CN108181419B - Detection method of diethyl naphthalene cholamine raw material or preparation related substances thereof - Google Patents
Detection method of diethyl naphthalene cholamine raw material or preparation related substances thereof Download PDFInfo
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- 239000002994 raw material Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000001514 detection method Methods 0.000 title claims abstract description 29
- UUCHLIAGHZJJER-UHFFFAOYSA-N 1,2-diethylnaphthalene Chemical compound C1=CC=CC2=C(CC)C(CC)=CC=C21 UUCHLIAGHZJJER-UHFFFAOYSA-N 0.000 title description 5
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims abstract description 37
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- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 claims abstract description 9
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- 239000012085 test solution Substances 0.000 claims description 13
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 claims description 12
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Images
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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
- G01N30/89—Inverse chromatography
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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)
- Investigating Or Analysing Biological Materials (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a detection method of a naphthalene disulfonic acid ethyol cholamine raw material or related substances of a preparation thereof, which comprises the following steps: the reversed-phase high performance liquid chromatography of a reversed-gradient post-column compensation mode is adopted, octadecylsilane chemically bonded silica is used as a chromatographic column filler, an electric spray detector (CAD) is adopted, and volatile negative ions are selected to elute a mobile phase of the reagent. The detection method has strong specificity, high sensitivity, higher precision and accuracy and good durability, is suitable for the inspection and quality control of the related substances of the raw material of the diethylcholammonium naphthalene sulfonate or the preparation thereof, can accurately reflect the content of the related substances in the raw material of the diethylcholammonium naphthalene sulfonate or the preparation thereof, and provides reasonable basis for the formulation of quality standard so as to better control and master the quality of the product, thereby improving the safety of clinical medication.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a detection method of a raw material of diethylcholamine naphthalene sulfonate or related substances of a preparation of the raw material.
Background
The gastrokinetic drug has been clinically applied for more than forty years, and metoclopramide (metoclopramide) is published in the 60 s, has the effects of promoting gastrointestinal motility and stopping vomiting, and has definite curative effect, but the metoclopramide can cause extrapyramidal adverse reactions. The morpholine is a peripheral dopamine receptor antagonist, and is characterized by small side effect of the central nervous system, narrow pharmacological action and treatment range, side effect of causing prolactin level to increase, and low oral bioavailability due to first pass effect. Cisapride, marketed by Yangsen corporation in the 80 s, is a toluamide derivative, the site of action of which is the 5-HT4 receptor located in cholinergic interneurons and motor neurons of the intermuscular plexus, is more extensive in terms of treatment and application than the previous gastrokinetic drugs, and has good curative effects on gastroesophageal reflux, gastroparesis syndrome, non-ulcer dyspepsia and the like, but has serious side effects causing arrhythmia, and 80 patients die due to the side effects, and the use of cisapride 14, 7.7.14.Feiz is declared to stop. In recent years, with the increase of the elderly and the widespread use of digestive tract surgery, the proportion of people suffering from digestive tract dysfunction has been increasing, and parasympathetic agonists and central digestive tract motor function improvers have been widely used in order to improve this phenomenon. However, the conventional parasympathetic agonist is difficult to degrade in the human body, may exert adverse effects on other parts than the organs of the digestive tract, and may cause hypersecretion of gastric juice, and in addition, the central digestive tract motor function improver may act on the digestive tract through the central system, thereby causing central side effects or abnormalities of the endocrine system.
In summary, there are four generations of gastrointestinal motility drugs commonly used in clinic: the first generation is metoclopramide and metoclopramide; the second generation of prokinetic drugs is domperidone, namely, morpholine; the third generation is cisapride; the fourth generation is mosapride and diethylcholammonium naphthalene sulfonate, the former is a non-selective 5-HT4 receptor agonist, is a novel gastrointestinal motility promoting drug and is widely used clinically, but has potential safety hazard; the latter is a digestive system motor function improving agent developed by Fushan chemical industry (strain), which is prepared by semi-synthesizing Kassein R extracted from radix Puerariae and having digestive system motor function promoting effect as matrix, and shows similar acetylcholine effect, so the product does not act on vagus nerve, but directly acts on acetylcholine receptor in smooth muscle, and promotes hypermotility of digestive tract, and adverse reaction is only 0.83%.
