CN114527202A - Method for determining salt forming rate of methylergometrine maleate raw material - Google Patents
Method for determining salt forming rate of methylergometrine maleate raw material Download PDFInfo
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- CN114527202A CN114527202A CN202111674251.4A CN202111674251A CN114527202A CN 114527202 A CN114527202 A CN 114527202A CN 202111674251 A CN202111674251 A CN 202111674251A CN 114527202 A CN114527202 A CN 114527202A
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- raw material
- maleic acid
- maleate
- methylergometrine
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- 238000000034 method Methods 0.000 title claims abstract description 40
- NOFOWWRHEPHDCY-DAUURJMHSA-N Methylergonovine Maleate Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CNC3=C1 NOFOWWRHEPHDCY-DAUURJMHSA-N 0.000 title claims abstract description 39
- 239000002994 raw material Substances 0.000 title claims abstract description 29
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 50
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- 239000011976 maleic acid Substances 0.000 claims abstract description 48
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- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical group C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
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Images
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
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
-
- 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
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
-
- 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
- G01N2030/042—Standards
- G01N2030/047—Standards external
Abstract
The invention relates to the field of pharmaceutical analysis and detection, and provides a method for determining the salt forming rate of methylergometrine maleate serving as a raw material. The invention comprises the following steps: respectively adding the system applicability solution, the blank solution, the reference solution and the test solution into an ion chromatograph, recording a chromatogram, calculating the content of maleic acid in the methylergometrine maleate raw material medicine by peak area according to an external standard method, and substituting the content into the formula (1) to calculate the salt forming rate of the methylergometrine maleate raw material. The method has the advantages of strong specificity, high sensitivity, simple operation and accurate result.
Description
Technical Field
The invention belongs to the field of drug analysis and detection, and particularly relates to a method for determining the salt content in a methylergometrine maleate raw material.
Background
Ergot alkaloid is a kind of natural alkaloid and its series of derivatives, the basic structure is lysergic acid, can act on receptors such as 5-hydroxytryptamine, norepinephrine and dopamine, etc., have pharmacological actions such as uterus excitation, blood vessel contraction, alpha receptor blocking, etc., can be used for treating various diseases such as metrorrhagia, postpartum uterus recovery, migraine, central nervous system, cardiovascular and cerebrovascular diseases, etc. clinically.
At present, ergot alkaloid which is recognized as 'gold standard' by international (WHO) has an action mechanism which is not influenced by physiological factors, and is the first choice medicine for preventing and treating postpartum hemorrhage of pregnant and lying-in women. Enterprises in our province undertake the major new drug creation topic of China, firstly develop raw materials of ergot alkaloid drugs and preparations thereof, and imitate the raw material of ergot neoline maleate for the first time, so that the blank that China lacks new treatment means in the field of treating postpartum hemorrhage for years is filled, and the pharmaceutical composition has very important clinical significance for China.
The methylergometrine maleate is a biological fermentation alkaloid, is a maleate of methylergometrine, contains more impurities in a fermentation solution, is separated and purified by adopting a crystallization mode in a production process, has stable properties after salification, and is easy to store.
According to the literature, the British pharmacopoeia (BP2020), European pharmacopoeia (EP10.0) and Japanese pharmacopoeia (JP17) contain the quality standard of the raw material medicine of the product, and the United states pharmacopoeia (USP44) contains the quality standard of the raw material medicine, the tablet and the injection, and the comparison shows that the existing quality standard items can not comprehensively reflect the product quality in the production process. The United states pharmacopoeia and the Japanese pharmacopoeia contain methods for measuring the content of methylergometrine maleate, which are respectively High Performance Liquid Chromatography (HPLC) and ultraviolet absorption spectroscopy (UV), and the principles of the methods are that the response value of methylergometrine with an ultraviolet absorption functional group is detected, but the methods can not be distinguished into salification type or free type,
when the methylergometrine maleate is completely salified, the molar ratio of the maleic acid to the methylergometrine is 1: 1; when salt formation of the ergometrine hydrochloride is excessive, free maleic acid can be dehydrated into maleic anhydride after being heated, and experiments show that the degraded impurities can cause renal tubular injury; when the salt formation of the ergometrine is incomplete, the free alkaloid is specifically combined with plasma protein, so that the onset time of the medicament is prolonged; meanwhile, the salt forming rate has influence on the pH value, the color and related substances of the preparation.
