CN113049699A - Method for detecting biphenyl anhydride and related substances thereof and application - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting biphenyl anhydride and related substances thereof and application thereof, wherein the method comprises the following steps: adding a derivatization reagent to perform derivatization on the to-be-detected biphenyl anhydride to prepare a test solution; respectively derivatizing a biphenyl anhydride reference substance and a related substance reference substance thereof by using the derivatization reagent to prepare a reference substance solution, wherein the related substance is biphenyldioic acid; and (3) carrying out high performance liquid chromatography analysis on the test solution and the reference solution, wherein the detection conditions are as follows: the chromatographic column is a C18 chromatographic column; the mobile phase A is 0.01-0.03% (V/V) acetic acid solution, and the mobile phase B is acetonitrile; the flow rate is 0.9-1.1 mL/min; the elution mode is gradient elution. The detection method provided by the invention is accurate, has strong specificity and good separation effect, and can effectively control the quality of the biphenyl anhydride.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting biphenyl anhydride and related substances thereof and application thereof.
Background
Bicyclol (Bicyclol) is the first innovative anti-hepatitis medicine with independent intellectual property rights in China. The Ministry of health approved bicyclol to enter clinical trials in 1996, 12 months, and 2001 acquired new drug certificates issued by the State food and drug administration, acquired production batch of bicyclol issued by CFDA, and produced and marketed by Beijing collaborators and pharmaceutical factories.
The bicyclol is white or off-white crystalline powder, is odorless and tasteless, is easily soluble in chloroform and acetone, is soluble in acetonitrile, is slightly soluble in ethyl acetate, is slightly soluble in ethanol, is insoluble in water and has a trade name of penciclovir and a structural formula:
the synthesis method disclosed in patent CN1275961C uses biphenyldicarboxylate as an initial material, and obtains biphenyldicarboxylic acid through hydrolysis; then refluxing, dehydrating and ring closing are carried out under the condition that acetic anhydride is used as a solvent to obtain the biphenyl anhydride; then, the biphenyl alcohol acid is prepared by potassium borohydride reduction, and finally, the bicyclol is prepared by nitroso-methyl urea methylation, wherein the synthetic route is as follows:
the biphenyl anhydride is an important intermediate for synthesizing the bicyclol, and the quality control effect of the biphenyl anhydride directly influences the yield and the quality of the final bicyclol finished product. In the process for synthesizing the biphenyl anhydride, various impurities such as the biphenyl dicarboxylic acid are possibly generated, the biphenyl anhydride has active chemical properties, the biphenyl dicarboxylic acid is particularly generated when meeting water, the high performance liquid chromatography detection is difficult and can not be directly carried out, and the real content of the biphenyl anhydride can not be accurately detected by adopting a conventional detection method. Therefore, in order to control the quality of the biphenyl anhydride, it is necessary to measure the biphenyl dicarboxylic acid which is the biphenyl anhydride and the related substances thereof, but the literature has not described an analytical detection method for the biphenyl anhydride and the related substances thereof so far, so that establishing a detection method which is accurate, has strong specificity and has good separation effect has important significance in the quality control of the biphenyl anhydride.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a method for detecting biphenyl anhydride and related substances thereof and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a method for detecting biphenyl anhydride and related substances thereof, wherein the method for detecting biphenyl anhydride and related substances thereof adopts high performance liquid chromatography, and the method for detecting biphenyl anhydride and related substances thereof comprises the following steps:
preparing a test solution:
and (3) adding a derivatization reagent to derivatize the to-be-detected biphenyl anhydride to prepare a test solution, wherein the chemical structural formula of the biphenyl anhydride is shown as a formula II:
preparation of control solutions:
respectively derivatizing a biphenyl anhydride reference substance and a related substance reference substance thereof by using the derivatization reagent to prepare a reference substance solution, wherein the related substance is biphenyldioic acid, and the chemical structural formula of the biphenyldioic acid is shown as a formula I:
and (3) carrying out high performance liquid chromatography analysis on the test solution and the reference solution, wherein the detection conditions are as follows:
the chromatographic column is a C18 chromatographic column;
the mobile phase A is 0.01-0.03% (V/V) acetic acid solution, and the mobile phase B is acetonitrile;
the flow rate is 0.9-1.1 mL/min;
the elution mode is gradient elution.
Preferably, the derivatizing agent is di-n-butylamine, diethylamine or dimethylamine; the chromatographic column is an Agilent ZORBAX Eclipse Plus C18 chromatographic column or an Asahi Ultimate XB-C18 liquid chromatographic column; the high performance liquid chromatography adopts an ultraviolet detector for detection, and the detection wavelength is 220 nm-240 nm; the column temperature is 35-45 ℃.
Preferably in any of the above schemes, the chromatography column further comprises a capture column, which is a Welch Ghost-Buster capture column.
Preferably, in any of the above schemes, the gradient elution is specifically:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (70-90) to (10-30) to (40-50) to (50-60) at a constant speed;
the volume ratio of the mobile phase A to the mobile phase B is kept constant within 15-35 minutes, wherein the volume ratio of the mobile phase A to the mobile phase B is (40-50) to (50-60);
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (40-50) to (50-60) to (70-90) to (10-30) at a constant speed;
and the volume ratio of the mobile phase A to the mobile phase B is kept constant within 36-45 minutes at (70-90) to (10-30).
Preferably, in any of the above schemes, the gradient elution is specifically:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 80: 20 to 45: 55 at a constant speed:
the volume ratio of the mobile phase A to the mobile phase B is kept constant at 45: 55 within 15-35 minutes;
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 45: 55 to 80: 20 at a constant speed;
and the volume ratio of the mobile phase A to the mobile phase B is kept constant at 80: 20 within 36-45 minutes.