In 1976 to 1978, 787 patients were clinically studied in 26 research institutes in japan. As a result, the medicine has the effect of rapidly improving chronic gastritis, bile duct insufficiency and various digestive tract hypokinesia accompanied with digestive tract operation, and has good clinical effect. In addition, in a double-blind comparison test, compared with a control drug metoclopramide, the effect is obvious. The diethyl naphthalene cholamine sulfonate is (2-acetyl lactoyl oxyethyl) trimethyl ammonium salt-semi-1, 5-naphthalene disulfonate, and the structural formula is as follows:
at present, only a dissolution analysis method collected in Japanese orange peel book is available in a relevant document of an analysis method for a raw material of diethylstilbestrol choline naphthalene or a preparation thereof, an ultraviolet detector is used for detection in the method, detection impurities are not involved, and even if the method is optimized on the basis of the method, the specificity and the sensitivity of the optimized method cannot meet the requirement of quality control. Therefore, the development of a method for effectively detecting various related substances in the raw material of the diethylcholamine naphthalene sulfonate or the preparation thereof has important significance for the quality control.
Disclosure of Invention
The inventor of the application develops a detection method of the raw material of the diethylcholammonium naphthalene sulfonate or related substances of the preparation thereof, the method has good specificity, and possible process impurities and degradation impurities can be effectively separated from the main component; the method has high sensitivity, can carry out quantitative analysis on impurities without ultraviolet absorption and with weak ultraviolet absorption, has good repeatability and high accuracy, and can be applied to quality control of the raw material of the diethylstilbestrol cholamine naphthalene or related substances of preparations thereof.
In an embodiment of the present invention, the present invention provides a method for detecting a substance related to a raw material of diethylstilbestrol choline or a preparation thereof, comprising
Adopting reversed-phase high performance liquid chromatography with reversed-gradient post-column compensation mode, taking octadecylsilane chemically bonded silica as chromatographic column filler, adopting a spray detector (CAD), and eluting the mobile phase of the reagent by using volatile negative ions; here, the mobile phase is mobile phase a and/or mobile phase B.
In an embodiment of the invention, the invention provides a detection method of the material of the diethylstilbesulfate naphthalene or related substances of a preparation thereof, wherein the specification of the chromatographic column is 4.6 by 250mm and 5 μm, and the preferred brand and model is Waters outlastis T3.
In the embodiment of the invention, the detection method of the raw material of the diethylcholammonium naphthalene sulfonate or the relevant substances of the preparation thereof is provided, wherein in the reversed-phase high performance liquid chromatography, the flow rate of the mobile phase is 0.9-1.1 ml/min, preferably 1.0 ml/min; the sample amount is 20 mul;
in an embodiment of the present invention, the present invention provides a method for detecting a material of diethylcholammonium naphthalene sulfonate or a relevant substance of a preparation thereof, wherein the volatile negative ion pair reagent is preferably pentafluoropropionic acid.
In an embodiment of the present invention, the present invention provides a method for detecting a substance related to a raw material of diethylstilbestrol naphthalene or a preparation thereof, wherein the mobile phase a is: adding 0.5-2 ml of volatile ion-pair reagent into every 1L of purified water, preferably 1 ml; the mobile phase B is as follows: methanol.
In an embodiment of the present invention, the present invention provides a method for detecting a substance related to a raw material of diethylstilbestrol naphthalene or a preparation thereof, wherein the elution procedure is as follows:
in a preferred embodiment of the present invention, the present invention provides a method for detecting materials related to a raw material of diethylstilbestrol naphthalene or a preparation thereof, wherein a mode of back-gradient column compensation is used, and the compensation method comprises: the mobile phase A contains 1ml of pentafluoropropionic acid per 1L of purified water; the mobile phase B is methanol; post column compensation was performed according to the following gradient:
in an embodiment of the present invention, the present invention provides a method for detecting a substance related to a raw material of diethylstilbestrol choline naphthalene or a preparation thereof, further comprising the steps of: weighing appropriate amount of the raw material or preparation of the diethylcholammonium naphthalene sulfonate, dissolving and diluting with the mobile phase A to prepare a solution containing 10.0mg of the diethylcholammonium naphthalene sulfonate per 1ml as a test solution; precisely measuring a proper amount of a test solution, and quantitatively diluting the precisely measured test solution by using a mobile phase A to prepare a solution containing 10.0 mu g of the naphthalene disulfonic acid emulsion cholamine per 1ml as a reference solution when detecting related substances of the naphthalene disulfonic acid emulsion cholamine raw material; when detecting related substances of the preparation of the diethylstilbestrol choline naphthalene, a precisely measured sample solution is quantitatively diluted by using the mobile phase A to prepare a solution containing 50.0 mu g of the diethylstilbestrol choline naphthalene per 1ml as a control solution.