In the research, an ion chromatography-conductivity detector method is established for measuring the content of maleic acid in the raw material of ergometrine maleate, meanwhile, the content of ergometrine maleate is measured according to a method for measuring the content of ergometrine maleate received by the United states Pharmacopeia (USP43), the salt forming rate of maleic acid in the raw material of ergometrine maleate is obtained by calculating the molar ratio of the maleic acid to the ergometrine maleate, accurate and effective data are provided for subsequent research, industrial feeding stability is controlled in the process of a production enterprise, and technical support is provided for ensuring the quality stability of subsequent products.
Disclosure of Invention
The invention aims to solve the problems, and provides a method for measuring the salt content in a methylergometrine maleate raw material, which comprises the following steps:
respectively injecting the system applicability solution, the blank solution, the reference solution and the test solution into an ion chromatograph, recording a chromatogram, calculating the content of maleic acid in the methylergometrine maleate raw material drug by peak area according to an external standard method, and substituting the peak area into the formula (1) to calculate the salt forming rate of the methylergometrine maleate raw material;
A＝(B/116.0722)/(C/445.5) (1)
wherein A is the salification rate of the raw material of methylergometrine maleate, B is the content of maleic acid, and C is the content of methylergometrine maleate in the raw material;
the ion chromatographic conditions are as follows:
a chromatographic column: dionex IonPac AS19(250 mm. times.4 mm, 5 μm);
protection of the column: dionex IonPac AG19(50 mm. times.4 mm, 5 μm);
leacheate: 100mmol/L sodium hydroxide solution;
and (3) an elution mode: gradient elution;
flow rate of eluent: 1.0 mL/min;
temperature of the column: 30 ℃;
detecting the temperature of the cell: 35 ℃;
sample introduction amount: 20 mu L of the solution;
a detector: a conductance detector;
a suppressor: anion suppressor (ASRS-4mm), suppression current: 50 mA;
the nitrogen pressure was 27.6 kPa.
Preferably, the blank solution is ultrapure water.
Preferably, the preparation of the control solution:
(1) accurately weighing 50.12mg of maleic acid reference substance, placing in a 50mL measuring flask, diluting with ultrapure water to scale, shaking up, and making into solution containing maleic acid 1000 μ g per 1mL as reference substance stock solution;
(2) precisely measuring 1mL of the reference stock solution, placing in a 100mL measuring flask, diluting with ultrapure water to scale, shaking to obtain a solution containing 10 μ g of maleic acid per 1mL as a reference solution.
Preferably, the test sample solution is prepared by placing the test sample solution into a 250mL measuring flask, adding ultrapure water for dissolving, diluting to a scale mark, and shaking up.
Preferably, preparation of the system suitability solution: mixing the test solution and the reference solution at a ratio of 1: 1.
Preferably, the gradient elution is performed by: the concentration of the leacheate is 20mmol/L after 0-15 minutes; 15-22 minutes, and the concentration of leacheate is 250 mmol/L; 22-30 minutes, and the concentration of the leacheate is 20 mmol/L.
Compared with the prior art, the invention has the following beneficial effects:
the method adopts the conductivity detection-ion chromatography, and according to an external standard method, the content of maleic acid in the raw material medicine of methylergometrine maleate is measured by peak area calculation, and the salt forming rate is calculated. The method establishes an ion chromatography-conductivity detector method for measuring the maleic acid content in the methylergometrine maleate, and has the advantages of strong specificity, high sensitivity, simple operation and accurate result.
Drawings
FIG. 1 is a typical map of system applicability;
FIG. 2 is a chromatogram of a control solution;
FIG. 3 is a chromatogram of a sample solution;
FIG. 4 is a linear relationship diagram of maleic acid.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
1. Instrument and reagent
The instrument comprises the following steps: dionex ICS 3000 ion chromatograph (Thermo corporation, usa);
ASRS-4mm suppressors (Thermo corporation, USA);
Milli-Q ultrapure water system (18.2M' omega/cm 3, 25 ℃, Millipore, USA);
an electronic analytical balance of the type Mettler Toledo XS 205 (Mettler, Switzerland).
Reagent: sodium hydroxide solution, purchased from Fluka Sigma-ALDRICH,
purity grade: ion chromatography specific, concentration: 50% -52%;
ultrapure water is self-made in laboratories.
Comparison products: the maleic acid reference substance is purchased from China institute for testing and testing food and drug,
batch number: 190015-202003, content: 99.6 percent.
And (3) testing the sample: the raw material of methylergometrine maleate is collected from a pharmaceutical factory in Hebei,
batch number: 190826, 200424, 180322.
