CN116699007A - Analysis method of related substances in tolterodine tartrate - Google Patents
Analysis method of related substances in tolterodine tartrate Download PDFInfo
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- CN116699007A CN116699007A CN202310368694.3A CN202310368694A CN116699007A CN 116699007 A CN116699007 A CN 116699007A CN 202310368694 A CN202310368694 A CN 202310368694A CN 116699007 A CN116699007 A CN 116699007A
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- YYSCJLLOWOUSHH-UHFFFAOYSA-N 4,4'-disulfanyldibutanoic acid Chemical compound OC(=O)CCCSSCCCC(O)=O YYSCJLLOWOUSHH-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960003553 tolterodine tartrate Drugs 0.000 title claims abstract description 70
- 239000000126 substance Substances 0.000 title claims abstract description 39
- 238000004458 analytical method Methods 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 34
- 238000010828 elution Methods 0.000 claims abstract description 15
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007853 buffer solution Substances 0.000 claims abstract description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 239000000243 solution Substances 0.000 claims description 37
- 238000001514 detection method Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000012488 sample solution Substances 0.000 claims description 12
- 239000000523 sample Substances 0.000 claims description 11
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 claims description 10
- 229910001488 sodium perchlorate Inorganic materials 0.000 claims description 10
- 239000012085 test solution Substances 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 238000004811 liquid chromatography Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 10
- 238000000926 separation method Methods 0.000 abstract description 5
- 239000011259 mixed solution Substances 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 238000005259 measurement Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 66
- 238000011084 recovery Methods 0.000 description 26
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 10
- 239000012490 blank solution Substances 0.000 description 9
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 5
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 5
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 5
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- 206010027566 Micturition urgency Diseases 0.000 description 2
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- PMOYGPUADPCBHF-UHFFFAOYSA-N acetonitrile;perchloric acid;hydrate Chemical compound O.CC#N.OCl(=O)(=O)=O PMOYGPUADPCBHF-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- 208000020629 overactive bladder Diseases 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- KUFFULVDNCHOFZ-UHFFFAOYSA-N 2,4-xylenol Chemical compound CC1=CC=C(O)C(C)=C1 KUFFULVDNCHOFZ-UHFFFAOYSA-N 0.000 description 1
- -1 2-hydroxy-5-methylphenyl Chemical group 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 239000006012 monoammonium phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 208000022934 urinary frequency Diseases 0.000 description 1
- 230000036318 urination frequency Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to an analysis method of related substances in tolterodine tartrate, which adopts high performance liquid chromatography, and specifically comprises the following steps: octadecyl bonded silica gel is adopted as chromatographic column filler, and mixed solution of perchlorate buffer solution and organic solvent is adopted as mobile phase for gradient elution, and the method has the characteristics of simplicity, specificity, accuracy and high sensitivity. The application solves the separation and measurement problems of the related substances of tolterodine tartrate, and provides technical guarantee for ensuring the quality of tolterodine tartrate and the safety of subsequent medicines.
Description
Technical Field
The application belongs to the technical field of medicine analysis, and particularly relates to an analysis method of related substances in tolterodine tartrate.
Background
Tolterodine tartrate, chemical name (R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-amphetamine L (+) -tartrate, of formula C 22 H 31 NO·C 4 H 6 O 6 The molecular weight is 475.57, and the structural formula is shown as follows:
。
tolterodine tartrate is a generally non-hygroscopic, white or off-white crystalline powder. Tolterodine tartrate is a competitive M receptor antagonist drug, mainly for the treatment of urinary frequency, urgency or urgency and/or urge incontinence symptoms caused by overactive bladder (OAB).
During the production of tolterodine tartrate as a bulk drug or during the preparation of a formulation, some impurities may be generated. The european pharmacopoeia version 10.8 lists 6 impurities of tolterodine tartrate and the us pharmacopoeia 2021 lists 8 impurities, but according to the process of tolterodine tartrate (shown below), the above impurities are not all impurities of tolterodine tartrate related substance studies. Analysis of tolterodine tartrate process: the starting materials p-cresol and cinnamyl alcohol may have residues; intermediate 1 may have residues; p-cresol and the intermediate 1 undergo side reaction to generate an impurity M and an impurity N; m-cresol, o-cresol, 2, 4-m-xylenol and phenol impurities possibly remain in the p-cresol, and can undergo side reaction with the intermediate 1 to generate impurities H, J, K and L; impurities 1B, 1C, and cinnamyl alcohol remaining in intermediate 1 may react with p-cresol to form impurities C, D, and G. Through the analysis, the prior analysis technology can not effectively detect and separate tolterodine tartrate and 14 impurities.
