CN111351874A

CN111351874A - Method for detecting residual solvent in ibudilast bulk drug

Info

Publication number: CN111351874A
Application number: CN202010180478.2A
Authority: CN
Inventors: 付丙月; 王金虎; 崔新强; 赵思太; 张宁; 吴伟山; 张云; 鲜婧; 张相军
Original assignee: Shandong Academy of Pharmaceutical Sciences
Current assignee: Shandong Academy of Pharmaceutical Sciences
Priority date: 2020-03-16
Filing date: 2020-03-16
Publication date: 2020-06-30

Abstract

The invention relates to a method for detecting residual solvent in ibudilast bulk drug, which adopts a gas chromatography method and specifically comprises the following steps: and detecting six organic solvents of ethanol, dichloromethane, normal hexane, ethyl acetate, tetrahydrofuran and toluene by using a hydrogen Flame Ionization Detector (FID) through temperature programming and a headspace sampling mode according to an external standard method. The method is simple to operate, high in sensitivity and good in accuracy, and is suitable for detecting six 2 solvent residual solvents in the ibudilast bulk drug.

Description

Method for detecting residual solvent in ibudilast bulk drug

Technical Field

The invention relates to a method for detecting residual solvent in ibudilast bulk drug, which adopts gas chromatography to detect the content of ethanol, dichloromethane, normal hexane, ethyl acetate, tetrahydrofuran and toluene in ibudilast according to an external standard method, and belongs to the field of drug analysis and detection.

Technical Field

The residual solvent in the medicine refers to organic volatile compounds which are used in the production of raw material medicines, auxiliary materials and preparations and cannot be completely removed in the process. The research results published by the authorities of world health organization and the like show that many organic solvents have certain harm to the environment and human bodies. When the residual solvent contained in the medicine is higher than a safe value, the stability of the medicine is influenced, and the human body or the surrounding environment is influenced, so that the pharmacopoeias of various countries require to control the residual quantity of the organic solvent or the volatile impurities used in the production process.

Ibudilast (Ibudilast) was developed by the japanese apricot pharmaceutical company and marketed in 1989, is a leukotriene receptor antagonist and phosphodiesterase inhibitor, and belongs to a novel non-hormonal anti-inflammatory drug. The traditional Chinese medicine composition is widely used for treating bronchial asthma, chronic asthmatic bronchitis and cerebrovascular diseases in clinic, can relieve airway smooth muscle spasm of guinea pigs caused by inflammatory mediators, and can inhibit passive skin allergy of experimental animals.

The method accurately measures the content of six residual solvents by using gas chromatography aiming at organic solvents of ethanol, dichloromethane, normal hexane, ethyl acetate, tetrahydrofuran and toluene used in the ibudilast bulk drug synthesis process.

Disclosure of Invention

The invention aims to establish a method for detecting organic residual solvents in ibudilast bulk drug, which can quickly and accurately detect the residual amounts of six organic solvents, namely ethanol, dichloromethane, normal hexane, ethyl acetate, tetrahydrofuran and toluene in ibudilast by using a gas chromatography. The method has the advantages that: 1. the method is universal, high in practicability and simple to operate; 2. has enough sensitivity and good separation degree, and can effectively control the magazines.

The invention provides a method for detecting a residual solvent in an ibudilast bulk drug, which comprises the following steps:

(1) respectively taking a proper amount of each component to be detected, placing the components in the same 100ml volumetric flask, adding DMF solvent, diluting to scale, shaking up, and preparing mixed reference substance solutions with ethanol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran and toluene respectively at 500, 200, 300, 500, 75 and 15 mu g/ml;

(2) accurately weighing 60mg of ibudilast, placing the ibudilast in a 10ml headspace bottle, adding 5ml of DMF, sealing, and shaking up gently to obtain a test solution;

(3) adopting gas chromatography and FID detector, heating, introducing sample at headspace, detecting blank solution, reference solution and sample solution, recording chromatogram, and calculating residual solvent content of ethanol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran and toluene by external standard method.

