CN114428124A - Method for separating and detecting genotoxic impurities in mesalazine sustained-release preparation - Google Patents
Method for separating and detecting genotoxic impurities in mesalazine sustained-release preparation Download PDFInfo
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- CN114428124A CN114428124A CN202011176339.9A CN202011176339A CN114428124A CN 114428124 A CN114428124 A CN 114428124A CN 202011176339 A CN202011176339 A CN 202011176339A CN 114428124 A CN114428124 A CN 114428124A
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- 238000000034 method Methods 0.000 title claims abstract description 69
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960004963 mesalazine Drugs 0.000 title claims abstract description 67
- 239000012535 impurity Substances 0.000 title claims abstract description 55
- 230000001738 genotoxic effect Effects 0.000 title claims abstract description 45
- 231100000024 genotoxic Toxicity 0.000 title claims abstract description 44
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000002253 acid Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000741 silica gel Substances 0.000 claims abstract description 5
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 5
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims description 128
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims description 128
- 239000000523 sample Substances 0.000 claims description 31
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 30
- 238000001514 detection method Methods 0.000 claims description 24
- 239000012488 sample solution Substances 0.000 claims description 20
- 238000010828 elution Methods 0.000 claims description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 11
- 238000004587 chromatography analysis Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 28
- 230000035945 sensitivity Effects 0.000 abstract description 7
- 239000000945 filler Substances 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 118
- 239000000243 solution Substances 0.000 description 77
- 239000003085 diluting agent Substances 0.000 description 49
- 239000011550 stock solution Substances 0.000 description 39
- 238000007865 diluting Methods 0.000 description 26
- 239000013558 reference substance Substances 0.000 description 25
- 238000005303 weighing Methods 0.000 description 21
- 239000012085 test solution Substances 0.000 description 18
- 239000012490 blank solution Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 12
- 239000007939 sustained release tablet Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000012088 reference solution Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
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- 238000002474 experimental method Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 101000891579 Homo sapiens Microtubule-associated protein tau Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
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Abstract
The invention relates to an HPLC method for separating and detecting genotoxic impurities in a mesalazine sustained-release preparation, belonging to the field of analytical chemistry. The method adopts a chromatographic column with pentafluorophenyl bonded silica gel as a filler, and elutes by using a mobile phase A and a mobile phase B, wherein the phase A is an acid water solution, and the phase B is acetonitrile. The method has the advantages of high sensitivity, good specificity and reliable accuracy.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a method for separating and detecting genotoxic impurities in a mesalazine sustained-release preparation.
Background
Inflammatory bowel disease is a chronic nonspecific intestinal disease with unknown etiology, and comprises ulcerative colitis and Crohn's disease, and a large number of clinical tests prove that mesalazine is effective in treating acute ulceration and stable ulceration, and has few adverse reactions. Because the diseases are chronic diseases, are easy to repeatedly attack and need to be taken for a long time, and the 2-aminophenol and the 4-aminophenol are used as possible degradation impurities of the mesalazine and have genotoxicity warning structures, the two impurities need to be strictly controlled.
The control of 2-aminophenol and 4-aminophenol in mesalazine is mostly controlled by a gas phase method in literature reports, a liquid phase method is less, and a liquid phase method adopting a pentafluorophenyl bonded silica gel column is not reported. In the EP method, the pH value of a mobile phase is extremely low, the liquid phase is corroded, and when a C18 chromatographic column is adopted, unknown impurities in a sample interfere the separation of 4-aminophenol, the specificity is poor, and the separation degree requirement cannot be met through method adjustment and chromatographic column screening. The method disclosed in CN108169344A uses a phenyl column for analysis, and adds an ion pair reagent in the mobile phase, which has the problems of reduced retention and non-existent method during the use process, and is not favorable for the life cycle management of the method.
In order to control the impurities in the product more accurately and ensure the quality of the medicine, research on an analysis and detection method suitable for genotoxic impurities 2-aminophenol and 4-aminophenol in the mesalazine sustained-release preparation is needed.
Disclosure of Invention
The invention aims to provide a method for separating and detecting genotoxic impurities in a mesalazine sustained-release preparation, so that the separation and determination of genotoxic impurities 2-aminophenol and 4-aminophenol in a mesalazine sustained-release medicine are realized. The method provided by the invention can effectively separate and measure the contents of 2-aminophenol and 4-aminophenol which are genotoxic impurities in the mesalazine sustained-release medicine, has high sensitivity, good specificity and reliable accuracy, and can be used for quality control of the genotoxic impurities in the mesalazine sustained-release medicine.
A method for separating and detecting genotoxic impurities in a mesalazine sustained-release preparation comprises the following steps: taking a mesalazine sustained release preparation sample solution, adopting a pentafluorophenyl bonded silica gel chromatographic column, and eluting with a mobile phase A and a mobile phase B, wherein the phase A is an acid water solution, and the phase B is acetonitrile.
The genotoxic impurity in the mesalazine sustained-release preparation is at least one of 2-aminophenol and 4-aminophenol.
