CN113063882A - Method for analyzing related substances of pidotimod oral solution - Google Patents
Method for analyzing related substances of pidotimod oral solution Download PDFInfo
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- CN113063882A CN113063882A CN202110404834.9A CN202110404834A CN113063882A CN 113063882 A CN113063882 A CN 113063882A CN 202110404834 A CN202110404834 A CN 202110404834A CN 113063882 A CN113063882 A CN 113063882A
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- UUTKICFRNVKFRG-WDSKDSINSA-N (4R)-3-[oxo-[(2S)-5-oxo-2-pyrrolidinyl]methyl]-4-thiazolidinecarboxylic acid Chemical compound OC(=O)[C@@H]1CSCN1C(=O)[C@H]1NC(=O)CC1 UUTKICFRNVKFRG-WDSKDSINSA-N 0.000 title claims abstract description 60
- 229960001163 pidotimod Drugs 0.000 title claims abstract description 60
- 239000000126 substance Substances 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 28
- 229940100688 oral solution Drugs 0.000 title claims abstract description 25
- 239000012535 impurity Substances 0.000 claims abstract description 47
- 239000007853 buffer solution Substances 0.000 claims abstract description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010828 elution Methods 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 3
- 238000001514 detection method Methods 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- FPWNQPQTICPCOM-UHFFFAOYSA-N acetonitrile;propan-2-ol Chemical group CC#N.CC(C)O FPWNQPQTICPCOM-UHFFFAOYSA-N 0.000 claims description 13
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 9
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 9
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 9
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 238000007865 diluting Methods 0.000 claims description 7
- 239000008055 phosphate buffer solution Substances 0.000 claims description 7
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 6
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- HBZVNWNSRNTWPS-UHFFFAOYSA-N 6-amino-4-hydroxynaphthalene-2-sulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C(O)C2=CC(N)=CC=C21 HBZVNWNSRNTWPS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 5
- 238000012856 packing Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 description 4
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000009658 destructive testing Methods 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- -1 5-oxo-2-pyrrolidinyl- Chemical group 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
Classifications
-
- 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
- G01N30/74—Optical detectors
Abstract
The invention discloses a method for analyzing related substances of pidotimod oral solution, which adopts high performance liquid chromatography, takes octadecylsilane chemically bonded silica as chromatographic column packing, adopts an ultraviolet detector, selects proper organic solvent and buffer solution as mobile phase, and performs gradient elution to effectively complete the separation of pidotimod and related impurities thereof. The method has strong specificity, good repeatability and high accuracy, and can ensure the controllability of the pidotimod related substances.
Description
Technical Field
The invention relates to the technical field of determination of related substances of medicaments, in particular to an analysis method of related substances of a pidotimod oral solution.
Background
The related substances are closely related to the quality, safety and curative effect of the medicine, and the existence of the related substances may reduce the curative effect of the medicine and even cause toxic and side effects, so the types and the contents of the related substances in the medicine must be controlled by a proper detection and analysis method to ensure the quality of the medicine.
Pidotimod is a commonly used immune enhancer, chemical name: (R) -3- [(s) - (5-oxo-2-pyrrolidinyl-) carbonyl ] -thiazolidine-4-carboxylic acid. The detection method of the pidotimod oral solution related substances in pharmacopoeias of various countries is not carried, the registration standard (YBH08282006) of the pidotimod raw material is obtained through inquiry, the detection method is reproduced, and the proportion of an organic phase (methanol) in a chromatographic condition is low; therefore, the detection capability is not high, and the control of impurities is not strict enough.
In order to ensure the safety of the patient in drug administration, a method for analyzing related substances in the pidotimod oral solution, which is more strictly controlled in impurity detection, is urgently needed to be developed so as to ensure the safety of the patient in drug administration.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for analyzing related substances of pidotimod oral solution.
The invention provides an analysis method for relevant substances of pidotimod oral solution, wherein the relevant substances are the following 7 substances: impurity A, impurity B, impurity C, impurity E, impurity X, impurity Y and L-pyroglutamic acid. The pidotimod and related impurities are effectively separated by adopting high performance liquid chromatography, using octadecylsilane chemically bonded silica as chromatographic column packing, adopting an ultraviolet detector, selecting proper organic solvent and buffer solution as mobile phases, and performing gradient elution.
Wherein, the impurity A, the impurity B, the impurity C, the impurity E, the impurity X, the impurity Y and the L-pyroglutamic acid. The chemical formulas are respectively as follows:
preferably, the organic solvent is acetonitrile-isopropanol (6:1), the buffer solution is sodium dihydrogen phosphate aqueous solution, the concentration of the sodium dihydrogen phosphate is 0.01-0.02M, and the pH value is adjusted to 2.0-4.0 by using phosphoric acid.