2. Method of producing a composite material
2.1 chromatographic conditions
A chromatographic column: dionex IonPac AS19(250 mm. times.4 mm, 5 μm);
protection of the column: dionex IonPac AG19(50 mm. times.4 mm, 5 μm);
leacheate: 100mmol/L sodium hydroxide solution;
and (3) an elution mode: gradient elution (see table below);
flow rate of eluent: 1.0 mL/min;
temperature of the column: 30 ℃;
detecting the temperature of the cell: 35 ℃;
sample introduction amount: 20 mu L of the solution;
a detector: a conductance detector;
a suppressor: anion suppressor (ASRS-4mm), suppression current: 50 mA;
the nitrogen pressure was 27.6 kPa.
TABLE 1 gradient elution Table for leacheate
2.2 preparation of the solution
Preparing a blank solution: ultrapure water;
preparation of a reference stock solution: accurately weighing 50.12mg of maleic acid reference substance, placing in a 50mL measuring flask, diluting with ultrapure water to scale, shaking up, and making into solution containing maleic acid 1000 μ g per 1mL as reference substance stock solution;
preparing a reference substance solution: precisely measuring 1mL of reference stock solution, placing in a 100mL measuring flask, diluting with ultrapure water to scale, shaking to obtain solution containing maleic acid 10 μ g per 1mL as reference solution;
preparing a test solution: weighing 10mg of raw material methylergometrine maleate, precisely weighing, placing into a 250mL measuring flask, adding ultrapure water for dissolving, diluting to scale, and shaking up to obtain a sample solution;
preparation of system applicability solution: mixing the test solution and the reference solution at a ratio of 1: 1.
3. Methodology validation
3.1 specificity experiments
Injecting the system applicability solution, blank solution, reference solution and sample solution into ion chromatograph, respectively, and recording chromatogram, with the results shown in figures 1-4.
The result shows that under the chromatographic condition, the solvent does not interfere with the sample measurement, and the maleic acid ion peak and the front and rear impurity peaks can both achieve baseline separation.
3.2 limit of quantitation and detection
Preparing a quantitative limiting solution: diluting the reference solution step by step, injecting into a liquid chromatograph, and recording chromatogram until the signal-to-noise ratio s/n is about 10.
The limit solution was measured 6 times continuously according to a building-up method and the chromatogram was recorded.
TABLE 2 limit of quantitation test
Precisely measuring the reference solution, diluting step by step, injecting into a liquid chromatograph, and recording chromatogram (figure 2) until the signal-to-noise ratio s/n is about 3, which is the detection limit solution.
From the above test results, it can be seen that: the peak area RSD of the results of 6 times of determination of the quantitative limit of maleic acid is 1.5 percent, and the quantitative limits are 18.107 mu g respectively; the detection limit was 6.036. mu.g.
3.3 Linearity and Range
Preparation of linear stock solutions: precisely measuring 5.0mL of the reference stock solution, placing in a 50mL measuring bottle, adding ultrapure water to dilute to scale, shaking up, and making into linear stock solution.
Preparation of a series of linear solutions: precisely measuring linear solution stock solutions 0.1mL, 1.0mL, 2.5mL, 5.0mL, 10.0mL and 15.0mL respectively, placing in 50mL measuring bottles, adding ultrapure water to dilute to scale, shaking up, and making into series of control solutions. And (5) carrying out sample injection measurement according to the chromatographic conditions, and recording the peak area.
TABLE 3 maleic acid Linear relationship test results
Taking the peak area as the ordinate and the concentration as the abscissa to perform linear regression, wherein the linear relationship is shown in the attached figure 4:
the maleic acid is in the range of 0.2 mu g/ml to 30 mu g/ml, the linear equation is that y is 0.045x +0.0078, the correlation coefficient R2 is 0.9998, and the peak area A and the concentration C (mu g/ml) are in a remarkable linear relation.
3.4 accuracy test
Preparation of standard addition solution: precisely measuring 8.0mL, 10.0mL and 12.0mL of reference substance stock solutions, placing into a 1000mL measuring flask, adding ultrapure water to dilute to scale, and shaking to obtain standard addition solutions (1)8 μ g/mL, (2)10 μ g/mL and (3)12 μ g/mL;
preparing a test solution: precisely weighing about 10mg of the product (batch number: 200424), 9 parts in total, dividing into 3 groups, placing into 250mL measuring bottles, respectively adding the above mixed control solution to dissolve and dilute to scale, and shaking up. Injecting the solution into an ion chromatograph, and recording a chromatogram; the ratio of the measured amount to the added amount is the recovery rate.
TABLE 4 recovery test
From the above test results, it can be seen that: the recovery rate of the maleic acid ranges from 96.30% to 101.15% (RSD ═ 1.92), and the method meets the verification requirement, and has good accuracy.
