Method for simultaneously detecting multiple residual impurities in recovered ethanol

Abstract

The invention provides a method for simultaneously detecting multiple residual impurities in recycled ethanol, belonging to the technical field of impurity analysis methods. The method comprises the following steps: preparing a sample solution of recycled ethanol to be detected and diluting it to obtain a sample solution of recycled ethanol to be detected; using gas chromatography to detect the impurity residues in the sample solution of recycled ethanol to be detected; using an external standard method to calculate the residual amount of multiple residual impurities in the recycled ethanol sample; wherein the multiple residual impurities are a mixture of any several impurities in benzyl alcohol, benzaldehyde, ethyl formate, ethyl acetate, benzyl ethyl ether, isopropanol, and n-propanol or all impurities. The method can directly characterize the residual conditions of multiple impurities in recycled ethanol, and the method is simple and fast.

Description

Technical Field

[0001] The invention belongs to the technical field of impurity analysis methods, and in particular relates to a method for simultaneously detecting multiple residual impurities in recovered ethanol. Background Art

[0002] Ethanol (pharmaceutical excipient grade) is widely used in the production process of API products. Since the large-scale use of ethanol in commercial production causes high production costs and waste of resources for APIs, more and more manufacturers are currently studying and applying for the use of recycled ethanol for commercial production of APIs.

[0003] Drug regulatory agencies in various countries have strict requirements for the use of recycled solvents in production processes. For example, the U.S. FDA requires the following: 1. Quality comparison of fresh ethanol and recycled ethanol; 2. Quality comparison of intermediates or APIs produced using recycled ethanol; 3. Clarification of whether ethanol is recycled internally or on behalf of others; EDQM requirements: 1. In section 3.2.S.2.2, explain from which stage the solvent is recovered, how it is recovered, and in which production stage it is used; 2. Support from finished product analysis data; 3. Provide recycled solvent quality standards in 3.2.S.2.3; 4. Study the effects of the use of recycled solvents on impurities. 5. It is recommended to compare the quality with fresh solvent; China NMPA requirements: three batches of process validation and stability data are required; South Korea stipulates that the following must be provided: 1. Detailed comparison before and after the change; 2. Revised 3.2.S.2; 3. Impurity spectrum research and control strategy after the change; 4. Quality standards and test methods for recovered ethanol, and report on recovered ethanol; 5. Physical and chemical properties after the change (at least three instrument tests such as UV, IR, NMR, Mass, XRD, etc.); 6. Quality consistency data: 3 batches of COA + one batch of original data after the change; comparison of three consecutive batches before and after the change.

[0004] Therefore, the application of recycled ethanol urgently needs to establish its quality standards through the study of impurities in recycled ethanol. At present, the methods for detecting and analyzing volatile impurities in ethanol are included in the 2020 edition of the Chinese Pharmacopoeia, the USP Pharmacopoeia, and the EP Pharmacopoeia, but the types of impurities detected are relatively small, and the recycling of ethanol involves the introduction and enrichment of process impurities, and it is impossible to identify such new impurities. The conventional method for detecting impurities in recycled ethanol only detects a small number of types of impurities in the same method, and the detection and analysis steps are relatively complicated and consume more manpower and material resources. Therefore, it is particularly important to provide a method that can simultaneously detect multiple residual impurities in recycled ethanol, so that it can directly characterize the residual conditions of multiple impurities in recycled ethanol. Summary of the invention

[0005] The invention provides a method for simultaneously detecting multiple residual impurities in recycled ethanol, which can directly characterize the residual conditions of multiple impurities in the recycled ethanol, and the method is simple and rapid.

[0006] In order to achieve the above object, the present invention provides a method for simultaneously detecting multiple residual impurities in recovered ethanol, comprising the following steps:

[0007] Prepare and dilute a recovered ethanol sample solution to be tested to obtain a recovered ethanol sample solution to be tested;

[0008] Using gas chromatography to detect the impurity residues in the recovered ethanol sample liquid to be tested;

[0009] The external standard method was used to calculate the residual amounts of various residual impurities in the recovered ethanol samples;

[0010] The plurality of residual impurities are a mixture of any several of benzyl alcohol, benzaldehyde, ethyl formate, ethyl acetate, benzyl ethyl ether, isopropanol and n-propanol or all of the impurities.

[0011] Preferably, the concentration of recovered ethanol in the recovered ethanol sample solution to be detected is not less than 95% to reduce interference from impurities.

[0012] Preferably, before or after preparing the recovered ethanol sample solution to be tested and diluting it, the method further includes the step of preparing a plurality of residual impurity reference solutions.

[0013] Preferably, the preparation of multiple residual impurity reference solutions is specifically as follows:

[0014] preparing a plurality of stock solutions of residual impurities respectively, and preparing a plurality of intermediate solutions of residual impurities respectively based on the stock solutions, and then preparing a plurality of reference solutions of residual impurities respectively based on the intermediate solutions;

[0015] The concentrations of the reference solutions were benzyl alcohol: 37.125 μL / L, benzaldehyde: 36.938 μL / L, ethyl formate: 37.312 μL / L, ethyl acetate: 37.425 μL / L, benzyl ethyl ether: 35.625 μL / L, isopropanol: 37.425 μL / L, and n-propanol: 37.125 μL / L.

[0016] As a preferred method, the gas chromatography uses a chromatographic column Thermo TG-624SilMS 60m×0.25mm×1.4μm with a 6% cyanopropylphenyl-94% dimethylpolysiloxane stationary phase. This column provides high thermal stability and a maximum temperature of 320°C, which is very suitable for volatile organic compound analysis. This product has high inertness and perfect peak shape, and is suitable for a variety of compounds.

[0017] Preferably, when gas chromatography is used, programmed temperature is used, and the process is as follows:

[0018] Heat to 40℃, hold for 5 min; heat to 80℃ at a heating rate of 5℃ / min, hold for 2 min; heat to 110℃ at a heating rate of 5℃ / min, hold for 5 min; heat to 150℃ at a heating rate of 15℃ / min, hold for 6 min; heat to 240℃ at a heating rate of 30℃ / min, hold for 4 min; heat to 280℃ at a heating rate of 35℃ / min, hold for 1 min.

[0019] Preferably, the detection conditions are as follows:

[0020] The injection volume was 1 μL; the carrier gas was nitrogen; the split ratio was 10:1; the injection port temperature was 250°C; the constant flow rate was 1.0 ml / min; hydrogen: 35 ml / min; air: 350 ml / min; tail gas: 30 ml / min; the detector was FID; the detector temperature was 300°C; and the total running time was 43.81 min.

[0021] Preferably, the residual amount of various residual impurities in the recovered ethanol sample is calculated by the external standard method as follows:

[0022] Content (μL / L) = (C1-C0) × V / m, where:

[0023] m is the amount of the test sample (ml); V is the fixed volume (ml); C1 is the amount in the test solution (μL / L); C0 is the amount in the blank solvent (ethanol) (μL / L).

[0024] Compared with the prior art, the advantages and positive effects of the present invention are:

[0025] 1. The method for simultaneously detecting multiple residual impurities in recovered ethanol provided by the present invention can directly reflect the residual conditions of multiple impurities in recovered ethanol, and the method is simple to operate and easy to analyze;

[0026] 2. The method provided by the present invention can simultaneously carry out impurity determination of multiple batches of recovered ethanol samples, greatly shortening the detection time and preparation time. Compared with traditional methods, this method is fast and efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The reference sample spectrum obtained by gas chromatography detection provided in the embodiment of the present invention. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] Example 1

[0030] 1. Instrument

[0031]

[0032]

[0033] 2. Reagents and test solutions

[0034] Reagent name source purity(%) Benzyl alcohol Maclean 99 Benzaldehyde Maclean 98.5 Ethyl formate Aladdin 99.5 Ethyl acetate Maclean 99.8 Benzyl ethyl ether Maclean 95 Isopropyl alcohol Merck 99.8 n-Propanol Maclean 99.0

[0035] 3. Sample processing

[0036] Preparation of stock solution:

