CN111474270B - Method for preparing related detection and test solution in misoprostol solid preparation - Google Patents
Method for preparing related detection and test solution in misoprostol solid preparation Download PDFInfo
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- CN111474270B CN111474270B CN202010107703.XA CN202010107703A CN111474270B CN 111474270 B CN111474270 B CN 111474270B CN 202010107703 A CN202010107703 A CN 202010107703A CN 111474270 B CN111474270 B CN 111474270B
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Abstract
The invention provides a preparation method of a test solution for detecting related substances in a misoprostol solid preparation with the specification of 5-80 mu g and an HPLC method for detecting the related substances in the misoprostol solid preparation with the specification of 5-80 mu g. The preparation method of the test solution provided by the invention can prepare the test solution suitable for detecting related substances by an HPLC method for the misoprostol solid preparation with the specification of 5-80 mug.
Description
Technical Field
The invention relates to the technical field of preparation analysis methods, in particular to an HPLC (high performance liquid chromatography) detection method for related substances of a low-dose misoprostol solid preparation (specification: 5-80 mu g) and a preparation method for a test solution used in detection.
Background
Misoprostol, a prostaglandin E1 derivative, is extremely active and only needs microgram level for clinical application. Misoprostol has been successfully developed and approved for the treatment of gastric ulcers or abortions, on a 200 μ g scale.
Clinical application further shows that the misoprostol has multiple purposes, such as being used for labor induction at term under a lower dosage (such as 5-80 mug). Researchers need to develop misoprostol preparations with different specifications aiming at different indications, and the misoprostol solid preparation is a better choice due to the convenience in carrying and using.
Quality control, especially related substance control, is especially important in the development of formulations. The misoprostol degradation impurities comprise known 8-epi-misoprostol, A-configuration misoprostol, B-configuration misoprostol, unknown impurities and the like. An important problem in the development of related substance analysis methods of the misoprostol solid preparation is that the smaller the specification is, the lower the proportion of misoprostol in the preparation is, the larger the interference of auxiliary materials is, the more difficult the detection is, and the sensitivity can not meet the requirements.
Some attempts have been made by those skilled in the art to detect misoprostol related substances.
USP42-NF37 discloses a method for detecting related substances of misoprostol dispersion and a method for preparing a test solution. She Hao, et al, published a text of "simultaneous determination of contents of two components and related substances in ohinck tablets by high performance liquid chromatography", and the contents of diclofenac sodium and misoprostol (200 μ g) and related substances are simultaneously determined by high performance liquid chromatography, the method has low sensitivity, the detection limit of 8-epi-misoprostol is 0.16%, the detection limit of A-configuration misoprostol is 0.13%, both are greater than the report limit of 0.1%, and the detection requirements are not met; carr et al, issued in the article Analytical methods to determinines the potency and quality of misoprostol tables, describe a method for HPLC isocratic elution detection of 200 μ g misoprostol tablets; getu Kahsay et al, published in the section of Development and evaluation of LC methods for the separation of misoprostol related substructures and diasterieomers, describe the use of LC methods for separating misoprostol drug substance, 4% dispersion and related substances in 100. Mu.g and 200. Mu.g tablets.
However, all the above methods are only applicable to misoprostol, misoprostol-dispersion and/or misoprostol formulations with a specification ≧ 100 μ g. According to the preparation method and the detection method of the test solution provided by the above documents, the method cannot be used for detecting misoprostol solid preparations with the specification of 5-80 μ g, and the interference of auxiliary materials is large or the detection limit cannot meet the requirement.
Therefore, there is a need for a method for detecting substances suitable for a low-dose (specification: 5 μ g to 80 μ g) misoprostol solid preparation, which is capable of detecting known impurities and unknown impurities simultaneously, has high sensitivity and good separation effect, and a method for preparing a test solution suitable for the detection, so as to control the quality of the low-dose (specification: 5 μ g to 80 μ g) misoprostol solid preparation.
Disclosure of Invention
Based on the technical problems, in order to overcome the defects in the prior art, the invention provides an HPLC method for detecting related substances in a low-dose (specification: 5-80 mu g) misoprostol solid preparation and a preparation method of a test solution for detection.
