CN113759048B - Inspection method of mono-tert-butyl octadecanedioate - Google Patents
Inspection method of mono-tert-butyl octadecanedioate Download PDFInfo
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- CN113759048B CN113759048B CN202111196871.1A CN202111196871A CN113759048B CN 113759048 B CN113759048 B CN 113759048B CN 202111196871 A CN202111196871 A CN 202111196871A CN 113759048 B CN113759048 B CN 113759048B
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Abstract
The invention discloses a method for detecting mono-tert-butyl octadecanedioate, which belongs to the technical field of medical raw material detection and comprises the following steps: s1, preparing a test solution and a system adaptability solution; s2, detecting by using a high performance liquid chromatography, wherein the chromatographic conditions comprise: gradient elution is carried out by taking Agilent ZORBAX SB-C18 as a chromatographic column, taking 0.1% phosphoric acid water solution as a mobile phase A and acetonitrile as a mobile phase B, the column temperature is 35 ℃, the flow rate is 1.0mL/min, and the detection wavelength is 210 nm; and S3, calculating the purity of the sample according to an area normalization method, and observing the sizes of known impurities and other unknown impurity substances in the chromatogram. The method for detecting the quality of the finished product can detect the finished product before the raw materials are used, can reduce the preparation cost of the finished product, can be directly replaced if the quality requirements are not met, and reduces the detection and analysis work of the finished product at the later stage.
Description
Technical Field
The invention belongs to the technical field of medical raw material detection, and particularly relates to a method for detecting mono-tert-butyl octadecanedioate.
Background
Octadecanedioic acid mono-tert-butyl ester (CAS number: 843666-40-0) is a preparation raw material of the side chain of the somaglutide. The technical scheme is that a purchased raw material with the main component of octadecanedioic acid mono-tert-butyl ester is detected, whether the purity of the raw material substance is within a quality control standard or not is verified, and the purpose of detecting the purity of the raw material substance is to ensure the synthesis yield of a finished product of the side chain of the later-stage somnautide. If the content of other substances (i.e. impurities) in the raw materials is too high, the synthesis efficiency of the finished product is affected, or the reaction is possibly affected to introduce more impurities in the finished product (other related substances react with other raw materials in the synthesis of the side chain of the somaglutide), the later analysis amount of the finished product is large, the difficulty is high, and the cost is high. For process reasons, raw materials usually comprise impurities such as octadecanedioic acid, tetradecanedioic acid mono-tert-butyl ester, hexadecanedioic acid mono-tert-butyl ester, octadecanedioic acid mono-methyl ester and octadecanedioic acid mono-methyl ester, and the current detection method mainly bases on the general rule of the four departments of the 2015 version of Chinese pharmacopoeia, but no method for separately detecting the octadecanedioic acid mono-tert-butyl ester exists, and the product is a long-chain alkane series, has long retention time in a chromatographic column and is difficult to elute in a proper time; meanwhile, the product has more impurities such as homologues, has similar properties, has equivalent adsorption capacity in a column and is difficult to separate, so the requirements on the elution gradient, the mobile phase proportion and the system of an analysis method are high, the product is difficult to dissolve in a common solvent, the ultraviolet absorption is weak, the requirement on the sensitivity of the method is high, and the requirements on the wavelength setting, the sample preparation concentration and the sample injection quantity are required.
Disclosure of Invention
The invention aims to provide a method for detecting mono-tert-butyl octadecanedioate, which solves the technical problem that no method for separately detecting the mono-tert-butyl octadecanedioate exists in the prior art.
The invention discloses a method for detecting mono-tert-butyl octadecanedioate, which comprises the following steps:
s1, preparing a test solution and a system adaptability solution;
s2, detecting by using a high performance liquid chromatography, wherein the chromatographic conditions comprise: adopting Agilent ZORBAX SB-C18(250mm multiplied by 4.6mm 5 mu m) as a chromatographic column, taking 0.1% phosphoric acid aqueous solution as a mobile phase A, taking acetonitrile as a mobile phase B, carrying out gradient elution, wherein the column temperature is 35 ℃, the flow rate is 1.0mL/min, and the detection wavelength is 210 nm;
and S3, calculating the purity of the sample according to an area normalization method, and observing the sizes of known impurities and other unknown impurity substances in the chromatogram.