In an embodiment of the present invention, the method for detecting a raw material of diethylcholammonium naphthalene sulfonate or a related substance of a preparation thereof provided by the present invention, wherein the raw material of diethylcholammonium naphthalene sulfonate or the related substance of the preparation thereof includes impurities generated in a synthesis process and degradation of diethylcholammonium naphthalene sulfonate, preferably, the following 3 impurities are studied, and are respectively ammonium impurities, lactyl impurities, and acetyl impurities, and the chemical structures of the impurities are as follows:
in an embodiment of the invention, the formulation of the sulfolobutanil is a capsule.
The detection method of the material of the diethylcholammonium naphthalene sulfonate or the relevant substances of the preparation thereof uses an electric fog type detector (CAD), has high sensitivity and good universality, enables each impurity without ultraviolet absorption and with weak ultraviolet absorption to be detected (wherein, the anion part of the ammonium impurity has no ultraviolet absorption, and the anion parts of the lactyl impurity and the acetyl impurity have weak ultraviolet absorption), and can be quantitatively analyzed.
In addition, the invention provides a detection method of the raw material of the diethylcholammonium naphthalene sulfonate or related substances of the preparation thereof, which uses a water solution containing a certain concentration of pentafluoropropionic acid as a mobile phase A, and utilizes the negative ion pair effect provided by the pentafluoropropionic acid to properly reserve the main component and each impurity.
In a third aspect, the present invention provides a method for detecting materials related to a raw material of diethylcholammonium naphthalene sulfonate or a preparation thereof, wherein a mode of back-compensation of an inverse gradient column is adopted, so that eluents flowing through a detector at each time point can be kept consistent, thereby a baseline is stable, accurate integration is facilitated, and the responses of materials which peak at each time point tend to be consistent, so that the calculation and control of impurities by a quantitative method are more reasonable.
Drawings
FIG. 1 shows a chromatogram of a mixed solution of related substances of a NAPPA capsule in comparative example 1, wherein 1A shows a dissolution analysis method carried in Japan orange book, and 1B shows an optimization method of Japan orange book.
FIG. 2 shows a chromatogram for locating the target substance of the target substance.
FIG. 3 shows an undisrupted chromatogram of the crude drug of diethylcholammonium naphthalene or its capsule-related substances of example 4, wherein M indicates a crude drug of diethylcholammonium naphthalene and N indicates a capsule of diethylcholammonium naphthalene.
FIG. 4 shows a light damage chromatogram of the solution of the active pharmaceutical ingredient of delafosetyl naphthalene or its capsule-related substances of example 4, wherein M denotes the active pharmaceutical ingredient of delafosetyl naphthalene, and N denotes the capsule of delafosetyl naphthalene.
FIG. 5 shows a solid photo-destructive chromatogram of the active pharmaceutical ingredient of delafosetyl naphthalene or its capsule related substances of example 4, wherein M denotes the active pharmaceutical ingredient of delafosetyl naphthalene and N denotes the capsule of delafosetyl naphthalene.
FIG. 6 shows a high temperature destruction chromatogram of the solution of the active pharmaceutical ingredient of delafosetyl naphthalene or its capsule-related substances of example 4, wherein M denotes the active pharmaceutical ingredient of delafosetyl naphthalene, and N denotes the capsule of delafosetyl naphthalene.
FIG. 7 shows a solid high temperature destruction chromatogram of the target drug substance or its capsule related substances in example 4, where M denotes the target drug substance and N denotes the target capsule.
FIG. 8 shows an acid destruction chromatogram of the target drug substance or its capsule-related substance of the target drug substance of the embodiment 4, wherein M denotes the target drug substance of the target drug substance, and N denotes the target capsule of the target drug substance.
FIG. 9 shows an alkali destruction chromatogram of the crude drug of diethylcholammonium naphthalene or its capsule-related substance in example 4, where M denotes the crude drug of diethylcholammonium naphthalene and N denotes the capsule of diethylcholammonium naphthalene.
FIG. 10 shows an oxidative destruction chromatogram of the target drug substance or its capsule-related substance of the target drug substance of the embodiment 4, wherein M denotes the target drug substance of the target drug substance, and N denotes the target capsule of the target drug substance.