In any of the above schemes, preferably, in the step of preparing the test solution, the molar ratio of the derivatization reagent to the to-be-tested biphenyl anhydride is (5-30): 1; the derivatization time is 10 min-60 min.
In any of the above embodiments, preferably, in the step of performing high performance liquid chromatography on the test solution and the control solution, the sample injection volume is 5 μ L to 15 μ L.
Preferably, in any of the above embodiments, the preparing the test solution comprises the following steps:
dissolving the to-be-detected biphenyl anhydride by using acetonitrile, adding the derivatization reagent for derivatization to prepare a test solution in which 0.4-0.6 mg of the to-be-detected biphenyl anhydride is added per 1 mL.
Preferably, in any of the above embodiments, the preparing the control solution comprises the following steps:
dissolving the biphenyl anhydride reference substance by using acetonitrile, adding the derivatization reagent for derivatization to prepare a reference substance solution which is added with the biphenyl anhydride reference substance by 0.4-0.6 mu g per 1 mL;
and dissolving the related substance reference substance by using acetonitrile, adding the derivatization reagent for derivatization to prepare a reference substance solution which is added with 4-6 mu g of the related substance reference substance per 1 mL.
The detection method provided by the invention can indirectly detect the content and composition of the biphenyl anhydride by using the derivatization reagent to the biphenyl anhydride derivative obtained after the derivatization of the biphenyl anhydride, can well separate the biphenyl anhydride derivative from each impurity, has the advantages of accuracy, strong specificity, good separation effect and good repeatability, can truly and effectively reflect the content of the biphenyl anhydride and related substances thereof, can effectively control the quality of the biphenyl anhydride, and provides effective guarantee for the quality of the final product, namely the bicyclol.
In a second aspect, the invention provides an application of the method for detecting the biphenyl anhydride and the related substances thereof in content detection of the biphenyl anhydride and the related substances thereof.
Drawings
FIG. 1 is a high performance liquid chromatogram obtained by detecting a blank solvent according to the method provided in example 2 of the present invention;
FIG. 2 is a high performance liquid chromatogram obtained by detecting a biphenyldicarboxylic acid positioning solution as an impurity by the method provided in embodiment 2 of the present invention;
FIG. 3 is a table of peaks of a high performance liquid chromatogram of the impurity biphenyldicarboxylic acid positioning solution in FIG. 2;
FIG. 4 is a high performance liquid chromatogram obtained by detecting a test solution according to the method provided in embodiment 2 of the present invention;
FIG. 5 is a table of peaks of the HPLC chromatogram of the sample solution shown in FIG. 4;
FIG. 6 is a standard curve graph of concentration-peak area of biphenyl anhydride in example 5 of the present invention;
FIG. 7 is a graph showing a standard curve of concentration-peak area of biphenyldicarboxylic acid in example 5 of the present invention;
FIG. 8 is a high performance liquid chromatogram obtained by detecting a test sample solution according to the method of comparative example 2 of the present invention;
FIG. 9 is a peak table of the HPLC chromatogram of the sample solution shown in FIG. 8.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental reagents used in the following examples, unless otherwise specified, are either commercially available or can be prepared according to conventional methods in the art; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
In a first aspect, an embodiment of the present invention provides a method for detecting phthalic anhydride and related substances thereof, where the method is characterized by using a high performance liquid chromatography, and the method includes the following steps:
(1) preparing a test solution:
and (3) adding a derivatization reagent to derivatize the to-be-detected biphenyl anhydride to prepare a test solution, wherein the chemical structural formula of the biphenyl anhydride is shown as a formula II:
(2) preparation of control solutions:
respectively derivatizing a biphenyl anhydride reference substance and a related substance reference substance thereof by using the derivatization reagent to prepare a reference substance solution, wherein the related substance is biphenyldioic acid, and the chemical structural formula of the biphenyldioic acid is shown as a formula I:
(3) and (3) carrying out high performance liquid chromatography analysis on the test solution and the reference solution, wherein the detection conditions are as follows:
the chromatographic column is a C18 chromatographic column;
the mobile phase A is 0.01-0.03% (V/V) acetic acid solution, and the mobile phase B is acetonitrile;
the flow rate is 0.9-1.1 mL/min (for example, the flow rate can be 0.9mL/min, 1mL/min or 1.1 mL/min);
the elution mode is gradient elution.
According to the embodiment of the invention, the biphenyl anhydride to be detected is subjected to high performance liquid chromatography detection analysis, and the content of the biphenyl anhydride and related substances in the biphenyl anhydride to be detected is determined based on a high performance liquid chromatography detection result, wherein the biphenyl anhydride to be detected is subjected to derivatization treatment in advance, and the derivatization treatment is carried out in the following way: and reacting the to-be-detected biphenyl anhydride with the derivatization reagent so as to obtain the to-be-detected biphenyl anhydride derivative. The biphenyl anhydride is active in chemical property, particularly can generate biphenyl diacid when meeting water, and the biphenyl anhydride derivative with stable chemical property is obtained after the derivatization treatment is carried out on the biphenyl anhydride to be detected, so that the high performance liquid chromatography detection is carried out. The reaction conditions are not particularly limited, and a conventional method in the prior art may be employed.
The mobile phase A is 0.01-0.03% (V/V) acetic acid solution, for example, the volume fraction of acetic acid in the acetic acid solution can be 0.01%, 0.02% or 0.03%, if the concentration of acetic acid is too low, the buffering capacity is not enough, and if the concentration of acetic acid is too high, the pH is reduced, the peak-off time is later, and the detection time is increased.
