] Chromatographic conditions.

[0055] Agilent gas chromatograph.

[0056] The chromatographic column is CP-Volamine (30m*0.32μm).

[0057] Heating program: starting temperature 120 °C, maintain for 2 minutes, increase the temperature to 200 °C at a rate of 10 °C per minute, and maintain for 15 minutes.

[0058] The injection port temperature was 180 °C.

[0059] The detector temperature was 250°C.

[0060] The equilibrium temperature of the headspace bottle was 90°C.

[0061] The equilibration time was 30 minutes.

[0062] The injection volume was 1 ml.

[0063] result: N,N-Dimethylethylenediamine A (reference solution) A (test solution) A (spiked test solution) Recovery rate / % Measurement results 18127 Not detected 19004 104.84 .

Claims

1. A method for determining residual N,N-dimethylethylenediamine in metoclopramide hydrochloride, characterized in that: N,N-dimethylethylenediamine was determined by gas chromatography using a capillary column with dimethylpolysiloxane (or similar polarity) treated with MPD (multifunctional deactivation) technology as the stationary phase. Nitrogen was used as the carrier gas. The initial column temperature was 120°C, maintained for 2 minutes, then increased to 200°C at a rate of 10°C per minute and maintained for 15 minutes. Headspace injection was used, and metoclopramide hydrochloride was diluted with a high-boiling point organic solvent to prepare the test sample.

2. The headspace chromatography according to claim 1, wherein: The headspace conditions are described as an equilibrium temperature of 60-90°C and an equilibrium time of 20-40 minutes.

3. The organic solvent according to claim 1, characterized in that: The organic solvents mentioned can be N,N-dimethylformamide and N,N-dimethyl sulfoxide.

4. The test solution according to claim 1 is prepared, characterized in that: The concentration of the test product is 20 mg / ml.

5. The headspace condition according to claim 2, characterized in that: The conditions described are headspace equilibrium conditions, the equilibrium temperature is 90°C, and the equilibrium time is 30 minutes.

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