。
In European pharmacopoeia 10.8, a detection method is disclosed, wherein a mobile phase A adopts a mixed solution of a monoamine phosphate buffer solution and methanol, a mobile phase B adopts methanol, gradient elution is carried out, and a system applicability solution is detected according to the method: the impurity D does not generate a peak, the impurity C coincides with a main peak, and the main peak and each impurity peak are different in shape.
In the U.S. pharmacopoeia 2021 standard, a detection method is disclosed, wherein a mobile phase A adopts a mixed solution of acetonitrile-water-perchloric acid, a mobile phase B adopts a mixed solution of acetonitrile-water-perchloric acid, a mobile phase C adopts acetonitrile, gradient elution is carried out, and a system applicability solution is detected according to the method: tolterodine tartrate is coincident with impurity E, impurity J, impurity L, impurity H and impurity B, impurity M and impurity N do not show peaks, and impurity G and impurity F have poor separation degree.
Therefore, in the situation that the prior art has the problems, there is a need to improve the analysis method of tolterodine tartrate related substances, and establish a rapid and effective detection analysis method to distinguish and detect and analyze related substances in tolterodine tartrate bulk drugs.
Disclosure of Invention
The application aims to provide an analysis method of related substances in tolterodine tartrate, which is used for rapidly and effectively detecting and analyzing the related substances in tolterodine tartrate bulk drugs.
According to one aspect of the present application, there is provided a method for analyzing a substance of interest in tolterodine tartrate by high performance liquid chromatography under the following chromatographic conditions: the chromatographic column uses octadecyl bonded silica gel as filler, mobile phase A is perchlorate buffer solution, and mobile phase B is organic solvent, and gradient elution is carried out.
Further, the analysis method of the related substances in tolterodine tartrate is characterized in that the analysis of the detected related substances is as follows:
。
further, the mobile phase A is a sodium perchlorate buffer solution with a pH value of 2.0-6.0, and the mobile phase B is methanol.
Further, the mobile phase A is preferably a sodium perchlorate buffer solution with a pH value of 3.0.
Further, the analysis method of the related substances in tolterodine tartrate comprises the following steps:
1) Preparation of test solution: taking a proper amount of tolterodine tartrate raw material, and dissolving and diluting the tolterodine tartrate raw material by using a diluent to prepare a solution containing 2.0-3.0 mg of tolterodine tartrate in each 1ml serving as a sample solution;
2) Preparation of control solution: measuring a sample solution, quantitatively diluting the sample solution into a solution containing 10-15 mu g of tolterodine tartrate per 1ml by using a diluent, and taking the solution as a control solution;
3) And (3) measuring: adopting a C18 reversed phase chromatographic column, taking a sodium perchlorate buffer solution as a mobile phase A, taking methanol as a mobile phase B, taking a sample solution and a control solution, respectively injecting into a liquid chromatograph, and performing gradient elution.
Further, the analysis method of the related substances in tolterodine tartrate comprises the following gradient elution procedures:
。
further, the concentration of the test solution was 2.0mg/ml.
Further, the diluent is 40-60% methanol aqueous solution.
Further, the analysis method of the related substances in tolterodine tartrate, wherein the analysis conditions of the liquid chromatograph include one or more of the following (i) to (iv):
(i) The temperature of the chromatographic column is 35+/-5 ℃;
(ii) a flow rate of 0.8 to 1.2ml/min;
(iii) the sample injection amount is 10-20 μl;
(iv) the detection wavelength is 220nm.
The application has the beneficial effects that:
1. the analysis method of the related substances in tolterodine tartrate provided by the application has the advantages that the related substances which can be separated and detected are more than those in the prior art, the analysis of the raw material medicines is more comprehensive, the detection and separation can be effectively carried out, and the analysis method has the characteristics of simplicity, convenience, specificity, accuracy and high sensitivity;
2. the application screens out the optimal chromatographic analysis condition and solution preparation method. Experiments prove that the high performance liquid chromatography analysis method of the tolterodine tartrate related substances provided by the application has good stability and good separation degree, can effectively separate related substances and accurately detect the content of the related substances, is beneficial to objectively, accurately and comprehensively evaluating the quality of tolterodine tartrate, provides technical guarantees for ensuring the quality of tolterodine tartrate and the safety of subsequent medicines, and has important practical significance for controlling the quality of products;
3. the analysis method of related substances in tolterodine tartrate is simple and convenient to operate and suitable for practical application and popularization.