Preferably, the gradient elution procedure in the method is: 0-10 min, wherein the proportion of acetonitrile-isopropanol (6:1) is changed from 2% to 5%; the proportion of acetonitrile-isopropanol (6:1) is changed from 5% to 15% for 10-20 min; 20-40 min, wherein the proportion of acetonitrile-isopropanol (6:1) is 15%; 40-40.1 min, wherein the proportion of acetonitrile-isopropanol (6:1) is changed from 15% to 2%; 40.1-50 min, and the proportion of acetonitrile-isopropanol (6:1) is 2%.
Further, the detection conditions are: the detection wavelength is 205 nm-215 nm; the flow rate is 0.9-1.1 ml/min; the sample injection amount is 10-50 mu l; the concentration of the sodium dihydrogen phosphate in the buffer solution is 0.01-0.02M, and the pH value is 2.0-4.0.
Preferably, the detection wavelength is 210 nm; the flow rate is 1.0 ml/min; the sample amount is 20 mul; the concentration of the sodium dihydrogen phosphate aqueous solution in the buffer solution was 0.01M, and the pH was 2.5.
Further, the sample configuration method comprises the following steps: precisely measuring a proper amount of pidotimod oral solution, and diluting with a phosphate buffer solution (1.3 g of monopotassium phosphate and 1.55g of disodium hydrogen phosphate (anhydrous substance)) with the pH value of 6.8 by using water to dissolve and dilute the phosphate buffer solution to 1000ml, and adjusting the pH value to 6.80 by using phosphoric acid to prepare a solution containing 0.50-0.70 mg/ml of pidotimod.
Preferably, the concentration of the solution containing pidotimod is 0.57 mg/ml.
The invention has the beneficial effects that: 1. the method has the advantages of strong specificity, good repeatability and high accuracy, and can ensure the controllability of the pidotimod related substances; 2. compared with the detection method recorded in the pidotimod raw material registration standard (YBH08282006), the method has stricter control on impurities and can ensure the safety of medication of patients.
Drawings
FIG. 1 is a comparative chromatogram of the localization test of Pidotimod-related substances in example 1.
In the chromatogram: the curves are from top to bottom in sequence: solvent, blank auxiliary materials, impurity A, impurity B, impurity C, impurity D, impurity E, impurity X, impurity Y, levo-pyroglutamic acid and pidotimod.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments. The embodiments of the present invention have been presented for purposes of illustration and description, and are not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.
Example 1:
this example uses pidotimod-containing solutions as examples, and uses a methodology of a chromatographic method for verification.
1. Test for locating related substances
Preparing a pidotimod sample solution, a reference solution of each related substance and a mixed solution of pidotimod and each related substance, respectively injecting into a liquid chromatograph, and recording a chromatogram. The results are shown in Table 1 and the spectra are shown in FIG. 1.
TABLE 1 Pidotimod separation parameter results with each impurity
| Name of impurity | Retention time of single sample injection | Retention time of mixed sample introduction | Relative retention time | Degree of separation from prepeak |
| L-pyroglutamic acid | 6.435 | 5.805 | 0.40 | / |
| Impurity A | 13.719 | 12.948 | 0.89 | 17.844 |
| Pidotimod | 14.660 | 14.517 | 1.00 | 3.802 |
| Impurity C | 16.396 | 16.246 | 1.12 | 3.538 |
| Impurity E | 16.177 | 16.246 | 1.12 | 3.538 |
| Impurity X | 18.631 | 18.981 | 1.31 | 6.368 |
| Impurity Y | 22.198 | 22.428 | 1.54 | 11.262 |
| Impurity B | 25.190 | 25.154 | 1.73 | 8.081 |
The results show that: good separation can be achieved between the substances related to the pidotimod.
2. Limit of detection, limit of quantification test
And (3) determining the detection limit and the quantitative limit of the pidotimod and each related substance thereof by adopting a signal-to-noise ratio method. Respectively preparing stock solutions of pidotimod and related substances thereof, diluting to a certain concentration, injecting, calculating the ratio (signal-to-noise ratio) of peak height to noise, wherein the sample detection amount with the signal-to-noise ratio (S/N) of about 10 is the quantitative limit, and the sample detection amount with the signal-to-noise ratio (S/N) of about 3 is the detection limit, and the result is shown in table 2.
TABLE 2 quantitative limit and detection limit test results
The results show that: the method has high response to various related substances and can accurately control the content of the various related substances.
3. Standard curve
Pidotimod and 7 related substances thereof are precisely weighed and prepared into 7 parts of solutions with different concentrations by using phosphate buffer solution with pH of 6.8 (1.3 g of monopotassium phosphate and 1.55g of disodium hydrogen phosphate (anhydrous substance) are taken and dissolved in water and diluted to 1000ml, and the pH is adjusted to 6.80 by using phosphoric acid). And (3) respectively injecting samples and recording chromatograms, and obtaining linear regression equations of the pidotimod and all related substances thereof by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate, wherein the results are shown in table 3.
TABLE 3 results of the standard curve experiment
| