CN112834627B - Method for separating and measuring lansoprazole related substances for injection by high performance liquid chromatography - Google Patents
Method for separating and measuring lansoprazole related substances for injection by high performance liquid chromatography Download PDFInfo
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Abstract
The invention discloses a method for separating and measuring lansoprazole related substances for injection by using a high performance liquid chromatography, wherein a methanol or acetonitrile-triethylamine aqueous solution system is used as a mobile phase for elution, the method can effectively separate lansoprazole and various impurities thereof, and the main component self-contrast method is used for accurately quantifying the various impurities. Experimental results show that the method is accurate and reliable, high in sensitivity and good in reproducibility, and can be used for analyzing the impurities of the lansoprazole for injection and controlling the quality of the lansoprazole.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis and quality control, and particularly relates to a method for separating and determining lansoprazole related substances for injection by an HPLC method.
Background
With the increase of smoking people, the increase of working pressure of people and the change of life and eating habits in China, the incidence rate of peptic ulcer is gradually increased, which accounts for about 10% of the total population, and the health and life of people are seriously influenced. Compared with omeprazole, the lansoprazole is a fluorine element substituted benzimidazole compound in a side chain, the bioavailability of the lansoprazole is improved by more than 30%, and the bacteriostatic activity of the lansoprazole on helicobacter pylori is improved by 4 times. In addition, the common administration modes of the lansoprazole are oral enteric-coated tablets and enteric-coated capsules, but the effect is slow; the Lansoprazole for injection which is administrated intravenously can improve the bioavailability of the drug, thereby shortening the onset time of the drug.
Through retrieval, only known impurities A, B, C, D and E are controlled according to related patents, documents and pharmacopoeia standards of various countries aiming at analytical methods of related substances of lansoprazole for injection at present, and lansoprazole has poor photo-thermal stability and is easy to degrade under the photo-thermal condition; meanwhile, lansoprazole and auxiliary materials can also generate impurities, and the impurities have risks in the aspect of drug quality control, can influence the drug effect of the drug and can generate adverse effects clinically. Therefore, the method for simultaneously detecting various impurities of lansoprazole for injection is developed, and has important significance for quality control.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the invention.
Lansoprazole impurity O and impurity M are impurities generated by degradation of injection lansoprazole under high temperature and light conditions, degradation impurity P generated by lansoprazole and auxiliary material meglumine under high temperature or light conditions is a special impurity of injection lansoprazole, and the impurities have risks in the aspect of drug quality control, possibly influence the drug effect of the drug and generate adverse effects clinically, and no report is made to research on the degradation impurities so far.
The inventor of the application develops a method for separating and measuring related substances of lansoprazole for injection, the method is good in specificity, can effectively separate 8 process impurities and degradation impurities from main components, is high in sensitivity, good in repeatability and high in accuracy, and can be applied to quality control of the related substances of lansoprazole for injection.
The invention provides a method for separating and measuring lansoprazole related substances for injection by high performance liquid chromatography, which comprises the following steps:
1) taking a proper amount of lansoprazole for injection, and diluting the lansoprazole with a diluent to prepare a sample solution containing 0.2-5.0 mg of lansoprazole per 1 ml;
2) taking a proper amount of the sample solution obtained in the step 1), and diluting the sample solution with a diluent to prepare a control solution containing 0.2 to 5.0 mu g of lansoprazole in each 1ml of the sample solution;
3) respectively injecting 5-50 mu l of the sample solution obtained in the step 1) and the control solution obtained in the step 2) into a high performance liquid chromatograph, and recording a chromatogram;
4) calculating the impurity content by adopting a main component self-comparison method with a correction factor or a main component self-comparison method without the correction factor or an external standard method;
the chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: octadecylsilane chemically bonded silica packed column;
temperature of the column: 20-30 ℃;
flow rate: 0.5 ml/min-1.5 ml/min;
detection wavelength: 283nm to 287 nm;
mobile phase: composed of a mobile phase A and a mobile phase B, the triethylamine water solution 1 is taken as the mobile phase A, methanol or acetonitrile is taken as the mobile phase B, and gradient elution is carried out;
the diluent in the step 1) and the step 2) is a mixed solution of methanol or acetonitrile and triethylamine water solution 2; the preparation method of the mobile phase A and the triethylamine aqueous solution in the diluent comprises the following steps: triethylamine is taken, water is added, and the pH value is adjusted by phosphoric acid.
