Method for detecting impurities in valproic acid prepared by methyl cyanoacetate method

Abstract

The present application relates to a method for detecting impurities in valproic acid or sodium valproate prepared by methyl cyanoacetate method by gas chromatography, characterized in that the impurities in valproic acid or sodium valproate prepared by methyl cyanoacetate method are detected by gas chromatography; the impurities are selected from valeric acid (A), 2-methyl valeric acid (L), 2-isopropyl valeric acid (C), valproic amide (F) or 2-propyl hexanoic acid (X):

Description

TECHNICAL FIELD

[0001] The present application relates to the detection of impurities in valproic acid or sodium valproate products using gas chromatography. BACKGROUND

[0002] Methyl cyanoacetate and 1-chloropropane, under the action of base, are complex catalytically dipropylated to obtain methyl 2-cyano-2-propylvalerate [a complex catalytic preparation method of methyl 2-cyano-2-propylvalerate, ZL2022101320660, granted on March 31, 2023]; methyl 2-cyano-2-propylvalerate is hydrolyzed and deacidified to obtain valpropanitrile; valpropanitrile is hydrolyzed under acid catalysis to obtain valproic acid (P):

[0003]

[0004] Valproic acid prepared by the methyl cyanoacetate method [Hunan Xiangzhong Pharmaceutical Co., Ltd., Hunan University. A complex catalytic preparation method of methyl 2-cyano-2-propylvalerate, ZL2022101320660, granted on March 31, 2023] process may produce valeric acid (A), 2-methylvaleric acid (L), 2-isopropylvaleric acid (C), dipropylvaleric acid (D), valproamide (F), and 2-propylvaleronitrile (I) impurities; a new impurity, 2-propylhexanoic acid (X), was also found:

[0005]

[0006] European Pharmacopoeia EP9.0 and British Pharmacopoeia BP2019 report impurities in sodium valproate, such as valeric acid (A), valeronitrile (H), valeramide (E), 2-methylvaleric acid (L), 2-ethylvaleric acid (B), 2-isopropylvaleric acid (C), 2-methyl-2-ethylvaleric acid (K), dipropylvaleric acid (D), valproamide (F), 2-propylvaleronitrile (I), dipropylvaleramide (G), and dipropylvaleronitrile (J):

[0007]

[0008] Chongqing Jieneng Pharmaceutical Development Co., Ltd. [Li Chaoyang, Wang Zuhuan, Liu Ping. A qualitative analysis method for trace impurities in sodium valproate raw materials by HPLC-MS, CN2020115724317, May 7, 2021] describes the detection of trace impurities L and B in sodium valproate products.

[0009] Sichuan Koreder Pharmaceutical Co., Ltd. [A method for preparing propylidene acid intermediate diethyl dipropylmalonate, CN202111473302.7, published on June 6, 2023; A detection method for related impurities of dipropylmalonic acid, ZL2019112294367, granted on October 28, 2022] uses high performance liquid chromatography to detect impurities in the dipropylmalonic acid intermediate, which are diethyl dipropylmalonate, monoethyl dipropylmalonate, monomethyl dipropylmalonate, monoethyl propylmalonate, monomethyl propylmalonate and propylmalonic acid. It may also contain diethyl propylmalonate; their structural formulas are as follows:

[0010]

[0011] Beijing Yuke Kangkechuang Pharmaceutical Technology Co., Ltd. [A preparation method of sodium valproate, CN202310028759.X, published on May 9, 2023] uses gas chromatography to detect impurities in sodium valproate products prepared by the ethyl malonate method, which may include valeric acid (A), 2-methyl valeric acid (L), 2-ethyl valeric acid (B), 2-isopropyl valeric acid (C), 2-methyl-2-ethyl valeric acid (K) and dipropyl valeric acid (D).

[0012] Valeric acid (A), 2-methyl valeric acid (L), 2-isopropyl valeric acid (C), 2-propyl hexanoic acid (X), dipropyl valeric acid (D), propylvaleric amide (F) and 2-propylvaleronitrile (I) are impurities that may be produced during the production of sodium valproate raw material drugs prepared by the method of methyl cyanoacetate. They play a key role in the detection and control of related substances in the production of sodium valproate or sodium valproate raw material drugs. European Pharmacopoeia EP9.0 and British Pharmacopoeia BP2019 report the research and control of impurities in sodium valproate. Therefore, the related research on impurities in sodium valproate or sodium valproate has practical significance, which can be used for qualitative and quantitative analysis of impurities in the production of sodium valproate or sodium valproate, thereby improving the quality standard of sodium valproate and providing guidance for safe medication. SUMMARY

[0013] The purpose of the present application is to provide a gas chromatography method for detecting impurities in the process of preparing valproic acid or sodium valproate by methyl cyanoacetate method, characterized in that a gas chromatograph (Agilent 8890) is used to detect valproic acid prepared by methyl cyanoacetate method; the detection conditions of the gas chromatography method are as follows: chromatographic column: DB-FFAP (0.32 mm x 60 m, 0.5 μm); carrier gas: nitrogen; detector: FID; flow rate: 2 ml / min; sample injection volume: 2 μl; sample injection port temperature: 220°C; column temperature: 100°C; temperature rising program: initial temperature of 100°C, holding for 5 min, then rising at a rate of 4°C / min to 140°C, holding for 5 min, then rising at a rate of 4°C / min to 200°C, holding for 15 min; running time: 50 min; detector temperature: 220°C; sample injection mode: direct injection.

