CN109596756B - Composition and detection method of related substances in pramipexole starting material - Google Patents
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Abstract
The invention provides a composition and a method for detecting related substances in pramipexole starting material, wherein the composition comprises (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole and impurities, and the impurities comprise PMH-SM1-Z1 and/or PMH-SM1-Z3, wherein the content of (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole is more than 99%, the content of PMH-SM1-Z1 is not more than 0.5%, and the content of PMH-SM1-Z3 is not more than 0.1%. The composition is used as a pramipexole starting material, and the impurity content is clear and controllable. The invention provides an accurate and effective detection method for detecting related substances in the pramipexole starting material, and ensures the quality of the pramipexole product.
Description
Technical Field
The invention belongs to the field of chemical analysis and detection of medicine impurities, and particularly relates to a method for detecting impurities in a pramipexole starting material.
Background
Pramipexole (Pramipexole), also known as melapa, is a white to off-white crystalline powder chemical, typically in the form of a hydrochloride hydrate (dihydrochloride monohydrate). The chemical name is (S) -2-amino-4, 5,6, 7-tetrahydro-6-propylamine-benzothiazole, the molecular formula is C10H17N3S, and the molecular weight is 211.33. Pramipexole is an antihistamine and is mainly used for clinically treating Parkinson's disease and syndromes thereof. Can be used alone or in combination with levodopa.
Pramipexole starting material (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole (PMH-SM1), the structural formula is as follows:
impurities from synthesis processes and the like exist in the starting material (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, detection and control of the impurities have important significance for controlling the purity of synthesized pramipexole, and research and report about the related impurities in the starting material are not found in the prior art.
Disclosure of Invention
In the synthesis of pramipexole, starting material (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole was used (starting material refers to (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole and impurities contained therein, hereinafter referred to as starting material), and the inventors found that the following process impurities were present in the starting material:
compound 1 (hereinafter PMH-SM 1-Z1):
compound 2 (hereinafter PMH-SM 1-Z3):
the presence of these impurities affects the purity of the pramipexole product and it is necessary to detect and control the aforementioned impurities in the purchased starting material in order to improve the quality of the pramipexole product.
The invention obtains a starting material with definite and controllable impurity type and content by detecting and controlling related substances in the starting material. Specifically, the invention provides a composition comprising (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole and impurities, wherein the impurities comprise PMH-SM1-Z1 and/or PMH-SM1-Z3, the content of the (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole is more than 99%, the content of the PMH-SM1-Z1 is not more than 0.5%, the content of the PMH-SM1-Z3 is not more than 0.1%, and the impurities have the following structural formula:
PMH-SM1-Z1：
PMH-SM1-Z3：
the invention provides a method for detecting related substances in pramipexole starting materials, which uses high performance liquid chromatography to qualitatively and/or quantitatively detect related substances in the starting materials (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole, wherein the chromatographic conditions comprise the following contents:
stationary phase: chromatographic column with octadecylsilane chemically bonded silica as filler;
mobile phase: phosphate buffer solution is used as a mobile phase A, and the volume ratio of acetonitrile to the mobile phase A is 50:50, so that fluidity B is obtained;
detection wavelength: 190-215nm or 230-285 nm;
gradient elution was performed as follows:
the gradient elution procedure is preferably as follows:
further, the impurities detected include PMH-SM1-Z1 and/or PMH-SM1-Z3, the structural formulas are respectively as follows:
PMH-SM1-Z1：
PMH-SM1-Z3：
wherein, when detecting PMH-SM1-Z1, the 190-215nm wave band is selected.
Furthermore, the impurities with the wavelength of 190-210nm for detection are selected to comprise PMH-SM1-Z3 and PMH-SM1-Z1, and the detection is preferably carried out with the wavelength of 205-210 nm.
Furthermore, the impurities are detected by selecting the wavelength of 250-280nm to include PMH-SM1-Z3, and the preferable wavelength is 255-270 nm for detection.
Further, a column size of 4.6mm × 150mm, 5 μm was used; the column temperature was measured at 35-45 ℃.
Further, the flow rate of the mobile phase is 0.8ml/min to 1.2 ml/min.
