CN108872405B - HPLC analysis detection method for relative substances of lodoxylamine tromethamine - Google Patents
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Abstract
The invention belongs to the technical field of analysis methods, and particularly discloses a high performance liquid chromatography for detecting relative substances of lodoxylamine tromethamine, which is used for separating and detecting 6 impurities in a raw material drug or a preparation of the lodoxylamine tromethamine. The method creatively adds the amine substances into the mobile phase for the first time, thoroughly solves the separation problem between the main peak and the impurity peak and between the impurity peak and the auxiliary material peak, and has simple operation and high sensitivity. Greatly improves the specificity of the prior method and provides more effective basis for the research on the safety of the preparation containing the lodoxylamine tromethamine.
Description
Technical Field
The invention relates to the technical field of analysis methods, in particular to a high-efficiency liquid chromatography analysis method for detecting relative substances of lodoxylamine tromethamine, which is used for separating and detecting 6 impurities in a raw material drug or a preparation of the lodoxylamine tromethamine.
Background
The chemical structural formula of the lodoxylamine tromethamine is as follows:
is mainly used for the local treatment of ophthalmic diseases, such as catarrhal keratitis, catarrhal conjunctivitis and the like in spring. Eye drops prepared from lodoxylamine tromethamine are approved to be marketed in China under the trade name of
In the course of research on the bulk drug of the lodoxylamine tromethamine, the inventors of the present application found that there were 6 impurities that could be introduced by the process, starting materials or degradation reactions, and the impurity information is shown in table a below.
TABLE A Lodoxamine tromethamine impurity information Table
However, there are few reports on the research on the related substances of the lodoxylamine tromethamine. At present, the quality standards of the raw materials and the preparations of the lodoxylamine tromethamine are not collected in United states pharmacopoeia, British pharmacopoeia, daily medicine local prescription and 2015 Chinese pharmacopoeia. Related substances are not researched in the imported registration standard JX19980121 of the original Rodoxylamine eye drop developer manufacturer. Through investigation, only the lorentzamine tromethamine raw material drug standard YBH20722004 and the lorentzamine eye drop import registration standard YBH19932004 study related substances in the lorentzamine eye drops, and the methods adopted by the two methods are the same.
The inventor of the application researches and discovers that baseline separation cannot be realized on the 6 known impurities by adopting the method in the Lodoxylamine tromethamine bulk drug standard YBH20722004, and the baseline separation cannot be realized on the 6 known impurities after chromatographic parameters are adjusted on the basis of the method. Meanwhile, under the condition of the method, the impurity A is relatively fast to peak, and is mixed with edetate disodium, sodium citrate and citric acid (citric acid) which are auxiliary materials in the lodoxylamine eye dropsThe published auxiliary materials in the original prescription comprise edetate disodium, benzalkonium chloride, mannitol, citric acid, sodium citrate, hydroxypropyl methylcellulose and tyloxapol) which are overlapped together, so that the determination of the impurity A is interfered.
Disclosure of Invention
In order to solve the problems, the invention provides a high performance liquid chromatography detection method for simultaneously detecting 6 known impurities in a bulk drug or a preparation of the lodoxylamine tromethamine.
The method comprises the following steps:
the filler of the reversed phase chromatographic column is alkyl bonded silica gel; taking an aqueous solution of an amine substance-an organic solvent as a mobile phase, wherein the organic solvent is methanol and/or acetonitrile; gradient elution is adopted, and the flow rate is 0.8ml/min to 1.2 ml/min; the column temperature is 25-45 ℃; the detection wavelength is 240-250 nm;
the filler of the reversed phase chromatographic column is octadecylsilane chemically bonded silica or octylsilane chemically bonded silica, preferably octadecylsilane chemically bonded silica.
The specification of the reversed phase chromatographic column is 250 multiplied by 4.6mm, 5 mu m.
The amine substance is diethylamine and/or triethylamine, preferably triethylamine.
The pH value of the aqueous solution of triethylamine is 5.0-8.0, preferably 6.0-7.0, and more preferably 6.8.