In the embodiments of the present application, the lansoprazole related substances (or impurities) for injection include, but are not limited to, the following 8:
in the method for separating and detecting lansoprazole for injection, correction factors of impurity A, impurity B, impurity C, impurity D, impurity E, impurity M, impurity O and impurity P relative to lansoprazole are respectively 0.8, 0.9, 1.1, 0.4, 0.6, 1.2 and 1.6. The content of each impurity can be calculated by adopting a main component self-contrast method added with a correction factor; or calculating the contents of the impurities B, C and D by adopting a main component self-contrast method without adding a correction factor; and the content of the 8 impurities can be calculated by adopting an impurity external standard method.
In an embodiment of the invention, the volume ratio of methanol to aqueous triethylamine solution 2 in the diluent is 65: 35; or the volume ratio of the acetonitrile to the triethylamine aqueous solution 2 in the diluent is 40: 60.
In the embodiment of the invention, the mobile phases in the separation and detection method provided by the invention are triethylamine aqueous solution 1 (mobile phase A) and acetonitrile (mobile phase B), and gradient elution is carried out; or the mobile phase is triethylamine water solution 1 (mobile phase A) and methanol (mobile phase B), and gradient elution is carried out;
preferably, the gradient elution is: changing the volume percent of the mobile phase B from 10 to 65 percent in 0-20 min, keeping the volume percent of the mobile phase B65 for 20min, returning to the original gradient in 1min, and balancing for 9 min; or
Changing the volume percent of the mobile phase B from 20 to 65 percent in 0-20 min, keeping the volume percent of the mobile phase B65 for 20min, returning to the original gradient in 1min, and balancing for 9 min; or
And (3) 0-30 min, changing the volume percent of the mobile phase B from 20 to 65, keeping the volume percent of the mobile phase B65 for 15min, returning to the original gradient after 1min, and balancing for 9 min.
More preferably, the gradient elution is:
| time (min) | Mobile phase a (% by volume) | Mobile phase B (% by volume) |
| 0 | 80 | 20 |
| 30 | 35 | 65 |
| 45 | 35 | 65 |
| 46 | 80 | 20 |
| 55 | 80 | 20 |
Preferably, mobile phase B is acetonitrile.
Preferably, the pH value of the mobile phase A triethylamine water solution 1 is 6.2-7.7; preferably, the pH is 7.3-7.7; more preferably, the pH is 7.5; the preparation method of the triethylamine water solution 1 with the pH value of 7.5 comprises the following steps: 10ml of triethylamine is taken, 600ml of water is added, and the pH value is adjusted to 7.5 by phosphoric acid.
Preferably, the pH value of the triethylamine aqueous solution 2 in the diluent is 10.5; the preparation method of the triethylamine water solution 2 comprises the following steps: 10ml of triethylamine is taken, 600ml of water is added, and the pH value is adjusted to 10.5 by phosphoric acid.
In an embodiment of the invention, the column temperature is preferably 25 ℃;
in an embodiment of the present invention, the detection wavelength is preferably 285 nm.
In an embodiment of the invention, the flow rate is preferably 1.0 ml/min.
The separation and determination method can effectively separate 8 impurities from the main component of the lansoprazole for injection, has high sensitivity and good repeatability, and can be applied to quality control of lansoprazole related substances for injection.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and drawings.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the example serve to explain the principles of the invention and not to limit the invention.
FIG. 1 shows a chromatogram of a mixed solution of lansoprazole related substances for injection in example 1.
FIG. 2 shows the substance detection profiles of Lansoprazole accelerating 6-month samples for injection in example 1.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
Mixing the solution: weighing about 10mg of each of impurity A (batch No. 30193, Source: LGC), impurity B (batch No. 33121, Source: LGC), impurity C (batch No. 37738, Source: LGC), impurity D (batch No. 37957, Source: LGC), impurity E (batch No. 35254, Source: LGC), impurity M (batch No. F0L165, Source: USP), impurity O (batch No. L1522133, Source: Alantin), and impurity P (preparation method: in this application example 6), into the same 10ml measuring flask, adding a diluent (the volume ratio of methanol to triethylamine aqueous solution 2 is 65: 35. the preparation method of triethylamine aqueous solution 2 is to take 10ml, adding 600ml of water, adjusting pH to 10.5 with phosphoric acid) to dissolve and dilute to scale, shaking up, precisely taking 1ml to 10ml measuring flask, diluting to scale with the diluent (the same as before), shaking up to obtain solution A. Weighing lansoprazole (batch number: 100709) -201705, source: middle hospital) about 25mg to a 25ml measuring flask, measuring the solution A1ml to the same measuring flask, dissolving and diluting to scale with diluent (same as before), and shaking up to obtain a mixed solution.