The pentafluorophenyl bonded silica gel chromatography column can be Phenomenex Luna PFP (2).
The acid in the mobile phase A is at least one of phosphoric acid, trifluoroacetic acid, formic acid and acetic acid. In some embodiments, the mobile phase a acid is phosphoric acid.
The concentration of the acid in the mobile phase A is 0.10-0.20%, and V/V. In some embodiments, the concentration of acid in mobile phase a is 0.10% to 0.13%, V/V. In some embodiments, the concentration of acid in mobile phase a is 0.10% to 0.15%, V/V. In some embodiments, the concentration of acid in mobile phase a is 0.15% to 0.20%, V/V. In some embodiments, the concentration of acid in the mobile phase a is 0.10%, V/V. In some embodiments, the concentration of acid in the mobile phase a is 0.13%, V/V. In some embodiments, the concentration of acid in the mobile phase a is 0.15%, V/V. In some embodiments, the concentration of acid in the mobile phase a is 0.20%, V/V.
The pH value of the mobile phase A ranges from 1.9 to 2.2. In some embodiments, the pH of mobile phase a ranges from 1.9 to 2.1. In some embodiments, the mobile phase a has a pH in the range of 1.9. The pH range of the mobile phase a was 2.0. In some embodiments, the mobile phase a has a pH in the range of 2.1. In some embodiments, the mobile phase a has a pH in the range of 2.2.
In some embodiments, the mobile phase a is a 0.15% aqueous phosphoric acid solution having a pH of 2.0.
The elution procedure was, by volume:
| time (min) | Mobile phase A | |
| 0 | 100 | 0 |
| 10.00 | 100 | 0 |
| 25.00 | 40 | 60 |
| 25.01 | 100 | 0 |
| 35 | 100 | 0 |
。
The method for separating and detecting genotoxic impurities in the mesalazine sustained-release preparation can comprise the following steps or can be realized by the following steps:
1) taking a mesalazine sustained release preparation sample, and preparing a sample solution with the concentration of 1.0 mg/mL;
2) setting instrument parameters: the flow rate of the mobile phase, the column temperature of the chromatographic column, the elution procedure and the detection wavelength;
3) injecting the sample solution obtained in the step 1) into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and determination of genotoxic impurities in the mesalazine sustained-release preparation.
The flow rate of the mobile phase is 0.5mL/min to 1.5 mL/min. In some embodiments, the flow rate of the mobile phase is from 0.5mL/min to 1.0 mL/min. In some embodiments, the flow rate of the mobile phase is from 1.0mL/min to 1.5 mL/min. In some embodiments, the flow rate of the mobile phase is 0.5 mL/min. In some embodiments, the flow rate of the mobile phase is 1.0 mL/min. In some embodiments, the flow rate of the mobile phase is 1.5 mL/min.
The column temperature of the chromatographic column is 35-45 ℃. In some embodiments, the column temperature of the chromatography column is between 35 ℃ and 40 ℃. In some embodiments, the column temperature of the chromatography column is between 40 ℃ and 45 ℃. In some embodiments, the column temperature of the chromatography column is 35 ℃. In some embodiments, the column temperature of the chromatography column is 40 ℃. In some embodiments, the column temperature of the chromatography column is 45 ℃.
The elution procedure is 0min-10 min: mobile phase a mobile phase B is 100:0(V: V), 10min-25 min: mobile phase a mobile phase B is 40:60(V: V), 25.01min-35 min: mobile phase a mobile phase B is 100:0(V: V).
The injection volume is 40-60 muL. In some embodiments, the sample injection volume is 50 μ Ι _.
The diluent is 0.15% phosphoric acid aqueous solution.
The detection wavelength is 215nm-225 nm. In some embodiments, the detection wavelength is 215 nm. In some embodiments, the detection wavelength is 220 nm. In some embodiments, the detection wavelength is 225 nm.
In some embodiments, the method for separating and detecting genotoxic impurities in the mesalazine sustained-release preparation comprises or is realized by the following steps:
1) taking a mesalazine sustained release preparation sample, and preparing a sample solution with the concentration of 1.0 mg/mL;
2) setting the flow rate of a mobile phase to be 0.5mL/min-1.5mL/min, the column temperature of a chromatographic column to be 35-45 ℃, the detection wavelength to be 215nm-225nm, and the elution procedure to be 0min-10 min: mobile phase a mobile phase B is 100:0(V: V), 10min-25 min: mobile phase a mobile phase B is 40:60(V: V), 25.01min-35 min: mobile phase a: mobile phase B ═ 100:0(V: V);
3) and (2) injecting 40-60 mu L of the sample solution obtained in the step 1) into a high performance liquid chromatograph, recording a chromatogram, and completing separation and determination of genotoxic impurities in the mesalazine sustained-release preparation.
