CN116165306B - Analysis and determination method and application of related substances in ketoprofen gel plaster - Google Patents
Analysis and determination method and application of related substances in ketoprofen gel plaster Download PDFInfo
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- 229960000991 ketoprofen Drugs 0.000 title claims abstract description 88
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 46
- 239000000126 substance Substances 0.000 title claims abstract description 32
- 239000011505 plaster Substances 0.000 title claims abstract description 19
- 238000004458 analytical method Methods 0.000 title claims abstract description 9
- PPNGALBGZJBTRY-UHFFFAOYSA-N 1-(3-benzoylphenyl)ethanone Chemical compound CC(=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 PPNGALBGZJBTRY-UHFFFAOYSA-N 0.000 claims abstract description 35
- CQSMNXCTDMLMLM-UHFFFAOYSA-N ethyl 2-(3-benzoylphenyl)propanoate Chemical compound CCOC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 CQSMNXCTDMLMLM-UHFFFAOYSA-N 0.000 claims abstract description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010828 elution Methods 0.000 claims abstract description 11
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 6
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000012488 sample solution Substances 0.000 claims description 21
- 239000012085 test solution Substances 0.000 claims description 14
- 238000001514 detection method Methods 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000004811 liquid chromatography Methods 0.000 claims description 5
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 5
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 5
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 5
- 238000003908 quality control method Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000010008 shearing Methods 0.000 claims description 4
- 230000001502 supplementing effect Effects 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 238000009210 therapy by ultrasound Methods 0.000 claims description 2
- 238000012801 analytical assay Methods 0.000 claims 5
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 17
- 238000012937 correction Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 8
- 239000013558 reference substance Substances 0.000 description 7
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229960000381 omeprazole Drugs 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- -1 aryl propionic acid Chemical compound 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- NJTGANWAUPEOAX-UHFFFAOYSA-N molport-023-220-454 Chemical compound OCC(O)CO.OCC(O)CO NJTGANWAUPEOAX-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
-
- 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
-
- 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
- G01N30/14—Preparation by elimination of some components
-
- 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
-
- 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
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
-
- 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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an analysis and determination method and application of related substances in ketoprofen gel plaster. The chromatographic condition of the method uses octadecylsilane chemically bonded silica as a filler, adopts water-phosphate buffer solution as a mobile phase A and acetonitrile as a mobile phase B, and carries out gradient elution. The method of the invention can better separate and measure related substances in the ketoprofen gel plaster, wherein the related substances comprise, but are not limited to, ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester; the method has the advantages of high specificity, high sensitivity, good repeatability and stability and high accuracy.
Description
Technical Field
The invention relates to the technical field of chemical analysis, in particular to an analysis and determination method and application of related substances in ketoprofen gel plaster.
Background
Ketoprofen is an aryl propionic acid non-steroidal anti-inflammatory drug, belongs to a derivative of phenylpropionic acid, and has good antipyretic, analgesic and anti-inflammatory effects. The main action mechanism is to inhibit the synthesis of prostaglandin and leukotriene by reversible inhibition of cyclooxygenase and lipoxygenase, and is widely applied to rheumatic arthritis, rheumatoid arthritis, ankylosing spondylitis and arthritis symptoms caused by gout, as well as general joint pain, swelling and other pains, such as dysmenorrheal, toothache, postoperative pain and the like.
However, the carboxyl in the structural formula is easy to carry out esterification reaction with hydroxyl, in particular, the ketoprofen gel plaster takes glycerol (glycerol) as an auxiliary material to be used as a humectant, and the prescription dosage is only inferior to purified water, so that the hydroxyl in the glycerol is easy to carry out esterification reaction with the carboxyl in the ketoprofen molecule serving as an active ingredient, and impurities shown in the following chemical structural formula are generated or exist:
。
wherein the ketoprofen impurity A mainly originates from raw materials, and the related impurities can reduce the content of the ketoprofen serving as an effective component and influence the treatment effect. And meanwhile, the separation and determination of various impurities such as ketoprofen glyceride, ketoprofen impurity A, ketoprofen ethyl ester and the like have certain technical difficulty.
For example, CN201510341915.3 discloses a method for determining the content of compound ketoprofen and omeprazole sustained-release capsules, which can determine the content of ketoprofen and omeprazole in the compound ketoprofen and omeprazole sustained-release capsules. However, the publication and patent do not report about the detection method of the above-mentioned substances in ketoprofen gel patches.