Example 1
Instrument and chromatographic conditions:
adopting a high performance liquid chromatograph, wherein a chromatographic column is an octadecylsilane chemically bonded silica packed column; the column temperature is 30 ℃; the flow rate is 1.0 ml/min; the detection wavelength is 285 nm;
taking triethylamine aqueous solution 1 (10 ml of triethylamine is taken, 600ml of water is added, and the pH value is adjusted to 7.5 by phosphoric acid) as a mobile phase A, taking methanol as a mobile phase B, and carrying out gradient elution according to the following table:
| time (min) | Mobile phase a (% by volume) | Mobile phase B (% by volume) |
| 0 | 80 | 20 |
| 30 | 35 | 65 |
| 45 | 35 | 65 |
| 46 | 80 | 20 |
| 55 | 80 | 20 |
Test solution: taking a proper amount (about equivalent to 25mg of lansoprazole) of lansoprazole for injection (batch number: 18081261, source: Yangziang pharmaceutical industry group Limited, placed under the environment of 40 ℃ plus or minus 2 ℃ and humidity of 65% + orminus 5% for 6 months), placing the lansoprazole into a 25ml measuring flask, and preparing a sample solution containing about 1.0mg of lansoprazole in each 1ml by using a diluent (a mixed solution of methanol and triethylamine water solution 2 with a volume ratio of 65: 35. the preparation method of the triethylamine water solution 2 is that 10ml of triethylamine is taken, 600ml of water is added, and the pH value is adjusted to 10.5 by using phosphoric acid).
Control solution: precisely measuring a proper amount of the test solution, and adding the diluent to prepare a control solution containing 2.0 mu g of lansoprazole in each 1 ml.
Precisely measuring 10 μ l of each of the mixed solution, the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram;
the retention time and separation degree results of lansoprazole and various impurities in the mixed solution are shown in the following table:
and calculating the impurity content in the test solution by adopting a main component self-contrast method added with a correction factor. The results were: the content of impurity P is 0.13%, the content of impurity D is 0.04%, the content of impurity E is 0.04%, and the content of impurity B is 0.15%.
Example 2
Instrument and chromatographic conditions:
adopting a high performance liquid chromatograph, wherein a chromatographic column is an octadecylsilane chemically bonded silica packed column; the column temperature was 10 ℃; the flow rate is 0.5 ml/min; the detection wavelength is 287 nm;
taking triethylamine aqueous solution 1 (10 ml of triethylamine is taken, 600ml of water is added, and the pH value is adjusted to 7.3 by phosphoric acid) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out gradient elution according to the following table:
| time (min) | Mobile phase a (% by volume) | Mobile phase B (% by volume) |
| 0 | 90 | 10 |
| 30 | 35 | 65 |
| 45 | 35 | 65 |
| 46 | 90 | 10 |
| 55 | 90 | 10 |
The experimental steps are as follows:
precisely measuring 10 mu l of the mixed solution, injecting the mixed solution into a liquid chromatograph, and recording a chromatogram;
the retention time and separation degree results of lansoprazole and various impurities in the mixed solution are shown in the following table:
the results show that: lansoprazole in the lansoprazole for injection can be well separated from various related substances and among the related substances.
Example 3
Specificity failure test
Instrument and chromatographic conditions were the same as in example 1
The experimental steps are as follows:
taking a proper amount of lansoprazole powder for injection after 10 days of mixed illumination, preparing a test solution of 5mg/ml by using a diluent (the volume ratio of acetonitrile to triethylamine aqueous solution 2 is 40:60), precisely measuring the proper amount of the test solution, adding the diluent to prepare a control solution containing 5.0 mu g of lansoprazole in each 1ml, precisely measuring 2 mu l of the test solution, injecting into a liquid chromatograph, and recording a chromatogram.