In some embodiments, the method for separating and detecting genotoxic impurities in the mesalamine sustained-release preparation can comprise or be realized by the following steps:
1) taking a mesalazine sustained release preparation sample, and preparing a sample solution with the concentration of 1.0 mg/mL;
2) setting the flow rate of a mobile phase to be 1.0mL/min, the column temperature of a chromatographic column to be 40 ℃, the detection wavelength to be 220nm, and the elution program to be 0-10 min: mobile phase a mobile phase B is 100:0(V: V), 10min-25 min: mobile phase a mobile phase B is 40:60(V: V), 25.01min-35 min: mobile phase a: mobile phase B ═ 100:0(V: V);
3) and (2) injecting 50 mu L of the sample solution obtained in the step 1) into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and determination of genotoxic impurities in the mesalazine sustained-release preparation.
The HPLC may be an Agilent model 1260 HPLC system and workstation or other suitable and feasible system.
In some embodiments, the method for separating and detecting genotoxic impurities in a mesalamine sustained-release preparation comprises the following steps: preparing a mesalazine sustained release preparation sample into a solution with the concentration of 1.0mg/mL, and detecting genotoxic impurities in the solution by an HPLC method; the genotoxic impurity is at least one of 2-aminophenol and 4-aminophenol; the chromatographic column used is selected from Phenomenex Luna PFP (2).
In some embodiments, the method for separating and detecting genotoxic impurities in a mesalamine sustained-release preparation comprises the following steps: preparing a mesalazine sustained release preparation sample into a solution with the concentration of 1.0mg/mL, and detecting genotoxic impurities in the solution by an HPLC method; the genotoxic impurity is at least one of 2-aminophenol and 4-aminophenol; the chromatographic column is selected from Phenomenex Luna PFP (2); eluting with mobile phase A and mobile phase B, wherein phase A is acid water solution, and phase B is acetonitrile.
In some embodiments, the method for separating and detecting genotoxic impurities in a mesalamine sustained-release preparation comprises the following steps: preparing a mesalazine sustained release preparation sample into a solution with the concentration of 1.0mg/mL, and detecting genotoxic impurities in the solution by an HPLC method; the genotoxic impurity is at least one of 2-aminophenol and 4-aminophenol; the chromatographic column is selected from Phenomenex Luna PFP (2); eluting with mobile phase A and mobile phase B, wherein phase A is 0.15% phosphoric acid water solution, and phase B is acetonitrile.
In some embodiments, the method for separating and detecting genotoxic impurities in a mesalamine sustained-release preparation comprises the following steps: preparing a mesalazine sustained release preparation sample into a solution with the concentration of 1.0mg/mL, and detecting genotoxic impurities in the solution by an HPLC method; the genotoxic impurity is at least one of 2-aminophenol and 4-aminophenol; the chromatographic column is selected from Phenomenex Luna PFP (2); eluting with mobile phase A and mobile phase B, wherein the mobile phase A is 0.15% phosphoric acid water solution with pH of 2.0, and the phase B is acetonitrile.
In some embodiments, the method for separating and detecting genotoxic impurities in a mesalamine sustained-release preparation comprises the following steps: preparing a mesalazine sustained release preparation sample into a solution with the concentration of 1.0mg/mL, and detecting genotoxic impurities in the solution by an HPLC method; the genotoxic impurity is at least one of 2-aminophenol and 4-aminophenol; the chromatographic column is selected from Phenomenex Luna PFP (2); eluting with mobile phase A and mobile phase B, wherein the mobile phase A is 0.15% phosphoric acid water solution with pH of 2.0, and the phase B is acetonitrile; the elution procedure is 0min-10 min: mobile phase a mobile phase B is 100:0(V: V), 10min-25 min: mobile phase a mobile phase B is 40:60(V: V), 25.01min-35 min: mobile phase a mobile phase B is 100:0(V: V).
In some embodiments, the method for separating and detecting genotoxic impurities in a mesalamine sustained-release preparation comprises the following steps: preparing a mesalazine sustained release preparation sample into a solution with the concentration of 1.0mg/mL, and detecting genotoxic impurities in the solution by an HPLC method; the genotoxic impurity is at least one of 2-aminophenol and 4-aminophenol; the chromatographic column is selected from Phenomenex Luna PFP (2); eluting with mobile phase A and mobile phase B, wherein the mobile phase A is 0.15% phosphoric acid water solution with pH of 2.0, and the phase B is acetonitrile; the elution procedure is 0min-10 min: mobile phase a mobile phase B is 100:0(V: V), 10min-25 min: mobile phase a mobile phase B is 40:60(V: V), 25.01min-35 min: mobile phase a: mobile phase B ═ 100:0(V: V); the flow rate of the mobile phase was 1.0 mL/min.