[0037] Benzyl alcohol stock solution (9900 μL / L): Accurately measure 100 μL of benzyl alcohol reference substance in a 10 ml volumetric flask, add ethanol to dilute to the mark, and shake well;

[0038] Benzaldehyde stock solution (9850 μL / L): Accurately measure 100 μL of benzaldehyde reference substance in a 10 ml volumetric flask, add ethanol to dilute to the mark, and shake well;

[0039] Ethyl formate stock solution (9950 μL / L): Accurately measure 100 μL of ethyl formate reference substance in a 10 ml volumetric flask, add ethanol to dilute to the mark, and shake well;

[0040] Ethyl acetate stock solution (9980 μL / L): Accurately measure 100 μL of ethyl acetate reference substance into a 10 ml volumetric flask, add ethanol to dilute to the mark, and shake well;

[0041] Benzyl ether stock solution (9500 μL / L): Accurately measure 100 μL of benzyl ether reference substance in a 10 ml volumetric flask, add ethanol to dilute to the mark, and shake well;

[0042] Isopropanol stock solution (9980 μL / L): Accurately measure 100 μL of isopropanol reference substance in a 10 ml volumetric bottle, add ethanol to dilute to the mark, and shake well. ;

[0043] n-Propanol stock solution (9900 μL / L): Accurately measure 100 μL of n-propanol reference substance, put it in a 10 ml volumetric flask, add ethanol to dilute to the scale, and shake well.

[0044] Preparation of reference intermediate solution:

[0045] Accurately measure 50 μL of benzyl alcohol stock solution, 50 μL of benzaldehyde stock solution, 50 μL of ethyl formate stock solution, 50 μL of ethyl acetate stock solution, 50 μL of benzyl ethyl ether stock solution, 50 μL of isopropanol stock solution, and 50 μL of n-propanol stock solution into a 1 ml volumetric flask, add ethanol to dilute to the scale, shake well, and obtain.

[0046] Among them, the concentrations are: benzyl alcohol 495.000 μL / L, benzaldehyde 492.500 μL / L, ethyl formate 497.500 μL / L, ethyl acetate 499.000 μL / L, benzyl ethyl ether 475.000 μL / L, isopropanol 499.000 μL / L, and n-propanol 495.000 μL / L.

[0047] Preparation of reference solution:

[0048] Accurately measure 75 μL of the intermediate solution of the reference substance into a 1 ml volumetric flask, add ethanol to dilute to the scale, shake well, and obtain.

[0049] Among them, the concentrations are: benzyl alcohol 37.125 μL / L, benzaldehyde 36.938 μL / L, ethyl formate 37.312 μL / L, ethyl acetate 37.425 μL / L, benzyl ethyl ether 35.625 μL / L, isopropanol 37.425 μL / L, and n-propanol 37.125 μL / L.

[0050] Preparation of recovered ethanol sample solution to be tested:

[0051] Accurately measure 0.5 ml of the recovered ethanol sample solution to be tested into a 1 ml volumetric flask, add ethanol to dilute to the scale, shake well, and obtain.

[0052] 4. Detection

[0053] The samples were tested by gas chromatography. The specific temperature program is shown in Table 1, and the test conditions are shown in Table 2.

[0054] Table 1 Temperature program

[0055]

[0056] Table 2 Test conditions

[0057]

[0058]

[0059] The spectrum of the reference substance was obtained by gas chromatography. Figure 1 shown.

[0060] The chromatographic peaks of ethyl formate, isopropanol, n-propanol, ethyl acetate, benzaldehyde, benzyl ethyl ether, and benzyl alcohol all have good separation. The residual amounts of various residual impurities in the recovered ethanol sample were calculated using the external standard method as follows:

[0061] Content (μL / L) = (C1-C0) × V / m, where:

[0062] m is the amount of the test sample (ml); V is the fixed volume (ml); C1 is the amount in the test solution (μL / L); C0 is the amount in the blank solvent (ethanol) (μL / L).