[0014] Take 2 μl of each of the diluent, reference solution and test solution and inject them into the gas chromatograph to record the chromatogram.

[0015] The impurities are selected from valeric acid (A), 2-methyl valeric acid (L), 2-isopropyl valeric acid (C), dipropyl valeric acid (D), valproamide (F), 2-valproyl cyanide (I) or 2-propyl hexanoic acid (X):

[0016]

[0017] Compared with the prior art, the present application has the following advantages:

[0018] The gas chromatography method for detecting impurities in valproic acid prepared by methyl cyanoacetate method is simple to operate and has good stability; and the new impurity 2-propyl hexanoic acid in the impurities in valproic acid prepared by methyl cyanoacetate method is confirmed for the first time. BRIEF DESCRIPTION OF DRAWINGS

[0019] ATTACHMENT Figure 1 Gas chromatogram of valproic acid (xzhd202301) prepared by methyl cyanoacetate method

[0020] ATTACHMENT Figure 2 Gas chromatogram of valeric acid reference sample

[0021] ATTACHMENT Figure 3 Gas chromatogram of valproic acid mixed with valeric acid

[0022] ATTACHMENT Figure 4 Gas chromatogram of 2-methyl valeric acid reference sample

[0023] ATTACHMENT Figure 5 Gas chromatogram of valproic acid mixed with 2-methyl valeric acid

[0024] ATTACHMENT Figure 6 Gas chromatogram of 2-isopropyl valeric acid reference sample

[0025] Appendix Figure 7 Gas chromatogram of a mixture of valproic acid and 2-isopropylvaleric acid

[0026] Appendix Figure 8 Gas chromatogram of 2-propylhexanoic acid reference sample

[0027] Appendix Figure 9 Gas chromatogram of a mixture of valproic acid and 2-propylhexanoic acid

[0028] Appendix Figure 10 Gas chromatogram of valproamide reference sample

[0029] Appendix Figure 11 Gas chromatogram of a mixture of valproic acid and valproamide

[0030] Appendix Figure 12 Gas chromatogram of valproic acid (xzhd202302) prepared by the methyl cyanoacetate method

[0031] Appendix Figure 13 Gas chromatogram of valproic acid (xzhd202303) prepared by the methyl cyanoacetate method

[0032] Appendix Figure 14 Gas chromatogram of valproic acid (xzhd202304) prepared by the methyl cyanoacetate method Detailed Implementation

[0033] The present invention will be further described in detail below with reference to the embodiments.

[0034] Example 1

[0035] Gas chromatography of valproic acid (xzhd202301) prepared by the methyl cyanoacetate method

[0036] A gas chromatograph (Agilent 8890) was selected to detect valproic acid (xzhd202301) prepared by the methyl cyanoacetate method.

[0037] The chromatographic conditions were as follows: Column: DB-FFAP (0.32 mm × 60 m, 0.5 μm); Carrier gas: Nitrogen; Detector: FID; Flow rate: 2 ml / min; Injection volume: 2 μl; Injector temperature: 220℃; Column temperature: 100℃; Temperature program: Initial temperature 100℃, hold for 5 min, then increase to 140℃ at a rate of 4℃ / min, hold for 5 min, then increase to 200℃ at a rate of 4℃ / min, hold for 15 min; Run time: 50 min; Detector temperature: 220℃; Injection method: Direct injection.

[0038] Take 2 μl each of the diluent, reference solution, and test solution, inject them into the gas chromatograph, and record the chromatogram.

[0039] The gas chromatography detection results of valproic acid (XZHD202301) prepared by the method of methyl cyanoacetate are shown in the following Figure 1 .

[0040] Peak 4 retention time 30.246 min, RRT = 1.00: valproic acid.

[0041] Example 2

[0042] Gas chromatography of valeric acid control sample

[0043] The gas chromatography determination conditions are the same as in Example 1.

[0044] The gas chromatography detection results of valeric acid control sample are shown in the following Figure 2 , retention time 23.228 min: valeric acid.

[0045] Example 3

[0046] Gas chromatography of valproic acid and valeric acid mixture

[0047] The gas chromatography determination conditions are the same as in Example 1.