In fig. 2, peak 1 is the ammonium impurity, peak 2 is the lactyl impurity, peak 3 is the acetyl impurity, peak 4 is the ethocholammonium, and the other figures can be located according to the corresponding retention times in fig. 2, M.
Detailed Description
The following examples are presented to further understand the present invention, but are not limited to the scope of the present examples.
Example 1
Detection of related substances of three batches of naphthalene disulfonate emulsion cholamine bulk drugs
Taking a proper amount of the product, dissolving with diluent (mobile phase A), and diluting to obtain solution containing 10mg per 1ml as test solution; a proper amount of the test solution is precisely measured and diluted with a diluent to prepare a solution containing about 10 mug of the test solution per 1ml as a control solution.
Adopting a Saimerfil Ultimate3000DGLC high performance liquid chromatograph, taking octadecylsilane chemically bonded silica as a filler (Waters Atalantis T3, 4.6 x 250mm, 5 mu m), and keeping the column temperature at 25 ℃; the flow rate is 1.0 ml/min; the detector is an electric fog type detector, and the temperature of the detector is 50 ℃;
the relevant substances are subjected to gradient elution and inverse gradient post-column compensation according to the following table by taking 0.1 percent of pentafluoropropionic acid aqueous solution as a mobile phase A and methanol as a mobile phase B:
precisely measuring 10 mul of each of the system applicability solution, the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording a chromatogram;
the detection results of three batches of the materials related to the raw material drug of the diethylcholamine naphthalene sulfonate are shown in the following table:
| batch number | Impurities of ammonium | Lactyl impurities | Acetyl impurities | Other maximum Single hetero (%) |
| 16090801 | Not detected out | Not detected out | Not detected out | 0.040 |
| 16101701 | Not detected out | Not detected out | ＜LOQ | 0.037 |
| 16102001 | ＜LOQ | Not detected out | ＜LOQ | 0.018 |
Example 2
Detection of related substances in two batches of naphthalene disulfonate emulsion cholamine capsules
Taking a proper amount of the product, dissolving and diluting the product by using a diluent (a mobile phase A) to prepare a solution containing about 10mg of the diethylcholamine naphthalene sulfonate in each 1ml of the product as a test solution; precisely measuring a proper amount of the test solution, and quantitatively diluting with a diluent to obtain a solution containing about 50 μ g of the diethylcholammonium naphthalene sulfonate per 1ml as a control solution.
Adopting a Saimerfil Ultimate3000DGLC high performance liquid chromatograph, taking octadecylsilane chemically bonded silica as a filler (Waters Atalantis T3, 4.6 x 250mm, 5 mu m), and keeping the column temperature at 25 ℃; the flow rate is 1.0 ml/min; the detector is an electric fog type detector, and the temperature of the detector is 50 ℃;
the relevant substances are subjected to gradient elution and inverse gradient post-column compensation according to the following table by taking 0.1 percent of pentafluoropropionic acid aqueous solution as a mobile phase A and methanol as a mobile phase B:
precisely measuring 10 mul of each of the system applicability solution, the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording a chromatogram;
the detection results of the two batches of the related substances of the diethylstilbestrol choline capsules are shown in the following table:
| batch number | Impurities of ammonium | Lactyl impurities | Acetyl impurities | Other maximum Single hetero (%) |
| 17011441 | 0.235 | 0.036 | 0.058 | 0.078 |
| 17011641 | 0.134 | 0.028 | 0.019 | 0.055 |
Example 3
Methodological validation of the chromatographic method:
1. naphthalenedisulfonic acid ethonium cholate raw material and capsule related substance positioning test thereof
Reference solutions of the raw material of the diethylcholammonium naphthalene sulfonate and its capsules as related substances, and mixed solutions of the raw material of the diethylcholammonium naphthalene sulfonate and its capsules as related substances were prepared according to the methods of example 1 and example 2, and injected into a liquid chromatograph, and chromatograms were recorded. The separation degree results of effective component, namely the peak of the effective component, namely the ethirimonium, and various impurities are shown in the following table, and the map is shown in figure 2:
the results show that: the peak of the diethyl cholamine in the naphthalene disulfonic acid diethyl cholamine raw material or the capsule thereof can be well separated from all related substances and all related substances.