Further, in step S1, the sample solution is dissolved in tetrahydrofuran-acetonitrile as a solvent and diluted quantitatively to a solution containing 13-16mg of the sample per 1 ml.
Further, the volume ratio of tetrahydrofuran to acetonitrile is 2: 1.
by setting the tetrahydrofuran-acetonitrile volume ratio, the solvent effect can be avoided while dissolving the product.
Further, the components of the system adaptive solution in step S1 include octadecanedioic acid, tetradecanedioic acid mono-tert-butyl ester, hexadecanedioic acid mono-tert-butyl ester, octadecanedioic acid monomethyl ester, octadecanedioic acid monoethyl ester, and octadecanedioic acid mono-tert-butyl ester.
Further, the weight ratio of octadecanedioic acid, tetradecanedioic acid mono-tert-butyl ester, hexadecanedioic acid mono-tert-butyl ester, octadecanedioic acid monomethyl ester, octadecanedioic acid monoethyl ester and octadecanedioic acid mono-tert-butyl ester in the system adaptability solution is 30: 3: 6: 6: 6: 40.
further, the preparation of the system adaptability solution comprises the following steps of respectively taking octadecanedioic acid, tetradecanedioic acid mono-tert-butyl ester, hexadecanedioic acid mono-tert-butyl ester, octadecanedioic acid monomethyl ester and octadecanedioic acid monoethyl ester reference substances, and then respectively dissolving and quantitatively diluting the reference substances by using a diluent until 1.5mg of the first reference substance solution, the second reference substance solution, the third reference substance solution, the fourth reference substance solution and the fifth reference substance solution are contained in each 1 ml;
dissolving a octadecanedioic acid mono-tert-butyl ester reference substance by using a diluent, and quantitatively diluting until each 1ml of the reference substance contains a sixth reference substance solution of 2 mg;
and mixing and diluting the first reference substance solution, the second reference substance solution, the third reference substance solution, the fourth reference substance solution, the fifth reference substance solution and the sixth reference substance solution according to the weight ratio.
Further, in the step S2, the gradient elution procedure is that at 0 minute, the mobile phase a is 40% and the mobile phase B is 60%; by 30 minutes, mobile phase a was 10% and mobile phase B was 90%; by 50 minutes, mobile phase a was 10% and mobile phase B was 90%; by 51 minutes, mobile phase a was 40% and mobile phase B was 60%; by 60 minutes, mobile phase a was 40% and mobile phase B was 60%.
Further, the separation degree between the main peak of the system adaptive solution and each impurity should be not less than 1.5.
The invention has the beneficial effects that:
1. the method for detecting the yield of the finished product can be used for detecting the raw materials before the raw materials are used, can reduce the preparation cost of the finished product, can be directly replaced if the raw materials do not meet the quality requirement, is favorable for ensuring the yield of the finished product, and reduces the later detection and analysis work of the finished product.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a liquid chromatogram of example 1 of the present invention;
FIG. 2 is a liquid chromatogram of comparative example 1 of the present invention;
FIG. 3 is a liquid chromatogram of comparative example 2 of the present invention.
Detailed Description
In addition, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Example 1
S1, taking about 300mg of the sample, placing the sample in a 20ml volumetric flask, dissolving the sample by taking tetrahydrofuran-acetonitrile (2: 1) as a solvent, and quantitatively diluting the solution until the solution contains about 15mg of the sample in each 1 ml.