Further, a mobile phase is used as a solvent for preparing a sample solution, a self-control solution, a system suitability solution and/or an impurity control solution, preferably, a mixed solvent of acetonitrile and mobile phase a is used as a solvent, and further preferably, a mixed solution of acetonitrile and mobile phase a in a volume ratio of 20:80 is used as a solvent.
Further, the phosphate buffer solution is prepared from sodium octane sulfonate, monopotassium phosphate, phosphoric acid and water, and the pH value of the phosphate buffer solution is 2.8-3.2.
Preferably, the phosphate buffer is prepared according to the mass ratio of sodium octane sulfonate: the mass of the potassium dihydrogen phosphate is as follows: the volume ratio of water is 1 (1.97-2) to 217-223, and the weight of sodium octane sulfonate is further as follows: the mass of the potassium dihydrogen phosphate is as follows: the volume ratio of water is 4.6:9.1:1000, wherein the mass unit is g and the volume unit is mL.
Further, the detection method further comprises the following steps:
(1) taking a proper amount of a test sample, precisely weighing, dissolving and diluting by using the solvent to prepare a solution containing about 1mg of the test sample in each 1ml of the solution as a test sample solution;
(2) precisely measuring a proper amount of the test solution, and diluting the test solution with the solvent to prepare a solution containing about 1 mu g of the test solution in each 1ml of the test solution as a self control solution. Taking another proper amount of impurities PMH-SM1-Z1, precisely weighing, dissolving with solvent, and diluting into solution containing about 5 μ g of PMH-SM1-Z1 per 1ml, as impurity reference solution of PMH-SM 1-Z1;
(3) precisely weighing impurities PMH-SM1-Z1 reference substance, PMH-SM1-Z3 reference substance and PMH-SM1 reference substance, dissolving and diluting by taking a mixed solution of acetonitrile and a mobile phase A in a volume ratio of 20:80 as a solvent to prepare a solution containing about 1mg of PMH-SM1, about 5 mu g of PMH-SM1-Z1 and about 1 mu g of PMH-SM1-Z3 in 1mL, and taking the solution as a system suitability solution;
(4) precisely measuring 20 μ l of each of the sample solution, the self-contrast solution and the impurity PMH-SM1-Z1 contrast solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
The invention has the following beneficial effects:
1. the invention provides the pramipexole starting material with definite and controllable impurities and impurity content, and is convenient for controlling the quality of pramipexole.
2. The method successfully separates the known impurities, clearly separates the two impurities on an HPLC spectrogram, accurately tests the impurities and the content of the impurities, and has good system applicability and specificity. The impurity PMH-SM1-Z1 is calculated by an external standard method at 190-215nm, the content is not more than 0.5 percent, the impurity PMH-SM1-Z3 and other single unknown impurities are detected at 190-215nm or 230-285nm, the main peak area (0.1 percent) of the self-contrast solution is not more than, the total amount of the impurities is not more than 1.0 percent, and the requirements of detection limit and quality control of the starting material are met.
Drawings
FIG. 1 is a diagram of a PMH-SM1 ultraviolet full wavelength scan;
FIG. 2 is a diagram of a PMH-SM1-Z3 ultraviolet full wavelength scan;
FIG. 3 is a diagram of a PMH-SM1-Z1 ultraviolet full wavelength scan;
FIG. 4 is a spectrum of method 1 in elution gradient screening;
FIG. 5 is a graph of method 2 in elution gradient screening;
FIG. 6 is a spectrum of method 3 in elution gradient screening;
FIG. 7 is a spectrum of the results of method 4 in column temperature screening;
FIG. 8 is a spectrum of the results of method 5 in the column temperature screening.
Detailed Description
The invention is further illustrated by the following specific examples.
The test sample is referred to as the "starting material" hereinafter.
An apparatus and a device
A chromatographic column: thermo hypersil Gold Aq 4.6mm x 150mm, 5 μm
Standard glassware
Second, reagent, standard substance and reference substance
Third, establishment of limits
The impurity PMH-SM1-Z1 is calculated at 210nm preferably by external standard method, and must not exceed 0.5%, and the impurity PMH-SM1-Z3 and other single unknown impurities are detected at 264nm preferably, and must not be larger than the main peak area (0.1%) of the control solution.
Fourth, establishment of analytical method and condition screening
4.1 Experimental design and overview
According to the synthetic process route and the data of the previous research, the impurities in the product which can be analyzed under HPLC are shown in the following table.
TABLE 4.1-1 reference information Table
4.2 screening and results of chromatographic conditions
4.2.1 Mobile phase System screening
The product is more polar and less retained in reversed phase chromatography, as presumed by PMH-SM1 and related impurity chemical structure. Phosphate buffer (weighing 4.6g of sodium octane sulfonate and 9.1g of monopotassium phosphate, adding 1000ml of water for dissolving, and adjusting the pH value to 3.0 by using phosphoric acid) is used as a mobile phase A, and acetonitrile and mobile phase A are used as a mobile phase B according to the volume ratio of 50: 50. Screening was carried out on the basis of this mobile phase system.
4.2.2 screening of detection wavelengths
Carrying out ultraviolet full-wavelength scanning on PMH-SM1, impurities PMH-SM1-Z1 and PMH-SM1-Z3, wherein the results are shown in a graph 1-3, the PMH-SM1 and the impurities PMH-SM1-Z3 are basically consistent due to chemical structures similar to an ultraviolet scanning spectrum, the peak top absorption wavelength is 190-; the absorption intensity is more than 200mAU, and the ultraviolet absorption intensity of PMH-SM1-Z3 is basically consistent with that of PMH-SM 1. The content of PMH-SM1-Z3 is detected by using a self-control method, and 190-215nm or 230-285nm can be selected as a detection wavelength.
While the impurity PMH-SM1-Z1 is absorbed at the tail end, and the peak absorption wavelength is 190-210 nm; at wavelengths greater than 215, the absorption intensity is <50mAU, and the response is too weak to be considered as system noise removal. The content of PMH-SM1-Z1 is detected by using an external standard method, and 190-215nm can be selected as a detection wavelength.
Based on the above results, impurities PMH-SM1-Z3 and other unknown impurities were selected as representative examples for detection at a wavelength of 210nm or 264nm, and impurities PMH-SM1-Z1 and PMH-SM1-Z3 were selected as representative examples.
4.2.2 screening of elution gradient
Phosphate buffer solution (4.6 g of sodium octane sulfonate and 9.1g of monopotassium phosphate are weighed, 1000ml of water is added for dissolution, the pH value is adjusted to 3.0 by phosphoric acid) is used as a mobile phase A, acetonitrile-mobile phase A (50:50) is used as a fluidity B, and gradient elution is carried out according to the following table; the solvent is a mixed solution of acetonitrile and mobile phase A (20: 80);
the method comprises the following steps: taking a proper amount of a test sample, precisely weighing, dissolving with a solvent, and diluting to prepare a solution containing about 1mg of the test sample in 1ml as a test sample solution; a proper amount of the test solution is precisely measured and diluted with a solvent to prepare a solution containing about 1 mu g of the test solution in each 1ml as a self control solution. And taking a proper amount of impurity PMH-SM1-Z1, precisely weighing, dissolving with a solvent, and diluting into a solution containing about 5 mu g of impurity PMH-SM1-Z1 per 1ml, wherein the solution is used as a reference solution of the impurity PMH-SM 1-Z1.
Precisely weighing impurities PMH-SM1-Z1 reference substance, PMH-SM1-Z3 reference substance and PMH-SM1 reference substance, and mixing the impurities with acetonitrile: the mixed solution of mobile phase A with the volume ratio of 20:80 is used as a solvent for dissolving and diluting to prepare a solution containing about 1mg of PMH-SM1, about 5 mu g of PMH-SM1-Z1 containing impurities and about 1 mu g of PMH-SM1-Z3 containing impurities per 1mL, and the solution is used as a system applicability solution.
Precisely measuring 20 μ l of each of the sample solution, the self-contrast solution, the system applicability solution and the impurity PMH-SM1-Z1 contrast solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
The method 01:
the results are shown in FIG. 4: the method has good impurity separation degree, but the gradient change is fast, the base line is difficult to balance due to the use of the ion pair reagent, and an obvious gradient peak exists in about 8 min. Therefore, this method is not adopted.
< Peak Table >
PDA Ch1 220nm
| Peak number | Retention time | Area of | Height | Area% | Theoretical plate number (USP) | |
| 1 | 4.750 | 135335 | 9551 | 7.118 | 2538 | 1.262 |
| 2 | 21.412 | 438217 | 74633 | 23.048 | 256226 | 1.142 |
| 3 | 23.049 | 1327763 | 305943 | 69.834 | 484146 | 0.949 |
| Total of | 1901316 | 390128 | 100.000 |
The method 02:
the results are shown in FIG. 5: the method optimizes the gradient on the basis of the method 01, but still has a significantly larger gradient peak, and the gradient should be optimized to increase the equilibrium time.
< Peak Table >
PDA Ch1 220nm
| Peak number | Retention time | Area of | Height | Area% | Theoretical plate number (USP) | |
| 1 | 3.870 | 140976 | 13104 | 7.304 | 2827 | 1.176 |
| 2 | 16.045 | 481326 | 77310 | 24.938 | 140623 | 1.168 |
| 3 | 17.736 | 1307793 | 300731 | 67.758 | 286408 | 0.952 |
| Total of | 1930095 | 391144 | 100.000 |
Method 03
The results are shown in FIG. 6: the method further optimizes the elution gradient, increases the equilibrium time, has better separation degree of known impurities and smooth base line, and is determined to be a PMH-SM1 detection method.
< Peak Table >
PDA Ch1 210nm
| Peak number | Retention time | Height | Area of | Area% | Tailing factor | Number of theoretical plate | Degree of separation | Name of |
| 1 | 2.977 | 3010 | 42388 | 0.337 | 1.071 | 1051 | -- | |
| 2 | 17.119 | 3640 | 31875 | 0.253 | 0.956 | 79057 | 46.305 | |
| 3 | 24.056 | 562590 | 12502806 | 99.410 | 1.146 | 26378 | 16.596 | |
| Total of | 569240 | 12577069 | 100.000 |
4.2.3 column temperature screening
Phosphate buffer solution (13.89 g of sodium octane sulfonate and 27.34g of monopotassium phosphate are weighed, 3000ml of water is added for dissolution, the pH value is adjusted to 3.0 by phosphoric acid) is used as a mobile phase A, acetonitrile-mobile phase A (50:50) is used as a fluidity B, and gradient elution is carried out according to the following table; the solvent is acetonitrile-mobile phase A (20: 80) mixed solution;
the method comprises the following steps: taking a proper amount of a test sample, precisely weighing, dissolving with a solvent, and diluting to prepare a solution containing about 1mg of the test sample in 1ml as a test sample solution; a proper amount of the test solution is precisely measured and diluted with a solvent to prepare a solution containing about 1 mu g of the test solution in each 1ml as a self control solution. And taking a proper amount of impurity PMH-SM1-Z1, precisely weighing, dissolving with a solvent, and diluting into a solution containing about 5 mu g of impurity PMH-SM1-Z1 per 1ml, wherein the solution is used as a reference solution of the impurity PMH-SM 1-Z1. Precisely weighing impurities PMH-SM1-Z1 reference substance, PMH-SM1-Z3 reference substance and PMH-SM1 reference substance, adding acetonitrile: the mixed solution of mobile phase A with the volume ratio of 20:80 is used as a solvent for dissolving and diluting to prepare a solution containing about 1mg of PMH-SM1, about 5 mu g of PMH-SM1-Z1 containing impurities and about 1 mu g of PMH-SM1-Z3 containing impurities as a system applicability solution in each 1 mL. Precisely measuring sample solution, self-contrast solution, system applicability solution and impurity PMH-SM1-Z1 contrast solution 20 μ l each, injecting into liquid chromatograph, recording chromatogram
Method 04
The results are shown in FIG. 7: the method reduces the column temperature for elution, and the separation degree of each known impurity is better and the baseline is smooth, so that the PMH-SM1 detection method which properly reduces the column temperature and keeps other conditions unchanged is still applicable.
< Peak Table >
Detector A Ch 1210 nm
| Peak number | Retention time | Height | Area of | Area% | Tailing factor | Number of theoretical plate | Degree of |
| 1 | 2.950 | 3084 | 41619 | 0.333 | 1.039 | 1151 | -- |
| 2 | 14.202 | 3072 | 29965 | 0.240 | 0.950 | 45616 | 36.666 |
| 3 | 20.323 | 529787 | 12439417 | 99.428 | 0.936 | 18053 | 14.055 |
| Total of | 535942 | 12511000 | 100.000 |
Method 05
The results are shown in FIG. 8: the method raises the column temperature for elution, and the base line with better separation degree of known impurities is relatively flat, so that the method is suitable for PMH-SM1 detection which raises the column temperature and keeps other conditions unchanged and still is suitable for use.
< Peak Table >
Detector A Ch 1210 nm
| Peak number | Retention time | Height | Area of | Area% | Tailing factor | Number of theoretical plate | Degree of |
| 1 | 2.908 | 3199 | 41446 | 0.331 | 1.028 | 1203 | -- |
| 2 | 13.884 | 3137 | 30870 | 0.247 | 0.921 | 43237 | 36.437 |
| 3 | 19.375 | 570459 | 12444937 | 99.422 | 0.898 | 19049 | 13.253 |
| Total of | 576795 | 12517253 | 100.000 |
Example 1 impurity detection Using screening results
The detection comprises the quantitative detection of impurities PMH-SM1-Z1 and PMH-SM1-Z3 in the starting material PMH-SM1 by using a high performance liquid chromatography analysis method, wherein the chromatographic conditions are as follows:
a chromatographic column: the model is Thermo hypersil Gold Aq, 4.6mm x 150mm, 5 μm.
Mobile phase: phosphate buffer solution (4.6 g of sodium octane sulfonate and 9.1g of monopotassium phosphate are weighed, 1000ml of water is added for dissolution, the pH value is adjusted to 3.0 by phosphoric acid) is taken as a mobile phase A, and acetonitrile-mobile phase A volume ratio of 50:50 is taken as fluidity B;
detection wavelength: the wavelength of 264nm is selected to detect impurities PMH-SM1-Z1 and other unknown impurities, and the wavelength of 210nm is selected to detect impurities PMH-SM 1-Z3.
Detecting the column temperature: at 40 ℃.
(1) Taking a proper amount of starting materials to be detected, precisely weighing, dissolving and diluting by using a solvent to prepare a solution containing about 1mg in each 1ml, and taking the solution as a test sample solution;
(2) precisely measuring a proper amount of a test solution by using acetonitrile: the mixed solution of mobile phase A in a volume ratio of 20:80 is used as a solvent, and diluted to prepare a solution containing about 1 mu g of the mixed solution in each 1ml as a self-control solution. Taking a proper amount of impurity PMH-SM1-Z1, precisely weighing, dissolving with solvent, and diluting to obtain solution containing 5 μ g per 1ml, as reference solution of impurity PMH-SM 1-Z1;
(3) precisely weighing impurities PMH-SM1-Z1 reference substance, PMH-SM1-Z3 reference substance and PMH-SM1 reference substance, dissolving and diluting by taking a mixed solution of acetonitrile and a mobile phase A in a volume ratio of 20:80 as a solvent to prepare a solution containing about 1mg of PMH-SM1, about 5 mu g of PMH-SM1-Z1 and about 1 mu g of PMH-SM1-Z3 in 1mL, and taking the solution as a system suitability solution;
(4) precisely measuring 20 μ l of the sample solution, the self-control solution, the impurity PMH-SM1-Z1 control solution and the system adaptability solution, respectively, injecting into a liquid chromatograph, and recording chromatogram.
Gradient elution was performed as follows:
the detection results are as follows: the detection result spectrum is the same as the spectrum obtained by the method 03 in the method screening (figure 6),
< Peak Table >
PDA Ch1 210nm
| Peak number | Retention time | Height | Area of | Area% | Tailing factor | Number of theoretical plate | Degree of separation | Name of |
| 1 | 2.977 | 3010 | 42388 | 0.337 | 1.071 | 1051 | -- | |
| 2 | 17.119 | 3640 | 31875 | 0.253 | 0.956 | 79057 | 46.305 | |
| 3 | 24.056 | 562590 | 12502806 | 99.410 | 1.146 | 26378 | 16.596 | |
| Total of | 569240 | 12577069 | 100.000 |
Compliance with detection limit regulations: the impurity PMH-SM1-Z1 can not exceed 0.5 percent when calculated at 210nm by an external standard method, and the impurity PMH-SM1-Z3 and other single unknown impurities are detected at 264nm and are not larger than the main peak area (0.1 percent) of the control solution. The total amount of impurities should not exceed 1.0%.