And calculating the impurity content in the test solution by adopting a main component self-contrast method without adding a correction factor. The results were: the content of impurity P is 0.28%, the content of impurity D is 0.02%, the content of impurity E is 1.05%, the content of impurity B is 0.39%, and the content of impurity C is 0.10%.
The separation degree of the main peak and adjacent impurities is larger than 2.0, DAD detection is adopted to carry out peak purity inspection, and the result shows that under each forced degradation test condition, the purity angle of the main peak is smaller than the purity threshold value, the peak purity meets the requirement, and the mass balance is between 90% and 110%, which indicates that the method has good specificity.
Example 4
Limit of quantification
Adopting a high performance liquid chromatograph, wherein a chromatographic column is an octadecylsilane chemically bonded silica packed column; the column temperature was 10 ℃; the flow rate is 1.5 ml/min; the detection wavelength is 283 nm;
taking triethylamine aqueous solution 1 (10 ml of triethylamine is taken, 600ml of water is added, and the pH value is adjusted to 7.3 by phosphoric acid) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out gradient elution according to the following table:
| time (min) | Mobile phase a (% by volume) | Mobile phase B (% by volume) |
| 0 | 90 | 10 |
| 30 | 35 | 65 |
| 45 | 35 | 65 |
| 46 | 90 | 10 |
| 55 | 90 | 10 |
The experimental steps are as follows:
and (3) determining the detection limit and the quantification limit of the lansoprazole and various related substances thereof by adopting a signal-to-noise ratio method. Taking lansoprazole and an impurity reference substance, preparing each solution by adopting a diluent (a mixed solution of methanol and triethylamine aqueous solution 2 with a volume ratio of 65: 35. the preparation method of the triethylamine aqueous solution 2 is to take 10ml of triethylamine, add 600ml of water and adjust the pH value to 10.5 by phosphoric acid), wherein the sample volume is 50 mul, injecting the solution into a chromatograph, calculating the ratio (signal-to-noise ratio) of peak height to noise, wherein when the sample detection volume of the signal-to-noise ratio (S/N) of about 10 is the quantitative limit, the sample detection volume of the signal-to-noise ratio (S/N) of about 3 is the detection limit, the specific preparation method comprises the following steps:
the results show that: quantitative limits of lansoprazole, impurity A, impurity B, impurity C, impurity D, impurity E, impurity M, impurity O and impurity P are all 0.02%, and quantitative limit concentrations of lansoprazole and related substances are all less than 0.05% of the concentration of a test sample, so that the content of the related substances can be accurately controlled.
Example 5
Accuracy test
Instrument and chromatographic conditions, dilutions equivalent to example 1
The experimental steps are as follows:
taking a proper amount of reference substances of the impurity A, the impurity C, the impurity D, the impurity E, the impurity M, the impurity O and the impurity P, and preparing a solution containing about 0.4 mu g/ml of impurities per ml by using a diluent (the volume ratio of acetonitrile to triethylamine aqueous solution 2 is 40:60) as a reference substance solution; taking a proper amount of lansoprazole powder for injection after 10 days of mixed illumination in example 3, preparing a solution containing 0.2mg/ml lansoprazole in each ml by using a diluent as a test solution, taking 50 μ l of each of the control solution and the test solution, injecting into a chromatograph, and recording a chromatogram:
the results show that: calculated by peak area according to an external standard method, the content of the impurity P is 0.27%, the content of the impurity D is 0.03%, the content of the impurity E is 1.08%, the content of the impurity B is 0.41% and the content of the impurity C is 0.11%.
Example 6
Preparation of lansoprazole impurity P for injection
2-chlorobenzimidazole (12.0g, 1.0eq.), meglumine (23.1g, 1.5eq.), N-diisopropylethylamine (DIPEA, 20.4g, 2.0eq.), and N, N-dimethylformamide (DMF, 120mL) are heated in a 250mL single-port bottle for 4h till the 2-chlorobenzimidazole reaction is finished, the solvent is removed by concentration under reduced pressure, column chromatography separation is carried out (petroleum ether: ethyl acetate is 20: 1-5: 1), after the concentration is finished, N-heptane is added, and then the product is concentrated to dryness, so as to obtain 6.5g of a white solid with the yield of 26.6 percent and the purity of 97.7 percent.