Further, in the detection method, a polysiloxane capillary chromatographic column is adopted, the initial temperature is 30-40 ℃, the injection port temperature is 180-230 ℃, the detection temperature is 200-260 ℃, the carrier gas is inert gas, the flow rate is 1.0-4.0 ml/min, and the split ratio is 5-20: 1.

furthermore, in the detection method, the chromatographic column is Agilent DB-624(30m × 0.53mm, 3.0 μm), the initial temperature is preferably 30-50 ℃, the optimal value is 35 ℃, the injection port temperature is preferably 200-210 ℃, the optimal value is 200 ℃, the detection temperature is preferably 210-230 ℃, the optimal value is 220 ℃, and the carrier gas is N₂(ii) a The flow rate is preferably 2.0 ml/min-4.0 ml/min, and the optimal value is 3.0 ml/min; the preferable flow dividing ratio is 10-15: 1, the optimal value is 10: 1.

compared with the prior art, the invention has the positive effects that:

1. the gas chromatography condition is suitable for detecting the residual organic solvent of the ibudilast bulk drug, and can quickly and accurately detect the content of 6 residual solvents of ethanol, dichloromethane, normal hexane, ethyl acetate, tetrahydrofuran and toluene.

2. The detection method provided by the invention is accurate, simple and convenient to operate, good in reproducibility and high in sensitivity, can fully meet the requirement of the determination of the residue of the organic solvent in the bulk drug of ibudilast, can better control the product quality and ensure the safety of the drug.

Drawings

FIG. 1 blank solvent gas chromatogram

FIG. 2. gas chromatogram for ethanol system applicability

FIG. 3 gas chromatogram for dichloromethane system applicability

FIG. 4 gas chromatogram for n-hexane system applicability

FIG. 5 gas chromatogram for ethyl acetate system applicability

FIG. 6. gas chromatogram for tetrahydrofuran System applicability

FIG. 7 gas chromatogram for toluene System applicability

FIG. 8 is an adaptive gas chromatogram of a hybrid system of ethanol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran, and toluene

FIG. 9 gas chromatogram for sample System applicability

Detailed Description

Examples

1. Instrument and reagent

The instrument comprises the following steps: agilent 7890A gas chromatograph, detector FID; an Agilent chromatography workstation;

reagent testing: all the reagents are chromatographically pure; ibudilast (homemade).

2. Chromatographic conditions

Chromatographic column Agilent DB-624(30m × 0.53mm, 3.0 μm);

column temperature: keeping the temperature at 35 deg.C for 4min, increasing the temperature to 200 deg.C at 45 deg.C/min, and keeping the temperature for 10 min;

sample inlet temperature: 200 ℃;

detecting the temperature: 220 ℃;

carrier gas: n is a radical of₂And the split ratio: 10: 1;

and (3) sample introduction mode: a headspace sampling method;

the balance time is as follows: 20 min;

equilibrium temperature: 80 ℃.

3. Solution preparation

Preparing a mixed reference substance solution: 250mg of ethanol, 100mg of dichloromethane, 150mg of n-hexane, 250mg of ethyl acetate, 375mg of tetrahydrofuran and 75mg of toluene are precisely weighed respectively, placed in a same 50ml volumetric flask, added with DMF solvent and diluted to the scale, shaken up to serve as a stock solution of a mixed reference substance. Weighing 1ml of mixed reference stock solution, placing in a 100ml volumetric flask, adding DMF solvent, diluting to scale, shaking up, and preparing into mixed reference solution with ethanol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran and toluene respectively at 500, 200, 300, 500, 75 and 15 μ g/ml.

Preparing a test solution: weighing ibudilast 600mg precisely, placing the ibudilast in a 100ml headspace bottle, adding DMF (dimethyl formamide) for diluting to a scale, and shaking up to obtain a test solution.

4. Sample assay

① System suitability test

Precisely measuring 5ml of each peak positioning solution of a blank solvent (DMF), ethanol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran and toluene and a mixed reference solution, and injecting a sample in a headspace.

The blank solvent does not interfere with the organic residual solvent, all components are completely separated, R is more than 1.5, and the retention time and the separation degree of all components are shown in table 1. The original map is shown in FIGS. 1-7.