The pH regulator is phosphoric acid, acetic acid and formic acid, preferably phosphoric acid.
The concentration of triethylamine in the aqueous solution of triethylamine is 0.05 v/v% -0.2 v/v%, preferably 0.1 v/v%.
The organic solvent is preferably methanol.
The gradient elution procedure is as follows:
compared with the prior art, the invention has the following advantages and beneficial effects:
according to the method for detecting the related substances of the bulk drug and the preparation of the lodoxylamine tromethamine, the amine substance is creatively added into the mobile phase for the first time through retrieval, the problem of difficult separation between a main peak and an impurity peak and between the impurity peak and an auxiliary peak is thoroughly solved, the operation is simple, and the sensitivity is high.
Drawings
FIG. 1 is a chromatogram of a mixed control of example 1;
FIG. 2 is a chromatogram of the mixed control of example 2;
FIG. 3 is a chromatogram of disodium edetate obtained in example 2;
FIG. 4 is a chromatogram of the mixed control of example 3;
FIG. 5 is a chromatogram of the mixed control of example 4.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention will be further described in detail by further disclosing some non-limiting examples.
The impurities a-E and the lodoxylamine tromethamine controls used in the examples were made by the applicant in accordance with the prior art, impurity F was provided by the pharmaceutical science and technology limited, knoevenagel, wuhan, and impurity F was commercially available, all of which were conventional reagents.
The preparation process flow of the lodoxylamine tromethamine is shown as follows, and the inventor of the application prepares three batches of the lodoxylamine tromethamine raw material medicines with the batch numbers of 20160501, 20160502 and 20160503 respectively.
In the above synthesis, the impurity A, B, C, D, E is generated in the first reaction step, and the impurity F is the starting material.
The preparation process of the impurities A to E is as follows: putting 20g of the lodoxylamine tromethamine bulk drug and 200ml of purified water into a 500ml three-necked bottle, stirring and dissolving at room temperature, adding tromethamine after solid is dissolved, adjusting the pH to 12-13, heating to 50 ℃ after the adjustment is finished, reacting for 3 hours, concentrating under reduced pressure until the solid is dry after the reaction is finished, pulping the solid with 20ml of 95 wt% ethanol for 30min, performing suction filtration and drying, and separating by preparative chromatography to obtain an impurity A, an impurity B, an impurity C, an impurity D and an impurity E reference substance.
The structure confirmation information of the impurities A to F and the lodoxylamine tromethamine is shown in the following tables B to C.
TABLE B structural decomposition of lodoxylamine tromethamine
Table C information for identifying the structures of impurities A to F and lodoxylamine tromethamine
Example 1 method 1
The method adjusts the chromatographic condition of the mobile phase proportion on the basis of the Lodoxylamine tromethamine bulk drug standard YBH 20722004: waters e2695 HPLC, Kromasil 100-5C 18 column (250X 4.6mm, 5 μm), mobile phase 0.025mol/l potassium dihydrogen phosphate solution (pH adjusted to 6.8 with ammonia water) -methanol, flow rate 1.0ml/min, detection wavelength 244nm, sample size 20 μ l, gradient elution as shown in Table 1 below:
TABLE 1
Sample preparation: taking appropriate amount of each of the impurities A-F and the lodoxylamine tromethamine reference substance, respectively adding 20% (v/v) methanol to prepare single solution with each reference substance concentration of about 0.5mg/ml, carrying out sample injection analysis under the chromatographic condition of the embodiment, and recording a chromatogram for the chromatographic peak positioning of the subsequent mixed impurity reference substance. In addition, appropriate amounts of impurities A to F and a reference substance of the lodoxylamine tromethamine are mixed, 20% (v/v) methanol is added for dissolution, a solution containing about 20 mu g of each impurity and about 0.5mg of the lodoxylamine tromethamine is prepared for each 1ml of the mixed impurity solution, the mixed impurity solution is used as a mixed impurity solution, sample injection analysis is carried out under the chromatographic condition of the embodiment, a chromatogram is recorded, and the result is shown in the following table 2 and the attached figure 1.
TABLE 2 table of impurity location information
The test results show that impurity C and impurity D fail to achieve baseline separation.