The mobile phase B is acetonitrile, the acetonitrile elution capability is strong, the peak emergence time of the derivatives of the biphenyl anhydride and related substances thereof is short, the detection time can be shortened, the methanol elution capability is weak, and if the acetonitrile is replaced by the methanol, the peak emergence time can be prolonged, so that the detection time is increased.
The detection method provided by the embodiment of the invention can indirectly detect the content and composition of the to-be-detected biphenyl anhydride by using the derivatization reagent for the biphenyl anhydride derivative obtained after the derivatization of the biphenyl anhydride, and based on a high performance liquid chromatography detection result, the peak areas corresponding to the biphenyl anhydride derivative and the biphenyl diacid are respectively determined, so that the content of the biphenyl anhydride and the biphenyl diacid is respectively determined.
Furthermore, the derivatization reagent is di-n-butylamine, diethylamine or dimethylamine, when the derivatization reagent is selected, the derivatization reagent is convenient and easy to obtain, good in universality, not harsh in reaction conditions and capable of being rapidly and quantitatively carried out, only one derivative is generated for a target substance, and reaction byproducts (including excessive derivatization reagent) do not interfere with separation and detection of the target substance. Therefore, in this embodiment, di-n-butylamine, diethylamine or dimethylamine are selected as the derivatizing agent, and in order to improve the separation degree of the biphenyl anhydride derivative from other components, the derivatizing agent is preferably di-n-butylamine, and the reaction route of the di-n-butylamine and the biphenyl anhydride is as follows:
further, the chromatographic column is an Agilent ZORBAX Eclipse Plus C18 chromatographic column or an Asahi Ultimate XB-C18 liquid chromatographic column, which has an important influence on the detection of the biphenyl anhydride and related substances, if the chromatographic column (e.g. Diamonsil C18(2) chromatographic column (4.6 mm. times.250 mm, 5 μm)) is not suitable, the separation effect of the biphenyl anhydride derivative from other components is not ideal or the peak shape obtained is not ideal, and in order to further improve the separation effect of the biphenyl anhydride derivative from other components and make the peak shape of the resulting chromatogram good, preferably, the chromatographic column is an Agilent ZORBAX Eclipse Plus C18 chromatographic column.
Further, the hplc analysis uses an ultraviolet detector for detection, and the detection wavelength is 220nm to 240nm, for example, the detection wavelength may be 220nm, 222nm, 224nm, 226nm, 228nm, 230nm, 235nm, 240nm, etc., preferably, the detection wavelength is 228nm, and the derivatized biphenyl anhydride has maximum absorption near the wavelength of 228nm, so that the detection wavelength of the ultraviolet detector is set to be between 220nm and 240nm, which can further improve the detection accuracy.
Further, the column temperature is 35 ℃ to 45 ℃ such as 35 ℃, 37 ℃, 39 ℃, 40 ℃, 42 ℃ or 45 ℃ and the like, and the separation process is accelerated by the increase of the column temperature, but the trouble of the detection work is increased because the sample retention time is unstable, and when the column temperature is decreased, the viscosity of the mobile phase is increased, the separation process time is lengthened, and the detection time is prolonged, preferably, the column temperature is 40 ℃.
Furthermore, the chromatographic column also comprises a small trapping column, wherein the small trapping column is a Welch Ghost-Buster small trapping column, and the small trapping column adsorbs impurities in the mobile phase, so that Ghost peaks are avoided, and the impurities in the mobile phase can be prevented from interfering the detection of the phthalic anhydride.
Further, the gradient elution is specifically:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (70-90) to (10-30) to (40-50) to (50-60) at a constant speed;
the volume ratio of the mobile phase A to the mobile phase B is kept constant within 15-35 minutes, wherein the volume ratio of the mobile phase A to the mobile phase B is (40-50) to (50-60);
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (40-50) to (50-60) to (70-90) to (10-30) at a constant speed;
and the volume ratio of the mobile phase A to the mobile phase B is kept constant within 36-45 minutes at (70-90) to (10-30).
By adopting the gradient elution method provided by the embodiment of the invention, the obtained chromatogram has sharp peak shape and reasonable peak appearance time, and the optimal separation effect between the main peak and each impurity can be achieved.
Further, the gradient elution is specifically:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (72-88) to (12-28) to (42-48) to (52-58) at a constant speed;
the volume ratio of the mobile phase A to the mobile phase B is kept constant within 15-35 minutes at (42-48) to (52-58);
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (42-48) to (52-58) to (72-88) to (12-28) at a constant speed;
the volume ratio of the mobile phase A to the mobile phase B is kept constant within 36-45 minutes, wherein the volume ratio of the mobile phase A to the mobile phase B is (72-88) to (12-28).
Further, the gradient elution is specifically:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (76-84) to (16-24) to (44-46) to (54-56) at a constant speed;
the volume ratio of the mobile phase A to the mobile phase B is kept constant within 15-35 minutes at (44-46): (54-56);
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (44-46) to (54-56) to (76-84) to (16-24) at a constant speed;
the volume ratio of the mobile phase A to the mobile phase B is kept constant within 36-45 minutes at (76-84) to (16-24).
Further, the gradient elution is specifically:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 80: 20 to 45: 55 at a constant speed:
the volume ratio of the mobile phase A to the mobile phase B is kept constant at 45: 55 within 15-35 minutes;
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 45: 55 to 80: 20 at a constant speed;
and the volume ratio of the mobile phase A to the mobile phase B is kept constant at 80: 20 within 36-45 minutes.