In order to achieve the purpose, the invention adopts the technical scheme that:
the preparation method of the test solution for detecting related substances in the misoprostol solid preparation (the specification is 5-80 mu g) by an HPLC method is provided, and the preparation method comprises the following steps:
1) Weighing: weighing a proper amount of misoprostol solid preparation as a test sample;
2) Extraction: dissolving a test sample by using a first solvent to obtain misoprostol extract, wherein the concentration of the extract is 5-80 mug/ml; preferably, the first solvent is at least one of ethyl acetate, methanol or ethanol, and more preferably, the first solvent is methanol. Therefore, the misoprostol in the test sample can be fully extracted, the extraction solution can be easily concentrated and dried to the required concentration of the test sample solution, and the increase of impurities in the extraction process is avoided.
3) Concentrating and drying: concentrating and drying appropriate amount of extractive solution to obtain sample extract;
4) Dissolving: dissolving the test sample extract by using a second solvent to prepare a test sample solution, wherein the concentration of the test sample solution is 100-200 mu g/ml, and the second solvent is a polar organic solvent capable of dissolving misoprostol, a polar organic solvent-aqueous solution or a polar organic solvent-buffer salt solution; preferably, the polar organic solvent is at least one of methanol, ethanol, isopropanol, and acetonitrile. Therefore, the concentration of the test solution can meet the detection sensitivity requirement, the specificity is good, and the interference of detection caused by excessive concentration of auxiliary materials can be avoided.
Preferably, wherein the manner of extraction is sonication or shaking, more preferably sonication.
Preferably, wherein the extraction time is 5 to 60min.
Preferably, the concentrating and drying mode is vacuum drying or inert gas blow drying, and more preferably nitrogen blow drying.
Preferably, the first solvent is methanol, the extraction mode is ultrasonic, the extraction time is 15-40 min, the concentration of the extracting solution is 10-50 mug/ml, the concentration drying mode is nitrogen blow drying, and the concentration of the test sample solution is 100-150 mug/ml, so that the main component and all impurities can be fully extracted, and the interference of auxiliary materials is small.
Preferably, the misoprostol solid preparation is misoprostol vaginal tablets.
Preferably, the specification of the misoprostol solid preparation is 25 μ g.
The test solution prepared by the preparation method of the test solution provided by the invention is suitable for detecting misoprostol related substances by an HPLC method. The invention also provides an HPLC method for detecting related substances in the misoprostol solid preparation with the specification of 5-80 mug, which is characterized by comprising the following steps:
1) Preparing a test solution: prepared according to the method;
2) Preparing a reference substance solution: taking a proper amount of misoprostol reference substance, precisely weighing, adding the second solvent for dissolving, and quantitatively diluting to prepare a reference substance solution, wherein the concentration of the reference substance solution is 1% of that of the test sample solution;
3) Preparing a system applicability solution: dissolving and diluting a control product with the second vehicle to obtain a system suitability solution, wherein the control product at least comprises misoprostol control product and 8-epi-misoprostol control product;
4) Chromatographic peak determination: injecting the prepared test solution and the reference solution into a liquid chromatograph, recording detection data, and calculating the content of misoprostol and the content of related substances in the test solution, wherein the chromatographic conditions are as follows: the method comprises the following steps of using octyl silane bonded silica gel as a chromatographic column of a filler, wherein the inner diameter of the chromatographic column is 4.6mm, the length of the chromatographic column is 150mm or 250mm, the particle size of the filler of the chromatographic column is 3-5 mu m, the column temperature is 35-55 ℃, the flow rate is 1.0-2.0 ml/min, using phosphate buffer solution-isopropanol as a mobile phase, carrying out isocratic elution, controlling the temperature of a sample tray to be 2-10 ℃, the sample feeding amount to be 50-250 mu l, the detection wavelength to be 200-210 nm, adjusting the pH value of the phosphate buffer solution to be 2.5-3.5 by using phosphoric acid, and controlling the volume ratio of the phosphate buffer solution to the isopropanol to be (680-780): (220-320), the phosphate is potassium dihydrogen phosphate or sodium dihydrogen phosphate.