Example 4
Specificity failure test
1. Raw material of diethyl naphthalene cholamine
Precisely weighing a proper amount of the raw material of the diethylcholammonium naphthalene sulfonate, and respectively carrying out forced destruction tests on the raw material under the conditions of 0.01mol/L hydrochloric acid solution, 0.01mol/L sodium hydroxide solution, high temperature of 40 ℃ and 60 ℃, mixed illumination of 4500Lx white light and ultraviolet light, 3% hydrogen peroxide solution and the like, wherein the preparation method and the result of each destruction sample are shown in the following table, and the map is shown in figures 3-10:
each proprietary failure sample solution was prepared according to the following table:
the mass balance results are shown in the following table:
the results show that: the separation degree of the ethocholammonium peak and the adjacent impurity peak meets the requirement under each damage condition of the crude drug of the diethylcholammonium naphthalene disulfonate, and the degraded impurity does not interfere the detection of the known impurity. Under each degradation condition, the mass balance is between 90% and 110%, and the method has good specificity.
2. Naphthaline disulfo-emulsion cholamine capsule
Precisely weighing a proper amount of the content of the capsule of the diethylcholamine naphthalene sulfonate, and respectively carrying out forced destruction tests on the capsule under the conditions of 0.1mol/L hydrochloric acid solution, 0.01mol/L sodium hydroxide solution, high temperature of 40 ℃/60 ℃, mixed illumination of 4500Lx white light and ultraviolet light, 30% hydrogen peroxide solution and the like, wherein the preparation method and the result of each destruction sample are shown in the following table, and the map is shown in figures 3-10:
the mass balance results are shown in the following table:
the results show that: the separation degree of the ethyl cholamine and the adjacent impurity peaks meets the requirement under each damage condition of the naphthalene disulfonic ethyl cholamine capsule, and the degraded impurities do not interfere the detection of the known impurities. Under each degradation condition, the mass balance is between 90% and 110%, and the method has good specificity.
Example 5
Quantitative limit and detection limit test
The detection limit and the quantitative limit of the diethylcholammonium naphthalene sulfonate and various related substances are determined by a signal-to-noise ratio method. Respectively preparing stock solutions of the diethylcholammonium naphthalene sulfonate and various related substances, diluting the stock solutions to a certain concentration, injecting a sample, calculating the ratio (signal-to-noise ratio) of peak height to noise, wherein when the sample detection amount with the signal-to-noise ratio (S/N) of about 10 is a quantitative limit, the sample detection amount with the signal-to-noise ratio (S/N) of about 3 is a detection limit, and the results are shown in the following table:
the results show that: the quantitative limit concentration of the diethylcholammonium naphthalene sulfonate and the related substances is less than the report limit, and the content of the related substances can be accurately controlled.
Example 6
Linear test
Accurately weighing appropriate amount of the diethylcholammonium naphthalene sulfonate and related substances, dissolving the appropriate amount of the diethylcholammonium naphthalene sulfonate and the related substances by using a diluent, preparing solutions with different concentrations, respectively injecting samples and recording chromatograms, and respectively obtaining linear regression equations of the diethylcholammonium naphthalene sulfonate and ammonium impurities, lactyl impurities and acetyl impurities (6 different concentrations) by taking the concentrations as horizontal coordinates and peak areas as vertical coordinates, wherein the results are shown in the following table:
the results show that: the diethylcholammonium naphthalene sulfonate and 3 related substances show good linear relationship in a certain concentration range.
Example 7
Accuracy test
1. Raw material of diethyl naphthalene cholamine
Accurately weighing a proper amount of the raw material of the diethylcholammonium naphthalene sulfonate and related substances respectively, and preparing a solution containing 10.0mg/ml of the diethylcholammonium naphthalene sulfonate and ammonium impurities, and 3 mug/ml (20 percent of the limit), 15 mug/ml (100 percent of the limit) and 22.5 mug/ml (150 percent of the limit) of the lactyl impurities and acetyl impurities respectively by using a diluent for an accuracy test, wherein each concentration is three parts; and (3) respectively injecting samples and recording chromatograms, and calculating the recovery rate, wherein the results are shown in the following table:
the results show that: the recovery rate of each related substance in the raw material of the diethylstilbestrol choline naphthalene is between 75 percent and 120 percent within the range of 20 percent limit level and 150 percent limit level, and the method has good accuracy.
