Method for detecting related substances in vortioxetine lactate bulk drug

Abstract

The invention provides a detection method for determining related substances of a vortioxetine lactate bulk drug, which is characterized in that separation and detection are carried out in an isocratic elution mode by adopting a high performance liquid chromatography method, taking a silica gel bonded octylsilane column as a chromatographic column and taking a certain proportion of inorganic salt buffer solution-organic phase as a mobile phase. The method for detecting the related substances of the vortioxetine lactate bulk drug can detect seven impurities of the bulk drug at a time, is high in specificity, high in precision and good in repeatability, and can effectively control the quality of the drug and ensure the safety of the drug.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drug analysis, and in particular to a method for detecting related substances in a raw material drug of vortioxetine lactate. The method uses high performance liquid chromatography to perform qualitative or quantitative analysis on vortioxetine and related substances. Background Art

[0002] Vortioxetine lactate, English name Vortixetine lactate, chemical name: 1-[2-(2,4-dimethylphenylthio)-phenyl]piperazine-2-hydroxypropionate, its molecular formula is C 18 H 22 N2S·C3H603, molecular weight is 388.52.

[0003] The structural formula of vortioxetine lactate is: .

[0004] Vortioxetine was jointly developed by Takeda Pharmaceuticals and Lundbeck Pharmaceuticals. It was approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States on September 30, 2013. Its trade name is Brintellix®, and its strengths are 5mg, 10mg, 15mg and 20mg. It is used to treat major depressive disorder in adults.

[0005] Related substances are starting materials, intermediates, side reaction products and degradation impurities introduced during the drug synthesis production process. Detection of related substances can control the quality and safety of drugs. For related substances introduced in the synthesis of vortioxetine, quality control is required in the raw materials. Therefore, separation of vortioxetine and other related substances and accurate quantification are of great practical significance in the quality control of the vortioxetine synthesis process. Summary of the invention

[0006] The invention provides an analysis method for related substances of a vortioxetine lactate raw material drug, thereby being able to quickly, effectively and accurately monitor the purity of vortioxetine lactate and achieve quality control of the raw material drug of the final product.

[0007] The invention provides a method for detecting related substances in a vortioxetine lactate raw material drug, which adopts a high performance liquid chromatography method, uses a chromatographic column with a fixed property of silica gel bonded with octylsilane, uses a certain proportion of an inorganic salt buffer solution as a mobile phase A and an organic phase as a mobile phase B, and performs isocratic elution.

[0008] The present invention provides a method for detecting related substances in a vortioxetine lactate raw material drug, wherein the isocratic elution procedure is: Time (min) A% B% 0 30 70 20 30 70 .

[0009] Preferably, the inorganic salt buffer solution is perchlorate, specifically sodium perchlorate, with a concentration of 0.05 mol / L and a pH value of 3.5.

[0010] Preferably, the organic phase is acetonitrile.

[0011] Preferably, the chromatographic column provided is ZORBAX RX-C8 (4.6 mm×250 mm, 5 µm).

[0012] The separation and determination method of the present invention can be implemented as follows: (1) Take an appropriate amount of vortioxetine lactate sample, dissolve the sample in 80% acetonitrile, and prepare a sample solution containing 0.3 mg of vortioxetine lactate per 1 ml.

[0013] (2) Set the mobile phase flow rate to 0.5-1.5 mL / min, preferably 1.0 mL / min, the detection wavelength to 220-260 nm, with the optimal detection wavelength being 254 nm, and the column oven temperature to 20-50 °C, with the optimal column oven temperature being 40 °C.

[0014] (3) Take 10 to 50 μl of the sample solution in (1) above and inject it into a liquid chromatograph to separate and determine vortioxetine and related substances. Wherein: High performance liquid chromatograph: Agilent 1260 InfinityII; Chromatographic column: ZORBAX RX-C8 (4.6 mm × 250 mm, 5 µm); Mobile phase A: 0.05 mol / L sodium perchlorate buffer solution (weigh 7.02 g of sodium perchlorate monohydrate, dissolve in water and dilute to 1000 ml, adjust pH to 3.5 with perchloric acid); mobile phase B: acetonitrile; elution was performed according to the following gradient: Time (min) A% B% 0 30 70 20 30 70 Flow rate: 1.0 mL / min; Column temperature: 40°C; Detection wavelength: 254nm; Injection volume: 10 μl; The detection method of the present invention has strong specificity and high stability. The detection method has good reproducibility and can effectively separate the related substances of vortioxetine lactate. The present invention solves the problem of separation and determination of the related substances of vortioxetine lactate, thereby reducing the occurrence of side reactions, improving the yield and purity of the product, and ensuring the controllable quality of vortioxetine lactate. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the blank solvent HPLC chart of vortioxetine lactate in Example 1.