Preferably, the concentration of the phosphate buffer solution is 0.01mol/L, the pH value is 2.9-3.1, and the phosphate is potassium dihydrogen phosphate.
Preferably, the chromatographic column is Phenomenex Luna C8 (2), the inner diameter is 4.6mm, the column length is 150mm, the filler particle size is 5 μm, the column temperature is 40-50 ℃, the flow rate is 1.0-2.0 ml/min, the temperature of the sample plate is controlled to be 2-10 ℃, the sample feeding amount is 100-250 μ L, the volume ratio of phosphate buffer solution to isopropanol is 730.
Preferably, the flow rate is 1.4 to 1.6ml/min.
Preferably, the sample amount is 100 to 200. Mu.l.
Preferably, the misoprostol solid preparation is misoprostol vaginal tablets.
Preferably, the specification of the misoprostol solid preparation is 25 μ g.
In order to verify the detection effect of the technical scheme, the scheme of the invention is adopted to prepare a test solution, 5-80 mu g of misoprostol solid preparation is detected by HPLC, and the result shows that the method can effectively separate and detect 8-epi-misoprostol, A-configurational misoprostol and B-configurational misoprostol at the same time.
In conclusion, the invention provides an HPLC method suitable for detecting related substances of a low-dose misoprostol solid preparation (the specification is 5-80 mug), and a preparation method of a test solution required for detection, the method can well separate the known impurities of misoprostol (8-epi misoprostol, A-configurational misoprostol and B-configurational misoprostol), the detection limit reaches 0.05%, the quantification limit is 0.1%, and the method has the advantages of strong specificity, high sensitivity and good accuracy.
Drawings
FIG. 1 is a high performance liquid chromatogram of an empty white solution of example one.
FIG. 2 is a high performance liquid chromatogram of a solution suitable for use in the system of the first embodiment.
FIG. 3 is a high performance liquid chromatogram of a solution of hollow-white excipient of example one.
FIG. 4 is a high performance liquid chromatogram of the test solution of example I.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example one
1. Using instruments and chromatographic conditions
The instrument comprises the following steps: high performance liquid chromatograph, shimadzu LC-20AT; the column temperature is 50 ℃; the flow rate is 1.5ml/min; the detection wavelength is 205nm; the liquid chromatography column uses Waters Xbridge C8 with specification of 4.6 × 150mm,5 μm;0.01mol/L potassium dihydrogen phosphate solution (pH3.0) -isopropanol is used as a mobile phase composition, and the optimal mixture ratio is (73; the sample amount is 100 mul; the sample pan was temperature controlled at 5 ℃.
Under the chromatographic condition, the misoprostol main peak has moderate retention time and better peak shape and column effect.
2. Solution preparation
(1) A second solvent: isopropanol-water (27.
(2) Preparing a reference substance solution: taking a proper amount of misoprostol reference substance, precisely weighing, adding a second solvent for dissolving, and quantitatively diluting to obtain a solution containing misoprostol 1.25 μ g per 1ml, as a reference substance solution.
(3) Preparing a sensitivity solution: taking a proper amount of precisely measured reference solution, and quantitatively diluting with a second solvent to obtain a solution containing 0.125 μ g of misoprostol in each 1ml as a sensitivity solution.
(4) Preparing a system applicability solution: taking the misoprostol reference substance and the 8-epi-misoprostol reference substance, adding a second solvent for dissolving and diluting to prepare a solution containing 125 mu g of misoprostol and 2.5 mu g of 8-epi-misoprostol in each 1ml, and using the solution as a system applicability solution.
(5) Preparing a test solution: taking 40 misoprostol vaginal tablets (specification: 25 mu g), precisely weighing, grinding, precisely weighing a proper amount, adding a proper amount of first solvent ethyl acetate, shaking for 60min to prepare a solution containing 25 mu g per 1ml, centrifuging, precisely weighing 5ml of supernatant, vacuum drying, precisely adding 1ml of second solvent into residues to dissolve, centrifuging, and taking the supernatant as a test solution (containing misoprostol 125 mu g/ml).