Drawings
FIG. 1 is a chromatogram of a blank solution of example 1.
FIG. 2 is a chromatogram of a solution suitable for use in the system of example 1.
FIG. 3 is a chromatogram of the sample solution of example 1.
FIG. 4 is a blank solution chromatogram at a pH of 2.0 for mobile phase A of example 3.
FIG. 5 is a system applicability solution chromatogram at pH 2.0 for mobile phase A of example 3.
FIG. 6 is a blank solution chromatogram at pH 6.0 for mobile phase A of example 3.
FIG. 7 is a system applicability solution chromatogram at pH 6.0 for mobile phase A of example 3.
FIG. 8 is a chromatogram of comparative example 1 system applicability solution.
FIG. 9 is a chromatogram of comparative example 2 system applicability solution.
Description of the embodiments
The application is further illustrated by the following examples. The following examples are merely illustrative of the present application and should not be construed as limiting the application.
The reagents and raw materials used in the application are all commercially available.
Example 1
A method for analyzing tolterodine tartrate-related substances, comprising the steps of:
(1) Preparation of test solution:
weighing a proper amount of tolterodine tartrate sample, precisely weighing, adding 50% methanol (namely methanol-water (50:50)) to dissolve and dilute to prepare tolterodine tartrate solution containing 2-3 mg per 1 ml;
(2) Preparation of control solution:
measuring a sample solution, and adding 50% methanol to dilute the sample solution to prepare a solution containing about 10-15 mug of tolterodine tartrate in each 1 ml;
(3) System applicability solution preparation:
system applicability solution: taking a proper amount of tolterodine tartrate sample, impurity cinnamyl alcohol, impurity p-cresol, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H, impurity J, impurity K, impurity L, impurity M and impurity N, adding 50% methanol to dissolve and dilute the tolterodine tartrate sample, the impurity cinnamyl alcohol, the impurity p-cresol, the impurity B, the impurity C, the impurity D, the impurity E, the impurity F, the impurity G, the impurity H, the impurity J, the impurity K, the impurity L, the impurity M and the impurity N, and preparing a solution containing about 2mg tolterodine tartrate per 1ml and about 1 mug of each impurity;
(4) Preparation of mobile phase: 14.05g of sodium perchlorate is weighed, 1L of water is added to dissolve the sodium perchlorate, the pH value is regulated to 3.0 by using perchloric acid, and a mobile phase A is prepared and methanol is used as a mobile phase B;
(5) And (3) measuring: the C18 chromatographic column with octadecyl bonded silica gel as stuffing and sodium perchlorate buffer solution of pH3.0 as mobile phase A and methanol as mobile phase B are adopted for gradient elution.
The procedure for gradient elution is as follows:
。
taking blank solution (the blank solution preparation method comprises dissolving tartaric acid in 50% methanol, diluting to obtain solution containing 0.6mg tartaric acid per lml), system applicability solution, and test solution, injecting 10 μl of control solution into liquid chromatograph, and recording chromatogram.
The substances of interest to be detected and isolated are shown in the following table:
。
wherein, the operation conditions of the liquid chromatography are as follows:
chromatographic column: welch Ultimate AQ-C18 (4.6X105 mm,3 μm), column temperature 35 ℃, flow rate 1.0ml/min, sample injection 10 μl, and detection wavelength 220nm.
The detected chromatograms are shown in fig. 1-3, wherein fig. 1 is a blank solution map, fig. 2 is a system applicability solution map, and fig. 3 is a sample solution map. Each impurity localization solution (1 μg/ml) was prepared and the method was subjected to specificity verification with the results shown in the following table:
。
from fig. 1 to fig. 3, it can be seen that the blank solution has no interference to sample detection, 14 impurities in tolterodine tartrate bulk drug and tolterodine tartrate can be completely detected and separated, the peak shape is good and no tailing exists, and the method provided by the application has the advantages of good detection effect, simplicity, convenience, specificity, accuracy and high sensitivity, and completely meets the actual needs. Under the same conditions, the test was conducted 6 times by the method of this example, and the reproducibility of the test was good.