Verification of detection method
According to the high performance liquid chromatography (China pharmacopoeia 2015 edition four-part general rules 0512) test, octadecylsilane chemically bonded silica is used as a filler (Thermo hypersil Gold Aq 4.6mm multiplied by 150mm, 5 μm or a chromatographic column with equivalent efficiency); phosphate buffer solution (4.6 g of sodium octane sulfonate and 9.1g of monopotassium phosphate are weighed, 1000ml of water is added for dissolution, the pH value is adjusted to 3.0 by phosphoric acid) is used as a mobile phase A, acetonitrile-mobile phase A (50:50) is used as a fluidity B, and gradient elution is carried out according to the following table; the solvent is acetonitrile-mobile phase A (20: 80) mixed solution; the flow rate was 1.0ml per minute; the detection wavelength is 210nm/264 nm; the column temperature was 40 ℃.
Accurately weighing appropriate amounts of impurities PMH-SM1-Z1 reference substance, PMH-SM1-Z3 reference substance and PMH-SM1 reference substance respectively, dissolving and diluting into a mixed solution containing about 1mg of PMH-SM1, about 5 mu g of impurity PMH-SM1-Z1 and about 1 mu g of impurity PMH-SM1-Z3 per 1ml by using a solvent, and taking the mixed solution as a system applicability solution. And precisely measuring 20 mu l of system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, wherein the peak emergence sequence comprises impurities PMH-SM1-Z1, impurities PMH-SM1-Z3 and PMH-SM1 in sequence, and the separation degree between peaks meets the regulation (see chromatogram figure 6).
Elution gradient:
example 2 application of the detection method
The pramipexole starting material (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole was subjected to multiple batches of impurity detection using the chromatographic conditions and detection method of example 1. The results are given in the table below.
TABLE 1 first batch test results
TABLE 2 second batch test results
TABLE 3 results of the third batch
The results show that the detection method has stability and repeatability, and can stably detect pramipexole starting materials of different manufacturers and batches.
Claims (10)
1. The method for detecting related substances in pramipexole starting materials is characterized in that the related substances in (S) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole are qualitatively and/or quantitatively detected by using high performance liquid chromatography, and the chromatographic conditions comprise the following contents:
stationary phase: chromatographic column with octadecylsilane chemically bonded silica as filler;
mobile phase: phosphate buffer solution is used as a mobile phase A, and acetonitrile to mobile phase A volume ratio of 50:50 is used as a mobile phase B;
the detection wavelength is 190-215nm or 230-285 nm; gradient elution was performed as follows:
The raw materials for preparing the phosphate buffer solution comprise sodium octane sulfonate, monopotassium phosphate, phosphoric acid and water, and the pH value of the phosphate buffer solution is 2.8-3.2;
the related substances comprise a compound 1 and a compound 2, wherein the structural formulas are respectively as follows:
compound 1:
compound 2:
。
2. the detection method according to claim 1, wherein the detection compound 1 is detected at a wavelength of 190-215 nm.
3. The detection method according to claim 2, wherein the wavelength of 190-210nm is selected to detect impurities including compound 2 and/or compound 1.
4. The detection method according to claim 3, wherein the detection is performed at a wavelength of 205 to 210 nm.
5. The detection method according to claim 2, wherein the detection impurity comprises compound 2 at a wavelength selected from the range of 250 to 280 nm.
6. The detection method according to claim 5, wherein the detection is carried out at a wavelength of 255 to 270 nm.
7. The detection method according to claim 1, wherein a chromatographic column having a size of 4.6mm x 150mm, 5 μm; the column temperature was measured at 35-45 ℃.
8. The detection method according to claim 1, wherein a mobile phase is used as a solvent for preparing a test solution, a self-control solution, a system suitability solution and/or an impurity control solution.
9. The detection method according to claim 1, wherein the phosphate buffer is prepared according to the mass ratio of sodium octane sulfonate: the mass of the potassium dihydrogen phosphate is as follows: the volume ratio of water is 1 (1.97-2) to 217-223.
10. The detection method according to claim 1, wherein the mass ratio of sodium octane sulfonate: the mass of the potassium dihydrogen phosphate is as follows: the water was formulated at a volume ratio of 4.6:9.1:1000, where the mass unit is g and the volume unit is mL.
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| CN112724102A (en) * | 2018-09-13 | 2021-04-30 | 石药集团中奇制药技术（石家庄）有限公司 | Pramipexole related compound and preparation method and application thereof |
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