2. Naphthaline disulfo-emulsion cholamine preparation
Precisely weighing the content of the capsule of the diethylcholamine naphthalene sulfonate and a proper amount of each related substance respectively, and preparing a solution containing 10.0mg/ml of the diethylcholamine naphthalene sulfonate and 16 [ mu ] g/ml (10 percent of the limit), 80 [ mu ] g/ml (100 percent of the limit) and 120 [ mu ] g/ml (150 percent of the limit) of ammonium impurity respectively by using a diluent, wherein the concentration of the lactyl impurity and the acetyl impurity are respectively 4 [ mu ] g/ml (20 percent of the limit), 20 [ mu ] g/ml (100 percent of the limit) and 30 [ mu ] g/ml (150 percent of the limit) for an accuracy test, and each concentration is three parts; and (3) respectively injecting samples and recording chromatograms, and calculating the recovery rate, wherein the results are shown in the following table:
| compound (I) | 20% limit horizontal return | 100% limit horizontal return | 150% limit horizontal return |
| Impurities of ammonium | 119.3 | 101.9 | 96.5 |
| Lactyl impurities | 93.3 | 94.6 | 93.3 |
| Acetyl impurities | 93.3 | 99.9 | 99.8 |
The results show that: the recovery rate of each related substance in the capsule of the diethylstilbestrol choline naphthalene is between 75 percent and 120 percent within the range of 10 percent limit level and 150 percent limit level, and the method has good accuracy.
Comparative example 1
The detection method adopts Japanese orange peel book and an optimized method thereof to detect the diethylstilbestrol-choline naphthalene capsules, and the detection conditions are as follows:
the detection result is shown in figure 1, the retention time of the main peak of the dissolution analysis method of Japanese hesperidins is short, the optimized method has proper analysis time, but the detected number of impurities is small, the ammonium impurities without ultraviolet absorption cannot be detected, and the specificity and the sensitivity cannot meet the requirements of quality control, thereby indicating the necessity of developing a method for effectively detecting various related substances in the raw material of the diethylstilbestrol choline naphthalene or the capsules thereof.
Claims (6)
1. A detection method of a material of diethylcholamine naphthalene sulfonate or related substances of a preparation thereof comprises the following steps:
adopting reversed-phase high performance liquid chromatography of a reverse gradient post-column compensation mode, taking octadecylsilane chemically bonded silica as a chromatographic column filler, adopting an electric spray type detector, and selecting volatile negative ions to elute a mobile phase of a reagent; here, the mobile phase is mobile phase a and mobile phase B;
the raw material of the diethylcholamine naphthalene sulfonate or related substances of the preparation of the raw material of the diethylcholamine naphthalene sulfonate comprise the following 3 impurities, namely ammonium impurities, lactyl impurities and acetyl impurities, wherein the chemical structures of the impurities are as follows:
the mobile phase A is as follows: adding 1ml of volatile ion-pair reagent into every 1L of purified water; the volatile negative ion pair reagent is pentafluoropropionic acid; the mobile phase B is as follows: methanol; the elution procedure was:
the mode of inverse gradient post column compensation is used, and the compensation method comprises the following steps: the mobile phase A contains 1ml of pentafluoropropionic acid per 1L of purified water; the mobile phase B is methanol, and post-column compensation is carried out according to the following gradient:
2. the test method according to claim 1, wherein the chromatography column is 4.6 x 250mm, 5 μm in size.
3. The method of detecting according to claim 2, wherein the chromatographic column is Waters Atlantis T3.
4. The detection method according to claim 1, wherein in the reversed-phase high performance liquid chromatography, the flow rate of the mobile phase is 0.9 to 1.1 ml/min; the amount of sample was 20. mu.l.
5. The detection method according to claim 4, wherein in the reversed-phase high performance liquid chromatography, the flow rate of the mobile phase is 1.0 ml/min.
6. The assay of any one of claims 1 to 5, further comprising sample formulation: weighing appropriate amount of the raw material or preparation of the Naphthalenedisulfolactocholamine, dissolving and diluting with the mobile phase A to prepare a solution containing 10.0mg of Naphthalenedisulfolactocholamine per 1ml as a test solution; precisely measuring a proper amount of a test solution, and quantitatively diluting the precisely measured test solution by using a mobile phase A to prepare a solution containing 10.0 mu g of the naphthalene disulfonic acid emulsion cholamine per 1ml as a reference solution when detecting related substances of the naphthalene disulfonic acid emulsion cholamine raw material; when detecting related substances of the preparation of the diethylstilbestrol choline naphthalene, a precisely measured sample solution is quantitatively diluted by using the mobile phase A to prepare a solution containing 50.0 mu g of the diethylstilbestrol choline naphthalene per 1ml as a control solution.
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