[0048] The gas chromatography of valproic acid and valeric acid mixture is shown in the following Figure 3

[0049] RRT = 0.77, peak area from 0.004% to 0.794%.

[0050] Conclusion: The Figure 1 and the Figure 3 No. 1 peak (RRT = 0.77) is valeric acid; one of the main impurities in valproic acid product prepared by the method of methyl cyanoacetate is valeric acid, and its structural formula is:

[0051]

[0052] Example 4

[0053] Gas chromatography of 2-methyl valeric acid control sample

[0054] The gas chromatography determination conditions are the same as in Example 1.

[0055] The gas chromatography detection results of 2-methyl valeric acid control sample are shown in the following Figure 4 , retention time 24.261 min: 2-methyl valeric acid.

[0056] Example 5

[0057] Gas chromatography of valproic acid mixed with 2-methylvaleric acid

[0058] The gas chromatography conditions were the same as in Example 1.

[0059] The results of the gas chromatography of valproic acid mixed with 2-methylvaleric acid are shown in Figure 2. Figure 5 .

[0060] The peak at 24.262 min, RRT = 0.80, increased from 0.027% to 1.161% in area.

[0061] Conclusion: Figure 2 shows that the peak at RRT = 0.80 in the sample of valproic acid mixed with 2-methylvaleric acid is 2-methylvaleric acid (L); and that 2-methylvaleric acid is a major impurity in the valproic acid product prepared by the method of methyl cyanidate. Figure 1 and Figure 2 shows that the peak at RRT = 0.80 in the sample of valproic acid mixed with 2-methylvaleric acid is 2-methylvaleric acid (L); and that 2-methylvaleric acid is a major impurity in the valproic acid product prepared by the method of methyl cyanidate. Figure 5 The peak at RRT = 0.80 in Figure 2 is 2-methylvaleric acid (L); and 2-methylvaleric acid is a major impurity in the valproic acid product prepared by the method of methyl cyanidate; the structure of 2-methylvaleric acid is:

[0062]

[0063] Example 6

[0064] Gas chromatography of 2-isopropylvaleric acid (C)

[0065] The gas chromatography conditions were the same as in Example 1.

[0066] The results of the gas chromatography of the control sample of 2-isopropylvaleric acid (C) are shown in Figure 4. Figure 6 , with a retention time of 29.078 min.

[0067] Example 7

[0068] Gas chromatography of valproic acid mixed with 2-isopropylvaleric acid (C)

[0069] The gas chromatography conditions were the same as in Example 1.

[0070] The results of the gas chromatography of valproic acid mixed with 2-isopropylvaleric acid (C) are shown in Figure 6. Figure 7 .

[0071] The peak at 29.093 min, RRT = 0.96, increased from 0.029% to 1.105% in area.

[0072] Conclusion: Figure 6 shows that the peak at RRT = 0.96 in the sample of valproic acid mixed with 2-isopropylvaleric acid (C) is 2-isopropylvaleric acid (C); and that 2-isopropylvaleric acid is a major impurity in the valproic acid product prepared by the method of methyl cyanidate. Figure 1 and Figure 6 shows that the peak at RRT = 0.96 in the sample of valproic acid mixed with 2-isopropylvaleric acid (C) is 2-isopropylvaleric acid (C); and that 2-isopropylvaleric acid is a major impurity in the valproic acid product prepared by the method of methyl cyanidate. Figure 7 The peak at RRT = 0.96 in Figure 6 is 2-isopropylvaleric acid (C); and 2-isopropylvaleric acid is a major impurity in the valproic acid product prepared by the method of methyl cyanidate; the structure of 2-isopropylvaleric acid is:

[0073]

[0074] Example 8

[0075] 2-propylhexanoic acid by gas chromatography

[0076] The gas chromatography conditions were the same as in Example 1.

[0077] The results of the gas chromatography of the 2-propylhexanoic acid control sample are shown in Figure 2. Figure 8 Retention time 32.859 min: 2-propylhexanoic acid.

[0078] Example 9

[0079] Gas chromatography of a mixture of valproic acid and 2-propylhexanoic acid

[0080] The gas chromatography conditions were the same as in Example 1.

[0081] The results of the gas chromatography of the mixture of valproic acid and 2-propylhexanoic acid are shown in Figure 4. Figure 9

[0082] Peak 5 retention time 32.890 min, RRT = 1.09, peak area increased from 0.051% to 0.183%.

[0083] Conclusion: Figure 2 shows that the peak with retention time 32.859 min (RRT = 1.09) is 2-propylhexanoic acid. Figure 1 and Figure 4 shows that the peak with retention time 32.890 min (RRT = 1.09) is 2-propylhexanoic acid. Figure 9 Peak 5 (RRT = 1.09) in Figures 2 and 4 is 2-propylhexanoic acid; one of the main impurities in valproic acid products prepared by the methyl cyanoacetate method is 2-propylhexanoic acid, which has the following structure:

[0084]

[0085] Example 10

[0086] Gas chromatography of valproic amide

[0087] The gas chromatography conditions were the same as in Example 1.