In some embodiments, the method for separating and detecting genotoxic impurities in a mesalamine sustained-release preparation comprises the following steps: preparing a mesalazine sustained release preparation sample into a solution with the concentration of 1.0mg/mL, and detecting genotoxic impurities in the solution by an HPLC method; the genotoxic impurity is at least one of 2-aminophenol and 4-aminophenol; the chromatographic column is selected from Phenomenex Luna PFP (2); eluting with mobile phase A and mobile phase B, wherein the mobile phase A is 0.15% phosphoric acid water solution with pH of 2.0, and the phase B is acetonitrile; the elution procedure is 0min-10 min: mobile phase a mobile phase B is 100:0(V: V), 10min-25 min: mobile phase a mobile phase B is 40:60(V: V), 25.01min-35 min: mobile phase a: mobile phase B ═ 100:0(V: V); the flow rate of the mobile phase is 1.0 mL/min; the column temperature of the chromatographic column is 40 ℃; the detection wavelength was 220 nm.
Definition of terms
In the foregoing or following text, all numbers disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. There may be a 1%, 2%, 5%, 7%, 8%, or 10% difference in the value of each number based on the disclosed value.
The method provided by the invention can effectively separate genotoxic impurities in the drug, the separation degree reaches more than 1.5 or more than 2.5 or more than 5, the separation is completely based on line, and the problems of poor sensitivity and poor stability when a prototype is directly detected can be solved. The method is simple, rapid, accurate and high in sensitivity.
In the present invention, HPLC means high performance liquid chromatography; VWD denotes ultraviolet detector; RSD denotes relative standard deviation; LOQ denotes limit of quantitation; LOD represents the limit of detection.
Ppm concentration (parts per million) in the present invention is a concentration expressed in parts per million of the mass of solute in the mass of the entire solution, and is also referred to as parts per million concentration.
In the present invention,. mu.L means microliter,. mu.L means milliliter,. degree.C.means centigrade,. mu.g means milligram,. mu.g/mL means microgram/milliliter,. min means minute,. mL/min means milliliter/minute,. mm means millimeter, and nm means nanometer.
The sample of the invention needs to be filtered by a 0.45 mu m filter membrane before sample injection.
Drawings
FIG. 1 shows an HPLC chromatogram of an empty white solution in example 1;
FIG. 2 shows an HPLC chromatogram of the test solution in example 1;
FIG. 3 shows a sensitive solution HPLC profile in example 1;
FIG. 4 shows an HPLC chromatogram of control solution 1 in example 1;
FIG. 5 shows a HPLC profile of a solution of suitability for use in the system of example 1;
FIG. 6 shows an HPLC chromatogram of an empty white solution in example 2;
FIG. 7 shows an HPLC chromatogram of the test solution in example 2;
FIG. 8 shows the HPLC profile of the sensitization solution in example 2;
FIG. 9 shows an HPLC chromatogram of the test solution 1 in example 5;
FIG. 10 shows an HPLC chromatogram of the test solution 2 in example 5;
FIG. 11 shows an HPLC chromatogram of the test solution 3 in example 5.
Detailed Description
The embodiment of the invention discloses a method for separating and detecting toxic impurities of a mesalazine sustained-release tablet base. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods described herein, as well as appropriate variations and combinations of the methods described herein, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
In the embodiment of the present invention, the content (ppm) of 2-aminophenol and 4-aminophenol in the test sample in the mesalazine labeled amount is calculated by the following formula:
in the formula:
v: the dilution factor of the test solution is mL;
p: purity of 2-aminophenol or 4-aminophenol control,%;
MSTD 1: weighing 2-aminophenol/4-aminophenol in the reference solution 1 in mg;
DSTD 1: dilution factor of control solution, mL;
ai: the chromatogram of the test solution is the peak area of 2-aminophenol or 4-aminophenol;
ASTD 1: the average peak area of 2-aminophenol or 4-aminophenol in the control solution 1;
l: the marked amount of the mesalazine sustained release tablet is 1200 mg;
m: the mesalazine sustained release tablets are weighed according to the average sample weight and mg;
m: weighing mesalazine sustained release tablet powder in a sample amount of mg.
The instrument and column specifications are given in the following table: an American Agilent 1260 type high performance liquid chromatograph system and a workstation automatically sample.
| Chromatographic column | Specification of | Filler material | Detector |
| Phenomenex Luna PFP(2) | 4.6*250mm，5μm | Pentafluorophenyl bonded silica gel | Ultraviolet detector |
For a further understanding of the present invention, reference will now be made in detail to the following examples.
Example 1: system applicability test, specificity test, and linearity test
Apparatus and conditions
A chromatographic column: phenomenex Luna PFP (2), 4.6 x 250mm, 5 μm;
a detector: VWD (ultraviolet detector);
flow rate: 1.0 mL/min;
column temperature: 40 ℃;
sample introduction amount: 50 mu L of the solution;
detection wavelength: 220 nm;
mobile phase A: 0.15% phosphoric acid aqueous solution (V: V) having a pH of 2.0;
mobile phase B: acetonitrile;
elution procedure:
operating time: and (5) 35 min.