Further, in the step of preparing the test solution, the molar ratio of the derivatization reagent to the to-be-tested biphenyl anhydride is (5-30): for example, the molar ratio of derivatizing agent to biphenyl anhydride can be 5:1, 7:1, 9:1, 10:1, 12:1, 14:1, 20:1, 25:1, or 30:1, etc.
Further, in the step of preparing the test solution, the derivatization time is 10min to 60min, for example, the derivatization time may be 10min, 15min, 20min, 25min, 30min, 40min, 50min, 60min, or the like, and preferably, the derivatization time is 10 min.
Further, in the step of preparing a test solution, the derivatization temperature is 25 ℃.
Further, in the step of subjecting the test solution and the control solution to high performance liquid chromatography, the sample injection volume is 5 μ L to 15 μ L, for example, the sample injection volume may be 5 μ L, 7 μ L, 9 μ L, 11 μ L, 13 μ L, or 15 μ L, and preferably 5 μ L in order to satisfy the sensitivity requirement and optimize the peak shape.
Further, the preparation of the test solution comprises the following steps:
dissolving the to-be-detected biphenyl anhydride by using acetonitrile, adding the derivatization reagent for derivatization to prepare a test solution in which 0.4-0.6 mg of the biphenyl anhydride is added per 1 mL.
Further, the preparation of the control solution comprises the following steps:
dissolving the biphenyl anhydride reference substance by using acetonitrile, adding the derivatization reagent for derivatization to prepare a reference substance solution which is added with the biphenyl anhydride reference substance by 0.4-0.6 mu g per 1 mL;
and dissolving the related substance reference substance by using acetonitrile, adding the derivatization reagent for derivatization to prepare a reference substance solution which is added with 4-6 mu g of the related substance reference substance per 1 mL.
Further, the detection method further comprises obtaining a standard curve, wherein the standard curve is obtained by the following steps: (1) the concentrations of the biphenyl dicarboxylic acid control samples are 10 mug/mL, 7.5 mug/mL, 6 mug/mL, 5 mug/mL, 4 mug/mL, 2.5 mug/mL and 1 mug/mL, the concentrations of the biphenyl dicarboxylic acid control samples are 1 mug/mL, 0.75 mug/mL, 0.6 mug/mL, 0.5 mug/mL, 0.4 mug/mL, 0.25 mug/mL and 0.1 mug/mL, and (2) the peak area is used as the ordinate, and the concentration is used as the abscissa to draw a standard curve. And (3) detecting peak areas corresponding to the unknown monoimpurity and the biphenyldioic acid in the to-be-detected biphenyl anhydride by using the standard curve, thereby obtaining the content of the unknown monoimpurity (according to a main component self-contrast method) and the content of the biphenyldioic acid in the to-be-detected biphenyl anhydride.
In a second aspect, the embodiment of the present invention provides an application of the method for detecting biphenyl anhydride and related substances thereof according to the first aspect in detecting the content of biphenyl anhydride and related substances thereof.
According to the method for detecting the biphenyl anhydride and the related substances thereof, the biphenyl anhydride and the related substances thereof can be effectively separated, the content of the biphenyl anhydride and the related substances thereof can be rapidly determined when the content of the biphenyl anhydride is detected, the reproducibility is good, and the method has important significance for effectively controlling the quality of the biphenyl anhydride.
The controls referred to in the following examples:
biphenyl anhydride control: the purity is 98.95%;
biphenyldioic acid control: the purity was 99.95%.
In the following examples, the apparatus used is as follows:
high performance liquid chromatograph: shimadzu HPLC-2030 (ultraviolet detector);
analytical balance: sartorius CPA 225D.
Example 1 derivatization reagent dosage and derivatization time considerations
Chromatographic conditions are as follows: the column was an Agilent ZORBAX Eclipse Plus C18 column (4.6 mm. times.250 mm, 5 μm); the trap column was Welch Ghost-Buster (4.6 mm. times.50 mm, 5 μm); the mobile phase A is 0.022% (V/V) acetic acid solution; the mobile phase B is acetonitrile; the column temperature was 40 ℃; the flow rate is 1.0 mL/min; the detection wavelength is 228 nm; the sample injection volume is 5 mu L;
gradient elution procedure
| Time (minutes) | Mobile phase A (V/V) | Mobile phase B (V/V) |
| 0 | 80 | 20 |
| 15 | 45 | 55 |
| 35 | 45 | 55 |
| 36 | 80 | 20 |
| 45 | 80 | 20 |
The experimental steps are as follows:
(1) preparing a test solution:
weighing about 100mg (0.27mmol) of the to-be-detected biphenyl anhydride respectively, placing the to-be-detected biphenyl anhydride into 4 different 20mL measuring bottles, precisely adding 1.6mL of acetonitrile respectively for dissolving, then adding 227 [ mu ] L (174mg, 1.35mmol) of di-n-butylamine, 454 [ mu ] L (348mg, 2.7mmol), 908 [ mu ] L (696mg, 5.4mmol) and 1362 [ mu ] L (1044mg, 8.1mmol) respectively for dissolving, performing ultrasonic treatment for 10 minutes, cooling to room temperature, then diluting with acetonitrile respectively to a scale, shaking up to obtain a sample stock solution, precisely measuring 1mL of the sample stock solution respectively, placing the sample stock solution into 4 different 10mL measuring bottles, diluting with acetonitrile respectively to a scale, shaking up to obtain the sample solution.