Disclosure of Invention
The invention aims to solve the technical problems that: provides an analysis and determination method and application of related substances in ketoprofen gel plaster. The method can effectively separate and measure various related substances including ketoprofen glyceride, ketoprofen impurity A, ketoprofen ethyl ester and the like in the ketoprofen gel plaster, and can effectively separate from surrounding impurity peaks.
In order to solve the technical problems, the invention adopts the following technical scheme:
firstly, the invention provides a method for analyzing and measuring related substances in ketoprofen gel plaster, wherein the testing method is high performance liquid chromatography, and the liquid chromatography conditions are as follows:
the chromatographic column uses octadecylsilane chemically bonded silica as filler, adopts water-phosphate buffer solution as mobile phase A and acetonitrile as mobile phase B, and performs gradient elution according to the following table program:
。
further, gradient elution was performed according to the following table procedure:
。
further, the method specifically comprises the following steps:
(1) Preparation of test solution: taking ketoprofen gel plaster, adopting 70-90% methanol ultrasonic vibration to fully separate out the medicine, filtering, and taking filtrate as a sample solution for later use;
(2) And (3) measuring: and under the liquid chromatography condition, sucking the sample solution, injecting the sample solution into a high performance liquid chromatograph, recording a chromatogram and reading data.
Further, the preparation of the sample solution is specifically as follows: taking ketoprofen gel paste, taking and shearing the middle part, placing the crushed middle part in a brown measuring flask, precisely measuring 70-90% of methanol, precisely weighing, performing ultrasonic treatment for 40-60 min, cooling, supplementing weight with 70-90% of methanol, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution for later use.
Further, the related substances tested by the high performance liquid chromatography comprise at least one of ketoprofen glyceride with a chemical structural formula shown in formula (1), ketoprofen impurity A with a chemical structural formula shown in formula (2) and ketoprofen ethyl ester with a chemical structural formula shown in formula (3):
。
further, the column was Apollo C18, 250X 4.6mm,5 μm.
Further, the water-phosphate buffer solution of the mobile phase A is specifically 68g/L potassium dihydrogen phosphate solution, and the pH is adjusted to 3.6+/-0.05 by phosphoric acid.
Further, the column temperature of the chromatographic column is 23-27 ℃; the flow rate is 0.9-1.1 mL/min, and the detection wavelength is 233+/-5 nm.
Preferably, the temperature of the chromatographic column is 25 ℃; the detection wavelength is 233nm; the flow rate was 1.0ml/min.
The invention also provides application of the analytical determination method of the related substances in the ketoprofen gel plaster in a quality control method of the ketoprofen gel plaster, which is used for separating and quantitatively determining the related substances in the ketoprofen gel plaster so as to effectively control the quality of medicines. The related substances include, but are not limited to, at least one of ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester.
Based on the similar principle, the invention is also applicable to the quality control of other medicaments which are intended to contain the relevant substances. Such as quality control of other dosage forms containing ketoprofen.
The invention has the following beneficial effects:
1. the method provided by the invention can be used for testing ketoprofen glyceride and ketoprofen ethyl ester in the ketoprofen gel plaster, and the prior testing method is not shown, so that the blank in the technical field can be made up.
2. The method provided by the invention can effectively separate the relevant substance peaks (ketoprofen glyceride, ketoprofen ethyl ester and ketoprofen impurity A) from the raw material medicine peaks and auxiliary material peaks, so that the content of the relevant substances can be accurately tested, and the quality of the ketoprofen gel plaster can be effectively controlled.
3. In the method provided by the invention, ketoprofen glyceride can be calculated by adopting a self-contrast method with a correction factor, ketoprofen ethyl ester can be calculated by adopting a self-contrast method without a correction factor, and a reference substance can be saved.
4. The method provided by the invention has the advantages of strong specificity, high sensitivity and good accuracy.
Drawings
In order to more clearly illustrate the technical solution of the embodiments of the present invention, the following description will briefly explain the drawings in the description of the embodiments.
FIG. 1 is a chromatogram of the control solution of example 1, wherein 1 (a) is ketoprofen glyceride, 1 (b) is ketoprofen impurity A, and 1 (c) is ketoprofen ethyl ester;
FIG. 2 is a chromatogram of the mixed impurity control solution, the test sample solution, and the test sample-plus-control solution in example 1, 2 (a) is the mixed impurity control solution, 2 (b) is the test sample solution, and 2 (c) is the test sample-plus-control solution;
FIG. 3 is a linear graph of example 2, 3 (a) is ketoprofen line, 3 (b) is ketoprofen impurity A, and 3 (c) is ketoprofen glyceride; 3 (d) is ketoprofen ethyl ester.
FIG. 4 is a chromatogram of the mixed impurity control solution and the sample solution in example 3, 4 (a) is the mixed impurity control solution, and 4 (b) is the sample solution;
FIG. 5 is a chromatogram of the mixed impurity control solution and the sample solution in example 4, wherein 5 (a) is the mixed impurity control solution, and 5 (b) is the sample solution;
FIG. 6 is a chromatogram of the sample solution in example 5;
FIG. 7 is a chromatogram of the sample solution in example 6.
Detailed Description
In order to better illustrate the invention, the invention is further verified by the following specific examples. The examples are presented herein only to more directly describe the invention and are merely a part of the invention and should not be construed as limiting the invention in any way.
The ketoprofen gel patches of the present invention were produced by the company of Hunan Jiujingzhu medicine Co., ltd.
Example 1
An analytical determination method for related substances in ketoprofen gel plasters comprises the following steps:
(1) Preparing related solutions:
ketoprofen glyceride control solution: the appropriate amount of ketoprofen glyceride reference is weighed, and 80% methanol is added to prepare a reference solution containing about 1.0 μg of ketoprofen glyceride per 1 mL.
Ketoprofen impurity a control solution: a proper amount of ketoprofen impurity A reference substance is weighed, and 80% methanol is added to prepare a reference substance solution containing about 1.0 mug of ketoprofen impurity A per 1 mL.
Ketoprofen ethyl ester control solution: the appropriate amount of ketoprofen ethyl ester control was weighed and 80% methanol was added to prepare a control solution containing about 1.0 μg of ketoprofen ethyl ester per 1 mL.
Mixing an impurity reference substance solution: the ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester were weighed in appropriate amounts to prepare a mixed impurity control solution containing approximately 1.0 μg of ketoprofen glyceride, 1.0 μg of ketoprofen Gan Zazhi A and 1.0 μg of ketoprofen ethyl ester per 1 mL.
Preparing a test solution: taking ketoprofen gel plaster 1, taking the middle part (about 21.4mg corresponding to ketoprofen), shearing, placing in a 150ml brown conical flask with a plug, precisely taking 100ml of 80% methanol, weighing, ultrasonic treating for 50 minutes, cooling, supplementing weight with 80% methanol, shaking uniformly, filtering, and taking the subsequent filtrate.
Adding a reference substance solution into a test sample: taking ketoprofen gel plaster 1 paste, and measuring 100cm of middle part 2 (corresponding to 21.4mg of ketoprofen), shearing, placing in 150ml brown conical flask with plug, adding ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester (according to the final concentration of ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester being about 1.0 μg/ml), adding 80% methanol to 100ml, precisely weighing, ultrasound for 50 minutes, cooling, supplementing with 80% methanol, shaking, filtering, and collecting filtrate.
(2) And (3) measuring: 20. Mu.l of each of the above solutions was poured into a liquid chromatograph, and the detection was performed under the following chromatographic conditions, and a chromatogram was recorded.
Octadecylsilane chemically bonded silica is used as packing material (Apollo C18, 250X4.6 mm,5 μm or column with equivalent potency); the temperature of the chromatographic column is 25 ℃; the detection wavelength is 233nm; the flow rate is 1.0ml/min; gradient elution was performed according to the procedure in Table 1 using water-phosphate buffer (68 g/L potassium dihydrogen phosphate solution, pH 3.6.+ -. 0.05 adjusted with phosphoric acid) (55:2) as mobile phase A and acetonitrile as mobile phase B.
TABLE 1 gradient elution
The results are shown in fig. 1 and 2, and it can be derived from fig. 1: under the above liquid phase test conditions, the peak position of ketoprofen glyceride was 14.299min, the peak position of ketoprofen impurity A was 25.082min, and the peak position of ketoprofen ethyl ester was 43.225min. As can be seen from fig. 2 (a), the peak time of the mixed impurity control was identical to that of the single control.
As can be seen from fig. 2 (b), the peak position of ketoprofen in the sample solution is about 19.4min, and impurity peaks of some auxiliary materials are also included in the spectrogram, so that ketoprofen glyceride, ketoprofen impurity a and ketoprofen ethyl ester are not detected; as can be seen from fig. 2 (c), after the mixed impurity reference substance solution is added, the peaks of the three reference substances can be effectively separated from the ketoprofen peak and the impurity peak of the auxiliary material, the separation degree is more than 1.5, and the existence of the auxiliary material does not interfere the detection of related substances of the sample, so that the method has good specificity, and can be used for simultaneously testing ketoprofen glyceride, ketoprofen impurity a and ketoprofen ethyl ester in ketoprofen.