3.5 precision test
3.5.1 sample introduction precision
Injecting the reference solution into an ion chromatograph, repeatedly injecting the sample for 6 times, recording the chromatogram, calculating the RSD, and inspecting the instrument precision of the method.
TABLE 5 sample introduction precision test
From the test results, it can be seen that: the retention time RSD of the maleic acid is 0.1 percent, the peak area RSD of the maleic acid is 1.7 percent, and the method has good sample injection precision.
3.5.2 repeatability experiments
Taking 1 batch (batch number: 200424) of methylergonovine maleate raw material and a reference solution, preparing 6 parts in parallel according to a drafting method, respectively injecting into an ion chromatograph, and recording chromatograms. The reproducibility of the method was examined.
TABLE 6 results of the repeatability tests
And (4) conclusion: the same experimenter repeats the measurement 6 times, and the detected amount of the maleic acid is basically consistent after 6 times of measurement. The method has good repeatability.
3.5.3 intermediate precision test
Different experimenters operated with the reference solution and the test solution to prepare 6 parts of the reference solution and 6 parts of the test solution (batch number: 200424). Injecting into ion chromatograph, and recording chromatogram.
TABLE 7 results of intermediate precision test
And (4) conclusion: different experimenters repeat the measurement 6 times, and the results of the 6 times of measurement are compared, so that the detected amount of the maleic acid is consistent. The method has good repeatability.
3.6 durability test
The flow rates of the leaching solution are respectively considered to be 0.8ml/min, 1.0ml/min and 1.2 ml/min; the concentration of the leacheate is 18mmol/L, 20mmol/L and 22mmol/L, the temperature of a chromatographic column is 25 ℃, 30 ℃ and 35 ℃, and the chromatographic retention behaviors of a main peak and adjacent impurity peaks are realized under the condition. The result shows that the main peak of the maleic acid ion is stable under the condition of small amplitude change of each chromatographic condition, the adjacent impurity peaks can be separated from the base line, and the method has good durability of the chromatographic condition.
3.7 stability test
Preparing according to the preparation method of the reference solution, standing at room temperature for 0, 1, 2, 3, 4, 5 and 6 hours, injecting the solutions with different standing times into an ion chromatograph, and recording the chromatogram.
TABLE 8 solution stability test results
From the test results, it can be seen that: after standing at room temperature for 6 hours, the control solution had an area RSD of 1.2% (n ═ 6), and was stable for 6 hours.
4. Sample assay
Taking 3 batches of raw materials, and carrying out batch number: 190826, 200424 and 180322 of 10mg each, which are measured by sampling according to a proposed method, recording peak area and calculating the content of maleic acid. The results are shown in the following table.
TABLE 9 results of sample measurement
Discussion of the related Art
5.1 confirmation of flow Rate of leacheate
The chromatographic retention behaviors of the main peak and the adjacent impurity peak are respectively considered under the conditions of flow rate of 0.8ml/min, 1.0ml/min and 1.2ml/min of the leaching solution. The results show that the main peak of the maleic acid ion is stable under the condition of small amplitude change of the various chromatographic conditions, the adjacent impurity peaks can be separated from the base line, and the flow rate of the leacheate is finally selected to be 1.0 ml/min.
TABLE 10 investigation of flow rates of the leachates
5.2 confirmation of eluent concentration
The chromatographic retention behaviors of a main peak and adjacent impurity peaks of the main peak under the conditions that the concentration of leacheate is 18mmol/L, 20mmol/L and 22mmol/L are respectively considered. The result shows that the main peak of the maleic acid ion is stable under the condition of small amplitude change of various chromatographic conditions, the adjacent impurity peaks can be separated from the base line, and the concentration of the eluting solution is finally selected to be 20 mmol/L.
TABLE 11 examination of leacheate concentration
5.3 confirmation of column temperature
The chromatographic retention behaviors of the main peak and the adjacent impurity peak are respectively considered under the conditions that the temperature of a chromatographic column is 25 ℃, 30 ℃ and 35 ℃. The result shows that the main peak of the maleic acid ion is stable under the condition of small amplitude change of various chromatographic conditions, the adjacent impurity peaks can be separated from the base line, and the temperature of the chromatographic column is selected to be 30 ℃.
TABLE 12 chromatographic column temperature investigation test results
Conclusion 6
6.1 maleic acid Limit determination
Ergometrine is known to have the formula C20H25N3O2The relative molecular weight is: 339.4278, maleic acid molecular formula: c4H4O4The relative molecular weight is: 116.0722, the theoretical maleic acid content was calculated to be 25.48% when 1 molecule of maleic acid was contained in the methylergometrine maleate.Referring to the guiding principle of 9003 medicine impurity inspection in the four parts of the 2020 edition of Chinese pharmacopoeia, the maleic acid content of methylergonovine maleate is controlled to be 80.0-120.0% of the theoretical value, and the limit of the maleic acid content is 20.4-30.6%.
6.2 examination of salt formation Rate
The content of the active ingredient of the methylergometrine maleate is determined according to an HPLC method in USP43, and the content result is the content of the methylergometrine maleate because a reference substance is calculated according to C20H25N3O 2. C4H4O 4. Calculating the salt forming rate by using the molar concentration, and dividing the ratio of the relative molecular weight of maleic acid divided by the relative molecular weight of methylergonovine maleate and the content of methylergonovine maleate divided by the relative molecular weight of methylergonovine maleate by using the formula: the maleic acid salt formation rate ═ (maleic acid%/116.0722)/(methylergometrine maleate%/445.5) [9 ].
TABLE 13 salt formation rate of methylergometrine maleate
6.2 product quality evaluation
Compared with pharmacopoeias of various countries, the detection of salt in salifying drugs usually only has chemical identification, and few salt-forming ions with strong specificity are quantitatively detected [10], and the research establishes an ion chromatography-conductivity detector method for determining the content of maleic acid in methylergonovine maleate.
The established method is applied to detect the 3 gathered samples, the content of the maleic acid is 25.18-25.33%, the average content is 25.24%, the salt forming rate is 0.97, the limit requirement is met, the production process of domestic production enterprises is stable, excessive free maleic acid does not exist in the products, and the quality is safe and controllable.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A method for determining the salt forming rate of methylergometrine maleate raw material is characterized by comprising the following steps:
respectively injecting the system applicability solution, the blank solution, the reference solution and the test solution into an ion chromatograph, recording a chromatogram, calculating the content of maleic acid in the methylergometrine maleate raw material drug by peak area according to an external standard method, and substituting the peak area into the formula (1) to calculate the salt forming rate of the methylergometrine maleate raw material;
A＝(B/116.0722)/(C/445.5) (1)
wherein A is the salification rate of the raw material of methylergometrine maleate, B is the content of maleic acid, and C is the content of methylergometrine maleate in the raw material;
the ion chromatography conditions were:
a chromatographic column: dionex IonPac AS19(250 mm. times.4 mm, 5 μm);
protection of the column: dionex IonPac AG19(50 mm. times.4 mm, 5 μm);
leacheate: 100mmol/L sodium hydroxide solution;
an elution mode: gradient elution;
flow rate of eluent: 1.0 mL/min;
temperature of the column: 30 ℃;
detecting the temperature of the cell: 35 ℃;
sample introduction amount: 20 mu L of the solution;
a detector: a conductance detector;
a suppressor: anion suppressor (ASRS-4mm), suppression current: 50 mA;
the nitrogen pressure was 27.6 kPa.
2. The method of claim 1, wherein the blank solution is ultrapure water.
3. The method for determining the salt formation rate of the methylergometrine maleate raw material according to claim 1, wherein the preparation of the control solution comprises:
(1) accurately weighing 50.12mg of maleic acid reference substance, placing in a 50mL measuring flask, diluting with ultrapure water to scale, shaking up, and making into solution containing maleic acid 1000 μ g per 1mL as reference substance stock solution;
(2) precisely measuring 1mL of the reference stock solution, placing in a 100mL measuring flask, diluting with ultrapure water to scale, shaking to obtain a solution containing 10 μ g of maleic acid per 1mL as a reference solution.
4. The method for determining the salt formation rate of a starting material of methylergonovine maleate according to claim 1, wherein the preparation of the test solution comprises: weighing 10mg of methylergometrine maleate raw material, precisely weighing, placing in a 250mL measuring flask, adding ultrapure water for dissolving, diluting to scale, shaking up, and using as a test solution.
5. The method for determining the salt formation rate of methylergonovine maleate according to claim 1, wherein the preparation of the system suitability solution comprises: mixing the test solution and the reference solution at a ratio of 1: 1.
6. The method for determining the salt formation rate of a starting material of methylergonovine maleate according to claim 1, wherein the gradient elution is carried out by: the concentration of the leacheate is 20mmol/L after 0-15 minutes; 15-22 minutes, and the concentration of leacheate is 250 mmol/L; 22-30 minutes, and the concentration of the leacheate is 20 mmol/L.
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| CN114527202A (en) * | 2021-12-31 | 2022-05-24 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for determining salt forming rate of methylergometrine maleate raw material |
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