The method is used for detecting limit and quantitative limit measurement, and the results are shown in the following table:
。
the accuracy test results are as follows:
in the range of 50% -150% of the limit concentration, the recovery rate of cinnamyl alcohol is 99.23% -101.04%, the average recovery rate is 99.87%, and the RSD is 0.67%; the recovery rate of the p-cresol is 94.32-96.14%, the average recovery rate is 95.05%, and the RSD is 0.79%; the recovery rate of the impurity B is 98.91-102.36%, the average recovery rate is 100.10%, and the RSD is 1.22%; the recovery rate of impurity C is 99.43-102.04%, the average recovery rate is 100.44%, and the RSD is 0.93%; the recovery rate of impurity D is 96.73% -100.55%, the average recovery rate is 98.22%, and the RSD is 1.56%; the recovery rate of the impurity E is 94.49-96.87%, the average recovery rate is 95.46%, and the RSD is 0.79%; the recovery rate of impurity F is 93.94-95.98%, the average recovery rate is 94.71%, and the RSD is 0.79%; the recovery rate of the impurity G is 95.35-97.61%, the average recovery rate is 96.41%, and the RSD is 0.87%; 94.06% -96.12% of impurity H, 94.82% of average recovery rate and 0.86% of RSD; the recovery rate of the impurity J is 100.55-103.13%, the average recovery rate is 102.15%, and the RSD is 0.96%; 96.94% -99.65% of impurity K recovery rate, 97.84% of average recovery rate and 0.80% of RSD; the recovery rate of the impurity L is 102.09-105.21%, the average recovery rate is 103.26%, and the RSD is 1.08%; the recovery rate of impurity M is 100.86-103.43%, the average recovery rate is 101.90%, and the RSD is 0.94%; 97.30% -99.98% of impurity N, 99.09% of average recovery and 0.83% of RSD; the result shows that the measuring method is accurate and reliable.
Example 2
The chromatographic conditions of example 1 were changed, and the operations were the same as in example 1 except for the changed parameters as shown in the following table.
。
Experiments are carried out according to the changed chromatographic condition parameters, chromatograms are recorded, and experimental results show that the 14 impurities in the tolterodine tartrate bulk drug and tolterodine tartrate can be completely separated by changing the flow rate (+ -0.2 ml/min), the column temperature (+ -5 ℃) and using chromatographic columns of different types and specifications, so that the analysis method provided by the application has good detection effect and better durability, and completely meets the actual needs.
Example 3
The mobile phase pH was examined.
Preparation of mobile phase: 14.05g of sodium perchlorate is weighed, 1L of water is added for dissolution, the pH is respectively adjusted to 2.0 and 6.0 by perchloric acid, a mobile phase A is prepared for standby, and methanol is used as a mobile phase B.
Other operating conditions were the same as in example 1.
Taking 10 mu l of each of the hollow white solution and the system applicability solution in the embodiment 1, respectively injecting into a liquid chromatograph, detecting and recording a chromatogram; fig. 4 is a chromatogram of a blank solution at a pH of 2.0 for mobile phase a, fig. 5 is a chromatogram of a system-suitable solution at a pH of 2.0, fig. 6 is a chromatogram of a blank solution at a pH of 6.0 for mobile phase a, and fig. 7 is a chromatogram of a system-suitable solution at a pH of 6.0.
As can be seen from fig. 4 to fig. 7, the pH value of the mobile phase a is changed to 2.0 to 6.0, and 14 impurities in the tolterodine tartrate bulk drug and tolterodine tartrate can be completely separated, so that the peak shape is good and no tailing exists.
Comparative example 1
The determination was carried out according to the European pharmacopoeia (EP 10.8) method, which is a method for determining tolterodine tartrate related substances:
a method for analyzing tolterodine tartrate-related substances, comprising the steps of:
preparation of test solution: the tolterodine tartrate sample is weighed in proper amount, precisely weighed, dissolved in methanol and diluted to prepare a solution containing about 1mg of tolterodine tartrate per 1 ml.
Wherein, the conditions of the liquid chromatography are as follows:
chromatographic column: thermo BDS Hypersil C18 (4.6X250 mm,5 μm); the flow rate is 1.5ml/min, the sample injection amount is 20 μl, and the detection wavelength is 220 nm;
mobile phase a:2.88g of monoammonium phosphate is dissolved by adding 450ml of water, added with 5ml of triethylamine and uniformly mixed, the pH value is regulated to 5.9 by 50% of phosphoric acid, 450ml is taken and uniformly mixed with 550ml of methanol;
mobile phase B: methanol;
gradient elution was used, and the procedure for gradient elution was as follows:
| time (min) | Mobile phase a | Mobile phase B |
| 0 | 100% | 0% |
| 25 | 100% | 0% |
| 45 | 80% | 20% |
。
Through detection, the chromatogram is shown in fig. 8, the impurity D does not generate a peak, the impurity C coincides with a main peak, the shape of the main peak is different from that of each impurity peak, and the actual requirement is not met.