(2) Preparing an impurity biphenyldicarboxylic acid positioning solution:
weighing about 10mg of a biphenyldicarboxylic acid reference substance, placing the biphenyldicarboxylic acid reference substance into a 10mL measuring flask, precisely adding 0.8mL of acetonitrile and 114 mu L of di-n-butylamine to dissolve, carrying out ultrasonic treatment for 10 minutes, taking out, cooling to room temperature, diluting to a scale with acetonitrile, and shaking up to obtain an impurity biphenyldicarboxylic acid stock solution; an appropriate amount of the impurity biphenyldicarboxylic acid stock solution is precisely measured and quantitatively diluted into a solution with the concentration of the biphenyldicarboxylic acid of 5 mu g/mL by using acetonitrile.
(3) Preparing a blank solvent:
precisely measuring acetonitrile 1.6mL, placing in a 20mL measuring flask, precisely adding 227 μ L of di-n-butylamine, diluting with acetonitrile to scale, shaking uniformly to obtain stock solution, precisely measuring stock solution 1mL, placing in a 10mL measuring flask, diluting with acetonitrile to scale, and shaking uniformly to obtain the final product.
(4) Respectively taking 5 mu L of each of the test solution, the impurity biphenyldicarboxylic acid positioning solution and the blank solvent, respectively injecting the test solution, the impurity biphenyldicarboxylic acid positioning solution and the blank solvent into a high performance liquid chromatograph according to the chromatographic conditions, carrying out high performance liquid chromatography analysis, calculating the content of the biphenylanhydride derivative and the biphenyldicarboxylic acid according to an area normalization method, and obtaining the analysis results shown in table 1.
And (3) modifying the '10 minutes of ultrasound' in the step (2) into '30 minutes of ultrasound', enabling the rest steps to be consistent with the steps (1) to (4), carrying out high performance liquid chromatography analysis, calculating the content of the biphenyl anhydride derivative and the biphenyl diacid according to an area normalization method, and enabling the analysis results to be shown in table 2.
Changing 'ultrasonic treatment for 10 minutes' in the step (2) into 'ultrasonic treatment for 60 minutes', enabling the rest steps to be consistent with the steps (1) to (4), carrying out high performance liquid chromatography analysis, calculating the content of the biphenyl anhydride derivative and the biphenyl diacid according to a peak area normalization method, and enabling the analysis results to be shown in table 3.
TABLE 1 derivatization results for different di-n-butylamine equivalents at 10min derivatization time
| Name (R) | Biphenyl anhydride derivative (%) | Biphenyldicarboxylic acid (%) | Number of impurities |
| Bifenac anhydride derivative-10 min-5eq | 98.908 | 0.923 | 4 |
| Bifenation anhydride derivative-10 min-10eq | 98.911 | 0.930 | 3 |
| Bifenac anhydride derivative-10 min-20eq | 98.866 | 0.959 | 3 |
| Bifenac anhydride derivative-10 min-30eq | 98.840 | 0.969 | 3 |
TABLE 2 derivatization results for different di-n-butylamine equivalents at a derivatization time of 30min
| Name (R) | Purity (%) | Biphenyldicarboxylic acid (%) | Number of impurities |
| Bifenac anhydride derivative-30 min-5eq | 98.908 | 0.941 | 3 |
| Bifenation anhydride derivative-30 min-10eq | 98.916 | 0.935 | 3 |
| Bifenac anhydride derivative-30 min-20eq | 98.832 | 0.982 | 3 |
| Bifenac anhydride derivative-30 min-30eq | 98.849 | 0.938 | 3 |
TABLE 3 derivatization results for different di-n-butylamine equivalents at a derivatization time of 60min
| Name (R) | Purity (%) | Biphenyldicarboxylic acid (%) | Number of impurities |
| Biphenyl anhydride derivative-60 min-5eq | 98.967 | 0.881 | 3 |
| Biphenyl anhydride derivative-60 min-10eq | 98.920 | 0.910 | 3 |
| Biphenyl anhydride derivative-60 min-20eq | 98.870 | 0.928 | 3 |
| Biphenyl anhydride derivative-60 min-30eq | 98.883 | 0.920 | 3 |
As can be seen from tables 1 to 3, the derivatization time was prolonged, the amount of the derivatization reagent was increased, and the differences in the results of HPLC analysis were small. Comprehensively, preferably, the sample to be detected is treated by derivatization with di-n-butylamine for 10min, and the molar ratio of the di-n-butylamine to the biphenyl anhydride is 5-10.
Example 2 Attribute validation
The experimental steps are as follows:
(1) preparing a test solution:
weighing about 100mg of biphenyl anhydride, precisely weighing, placing in a 20mL measuring flask, precisely adding 1.6mL of acetonitrile and 280 mu L (214.76mg, 1.66mmol) of di-n-butylamine to dissolve, carrying out ultrasonic treatment for 10 minutes, cooling to room temperature, diluting to a scale with acetonitrile, shaking up to obtain a sample stock solution, precisely weighing 1mL of sample stock solution, placing in a 10mL measuring flask, diluting to a scale with acetonitrile, and shaking up to obtain the final product.
(2) Preparing an impurity biphenyldicarboxylic acid positioning solution:
taking about 10mg of biphenyldicarboxylic acid reference substance, placing the biphenyldicarboxylic acid reference substance in a 10mL measuring flask, precisely adding 0.8mL of acetonitrile and 140 mu L (107.38mg, 0.83mmol) of di-n-butylamine to dissolve, carrying out ultrasonic treatment for 10 minutes, taking out, cooling to room temperature, diluting to a scale with the acetonitrile, and shaking up to obtain an impurity biphenyldicarboxylic acid stock solution; precisely measuring 2.5mL of impurity biphenyldicarboxylic acid stock solution, placing the stock solution in a 50mL measuring flask, diluting the stock solution to a scale with acetonitrile, and shaking up to obtain impurity biphenyldicarboxylic acid diluent; precisely measuring 1mL of impurity biphenyldicarboxylic acid diluent, placing the diluent in a 10mL measuring flask, diluting the diluent to a scale with acetonitrile, and shaking up to obtain the product.