Preparation of system adaptive solution:
about 15mg of reference substances of octadecanedioic acid (impurity A), tetradecanedioic acid mono-tert-butyl ester (impurity B), hexadecanedioic acid mono-tert-butyl ester (impurity C), octadecanedioic acid monomethyl ester (impurity D) and octadecanedioic acid monoethyl ester (impurity E) are respectively taken, precisely weighed, placed in a 10ml volumetric flask, dissolved by a diluent (tetrahydrofuran-acetonitrile volume ratio 2: 1), dissolved by the diluent and quantitatively diluted to a solution containing about 1.5mg per 1ml as a first reference substance solution, a second reference substance solution, a third reference substance solution, a fourth reference substance solution and a fifth reference substance solution.
20mg of a reference substance of mono-tert-butyl octadecanedioate was precisely weighed, placed in a 10ml volumetric flask, dissolved with a diluent and quantitatively diluted to a solution containing about 2mg per 1ml, as a sixth reference substance solution.
Precisely transferring 5ml of each of the first reference substance solution and the sixth reference substance solution, 0.5ml of each of the second reference substance solution, the third reference substance solution, the fourth reference substance solution and the fifth reference substance solution, 1ml of each of the first reference substance solution and the sixth reference substance solution into a 50ml volumetric flask, adding a diluent to a constant volume to scale, and shaking up to obtain a system adaptability solution.
S2, taking 0.1% phosphoric acid water solution as a mobile phase A (precisely measuring 1ml phosphoric acid into a volumetric flask of 1000ml, adding water to a constant volume, shaking up, and precisely filtering with a 0.45 mu m microporous filter membrane), and taking acetonitrile as a mobile phase B. The gradient elution procedure was, at 0 min, 40% for mobile phase a and 60% for mobile phase B; by 30 minutes, mobile phase a was 10% and mobile phase B was 90%; by 50 minutes, mobile phase a was 10% and mobile phase B was 90%; by 51 minutes, mobile phase a was 40% and mobile phase B was 60%; by 60 minutes, mobile phase a was 40% and mobile phase B was 60%; the column temperature was 35 ℃, the flow rate was 1.0mL/min, the detection wavelength was 210nm, and Agilent ZORBAX SB-C18(250 mm. times.4.6 mm 5 μm) was used as a chromatographic column, and the sample volume of the sample solution was 10. mu.L.
And taking the system adaptability solution to perform a system adaptability test.
The mobile phase equilibration system was used until a stable baseline was observed, then injected in the sequence of the table below.
| Serial number | Sample name | Number of samples taken | Investigation item |
| 1 | Blank space | At least 1 needle | —— |
| 2 | System adaptive solution | 1 | Degree of separation |
| 3 | Test solution | 1 | Related substances and purities |
System adaptability requirements: the separation degree between the main peak and each impurity should be not less than 1.5 (required by Chinese pharmacopoeia).
S3, observing a chromatogram, and calculating the purity of the product according to an area normalization method, wherein the purity of the octadecanedioic acid mono-tert-butyl ester is 99.55 percent, the content of total impurities is not more than 2.0 percent, and the raw material control requirement is met. Wherein the content of octadecanedioic acid is 0.26 percent, the content of octadecanedioic acid monomethyl ester is 0.02 percent, the content of octadecanedioic acid monoethyl ester is 0.04 percent, and the content of the other unknown impurities is not more than 0.50 percent.
The detection is carried out before the raw materials are used, firstly, the preparation cost of finished products is reduced, if the raw materials do not meet the quality requirement, the finished products can be directly replaced, secondly, the yield of the finished products is ensured, and thirdly, the detection and analysis work at the later stage of the finished products is reduced.
Comparative example 1
The only change on the basis of example 1 is the column temperature: 30 ℃, sample introduction: 20 μ L, mobile phase A: 0.05% TFA and elution procedure as shown in Table 1.
Table 1 comparative example 1 elution procedure
And (4) conclusion: the peak area is small, the base line is uneven, and the peak-off time is late.
Comparative example 2
The only change on the basis of example 1 is that the mobile phase a: 0.05% phosphoric acid, elution program as shown in table 2.
Table 2 comparative example 2 elution procedure
And (4) conclusion: the decrease in the phosphoric acid content in the mobile phase was 0.05%, and the tailing of the main peak was more serious than the decrease in the phosphoric acid content in the mobile phase at 0.1%.