[0088] The results of the gas chromatography of the valproic amide control sample are shown in Figure 6. Figure 10

[0089] Peak 6 retention time 36.028 min, RRT = 1.19: valproic amide.

[0090] Example 11

[0091] Gas chromatography of a mixture of valproic acid and valproic amide

[0092] The gas chromatography conditions were the same as in Example 1.

[0093] The results of the gas chromatography of the mixture of valproic acid and valproic amide are shown in Figure 8. Figure 11

[0094] ​​​Peak 6 retention time 35.876 min, RRT = 1.19: valproamide. The peak area of valproamide increased from 0.026% to 0.138%.

[0095] Conclusion: The Figure 1 and the Figure 11 Peak 6 (RRT = 1.19) in Figure 6 is valproamide (F); valproic acid product prepared by the method of methyl cyanoacetate is a major impurity, valproamide, whose structural formula is:

[0096]

[0097] Example 12

[0098] Identification of impurities in valproic acid (xzhd202301) prepared by the method of methyl cyanoacetate by gas chromatography

[0099] The gas chromatography determination conditions are the same as in Example 1.

[0100] Gas chromatography of valproic acid (xzhd202301) prepared by the method of methyl cyanoacetate is shown in Figure Figure 1 , in which the identification of peaks 1-6 is as follows: Gas chromatography of valproic acid (xzhd202301) is shown in Figure Figure 1 , in which peaks 1-6 are valeric acid (A), 2-methyl valeric acid (L), 2-isopropyl valeric acid (C), valproic acid (P), 2-propyl hexanoic acid (X) and valproamide (F), respectively, as shown in the following table:

[0101]

[0102] Example 13

[0103] Identification of impurities in valproic acid (xzhd202302) prepared by the method of methyl cyanoacetate by gas chromatography

[0104] The gas chromatography determination conditions are the same as in Example 1.

[0105] Gas chromatography of valproic acid (xzhd202302) prepared by the method of methyl cyanoacetate is shown in Figure Figure 12 , in which the identification of peaks 1-5 is as follows.

[0106]

[0107] Example 14

[0108] Identification of impurities in valproic acid (xzhd202303) prepared by the method of methyl cyanoacetate by gas chromatography

[0109] The gas chromatography determination conditions are the same as in Example 1.

[0110] Gas chromatography of valproic acid (xzhd202303) prepared by the method of methyl cyanoacetate is shown in FigureFigure 13 The peak assignment of peaks 1-4 is as follows.

[0111]

[0112] Example 15

[0113] Peak assignment of impurities in valproic acid (xzhd202304) prepared by methyl cyanoacetate method by gas chromatography

[0114] The gas chromatography conditions are the same as in Example 1.

[0115] The gas chromatography of valproic acid (xzhd202304) prepared by methyl cyanoacetate method is shown in the attached Figure 14 The peak assignment of peaks 1-4 is as follows.

[0116]

[0117] In the present specification, the present application has been described with reference to particular embodiments thereof. However, it is apparent that various modifications and changes can be made thereto without departing from the spirit and scope of the application. Therefore, the specification is to be considered in all respects as illustrative and not restrictive.

Claims

1. A method for detecting process impurities in the preparation of valproic acid or sodium valproate by the methyl cyanoacetate method, characterized in that The process impurities in valproic acid or sodium valproate prepared by a methyl cyanoacetate method are detected by gas chromatography; the detection conditions of the gas chromatography are as follows: a chromatographic column: DB-FFAP, with a specification of 0.32 mm*60 m, 0.5 μm; a carrier gas: nitrogen; a detector: FID; a flow rate: 2 ml / min; a sample injection volume: 2 μl; a sample injection port temperature: 220 ℃; a column temperature: 100 ℃; a temperature rising program: the initial temperature is 100 ℃, and is kept for 5 min, then is raised to 140 ℃ at a rate of 4 ℃ / min, and is kept for 5 min, then is raised to 200 ℃ at a rate of 4 ℃ / min, and is kept for 15 min; a running time: 50 min; a detector temperature: 220 ℃; a sample injection mode: direct injection; 2 μl of each of the diluent, the reference substance solution and the sample solution are injected into a gas chromatograph, and a chromatogram is recorded; the types and contents of the process impurities in the valproic acid or sodium valproate are determined by comparing with a control sample according to the detection results of the gas chromatography; the process impurities comprise valeric acid shown in formula A, 2-methyl valeric acid shown in formula L, 2-isopropyl valeric acid shown in formula C and valproamide shown in formula F: the specific process for preparing the valproic acid by the methyl cyanoacetate method is as follows: 。

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