(3) Preparing a blank solvent:
precisely measuring 1.6mL of acetonitrile, placing the acetonitrile into a 20mL measuring flask, precisely adding 280 mu L (214.76mg, 1.66mmol) of di-n-butylamine, diluting the solution to a scale with the acetonitrile, shaking up to obtain a stock solution, precisely measuring 1mL of the stock solution, placing the solution into a 10mL measuring flask, diluting the solution to a scale with the acetonitrile, and shaking up to obtain the compound.
(4) Respectively taking 5 mu L of each of the test solution, the impurity biphenyldicarboxylic acid localization solution and the blank solvent, respectively injecting the solution into a high performance liquid chromatograph under the chromatographic conditions of the embodiment 1, carrying out high performance liquid chromatographic analysis, and recording a chromatogram, wherein the blank solvent chromatogram is shown in figure 1, the impurity biphenyldicarboxylic acid localization solution chromatogram is shown in figure 2, the test solution chromatogram is shown in figure 4, and the specificity verification results are shown in table 4.
TABLE 4 results of the Attribute verification
| Name (R) | Retention time/min | Relative retention time |
| Biphenyl dicarboxylic acid | 10.385 | 0.43 |
| Biphenyl anhydride derivatives | 23.943 | / |
The retention time of the biphenyldioic acid is 10.385min, the retention time of the biphenylic anhydride derivative is 23.943min, and as can be seen from fig. 1 and 4, the blank solvent peak does not interfere with the detection of the biphenylic anhydride derivative and the biphenyldioic acid. From fig. 5, it can be seen that the degrees of separation of the peak of the biphenyl anhydride derivative from each impurity are greater than 1.5, and the degrees of separation of the biphenyldicarboxylic acid from each impurity are also greater than 1.5, which meets the requirements, and thus, the method according to the embodiment of the present invention can effectively separate the biphenyl anhydride derivative from the biphenyldicarboxylic acid and the reagent introduced during the derivatization process, and has good specificity.
Example 3 repeatability verification
(1) Preparing a test solution: the preparation method is the same as that of the step (1) in example 2, and 3 parts are prepared in parallel.
(2) Preparation of control solutions: taking 10mg of each of the biphenyl anhydride and the biphenyl diacid reference substance, placing the biphenyl anhydride and the biphenyl diacid reference substance into different 10mL measuring bottles, precisely adding 0.8mL of acetonitrile and 28 muL (21.48mg and 0.166mmol) of di-n-butylamine to dissolve, carrying out ultrasonic treatment for 10 minutes, taking out, cooling to room temperature, diluting to a scale with the acetonitrile, and shaking up to obtain a biphenyl anhydride reference substance storage solution and a biphenyl diacid reference substance storage solution; preparing 2 parts in parallel;
accurately measuring 0.25mL of a biphenyl anhydride reference substance storage solution and 2.5mL of a biphenyl diacid reference substance storage solution respectively, placing the solutions in the same 50mL measuring flask, diluting the solutions to a scale by using acetonitrile, shaking up to obtain a diluent, accurately measuring 1mL of the diluent, placing the solution in a 10mL measuring flask, diluting the solution to a scale by using the acetonitrile, and shaking up to obtain a reference substance solution; 2 parts are prepared in parallel.
(3) Preparing a blank solvent: the preparation method is the same as the step (3) in the example 2.
(4) Separately taking 5 μ L of each of the test solution, the reference solution and the blank solvent, injecting into a high performance liquid chromatograph under the chromatographic conditions of example 1, performing high performance liquid chromatography, calculating the content of each substance according to a peak area normalization method, and calculating the relative standard deviation, wherein the specific results are shown in Table 5.
TABLE 5 results of repeatability verification
As can be seen from table 5, the detected number of impurities and the detected amount of impurities are not significantly different, the content of the biphenyl anhydride derivative in each test solution is not significantly different, and the relative standard deviation is 0.011%, which shows that the detection method provided by the embodiment of the present invention has good repeatability.
Example 4 recovery verification
The experimental steps are as follows:
(1) preparing a blank solvent: the preparation method is the same as the step (3) in the example 2.
(2) Preparation of control solutions: the preparation method is the same as the step (2) in the example 3.
(3) Preparing a test solution: weighing about 100mg of biphenyl anhydride, precisely weighing, placing in a 20mL measuring flask, precisely adding 1.6mL of acetonitrile and 280 μ L (214.76mg, 1.66mmol) of di-n-butylamine to dissolve, carrying out ultrasonic treatment for 10 minutes, cooling to room temperature, diluting to a scale with acetonitrile, shaking up to obtain a sample stock solution, precisely weighing 1mL of sample stock solution, placing in a 10mL measuring flask, diluting to a scale with acetonitrile, and shaking up to obtain the final product; 3 parts are prepared in parallel.
(4) Preparation of recovery solution: precisely measuring 2.5mL of the bifendate reference substance stock solution, placing the solution in a 50mL measuring flask, diluting the solution to scale with acetonitrile, shaking up to obtain a recovery rate stock solution, precisely measuring 1mL of the sample stock solution and 1mL of the recovery rate stock solution, placing the solution in the same 10mL measuring flask, diluting the solution to scale with acetonitrile, and shaking up to obtain a recovery rate solution; 3 parts were prepared in parallel as 100% derivatized samples.