Experimental procedure
1) Diluent/blank solution: a mobile phase A;
2) 2-aminophenol stock solution: taking about 5mg of 2-aminophenol reference substance, precisely weighing, placing in a 1000mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, adding the diluent to achieve constant volume and diluting to a scale, shaking up to obtain 0.005mg/mL 2-aminophenol stock solution, and preparing two parts in parallel;
3) 4-aminophenol stock solution: taking about 5mg of 4-aminophenol reference substance, precisely weighing, placing in a 250mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, diluting with the diluent to a constant volume to scale, shaking up to obtain 4-aminophenol stock solution with a concentration of about 0.02mg/mL, and preparing two parts in parallel;
4) control solution: precisely transferring 2.0mL of the 2-aminophenol stock solution in the step 2) and 2.0mL to 200mL of the 4-aminophenol stock solution in the step 3) into volumetric flasks respectively, diluting the volumetric flasks to a constant volume to a scale by using a diluent, shaking up to obtain a reference solution with the 2-aminophenol content of about 50ppm and the 4-aminophenol content of about 200ppm, and preparing two parts in parallel;
5) sensitivity solution: precisely transferring 2.0mL to 20mL of the 4-aminophenol stock solution prepared in the step 3) into a volumetric flask, diluting the volumetric flask with a diluent to a constant volume to a scale, shaking up, respectively transferring 5.0mL of the solution and 2.0mL to 200mL of the 2-aminophenol stock solution prepared in the step 2) into volumetric flasks, fixing the volume to the scale with the diluent, and shaking up to obtain a sensitive solution with the concentration of about 50 ppm;
6) preparing a detection limiting solution: precisely transferring 2.0mL to 20mL of the 4-aminophenol stock solution prepared in the step 3) into a volumetric flask, diluting the volumetric flask with a diluent to a constant volume to a scale, shaking up, precisely transferring 2mL of the 2-aminophenol stock solution prepared in the step 2) into the same volumetric flask, diluting the volumetric flask with the diluent to a constant volume to a scale, and shaking up to obtain a detection limit solution with the concentration of about 20 ppm;
7) quantitative limiting solution: the same step as 5) sensitivity solution;
8) test solution: taking 10 mesalazine sustained-release tablets, grinding, precisely weighing about 117mg (equivalent to 100mg of mesalazine) of the tablet powder, putting the tablet powder into a 100mL volumetric flask, adding a diluent with half of the volume of the volumetric flask, ultrasonically dissolving, diluting with the diluent to a constant volume to a scale, shaking up, centrifuging (10000rpm for 10min), and taking supernatant to obtain a sample solution with the mesalazine concentration of about 1 mg/mL;
9) system applicability solution: precisely transferring 1.0mL to 200mL of the test solution in the step 8), diluting the test solution with a diluent to a constant volume to scale, shaking up, precisely transferring the diluted test solution in a 5.0mL to 10mL volumetric flask, diluting the test solution with a 2-aminophenol stock solution to a constant volume to scale, and shaking up to obtain the test solution;
10) preparing a 4-aminophenol and 2-aminophenol linear stock solution: taking about 5mg of each of a 4-aminophenol reference substance and a 2-aminophenol reference substance, precisely weighing the 4-aminophenol reference substance and the 2-aminophenol reference substance into a volumetric flask of 1000mL, adding a proper amount of diluent, ultrasonically dissolving, diluting with the diluent to a constant volume to a scale, and shaking up to obtain an impurity reference substance stock solution (the concentration is about 5000 ppm);
10) the linear solution formulations are shown in table 1 below:
table 1: 4-aminophenol/2-aminophenol Linear solution formulation Table
| Concentration level | Volume of transfer stock solution (mL) | Dilution volume (mL) |
| 20ppm | 1 | 250 |
| |
2 | 200 |
| |
2 | 100 |
| |
3 | 100 |
| |
2 | 50 |
| 250ppm | 2.5 | 50 |
11) Taking blank solution, sensitivity solution, reference solution, sample solution, and linear solution, performing high performance liquid chromatography according to the above conditions, introducing sample sequence as shown in figure 2, recording chromatogram as shown in figures 1-5, and the results are shown in tables 3-8.
Table 2: sample introduction sequence table
| Sample name | Number of sample introduction needles |
| |
1 |
| |
3 |
| |
2 |
| |
1 |
| |
1 |
| |
1 |
| |
1 |
| |
1 |
| |
1 |
| 20ppm 2- |
1 |
| 50ppm 2-aminophenol |
1 |
| 100ppm 2- |
1 |
| 150ppm 2-aminophenol |
1 |
| 200ppm 2-aminophenol |
1 |
| 250ppm 2-aminophenol |
1 |
| |
1 |
| 20ppm 4- |
1 |
| 50ppm 4- |
1 |
| 100ppm of 4- |
1 |
| 150ppm 4- |
1 |
| 200ppm 4- |
1 |
| 250ppm 4-aminophenol |
1 |
| |
1 |
| |
3 |
| |
3 |
Table 3: 4-aminophenol system applicability and recovery results
Table 4: 2-aminophenol system applicability and recovery results
Table 5: 4-aminophenol Linear results
Table 6: 2-aminophenol Linear results
Table 7: detection limit results of 2-aminophenol and 4-aminophenol
Table 8: quantitative limit results for 2-aminophenol and 4-aminophenol
Example 2: sensitization test
Apparatus and conditions
A chromatographic column: phenomenex Luna PFP (2), 4.6 x 250mm, 5 μm;
a detector: VWD (ultraviolet detector);
flow rate: 1.0 mL/min;
column temperature: 40 ℃;
sample introduction amount: 50 mu L of the solution;
detection wavelength: 220 nm;
mobile phase A: 0.15% phosphoric acid aqueous solution (V: V) having a pH of 2.0;
mobile phase B: acetonitrile;
elution procedure:
| time (min) | Mobile phase A | |
| 0 | 100 | 0 |
| 10.00 | 100 | 0 |
| 25.00 | 40 | 60 |
| 25.01 | 100 | 0 |
| 35 | 100 | 0 |
Operating time: and (5) 35 min.