Example 2
Preparing a linear test solution containing ketoprofen and ketoprofen impurity A, wherein the linear concentration of ketoprofen is between 0.0081 and 8.0879ug/ml, and the linear concentration of ketoprofen impurity A is between 0.0027 and 2.1618 ug/ml.
Preparing a linear test solution containing ketoprofen glyceride and ketoprofen ethyl ester, wherein the linear concentration of the ketoprofen glyceride is between 0.0319 and 3.8256ug/ml, and the linear concentration of the ketoprofen ethyl ester is between 0.0105 and 3.1616 ug/ml.
The linear test solution was tested under the conditions of the high performance liquid phase test in example 1, and according to the chromatogram, the impurity concentration (μg/m) was taken as the abscissa and the peak area (A) was taken as the ordinate, and the standard graph was drawn as shown in FIG. 3, and the specific results are shown in Table 2.
Table 2 table of results of linear experiments
As can be seen from fig. 3 and table 2, ketoprofen impurity a, ketoprofen glyceride and ketoprofen ethyl ester exhibit a better linear relationship between concentration and peak area within the above concentration ranges.
Calculation of correction factors
In the correction factor calculation method in this embodiment, a standard curve method is adopted, and the ratio of ketoprofen to the slope of the standard curve of known impurities is used as the correction factor. The results are shown in Table 3.
TABLE 3 correction factor results Table
The results from table 3 show that: the ketoprofen impurity A, ketoprofen glyceride and ketoprofen ethyl ester are respectively 0.23, 1.36 and 1.07 relative to the ketoprofen correction factor. According to the correction factors, the ketoprofen impurity A is calculated by adopting an external standard method, the ketoprofen glyceride is calculated by adopting a self-contrast method added with the correction factors, and the ketoprofen ethyl ester is calculated by adopting a self-contrast method; the ketoprofen glyceride and the ketoprofen ethyl ester can be calculated by adopting a self-contrast method and a self-contrast method by adding correction factors respectively in a specific test process, so that the contrast products can be saved.
Example 3
An analytical determination method for related substances in ketoprofen gel plasters comprises the following steps:
(1) Preparing a solution:
a mixed impurity control solution and a test solution were prepared in the same manner as in example 1.
(2) And (3) measuring: 20. Mu.l of each of the above solutions was poured into a liquid chromatograph, and the detection was performed under the following chromatographic conditions, and a chromatogram was recorded.
Octadecylsilane chemically bonded silica is used as packing material (Apollo C18, 250X4.6 mm,5 μm or column with equivalent potency); the temperature of the chromatographic column is 23 ℃; the detection wavelength is 235nm; the flow rate is 0.9ml/min; gradient elution was performed according to the procedure in Table 4 using water-phosphate buffer (68 g/L potassium dihydrogen phosphate solution, pH 3.5.+ -. 0.05 adjusted with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B.
TABLE 4 gradient elution
As shown in FIG. 4, the chromatogram was changed, the peak times of ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester were slightly delayed, and the peak times in the test solutions were slightly delayed, but the test results were substantially the same as in example 1, and no ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester were detected in the test solutions.
Example 4
An analytical determination method for related substances in ketoprofen gel plasters comprises the following steps:
(1) Preparing a solution:
the impurity control solution and the test solution were mixed and prepared in the same manner as the solution in example 1.
(2) And (3) measuring: 20. Mu.l of each of the above solutions was poured into a liquid chromatograph, and the detection was performed under the following chromatographic conditions, and a chromatogram was recorded.
Octadecylsilane chemically bonded silica is used as packing material (Apollo C18, 250X4.6 mm,5 μm or column with equivalent potency); the temperature of the chromatographic column is 27 ℃; the detection wavelength is 231nm; the flow rate is 1.1ml/min; gradient elution was performed according to the procedure in Table 5 using water-phosphate buffer (68 g/L potassium dihydrogen phosphate solution, pH 3.7.+ -. 0.05 adjusted with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B.
TABLE 5 gradient elution
As shown in FIG. 5, the chromatographic conditions were changed, the peak times of ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester were slightly advanced, and the peak times in the test solutions were also slightly advanced, but the test results were substantially the same as in example 1, and no ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester were detected in the test solutions.
The results of examples 1, 3 and 4 can be changed from the column temperature, flow rate, pH value and mobile phase ratio in a small fluctuation range, and the peak time can be changed to a certain extent, but the test results are not basically influenced, so that the method has better durability.
Example 5
An analytical determination method for related substances in ketoprofen gel plasters comprises the following steps:
(1) Preparing a solution:
a control solution and a test solution of ketoprofen impurity A (wherein the test sample is a ketoprofen gel patch subjected to a stability test at 25℃and RH 60%) were prepared according to the preparation method of the solution in example 1.