(5) Taking 5 μ L of each of the test solution, the reference solution, the blank solvent and the recovery solution, injecting into a high performance liquid chromatograph under the chromatographic conditions of example 1, performing high performance liquid chromatographic analysis, calculating the content of the biphenyldicarboxylic acid by peak area according to an external standard method, calculating the recovery rate, and calculating the relative standard deviation, wherein the specific results are shown in Table 6.
In addition, in this example, the case of the inter-group recovery rate was also examined, and in step (4), the "recovery rate stock solution 1 mL" was replaced with the "recovery rate stock solution 0.5 mL", as a 50% derivatized sample, the "recovery rate stock solution 1 mL" was replaced with the "recovery rate stock solution 2 mL", as a 200% derivatized sample, a 50% derivatized sample and a 200% derivatized sample, the hplc analysis method was the same as the hplc analysis method for a 100% derivatized sample, the content of biphenyldioic acid was calculated by the peak area according to the external standard method, the recovery rate was calculated, and the relative standard deviation was calculated, and the specific results are shown in table 6.
TABLE 6 Biphenyldioic acid recovery results
The background amount is equivalent to the content of the biphenyldicarboxylic acid in 200mL of test solution obtained by high performance liquid chromatography detection and analysis, the measured amount is equivalent to the content of the biphenyldicarboxylic acid in 200mL of recovery solution obtained by high performance liquid chromatography detection and analysis, and the added amount is equivalent to the content of the biphenyldicarboxylic acid actually added in 200mL of recovery solution.
The method has the advantages that the recovery rate in the group is 98-103%, the RSD is less than 2%, the requirement is met, the accuracy is good, and the derivatization process is proved to be capable of effectively detecting the content of the biphenyldicarboxylic acid.
Example 5 linearity and Range
The experimental steps are as follows:
(1) preparing a blank solvent: the preparation method is the same as the step (3) of the example 2.
(2) Preparation of control stock solutions: the preparation method was the same as that of the control stock solution in step (2) of example 3.
(3) Preparation of a linear stock solution: accurately measuring 0.25mL and 2.5mL of biphenyl anhydride and biphenyl diacid reference substance stock solutions respectively, placing the stock solutions into the same 50mL measuring flask, diluting the stock solutions to a scale by using acetonitrile, and shaking up; and (5) obtaining the product.
(4) Preparation of a linear solution:
2mL, 1.5mL, 1.2mL, 1.0mL, 0.8mL, 0.5mL, 0.2mL of the linear stock solutions were precisely measured, placed in different 10mL measuring flasks, diluted to the scale with acetonitrile, shaken well to obtain linear 200%, 150%, 120%, 100%, 80%, 50%, 20% solutions, respectively.
(5) 5. mu.L of each of the linear solutions having different concentrations was injected into a high performance liquid chromatograph under the chromatography conditions of example 1, and subjected to high performance liquid chromatography. Taking the concentration of the linear solution as an abscissa and the corresponding peak area as an ordinate to perform linear regression, wherein a biphenyl anhydride standard curve is shown in fig. 6, and a specific analysis result is shown in table 7, wherein the linear regression equation is that y is 35668.5806x-119.4129, r is 0.9997, and the linear range is 0.1-1 mug/mL; the biphenyldicarboxylic acid standard curve is shown in fig. 7, the specific analysis result is shown in table 8, the linear regression equation is that y is 30608.7097x +2047.2568, r is 0.9995, and the linear range is 1.0040-10.0400 μ g/mL.
TABLE 7 Biphenyl anhydride Linearity and Range
TABLE 8 Biphenyldioic acid linearity and range
Example 6 detection of Biphenyl anhydride and related substances
Chromatographic conditions are as follows:
essentially the same chromatographic conditions as in example 1, except that the mobile phase A was a 0.015% (V/V) acetic acid solution.
The experimental steps are as follows:
(1) preparing a test solution: the procedure was exactly the same as in step (1) of example 2.
(2) And (3) taking 5 mu L of the test solution, injecting the test solution into a high performance liquid chromatograph according to the chromatographic conditions, and recording a chromatogram.
According to the detection method provided by the embodiment of the invention, the biphenyl anhydride and the biphenyl diacid in the biphenyl anhydride can be quickly and effectively detected, the separation degree of the peak corresponding to the biphenyl anhydride and each related impurity is more than 1.5, and the separation degree of the peak corresponding to the biphenyl diacid and each related impurity is also more than 1.5, so that the requirement is met.
Example 7 detection of Biphenyl anhydride and related substances
Chromatographic conditions are as follows:
essentially the same chromatographic conditions as in example 1, except that the mobile phase A was a 0.03% (V/V) acetic acid solution.
The experimental steps are as follows:
(1) preparing a test solution: the procedure was exactly the same as in step (1) of example 2.
(2) The procedure was exactly the same as in step (2) of example 6.
According to the detection method provided by the embodiment of the invention, the biphenyl anhydride and the biphenyl diacid in the biphenyl anhydride can be quickly and effectively detected, the separation degree of the peak corresponding to the biphenyl anhydride and each related impurity is more than 1.5, and the separation degree of the peak corresponding to the biphenyl diacid and each related impurity is also more than 1.5, so that the requirement is met.
Comparative example 1
Chromatographic conditions are as follows:
essentially the same chromatographic conditions as in example 1, except that the mobile phase A was a 0.01mol/L diammonium phosphate solution.
The experimental steps are as follows:
(1) preparing a test solution: the procedure was exactly the same as in step (1) of example 2.
(2) The procedure was exactly the same as in step (2) of example 6.
According to the detection method provided by the comparative example, the main peak in the chromatogram of the test sample is forked.