Experimental procedure
1) Diluent/blank solution: a mobile phase A;
2) impurity control stock solution: taking about 5mg of each of the 4-aminophenol reference substance and the 2-aminophenol reference substance, precisely weighing the reference substances to a volumetric flask of 1000mL, adding a proper amount of diluent, ultrasonically dissolving, diluting with the diluent to a constant volume to a scale, and shaking up to obtain an impurity reference substance stock solution (the concentration is about 5000 ppm).
3) Taking 10 mesalazine sustained-release tablets, grinding, weighing about 117mg (equivalent to 100mg of mesalazine) of tablet powder, precisely weighing into a 100mL volumetric flask, adding a diluent with about half volume of the volumetric flask, ultrasonically dissolving, precisely transferring 4mL of the impurity reference substance stock solution into the same volumetric flask, adding a small amount of the diluent, washing the residual solution on the wall, shaking for 30min, diluting with the diluent to a constant volume, shaking uniformly, centrifuging (10000rpm, 10min), and taking supernatant to obtain the mesalazine sustained-release tablet.
4) Taking blank solution, test solution and sensitizing solution, performing high performance liquid chromatography analysis according to the above conditions, and recording chromatogram, as shown in FIG. 6-FIG. 8.
Example 3: precision test
Apparatus and conditions
A chromatographic column: phenomenex Luna PFP (2), 4.6 x 250mm, 5 μm;
a detector: VWD (ultraviolet detector);
flow rate: 1.0 mL/min;
column temperature: 40 ℃;
sample introduction amount: 50 mu L of the solution;
detection wavelength: 220 nm;
mobile phase A: 0.15% phosphoric acid aqueous solution (V: V) having a pH of 2.0;
mobile phase B: acetonitrile;
elution procedure:
operating time: and (5) 35 min.
Experimental procedure
1) Diluent/blank solution: a mobile phase A;
2) 2-aminophenol stock solution: precisely weighing about 5mg of 2-aminophenol reference substance, placing the reference substance into a 1000mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, adding the diluent to achieve constant volume and diluting to a scale, shaking up to obtain 2-aminophenol stock solution with the concentration of about 0.005mg/mL, and preparing two parts in parallel;
3) 4-aminophenol stock solution: taking about 5mg of 4-aminophenol reference substance, precisely weighing, placing in a 250mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, diluting with the diluent to a constant volume to scale, shaking up to obtain 4-aminophenol stock solution with the concentration of about 0.02mg/mL, and preparing two parts in parallel;
4) control solution: precisely transferring 2.0mL of the 2-aminophenol stock solution in the step 2) and 2.0mL to 200mL of the 4-aminophenol stock solution in the step 3) into volumetric flasks respectively, diluting the volumetric flasks to a constant volume to a scale by using a diluent, shaking up to obtain a reference solution with the 2-aminophenol content of about 50ppm and the 4-aminophenol content of about 200ppm, and preparing two parts in parallel;
5) impurity control stock solution: taking about 5mg of each of a 4-aminophenol reference substance and a 2-aminophenol reference substance, precisely weighing the reference substances into a volumetric flask of 1000mL, adding a proper amount of diluent, ultrasonically dissolving, diluting with the diluent to a constant volume to a scale, and shaking up to obtain the product (the concentration is about 5000 ppm);
6) test solution: taking 10 mesalazine sustained-release tablets, grinding, precisely weighing about 117mg (equivalent to 100mg of mesalazine) of the tablet powder, putting the tablet powder into a 100mL volumetric flask, adding a diluent with half of the volume of the volumetric flask, ultrasonically dissolving, precisely transferring 4mL of the impurity reference substance stock solution obtained in the step 5) into the same volumetric flask, diluting with the diluent to a constant volume to a scale, shaking up, centrifuging (10000rpm, 10min), taking supernatant to obtain a sample solution with the mesalazine concentration of about 1mg/mL, and preparing 6 parts in parallel;
7) the blank solution, the reference solution and the sample solution were respectively subjected to high performance liquid chromatography analysis under the above conditions, and chromatograms were recorded, with the results shown in tables 9 and 10.