Comparative example
Lansoprazole for injection is a chemical drug 3 class, the quality standards of raw material drugs and preparations of the Lansoprazole are loaded in USP, EP, BP, EP and 2015 version ChP, and the mixed solution in the example 1 is detected by adopting a method of related substances loaded in EP, and the results are as follows:
the experimental steps are as follows:
adopting a high performance liquid chromatograph, wherein a chromatographic column is an octadecylsilane chemically bonded silica packed column; the column temperature was 25 ℃; the flow rate is 1.0 ml/min; the detection wavelength is 285 nm;
the aqueous solution of triethylamine (10 ml of triethylamine was taken, 600ml of water was added, and pH was adjusted to 6.2 with phosphoric acid) -acetonitrile (60: 40) to conduct isocratic elution. 10. mu.l of the mixed solution obtained in example 1 was taken and injected into a liquid chromatograph, and a chromatogram was recorded.
The experimental results show that: the impurity M, the impurity O and the impurity P are coincided with the blank solvent, the peak is about 2min, and the separation and the accurate quantification cannot be realized; the peak emergence time of the main peak is about 10min, and other known impurities can be well separated from the main peak.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.
Claims (5)
1. A method for separating and measuring Lansoprazole related substances for injection by high performance liquid chromatography comprises the following steps:
1) taking a proper amount of lansoprazole for injection, and diluting the lansoprazole with a diluent to prepare a sample solution containing 0.2-5.0 mg of lansoprazole per 1 ml;
2) taking a proper amount of the sample solution obtained in the step 1), and diluting the sample solution with a diluent to prepare a control solution containing 0.2 to 5.0 mu g of lansoprazole in each 1ml of the sample solution;
3) respectively injecting 2-50 mu l of the sample solution obtained in the step 1) and the control solution obtained in the step 2) into a high performance liquid chromatograph, and recording a chromatogram;
4) calculating the impurity content by adopting a main component self-comparison method with a correction factor or a main component self-comparison method without the correction factor or an external standard method;
the chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: octadecylsilane chemically bonded silica packed column;
temperature of the column: 10-30 ℃;
flow rate: 0.5 ml/min-1.5 ml/min;
detection wavelength: 283nm to 287 nm;
mobile phase: composed of a mobile phase A and a mobile phase B, the triethylamine water solution 1 is taken as the mobile phase A, methanol or acetonitrile is taken as the mobile phase B, and gradient elution is carried out;
the diluent in the step 1) and the step 2) is a mixed solution of methanol or acetonitrile and triethylamine water solution 2; the preparation method of the triethylamine aqueous solution 1 of the mobile phase A or the triethylamine aqueous solution 2 in the diluent comprises the following steps: adding water into triethylamine, and adjusting the pH value with phosphoric acid; the pH value of the mobile phase A triethylamine water solution 1 is 7.3-7.7;
the lansoprazole related substances for injection comprise the following 8 substances:
taking triethylamine water solution 1 as a mobile phase A and methanol as a mobile phase B, and carrying out gradient elution according to the following table:
Taking triethylamine water solution 1 as a mobile phase A and acetonitrile as a mobile phase B, and carrying out gradient elution according to the following table:
。
2. The method for separating and determining Lansoprazole related substances for injection according to claim 1, wherein the column temperature is 25 ℃.
3. The method for separating and determining lansoprazole-related substances for injection according to claim 1, wherein the volume ratio of methanol to triethylamine aqueous solution 2 in the diluent is 65: 35.
4. The method for separating and determining lansoprazole-related substances for injection according to claim 1, wherein the volume ratio of acetonitrile to triethylamine aqueous solution 2 in the diluent is 40: 60.
5. The method for separating and determining lansoprazole-related substances for injection according to claim 1, wherein the mobile phase A triethylamine aqueous solution 1 has a pH of 7.5; the preparation method of the triethylamine water solution 1 with the pH value of 7.5 comprises the following steps: taking 10ml of triethylamine, adding 600ml of water, and adjusting the pH value to 7.5 by using phosphoric acid;
the pH value of the triethylamine aqueous solution 2 in the diluent is 10.5; the preparation method of the triethylamine aqueous solution 2 comprises the following steps: 10ml of triethylamine is taken, 600ml of water is added, and the pH value is adjusted to 10.5 by phosphoric acid.
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| CA2558535A1 (en) * | 2004-03-03 | 2005-10-06 | Teva Pharmaceutical Industries Ltd. | A stable pharmaceutical composition comprising an acid labile drug |
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