Example 2 method 2
Chromatographic conditions are as follows: waters e2695 high performance liquid chromatograph with Kromasil 100-5C 18 chromatographic column (250 × 4.6mm, 5 μm) as mobile phase phosphate buffer [ sodium hydrogen phosphate (Na)2HPO4.12H2O)5.7g and sodium dihydrogen phosphate (NaHPO)4.2H2O)1.43g of water was dissolved in 2000ml of water to give a solution having a pH of 7.0]Methanol (9:1), flow rate 1.0ml/min, detection wavelength 244nm, sample size 20. mu.l.
Sample preparation: taking appropriate amount of impurities A-F and a suitable amount of a lodoxylamine tromethamine reference substance, respectively adding 20% (v/v) methanol to prepare a single reference substance solution of about 0.5mg/ml, carrying out sample injection analysis under the chromatographic conditions of the embodiment, and recording a chromatogram. Mixing impurities A-F and a proper amount of a reference substance of the lodoxylamine tromethamine, adding 20% (v/v) methanol for dissolving, preparing a solution containing about 20 mu g of each impurity and about 0.5mg of the lodoxylamine tromethamine per 1ml, using the solution as a mixed impurity solution, carrying out sample injection analysis under the chromatographic condition of the embodiment, and recording a chromatogram, wherein the result is shown in the following table 3 and the attached figure 2; in the original specification of the lodoxylamine eye drops, the dosage of the edetate disodium serving as an auxiliary material is definitely written to be 0.01% (w/v, g/mL), for the specificity of the further investigation method, a proper amount of edetate disodium is taken in an experiment, 20% (v/v) methanol is added to dissolve the edetate disodium to prepare a solution containing about 0.05mg of edetate disodium per 1mL, the solution is subjected to sample injection analysis under the chromatographic condition of the embodiment, and a chromatogram is recorded, and the result is shown in the following table 3 and the attached figure 3.
TABLE 3 table of impurity location information
Chromatographic peak | Retention time (min) | Degree of separation |
Edetate disodium | 2.633 | / |
Impurity A | 2.579 | / |
Impurity B | 33.488 | 16.44 |
Impurity C | 5.633 | 3.18 |
Impurity D | 4.912 | 9.43 |
Impurity E | 11.583 | 6.70 |
Impurity F | 43.561 | 7.86 |
Ludoxamide tromethamine | 17.989 | 11.02 |
Test results show that the impurities A to F and the lodoxylamine tromethamine can realize baseline separation, but the edetate disodium and the impurity A in the auxiliary material of the lodoxylamine eye drops peak near dead time, and the edetate disodium interferes with the determination of the impurity A.
Example 3 method 3
Chromatographic conditions are as follows: waters e2695 HPLC, Kromasil 100-5C 18 column (250X 4.6mm, 5 μm), mobile phase 20mmol/l ammonium acetate solution (pH adjusted to 6.8 with phosphoric acid) -methanol, flow rate 1.0ml/min, detection wavelength 244nm, sample size 20 μ l, gradient elution:
sample preparation: the results are shown in Table 4 below and FIG. 4, as in example 1.
TABLE 4 table of impurity location information
The test results show that impurity C and impurity D do not achieve baseline separation.