Table 9: 4-aminophenol analysis repeatability investigation result
Table 10: 2-aminophenol analysis repeatability investigation result
Example 4: accuracy test
Apparatus and conditions
A chromatographic column: phenomenex Luna PFP (2), 4.6 x 250mm, 5 μm;
a detector: VWD (ultraviolet detector);
flow rate: 1.0 mL/min;
column temperature: 40 ℃;
sample introduction amount: 50 mu L of the solution;
detection wavelength: 220 nm;
mobile phase A: 0.15% phosphoric acid aqueous solution (V: V) having a pH of 2.0;
mobile phase B: acetonitrile;
elution procedure:
| time (min) | Mobile phase A | |
| 0 | 100 | 0 |
| 10.00 | 100 | 0 |
| 25.00 | 40 | 60 |
| 25.01 | 100 | 0 |
| 35 | 100 | 0 |
Operating time: and (5) 35 min.
Experimental procedure
1) Diluent/blank solution: a mobile phase A;
2) 2-aminophenol stock solution: precisely weighing about 5mg of 2-aminophenol reference substance, placing the reference substance into a 1000mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, adding the diluent to achieve constant volume and diluting to a scale, shaking up to obtain 2-aminophenol stock solution with the concentration of about 0.005mg/mL, and preparing two parts in parallel;
3) 4-aminophenol stock solution: taking about 5mg of 4-aminophenol reference substance, precisely weighing, placing in a 250mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, diluting with the diluent to a constant volume to scale, shaking up to obtain 4-aminophenol stock solution with the concentration of about 0.02mg/mL, and preparing two parts in parallel;
4) control solution: precisely transferring 2.0mL of the 2-aminophenol stock solution in the step 2) and 2.0mL to 200mL of the 4-aminophenol stock solution in the step 3) into volumetric flasks respectively, diluting the volumetric flasks to a constant volume to a scale by using a diluent, shaking up to obtain a reference solution with the 2-aminophenol content of about 50ppm and the 4-aminophenol content of about 200ppm, and preparing two parts in parallel;
5) 2-aminophenol, 4-aminophenol accuracy stock solutions: respectively weighing 5mg of 2-aminophenol and 5mg of 4-aminophenol as reference substances, precisely weighing, placing in a 1000mL measuring flask, ultrasonically dissolving, dissolving and diluting to a scale by using a diluent, shaking uniformly to obtain 3 parts in parallel;
6) test solution: taking 10 mesalazine sustained-release tablets, grinding, precisely weighing about 117mg (equivalent to 100mg of mesalazine) of the tablet powder, putting the tablet powder into a 100mL volumetric flask, adding a diluent with half of the volume of the volumetric flask, ultrasonically dissolving, diluting with the diluent to a constant volume to a scale, shaking up, centrifuging (10000rpm for 10min), and taking supernatant to obtain a sample solution with the mesalazine concentration of about 1 mg/mL;
7) preparing an accurate solution: accuracy solutions were prepared for each concentration level according to the following table, in parallel with 3 parts.
Table 11: table for 2-aminophenol/4-aminophenol accurate solutions
| Concentration level (%) | Detection limit | Limit of quantification | 100 | 125 |
| Accuracy stock solution (mL) | 1 | 2 | 4 | 5 |
| Volumetric flask (mL) | 250 | 200 | 100 | 100 |
| Test article (mg) | 117 | 117 | 117 | 117 |
| 2-aminophenol theoretical concentration (ppm) | 20 | 50 | 200 | 250 |
| Theoretical concentration of 4-aminophenol (ppm) | 20 | 50 | 200 | 250 |
8) Taking blank solution, reference solution, sample solution, and each concentration accuracy solution, performing high performance liquid chromatography analysis under the above conditions, and recording chromatogram, the results are shown in Table 12 and Table 13.
Table 12: 2-aminophenol accuracy results
Table 13: 4-aminophenol accuracy results
Example 5
Apparatus and conditions
A chromatographic column: phenomenex Luna PFP (2), 4.6 x 250mm, 5 μm;
a detector: VWD (ultraviolet detector);
flow rate: 1.0 mL/min;
column temperature: 40 ℃;
sample introduction amount: 50 mu L of the solution;
detection wavelength: 220 nm;
mobile phase A: 0.15% phosphoric acid aqueous solution (V: V) having a pH of 2.0;
mobile phase B: acetonitrile;
elution procedure:
| time (min) | Mobile phase A | |
| 0 | 100 | 0 |
| 10.00 | 100 | 0 |
| 25.00 | 40 | 60 |
| 25.01 | 100 | 0 |
| 35 | 100 | 0 |
Operating time: and (5) 35 min.