TABLE 1 measurement results of retention time and resolution of each component

② precision test

The mixed control solution was injected into the headspace continuously for 6 times with RSD within 5%, see table 2.

Table 2 precision test results (n ═ 6)

③ Linear test

Precisely measuring the mixed reference stock solutions 0.1 ml, 0.3 ml, 0.5 ml, 1.0 ml, 1.5 ml and 2.0ml, respectively placing in 100ml volumetric flasks, adding DMF to dilute to scale, shaking up, and making into a series of linear mixed reference solutions with different concentrations. And (3) introducing samples in a headspace, continuously introducing samples of each concentration solution for 2 times, performing linear regression by taking the peak area of a reference substance as a vertical coordinate and the concentrations of the reference substance solutions of ethanol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran and toluene as a horizontal coordinate, and obtaining the measurement result shown in table 3.

TABLE 3 results of the Linear test

④ recovery test

Accurately weighing 6 parts of ibudilast 100mg, respectively adding 5ml of ethanol, dichloromethane, normal hexane, ethyl acetate, tetrahydrofuran and toluene mixed reference stock solutions, adding DMF (dimethyl formamide) to dilute to a scale, shaking up to be used as recovery rate sample solutions, respectively sampling 5ml of headspace, recording a chromatogram, and calculating the recovery rate according to the following formula. The recovery rates that could be saved were between 90% and 110% (100% + -10%), and the results are shown in Table 4.

⑤ detection line and quantitative limit

Calculating a detection line by using the signal-to-noise ratio S/N ═ 5, calculating a quantification limit by using the signal-to-noise ratio S/N ═ 10, sequentially and respectively diluting ethanol, dichloromethane, normal hexane, ethyl acetate, tetrahydrofuran and toluene mixed reference substance stock solutions, taking 5ml of headspace for sample injection, recording a chromatogram, and recording the detection line and the quantification limit measurement result in a table 5.

TABLE 5 measurement results of each component detection line and quantitative limit

⑥ sample testing

Precisely measuring 5ml of each of a test solution and a reference solution under a '3 solution preparation' phase, introducing a sample in a headspace, recording a chromatogram, and calculating according to an external standard method by using a peak area, wherein the content of ethyl acetate is not more than 0.5%, the content of n-hexane is not more than 0.029%, the content of tetrahydrofuran is not more than 0.5%, the content of toluene is not more than 0.089%, the content of ethanol is not more than 0.5%, and the content of dichloromethane is not more than 0.06%.

The organic residual solvent of the sample, ethyl acetate 0%, n-hexane 0%, tetrahydrofuran 0%, toluene 0%, ethanol 0%, and dichloromethane 0% was detected according to the above method.

Claims

1. A method for detecting residual solvents in ibudilast is characterized in that a detection method combining a gas chromatography and an external standard method is adopted, and 6 organic residual solvents of ethyl acetate, n-hexane, tetrahydrofuran, toluene, ethanol and dichloromethane are simultaneously detected.

2. The detection method according to claim 1, wherein the chromatographic column used in the detection method is a polysiloxane capillary chromatographic column.

3. The detection method according to claim 1, wherein the detection method employs a programmed temperature rise.

4. The method of claim 1, wherein the detection method is initiated at a temperature of 20 ℃ to 50 ℃.

5. The detection method according to claim 1, wherein the injection port temperature is 180 ℃ to 230 ℃.

6. The method according to claim 1, wherein the detection temperature is 200 to 260 ℃.

7. The detection method according to claim 1, wherein the carrier gas is an inert gas and has a flow rate of 1.0 to 4.0 ml/min.

8. The detection method according to claim 1, wherein the flow split ratio is 5-20: 1.

9. the detection method according to claim 1, wherein headspace sampling is employed.

10. The detection method according to claim 1, wherein the sample detection step of the detection method is as follows:

the method comprises the following steps: preparing a reference substance solution of the residual solvent to be detected;

step two: preparing a test solution;

step three: detecting blank solution, reference solution and sample solution by gas chromatography, recording spectra, and calculating residual solvent content of ethanol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran and toluene by external standard method.