Comparative example 2
The determination was performed according to the method of the United states Pharmacopeia (USP 2021), which is a method of tolterodine tartrate related substance:
a method for analyzing tolterodine tartrate-related substances, comprising the steps of:
preparation of test solution: a proper amount of tolterodine tartrate sample is weighed, precisely weighed, dissolved in 50% methanol and diluted to prepare a solution containing about 10mg of tolterodine tartrate per 1 ml.
Wherein, the conditions of the liquid chromatography are as follows:
chromatographic column: thermo ODS Hypersil C18 (4.6X250 mm,5 μm); the flow rate is 1.0ml/min, the sample injection amount is 10 μl, and the detection wavelength is 220 nm;
mobile phase a: mixing 100ml of acetonitrile, 900ml of water and 1.5ml of perchloric acid uniformly;
mobile phase B: mixing 500ml of acetonitrile, 500ml of water and 1.5ml of perchloric acid uniformly;
mobile phase C: acetonitrile;
gradient elution was performed, and the procedure of gradient elution was as follows:
| time (min) | Mobile phase a | Mobile phase B | Mobile phase C |
| 0 | 75% | 25% | 0% |
| 5 | 75% | 25% | 0% |
| 22 | 0% | 100% | 0% |
| 47 | 0% | 0% | 100% |
| 57 | 0% | 0% | 100% |
。
Through detection, the chromatogram is shown in fig. 9, tolterodine tartrate is overlapped with impurity E, impurity J, impurity L, impurity H and impurity B, impurity M and impurity N do not show peaks, and impurity G and impurity F have poor separation degree and do not meet the actual needs.
The foregoing is a further detailed description of the application in connection with specific embodiments, and it is not intended that the application be limited to such description. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the application, and these should be considered to be within the scope of the application.
Claims (9)
1. A method for analyzing related substances in tolterodine tartrate, the method adopting high performance liquid chromatography, characterized in that the chromatographic conditions are as follows: the chromatographic column uses octadecyl bonded silica gel as filler, mobile phase A is perchlorate buffer solution, and mobile phase B is organic solvent, and gradient elution is carried out.
2. The method for analyzing a substance of interest in tolterodine tartrate according to claim 1, wherein said substance of interest is as follows:
。
3. the method for analyzing a substance of interest in tolterodine tartrate according to claim 1,
the mobile phase A is sodium perchlorate buffer solution with the pH value of 2.0-6.0, and the mobile phase B is methanol.
4. The method for analyzing a substance of interest in tolterodine tartrate according to claim 3,
the mobile phase A is sodium perchlorate buffer solution with pH value of 3.0.
5. The method for analyzing a substance of interest in tolterodine tartrate according to claim 1, wherein said analyzing method comprises the steps of:
1) Preparation of test solution: taking a proper amount of tolterodine tartrate raw material, and dissolving and diluting the tolterodine tartrate raw material by using a diluent to prepare a solution containing 2.0-3.0 mg of tolterodine tartrate in each 1ml serving as a sample solution;
2) Preparation of control solution: measuring a sample solution, quantitatively diluting the sample solution into a solution containing 10-15 mu g of tolterodine tartrate per 1ml by using a diluent, and taking the solution as a control solution;
3) And (3) measuring: adopting a C18 reversed phase chromatographic column, taking a sodium perchlorate buffer solution as a mobile phase A, taking methanol as a mobile phase B, taking a sample solution and a control solution, respectively injecting into a liquid chromatograph, and performing gradient elution.
6. The method for analyzing a substance of interest in tolterodine tartrate according to claim 5,
the procedure for the gradient elution was as follows:
。
7. the method for analyzing a substance of interest in tolterodine tartrate according to claim 5,
the concentration of tolterodine tartrate in the test solution was 2.0mg/ml.
8. The method for analyzing a substance of interest in tolterodine tartrate according to claim 5,
the diluent is 40-60% methanol aqueous solution.
9. The method for analyzing a substance of interest in tolterodine tartrate according to any one of claim 1 to 8, wherein,
wherein the analysis conditions of the liquid chromatography include one or more of the following (i) to (iv):
the temperature of the chromatographic column is 35+/-5 ℃,
(ii) a flow rate of 0.8 to 1.2ml/min;
(iii) the sample introduction amount is 10-20 μl,
(iv) the detection wavelength is 220nm.
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