(6) Preparing a blank auxiliary material solution: taking 40 pieces of blank auxiliary material tablets, and operating the same method as the test solution to be used as the blank auxiliary material solution.
3. Procedure for the preparation of the
And respectively taking 100 mul of the second solvent (blank solution), the sensitivity solution, the system applicability solution, the reference solution, the blank auxiliary material solution and the test solution, respectively injecting into a liquid chromatograph, and recording a chromatogram. If an impurity peak exists in the chromatogram of the test solution, a blank auxiliary material peak is deducted, and the impurity content is calculated according to a main component external standard method of dividing by a response factor, which all accords with the corresponding limit regulation in the table 1.
TABLE 1 misoprostol related substance detection limit requirements
4. Results of the experiment
FIG. 1 is a high performance liquid chromatogram of a blank solution of example one, FIG. 2 is a high performance liquid chromatogram of a system applicability solution of example one, FIG. 3 is a high performance liquid chromatogram of a blank excipient solution of example one, FIG. 4 is a high performance liquid chromatogram of a test sample solution of example one, and the data are shown in Table 3:
example two
1. The method adopts an instrument and chromatographic conditions: the column was purified using Phenomenex Luna C8 (2), as in example one.
2. Solution preparation
Preparing a test solution: taking 40 misoprostol vaginal tablets (specification: 25 mu g), precisely weighing, grinding, precisely weighing a proper amount, adding a proper amount of first solvent methanol, carrying out ultrasonic treatment for 30min to prepare a solution containing 25 mu g of misoprostol per 1ml, centrifuging, precisely weighing 5ml of supernate, drying by using nitrogen, precisely adding 1ml of second solvent into residues for dissolving, centrifuging, and taking the supernate as a test solution (containing misoprostol 125 mu g/ml).
Preparing a blank auxiliary material solution: taking 40 blank adjuvant sheets, and processing with the same method as the sample solution to obtain blank adjuvant solution.
The rest solutions are prepared in the same way as in the first embodiment.
3. The method comprises the following operation steps: the same as the first embodiment.
4. Sensitivity measurement
Taking appropriate amount of misoprostol, 8-epi-misoprostol, B-configuration misoprostol and A-configuration misoprostol, respectively preparing into 0.1 μ g/ml solution and 0.05 μ g/ml solution with second solvent, respectively injecting into liquid chromatograph, respectively, continuously measuring for 3 times, wherein S/N is greater than 10 and greater than 3, calculated according to the concentration of 100 μ g/ml at the time of related substance examination, the quantitative concentration is 0.1%, and the detected concentration is 0.05%. The result shows that the method has high sensitivity and can fully meet the requirements of checking and measuring related substances.
5. Results of the experiment
Three batches of test articles were tested in parallel and the results are shown in table 2:
table 2 example two 3 batches of samples test results
EXAMPLE III
The column temperature is 40 ℃, the flow rate is 1.0ml/min, the second solvent is mobile phase, the rest is the same as the first example, and the experimental results are shown in Table 3.
Example four
The column was filled with 200. Mu.l Phenomenex Luna C8 (2).
Preparing a test solution: taking 40 misoprostol vaginal tablets (specification: 10 mu g), precisely weighing, grinding, precisely weighing a proper amount, adding a proper amount of first solvent methanol, carrying out ultrasonic treatment for 30min to prepare a solution containing 10 mu g of misoprostol per 1ml, centrifuging, precisely weighing 10ml of supernate, drying by using nitrogen, precisely adding 1ml of second solvent into residues for dissolving, centrifuging, and taking the supernate as a test solution (containing 100 mu g/ml of misoprostol).
Preparing a blank auxiliary material solution: taking 40 pieces of blank auxiliary material tablets, and operating the same method as the test solution to be used as the blank auxiliary material solution.
The rest of the experimental results are shown in Table 3 as in the first example.
Example 5
The column was purified by Phenomenex Luna C8 (2).