Claims (9)
1. An inspection method of mono-tert-butyl octadecanedioate is characterized by comprising the following steps:
s1, preparing a test sample solution and a system adaptability solution, wherein the test sample is a raw material of which the main component is octadecanedioic acid mono-tert-butyl ester;
s2, detecting by using a high performance liquid chromatography, wherein the chromatographic conditions comprise: gradient elution is carried out by adopting Agilent ZORBAX SB-C18, 250mm multiplied by 4.6mm and 5 mu m as a chromatographic column and taking 0.1% phosphoric acid water solution as a mobile phase A and acetonitrile as a mobile phase B, wherein the mobile phase A is 40% and the mobile phase B is 60% at 0 minute; by 30 minutes, mobile phase a was 10% and mobile phase B was 90%; by 50 minutes, the mobile phase A is 10% and the mobile phase B is 90%; by 51 minutes, mobile phase a was 40% and mobile phase B was 60%; when the time is 60 minutes, the mobile phase A is 40 percent, the mobile phase B is 60 percent, the column temperature is 35 ℃, the flow rate is 1.0mL/min, and the detection wavelength is 210 nm;
and S3, calculating the purity of the sample according to an area normalization method, and observing the sizes of known impurities and other unknown impurity substances in the chromatogram.
2. The method for testing mono-tert-butyl octadecanedioate according to claim 1, wherein the sample solution in step S1 uses tetrahydrofuran-acetonitrile as solvent, dissolves the sample, and quantitatively dilutes to a solution containing 13-16mg of sample per 1 ml.
3. The method for testing mono-tert-butyl octadecanedioate of claim 2, wherein the sample is diluted quantitatively to a solution containing 15mg of sample per 1 ml.
4. The method for detecting mono-tert-butyl octadecanedioate according to claim 2, wherein the volume ratio of tetrahydrofuran to acetonitrile is 2: 1.
5. the method for testing mono-tert-butyl octadecanedioate according to claim 1, wherein the components of the system adaptability solution in step S1 comprise octadecanedioic acid, tetradecanedioic acid mono-tert-butyl ester, hexadecanedioic acid mono-tert-butyl ester, octadecanedioic acid monomethyl ester, octadecanedioic acid monoethyl ester and octadecanedioic acid mono-tert-butyl ester.
6. The method for testing mono-tert-butyl octadecanedioate according to claim 5, wherein the weight ratio of octadecanedioic acid, tetradecanedioic acid mono-tert-butyl ester, hexadecanedioic acid mono-tert-butyl ester, octadecanedioic acid monomethyl ester, octadecanedioic acid monoethyl ester and octadecanedioic acid mono-tert-butyl ester in the system adaptability solution is 30: 3: 6: 6: 6: 40.
7. the method for testing the mono-tert-butyl octadecanedioate according to claim 6, wherein the preparation of the system adaptability solution comprises the steps of taking the octadecanedioic acid, the mono-tert-butyl tetradecanedioate, the mono-tert-butyl hexadecanedioate, the monomethyl octadecanedioate and the monoethyl octadecanedioate control respectively, and then dissolving and quantitatively diluting the samples respectively with a diluent until 1.5mg of the first control solution, the second control solution, the third control solution, the fourth control solution and the fifth control solution is contained in each 1 ml;
dissolving a octadecanedioic acid mono-tert-butyl ester reference substance by using a diluent, and quantitatively diluting until each 1ml of the reference substance contains a sixth reference substance solution of 2 mg;
and mixing and diluting the first reference substance solution, the second reference substance solution, the third reference substance solution, the fourth reference substance solution, the fifth reference substance solution and the sixth reference substance solution according to the weight ratio.
8. The method for detecting mono-tert-butyl octadecanedioate according to claim 1, wherein the degree of separation between the main peak of the adaptive solution and each impurity is not less than 1.5.
9. Use of an assay according to any one of claims 1 to 8 for the detection of mono-tert-butyl octadecanedioate.
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