(2) And (3) measuring: 20. Mu.l of each of the above solutions was poured into a liquid chromatograph, and the solution was detected under the chromatographic conditions in example 1, and the chromatogram was recorded.
The chromatogram of the sample solution is shown in fig. 6, and as can be seen from the chromatogram, the peaks at 14.147min and 26.060min respectively correspond to the peaks of ketoprofen glyceride and ketoprofen impurity A, and the contents of ketoprofen glyceride and ketoprofen impurity A can be calculated to be 0.027% and 0.005% respectively according to the chromatogram.
Example 6
An analytical determination method for related substances in ketoprofen gel plasters comprises the following steps:
(1) Preparing a solution:
a control solution of ketoprofen impurity a and a test solution (wherein the test is a ketoprofen gel patch subjected to a 30-day high temperature stability test at 40 ℃) were prepared according to the solution formulation in example 1.
(2) And (3) measuring: 20. Mu.l of each of the above solutions was poured into a liquid chromatograph, and the solution was detected under the chromatographic conditions in example 1, and the chromatogram was recorded.
The chromatograms of the sample solutions are shown in fig. 7, and as can be seen from the chromatograms, the peaks at 14.100min, 26.147min and 43.133min respectively correspond to ketoprofen glyceride, ketoprofen impurity A and ketoprofen ethyl ester, and the contents of the ketoprofen glyceride, the ketoprofen impurity A and the ketoprofen ethyl ester can be calculated to be 0.114%,0.016% and 0.021% respectively.
It can be seen from examples 5 and 6 that ketoprofen gel patches may produce ketoprofen glyceride, ketoprofen impurity a and ketoprofen ethyl ester under specific conditions, so that monitoring the contents of three related substances by the method of the present invention is very important for quality control of ketoprofen gel patches.
The above description is only of a few preferred embodiments of the present invention and should not be taken as limiting the invention, but all modifications, equivalents, improvements and modifications within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (9)
1. A method for analyzing and measuring related substances in ketoprofen gel plasters, which is a high performance liquid chromatography, and is characterized in that the liquid chromatography conditions are as follows:
the chromatographic column uses octadecylsilane chemically bonded silica as filler, the detection wavelength is 233+ -5 nm, water-phosphate buffer solution is adopted as mobile phase A, acetonitrile is adopted as mobile phase B, and gradient elution is carried out according to the following table program:
the related substances tested by the high performance liquid chromatography comprise at least two of ketoprofen glyceride with a chemical structural formula shown as formula (1), ketoprofen impurity A with a formula (2) and ketoprofen ethyl ester with a formula (3):
or, as ketoprofen glyceride of formula (1), one of ketoprofen ethyl esters of formula (3).
2. The analytical measurement method according to claim 1, wherein the liquid chromatography is carried out by gradient elution according to the following table program:
3. analytical assay method according to claim 1 or 2, characterized in that it comprises in particular the following steps:
(1) Preparation of test solution: taking ketoprofen gel plaster, adopting 70-90% methanol ultrasonic vibration to fully separate out the medicine, filtering, and taking filtrate as a sample solution for later use;
(2) And (3) measuring: and under the liquid chromatography condition, sucking the sample solution, injecting the sample solution into a high performance liquid chromatograph, recording a chromatogram and reading data.
4. The analytical assay method of claim 3, wherein the sample solution is prepared as follows: taking ketoprofen gel plaster, taking the middle part, shearing, placing in a brown measuring flask, precisely measuring 70-90% of methanol, weighing, performing ultrasonic treatment for 40-60 min, cooling, supplementing weight with 70-90% of methanol, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution for later use.
5. The analytical measurement method according to claim 1 or 2, wherein the mobile phase A water-phosphate buffer is prepared by adjusting pH to 3.6.+ -. 0.05 with phosphoric acid in 68g/L of potassium dihydrogen phosphate solution.
6. The analytical assay method of claim 1 or 2, wherein, in the liquid chromatographic conditions: the column temperature of the chromatographic column is 23-27 ℃ and the flow rate is 0.9-1.1 mL/min.
7. The analytical measurement method according to claim 6, wherein the temperature of the column is 25 ℃, the detection wavelength is 233nm, and the flow rate is 1.0mL/min.
8. The analytical assay method of claim 1 or 2 wherein the chromatographic column is Apollo C18, 250 x 4.6mm,5 μm.
9. Use of the analytical assay according to any one of claims 1-8 in a method for quality control of a ketoprofen gel patch.
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