[0063] The RSD of the peak area of ​​the reference solution for 6 consecutive samples was ≤5%, which was significantly better than the conventional standard ≤10.0%, and the repeatability was good; the RSD of the peak area of ​​ethyl formate, isopropanol, n-propanol, ethyl acetate, benzaldehyde, benzyl ethyl ether, and benzyl alcohol for 6 samples were 0.6%, 1.1%, 0.8%, 0.9%, 0.9%, 0.8%, and 0.8%, respectively. After changing the flow rate (1.0±0.1ml / min) and the injection port temperature (250±25℃), the content RSD was ≤5%, which was significantly better than the conventional standard ≤10.0%, and the stability was good. Under the conditions of changing the flow rate, the RSDs of ethyl formate, isopropanol, n-propanol, ethyl acetate, benzaldehyde, benzyl ethyl ether and benzyl alcohol were 1.1%, 1.7%, 1.6%, 1.2%, 1.5%, 1.6% and 1.5%, respectively; under the conditions of changing the injection port temperature, the RSDs of the detected contents were 3.4%, 2.1%, 1.7%, 2.6%, 1.6%, 1.4% and 1.4%, respectively.

[0064] The results show that the method of the present invention has good applicability and can be used to identify various impurity residues in recovered ethanol.

Claims

1. A method for simultaneously detecting and recovering multiple residual impurities in ethanol, characterized in that: The steps include: Prepare a recovered ethanol sample solution to be tested and dilute it to obtain a recovered ethanol sample solution to be tested; Using gas chromatography to detect the impurity residues in the recovered ethanol sample liquid to be tested; The external standard method was used to calculate the residual amounts of various residual impurities in the recovered ethanol samples; Wherein, the plurality of residual impurities are benzyl alcohol, benzaldehyde, ethyl formate, ethyl acetate, benzyl ethyl ether, isopropanol and n-propanol; Among them, the gas chromatography used a chromatographic column Thermo TG-624SilMS 60m×0.25mm×1.4μm with a 6% cyanopropylphenyl-94% dimethylpolysiloxane stationary phase; Gas chromatography uses programmed temperature, the process is: Heat to 40℃, hold for 5min; heat to 80℃ at a heating rate of 5℃ / min, hold for 2min; heat to 110℃ at a heating rate of 5℃ / min, hold for 5min; heat to 150℃ at a heating rate of 15℃ / min, hold for 6min; heat to 240℃ at a heating rate of 30℃ / min, hold for 4min; heat to 280℃ at a heating rate of 35℃ / min, hold for 1min; The gas chromatography detection conditions are: The injection volume was 1µL; the carrier gas was nitrogen; the split ratio was 10:1; the injection port temperature was 250°C; the constant flow rate was 1.0ml / min; hydrogen: 35ml / min; air: 350ml / min; tail gas: 30ml / min; the detector was FID; the detector temperature was 300°C; and the total running time was 43.81min.

2. The method according to claim 1, characterized in that: The concentration of the recovered ethanol in the recovered ethanol sample solution to be detected is not less than 95% to reduce interference from impurities.

3. The method according to claim 1, characterized in that Before or after preparing the recovered ethanol sample solution to be tested and diluting it, the method also includes the step of preparing a plurality of residual impurity reference substance solutions.

4. The method according to claim 3, characterized in that The preparation of various residual impurity reference solutions is as follows: preparing a plurality of stock solutions of residual impurities respectively, and preparing a plurality of intermediate solutions of residual impurities respectively based on the stock solutions, and then preparing a plurality of reference solutions of residual impurities respectively based on the intermediate solutions; The concentrations of the reference solutions were benzyl alcohol: 37.125 μL / L, benzaldehyde: 36.938 μL / L, ethyl formate: 37.312 μL / L, ethyl acetate: 37.425 μL / L, benzyl ethyl ether: 35.625 μL / L, isopropanol: 37.425 μL / L, and n-propanol: 37.125 μL / L.

5. The method according to claim 1, characterized in that The residual amounts of various residual impurities in the recovered ethanol samples were calculated using the external standard method as follows: Content μL / L=(C1-C0)×V / m, where: m is the amount of the test sample, ml; V is the fixed volume, ml; C1 is the amount in the test solution, μL / L; C0 is the amount in the blank solvent, μL / L.

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