Experimental procedure
1) Diluent/blank solution: a mobile phase A;
2) 2-aminophenol stock solution: taking about 5mg of 2-aminophenol reference substance, precisely weighing, placing in a 1000mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, adding the diluent to achieve constant volume and diluting to a scale, shaking up to obtain 0.005mg/mL 2-aminophenol stock solution, and preparing two parts in parallel;
3) 4-aminophenol stock solution: taking about 5mg of 4-aminophenol reference substance, precisely weighing, placing in a 250mL volumetric flask, adding about half of volumetric flask volume of diluent, ultrasonically dissolving, diluting with the diluent to a constant volume to scale, shaking up to obtain 0.02mg/mL 4-aminophenol stock solution, and preparing two parts in parallel;
4) control solution: precisely transferring 2.0mL of the 2-aminophenol stock solution in the step 2) and 2.0mL to 200mL of the 4-aminophenol stock solution in the step 3) into volumetric flasks respectively, diluting the volumetric flasks to a constant volume to a scale by using a diluent, shaking up to obtain a reference solution with the 2-aminophenol content of about 50ppm and the 4-aminophenol content of about 200ppm, and preparing two parts in parallel;
5) test solution: taking 10 mesalazine sustained release tablets from three samples of different batches, grinding the three samples into powder, precisely weighing about 117mg (equivalent to 100mg of mesalazine) of the tablet powder, putting the powder into a 100mL volumetric flask, adding a diluent with half of the volume of the volumetric flask, ultrasonically dissolving, diluting the powder to a constant volume to a scale by using the diluent, shaking up, centrifuging (10000rpm for 10min), and taking supernatant to obtain a sample solution with the mesalazine concentration of about 1 mg/mL;
6) the blank solution, the reference solution and the sample solution were subjected to high performance liquid chromatography analysis under the above conditions, and chromatograms were recorded as shown in FIGS. 9 to 11, and the results are shown in Table 14.
Table 14: results of sample testing
Claims (10)
1. A method for separating and detecting genotoxic impurities in a mesalazine sustained-release preparation comprises the following steps: taking a mesalazine sustained-release preparation sample solution, adopting a pentafluorophenyl bonded silica gel chromatographic column, eluting with a mobile phase A and a mobile phase B, wherein the phase A is an acid water solution, the phase B is acetonitrile, and genotoxic impurities in the mesalazine sustained-release preparation are at least one of 2-aminophenol and 4-aminophenol.
2. The method of claim 1, wherein the chromatography column is Phenomenex Luna PFP (2).
3. The method according to claim 1, wherein the acid in the mobile phase A is phosphoric acid with a concentration of 0.10% -0.20%, and the pH value of the mobile phase A is in the range of 1.9-2.2.
4. A method according to any of claims 1-3, comprising the steps of:
1) taking a mesalazine sustained release preparation sample, and preparing a sample solution with the concentration of 1.0 mg/mL;
2) setting instrument parameters: the flow rate of the mobile phase, the column temperature of the chromatographic column, the elution procedure and the detection wavelength;
3) injecting the sample solution obtained in the step 1) into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and determination of genotoxic impurities in the mesalazine sustained-release preparation.
5. The method according to claim 4, wherein the elution procedure is from 0min to 10min by volume: mobile phase A, mobile phase B is 100: 0;
10min-25 min: mobile phase A, mobile phase B is 40: 60; 25.01min-35 min: mobile phase a and mobile phase B were 100: 0.
6. The method of claim 4, wherein the flow rate of the mobile phase is from 0.5mL/min to 1.5 mL/min.
7. The method of claim 4, wherein the detection wavelength is 215nm to 225 nm.
8. The method of claim 4, wherein the column temperature of the chromatography column is between 35 ℃ and 45 ℃.
9. The method according to any one of claims 1-8, comprising the steps of:
1) taking a mesalazine sustained release preparation sample, and preparing a solution with the concentration of 1.0 mg/mL;
2) setting the flow rate of a mobile phase to be 0.5mL/min-1.5mL/min, the column temperature of a chromatographic column to be 35-45 ℃, the detection wavelength to be 215nm-225nm, and the elution procedure to be 0min-10min according to the volume ratio: mobile phase A, mobile phase B is 100: 0; 10min-25 min: mobile phase A, mobile phase B is 40: 60; 25.01min-35 min: mobile phase A, mobile phase B is 100: 0;
3) and (2) injecting 40-60 mu L of the sample solution obtained in the step 1) into a high performance liquid chromatograph, recording a chromatogram, and completing separation and determination of genotoxic impurities in the mesalazine sustained-release preparation.
10. The method according to any one of claims 1-9, comprising the steps of:
1) taking a mesalazine sustained release preparation sample, and preparing a solution with the concentration of 1.0 mg/mL;
2) setting the flow rate of a mobile phase to be 1.0mL/min, the column temperature of a chromatographic column to be 40 ℃, the detection wavelength to be 220nm, and the elution procedure to be 0-10 min according to the volume ratio: mobile phase A, mobile phase B is 100: 0; 10min-25 min: mobile phase A, mobile phase B is 40: 60; 25.01min-35 min: mobile phase A, mobile phase B is 100: 0;
3) and (2) injecting 50 mu L of the sample solution obtained in the step 1) into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and determination of genotoxic impurities in the mesalazine sustained-release preparation.
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