Example 4 method 4
Chromatographic conditions are as follows: waters e2695 HPLC, Kromasil 100-5C 18 column (250X 4.6mm, 5 μm), mobile phase 0.1 v/v% triethylamine solution (pH adjusted to 6.8 with phosphoric acid) -methanol, flow rate 1.0ml/min, detection wavelength 244nm, sample size 20 μ l, gradient elution:
sample preparation: taking appropriate amount of impurities A-F and a reference substance of lodoxylamine tromethamine, respectively adding 20% (v/v) methanol to prepare a single solution containing about 0.5mg/ml, carrying out sample injection analysis under the chromatographic conditions of the embodiment, and recording a chromatogram. Mixing impurities A-F and appropriate amount of lodoxylamine tromethamine, adding 20% (v/v) methanol for dissolving to prepare a solution containing about 20 mu g of each impurity and about 0.5mg of lodoxylamine tromethamine per 1ml, taking the solution as a mixed impurity solution, carrying out sample injection analysis under the chromatographic condition of the embodiment, and recording a chromatogram, wherein the results are shown in the following table 5 and the attached figure 5; in the original specification of the lodoxylamine eye drops, the dosage of the disodium edetate is 0.01% (w/v, g/mL), the dosage of the citric acid is 0.0175% (w/v, g/mL), the dosage of the sodium citrate is 0.0415% (w/v, g/mL), for the specificity of a further investigation method, a proper amount of disodium edetate is taken in an experiment, and 20% (v/v) methanol is added to dissolve the disodium edetate to prepare a solution containing about 0.05mg of disodium edetate per 1 mL; taking a proper amount of citric acid, adding 20% (v/v) methanol for dissolving to prepare a solution containing about 0.10mg of citric acid per 1 ml; taking a proper amount of sodium citrate, adding 20% (v/v) methanol to dissolve to prepare a solution containing about 0.5mg of sodium citrate per 1 ml. The sample injection analysis under the chromatographic conditions of the example was carried out, and chromatograms of the three solutions were recorded, and the results are shown in Table 5 below.
TABLE 5 table of impurity location information
Chromatographic peak | Retention time (min) | Degree of separation |
Edetate disodium | 3.268 | / |
Citric acid | 3.522 | / |
Citric acid sodium salt | 3.527 | / |
Impurity A | 5.762 | / |
Impurity B | 18.330 | 7.62 |
Impurity C | 9.295 | 12.99 |
Impurity D | 6.999 | 5.36 |
Impurity E | 10.130 | 4.48 |
Impurity F | 20.453 | 6.25 |
Ludoxamide tromethamine | 14.994 | 4.72 |
The test result shows that under the liquid chromatography condition, all impurities and main peaks can be completely separated, the separation degree among the impurities is good, and disodium edetate, sodium citrate and citric acid do not interfere with the determination of the main components and all the impurities.
Example 5 methodological validation
The chromatographic conditions were the same as in example 4.
Preparing a sample solution:
(1) preparing self-made lodoxylamine eye drops: the reference lodoxylamine eye drops are prepared according to the formula and the proportion of the original preparation: rodolite 0.1% (w/v) (batch 20160501), benzalkonium chloride 0.007% (w/v), mannitol 4.7% (w/v), hypromellose 0.38% (w/v), sodium citrate 0.0415% (w/v), citric acid 0.0175% (w/v), edetate disodium 0.01% (w/v), and tyloxapol 0.025% (w/v), and is prepared according to the conventional eye drop process.
(2) Preparation of a linear solution: a series of mixed standard solutions containing the impurities A to F and the lodoxylamine tromethamine are prepared by respectively taking appropriate amounts of the impurities A to F and the lodoxylamine tromethamine reference substances and adding 20% (v/v) methanol, and the results are shown in the following table, wherein the area of the peak is taken as the ordinate Y and the concentration is taken as the abscissa X.
(3) Preparing a precision solution: taking 6 parts of a lodoxylamine tromethamine raw material drug, respectively adding impurities A to F as reference substances, adding 20% (v/v) methanol to dissolve and dilute the drug to prepare a solution which contains 5 mu g of each of the impurities A to F and 0.5mg of the lodoxylamine tromethamine per 1ml, and taking the solution as a test solution. An appropriate amount of the test solution was diluted with 20% (v/v) methanol to prepare a solution containing about 5. mu.g of Rodoxamine tromethamine per 1ml as a control solution, and the results are shown in Table 6 below.
Taking a proper amount of prepared lodoxylamine eye drops, respectively adding reference substances of impurities A to F, adding 20% (v/v) methanol for dissolving and diluting to prepare a solution containing 5 mu g of each impurity A to F and 0.5mg of lodoxylamine tromethamine per 1ml, and taking the solution as a test solution. An appropriate amount of the test solution was diluted with 20% (v/v) methanol to prepare a solution containing about 5. mu.g of lodoxylamine tromethamine per 1ml, which was used as a control solution for itself, and the results are shown in Table 6 below.