[0016] Figure 2 HPLC chart of vortioxetine lactate intermediate and its related substances in Example 1. Specific implementation method: The following examples are used to further understand the present invention, but are not limited to the scope of this embodiment.

[0018] Example 1 Instruments and conditions High performance liquid chromatograph: Agilent 1260 InfinityII; Chromatographic column: ZORBAX RX-C8 (4.6 mm × 250 mm, 5 µm); Mobile phase A: 0.05 mol / L sodium perchlorate buffer solution (weigh 7.02 g of sodium perchlorate, dissolve in water and dilute to 1000 ml, adjust pH to 3.5 with perchloric acid); mobile phase B: acetonitrile; elution was performed according to the following gradient: Time (min) A% B% 0 30 70 20 30 70 Flow rate: 1.0 mL / min; column temperature: 40°C; detection wavelength: 254 nm; injection volume: 10 μl; Take appropriate amount of vortioxetine lactate and its impurities, dissolve the sample in 80% acetonitrile, and prepare a sample solution containing 0.3 mg / mL vortioxetine and appropriate concentrations of its impurities. Perform HPLC analysis under the above conditions and record the chromatogram. The results are shown in the attached Figure 1 , Figure 1 The chromatographic peak with a retention time of 3.440 min is vortioxetine, and the other chromatographic peaks are the chromatographic peaks of various impurities of vortioxetine.

[0019] from Figure 1 - Figure 2 It is shown that the method of the present invention can separate vortioxetine from its impurities and can accurately perform quantitative detection, thereby effectively controlling the product quality of vortioxetine lactate.

Claims

1. A method for separating related substances of vortioxetine lactate raw material drug, using high performance liquid chromatography, the chromatographic column is a silica gel bonded octylsilane column, a certain proportion of inorganic salt buffer solution-organic phase as the mobile phase, and isocratic elution is performed to separate vortioxetine and various impurities.

2. The method for analyzing and detecting related substances of the vortioxetine lactate bulk drug according to claim 1, characterized in that: The organic phase is selected from one of the following compounds: methanol and acetonitrile.

3. The method for analyzing and detecting related substances of vortioxetine lactate raw material drug according to claim 1, characterized in that: The inorganic salt buffer solution is selected from one of the following inorganic salts: phosphate and perchlorate.

4. The method for analyzing and detecting related substances of vortioxetine lactate raw material drug according to claim 1, characterized in that: The isocratic process is:

5. The method for analyzing and detecting related substances of vortioxetine lactate raw material drug according to claim 1, characterized in that: The chromatographic column preferably has a length of 250 mm, a diameter of 4.6 mm, and a filler particle size of 5 μm.

6. The method for analyzing and detecting related substances of vortioxetine lactate raw material drug according to claims 1 and 3, characterized in that: The inorganic salt buffer solution is preferably perchlorate, with an optimal concentration of 0.05 mol / L and a pH value of 3.

5.

7. The method for analyzing and detecting related substances of the vortioxetine lactate bulk drug according to claims 1 and 2, characterized in that: The organic phase is preferably acetonitrile.

8. The method for analyzing and detecting related substances of vortioxetine lactate raw material drug according to claim 1, characterized in that: The method comprises the following steps: ① setting the flow rate to 0.5-1.5 ml / min; ② setting the detection wavelength to 220-260 nm; ③ setting the column temperature to 20-50° C.; and ④ setting the injection volume to 5-20 μl.

9. The method for analyzing and detecting related substances of vortioxetine lactate raw material drug according to claim 7, characterized in that: The chromatographic conditions are as follows: ① the flow rate is preferably 1.0 ml / min; ② the wavelength is preferably 254 nm; ③ the column temperature is preferably 40°C; ④ the injection volume is preferably 10 µl.

10. The method for analyzing related substances of vortioxetine lactate raw material drug according to claim 1, characterized in that: The impurities are:

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