Preparing a test solution: taking 40 tablets (specification: 50 mu g) of misoprostol, precisely weighing, grinding, precisely weighing a proper amount, adding a proper amount of first solvent ethanol, shaking for 30min to prepare a solution containing 50 mu g of misoprostol per 1ml, centrifuging, precisely weighing 4ml of supernatant, drying by using nitrogen, precisely adding 1ml of methanol into residues for dissolving, centrifuging, and taking the supernatant as a test solution (containing 200 mu g/ml of misoprostol).
Preparing a blank auxiliary material solution: taking 40 blank adjuvant sheets, and processing with the same method as the sample solution to obtain blank adjuvant solution.
The rest of the experimental results are shown in Table 3 as in the first example.
TABLE 3 test results of examples one, three to five
The experimental results show that the scheme of the invention can well separate the known impurities of misoprostol (8-epi-misoprostol, A-configuration misoprostol and B-configuration misoprostol), the detection limit reaches 0.05 percent, the quantification limit is 0.1 percent, the specificity is strong, the sensitivity is high, and the accuracy is good.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (1)
1. An HPLC method for detecting related substances in misoprostol vaginal tablets is characterized by comprising the following steps:
preparing a test solution;
preparing a reference substance solution: taking a proper amount of misoprostol reference substance, precisely weighing, adding a second solvent for dissolving, and quantitatively diluting to prepare a reference substance solution, wherein the concentration of the reference substance solution is 1% of that of the test sample solution;
preparing a system applicability solution: dissolving a reference substance in a second solvent and diluting to obtain a system applicability solution, wherein the reference substance at least comprises misoprostol reference substance and 8-epi-misoprostol reference substance;
chromatographic peak determination: injecting the prepared test solution and the reference solution into a liquid chromatograph, recording detection data, and calculating the content of misoprostol and the content of related substances in the test solution, wherein the chromatographic conditions are as follows: the chromatographic column is Phenomenex Luna C8 (2), the inner diameter of the chromatographic column is 4.6mm, the length of the chromatographic column is 150mm, the particle size of a chromatographic column filler is 5 mu m, the column temperature is 40-50 ℃, the flow rate is 1.4-1.6 ml/min, phosphate buffer solution-isopropanol is used as a mobile phase, isocratic elution is carried out, the temperature of a sample plate is controlled to be 2-10 ℃, the sample feeding amount is 100-200 mu L, the detection wavelength is 205nm, the pH value of phosphate buffer solution is adjusted to be 2.9-3.1 by phosphoric acid, the concentration of the phosphate buffer solution is 0.01mol/L, and the volume ratio of the phosphate buffer solution to the isopropanol is 730:270, the phosphate is potassium dihydrogen phosphate;
wherein the preparation of the test solution comprises the following steps:
weighing: weighing a proper amount of misoprostol vaginal tablets as a test sample;
extraction: dissolving a test sample by using a first solvent to obtain misoprostol extract, wherein the extraction mode is ultrasonic, the extraction time is 15-40 min, the concentration of the extract is 10-50 mug/ml, and the first solvent is methanol;
concentrating and drying: concentrating and drying appropriate amount of extractive solution to obtain sample extract; the concentration and drying mode is nitrogen blow-drying;
dissolving: dissolving the test sample extract by using a second solvent to prepare a test sample solution with the concentration of 100-150 mu g/ml, wherein the second solvent is an isopropanol-water solution;
wherein the misoprostol vaginal tablet has a specification of 25 mug.
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| CN102697746A (en) * | 2012-06-11 | 2012-10-03 | 广州朗圣药业有限公司 | Rapid melting misoprostol vaginal composition as well as preparation method and application of same |
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| CN102697746A (en) * | 2012-06-11 | 2012-10-03 | 广州朗圣药业有限公司 | Rapid melting misoprostol vaginal composition as well as preparation method and application of same |
Non-Patent Citations (4)
| Title |
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| Development and validation of LC methods for the separation of misoprostol related substances and diastereoisomers;Getu Kahsay et al;《Journal of Pharmaceutical and Biome dical Analysis》;20150402;91-99 * |
| Getu Kahsay et al.Development and validation of LC methods for the separation of misoprostol related substances and diastereoisomers.《Journal of Pharmaceutical and Biome dical Analysis》.2015,91-99. * |
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