(4) Preparing a recovery rate solution: taking the raw material medicines of the lodoxylamine tromethamine, respectively adding reference substances of impurities A to F to prepare solutions containing the impurities A to F of 4 mu g/ml, 5 mu g/ml and 6 mu g/ml respectively and containing the lodoxylamine tromethamine of 0.5mg/ml, and preparing three parts in parallel at each concentration, wherein the results are shown in the following table 6.
Taking a proper amount of self-prepared lodoxylamine eye drops, respectively adding a proper amount of reference substances of impurities A to F to prepare solutions containing 4 mu g/ml, 5 mu g/ml and 6 mu g/ml of the impurities A to F respectively and 0.5mg/ml of lodoxylamine tromethamine, and preparing three parts in parallel at each concentration.
(5) Preparation of stability samples: taking the raw material medicines of the lodoxylamine tromethamine, respectively adding reference substances of impurities A to F to prepare solutions containing 5 mu g/ml of the impurities A to F and 0.5mg/ml of the lodoxylamine tromethamine, placing the solutions at room temperature in a dark place, and inspecting the content change conditions of the impurities at different time points.
The prepared lodoxylamine eye drops are taken, impurities A to F are respectively added into reference substances to prepare solutions containing 5 mu g/ml of impurities A to F and 0.5mg/ml of lodoxylamine tromethamine, the solutions are placed at room temperature in a dark place, and the content change condition of each impurity is inspected at different time points. The test results are shown in table 6 below:
TABLE 6 methodological validation test results
The results in the table show that the method has good, precise and accurate linear relation.
EXAMPLE 6 sample testing
The chromatographic conditions were the same as in example 5.
Preparing a sample solution:
an appropriate amount of 160501, 160502 and 160503 raw materials was diluted with 20 v/v% methanol to give a solution containing about 0.5mg of tromethamine per 1ml, and the solution was used as a test solution, and an appropriate amount of the test solution was diluted with 20 v/v% methanol to give a solution containing about 5 μ g of tromethamine per 1ml as a control solution, and the experimental results are shown in table 7 below.
Taking a proper amount of prepared lodoxylamine eye drops and an original developer, namely Alsemide, respectively, diluting with 20 v/v% methanol to prepare a solution containing about 0.5mg of lodoxylamine tromethamine per 1ml, taking a proper amount of a sample solution as a sample solution, diluting with 20 v/v% methanol to prepare a solution containing about 5 mu g of lodoxylamine tromethamine per 1ml, and taking a self-control solution as shown in the following table 8:
TABLE 7 detection results of related substances of three batches of crude drugs
TABLE 8 detection results of related substances of self-made lodoxylamine eye drops and original developer
The test result shows that the analysis method can accurately detect the main impurity B in the raw material and the preparation of the lodoxylamine tromethamine and can detect the impurity A and the impurities C to F simultaneously, thereby greatly improving the specificity of the prior method and providing more effective basis for the research on the safety of the preparation containing the lodoxylamine tromethamine.
Claims (2)
1. A high performance liquid chromatography detection method for impurities in a lodoxylamine tromethamine bulk drug or a preparation is characterized in that the chromatographic conditions are as follows:
a reversed phase chromatographic column, wherein the filler is octadecylsilane chemically bonded silica or octylsilane chemically bonded silica;
taking an aqueous solution of an amine substance-an organic solvent as a mobile phase, wherein the organic solvent is methanol; gradient elution is adopted, and the flow rate is 0.8ml/min to 1.2 ml/min; the column temperature is 25-45 ℃; the detection wavelength is 240-250 nm;
the amine substance is triethylamine; the concentration of triethylamine in the aqueous solution of triethylamine is 0.1 v/v%; the pH value of the aqueous solution of the triethylamine is 6.8;
the pH regulator contained in the aqueous solution of the amine substance is phosphoric acid, acetic acid or formic acid;
the gradient elution procedure was:
;
2. The high performance liquid chromatography detection method according to claim 1, characterized in that: the amount of the sample was 20. mu.l.
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