Comparative example 2
Chromatographic conditions are as follows:
essentially the same chromatographic conditions as in example 1, except that the column was a Yuxu Ultimate XB-C18 liquid chromatography column.
The experimental steps are as follows:
(1) preparing a test solution: weighing about 100mg of the biphenyl anhydride, precisely weighing, placing in a 20mL measuring flask, diluting with acetonitrile to a scale, shaking up to obtain a sample stock solution, precisely weighing 1mL of the sample stock solution, placing in a 10mL measuring flask, diluting with acetonitrile to a scale, and shaking up to obtain the final product.
(2) The procedure was exactly the same as in step (2) of example 6.
According to the detection method provided by the comparative example, the chromatogram of the test solution is shown in fig. 8, the chromatographic peak corresponding to the retention time of 9.921min is the biphenyldicarboxylic acid chromatographic peak, and as can be seen from fig. 8, most of the biphenyldicarboxylic acid anhydride is converted into biphenyldicarboxylic acid and some is converted into other substances when the derivatization reagent is not added, so that the content of the biphenylacid anhydride in the test solution cannot be truly and effectively reflected by the detection result obtained by adopting the high performance liquid chromatography.
Comparative example 3
Chromatographic conditions are as follows:
essentially the same chromatographic conditions as in example 1, except that the volume ratio of mobile phase a to mobile phase B was 45: isocratic elution was used 55.
The experimental steps are as follows:
(1) preparing a test solution: the procedure was exactly the same as in step (1) of example 2.
(2) The procedure was exactly the same as in step (2) of example 6.
According to the detection method provided by the comparative example, the main peak in the chromatogram of the test sample is seriously tailing, and the main peak response is poor.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. The method for detecting the biphenyl anhydride and the related substances thereof is characterized in that the detection method adopts a high performance liquid chromatography, and comprises the following steps:
preparing a test solution:
and (3) adding a derivatization reagent to derivatize the to-be-detected biphenyl anhydride to prepare a test solution, wherein the chemical structural formula of the biphenyl anhydride is shown as a formula II:
preparation of control solutions:
respectively derivatizing a biphenyl anhydride reference substance and a related substance reference substance thereof by using the derivatization reagent to prepare a reference substance solution, wherein the related substance is biphenyldioic acid, and the chemical structural formula of the biphenyldioic acid is shown as a formula I:
and (3) carrying out high performance liquid chromatography analysis on the test solution and the reference solution, wherein the detection conditions are as follows:
the chromatographic column is a C18 chromatographic column;
the mobile phase A is 0.01-0.03% (V/V) acetic acid solution, and the mobile phase B is acetonitrile;
the flow rate is 0.9-1.1 mL/min;
the elution mode is gradient elution.
2. The detection method according to claim 1, wherein the derivatizing agent is di-n-butylamine, diethylamine or dimethylamine; the chromatographic column is an Agilent ZORBAX Eclipse Plus C18 chromatographic column or an Asahi Ultimate XB-C18 liquid chromatographic column; the high performance liquid chromatography adopts an ultraviolet detector for detection, and the detection wavelength is 220 nm-240 nm; the column temperature is 35-45 ℃.
3. The detection method according to claim 1, wherein the chromatographic column further comprises a capture column, and the capture column is a Welch Ghost-Buster capture column.
4. The detection method according to claim 1, wherein the gradient elution is in particular:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (70-90) to (10-30) to (40-50) to (50-60) at a constant speed;
the volume ratio of the mobile phase A to the mobile phase B is kept constant within 15-35 minutes, wherein the volume ratio of the mobile phase A to the mobile phase B is (40-50) to (50-60);
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from (40-50) to (50-60) to (70-90) to (10-30) at a constant speed;
and the volume ratio of the mobile phase A to the mobile phase B is kept constant within 36-45 minutes at (70-90) to (10-30).
5. The detection method according to claim 1, wherein the gradient elution is in particular:
in 0-15 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 80: 20 to 45: 55 at a constant speed:
the volume ratio of the mobile phase A to the mobile phase B is kept constant at 45: 55 within 15-35 minutes;
in 35-36 minutes, the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 45: 55 to 80: 20 at a constant speed;
and the volume ratio of the mobile phase A to the mobile phase B is kept constant at 80: 20 within 36-45 minutes.
6. The detection method according to claim 1, wherein in the step of preparing the test solution, the molar ratio of the derivatization reagent to the to-be-detected biphenyl anhydride is (5-30): 1; the derivatization time is 10 min-60 min.
7. The detection method according to claim 1, wherein, in the step of subjecting the test solution and the control solution to high performance liquid chromatography:
the injection volume is 5-15 mu L.
8. The detection method according to claim 1, wherein the preparing of the test solution comprises the steps of:
dissolving the to-be-detected biphenyl anhydride by using acetonitrile, adding the derivatization reagent for derivatization to prepare a test solution in which 0.4-0.6 mg of the to-be-detected biphenyl anhydride is added per 1 mL.
9. The assay of claim 1, wherein the preparing the control solution comprises the steps of:
dissolving the biphenyl anhydride reference substance by using acetonitrile, adding the derivatization reagent for derivatization to prepare a reference substance solution which is added with the biphenyl anhydride reference substance by 0.4-0.6 mu g per 1 mL;
and dissolving the related substance reference substance by using acetonitrile, adding the derivatization reagent for derivatization to prepare a reference substance solution which is added with 4-6 mu g of the related substance reference substance per 1 mL.
10. Use of the method for detecting biphenyl anhydride and related substances according to any one of claims 1 to 9 in content detection of biphenyl anhydride and related substances.
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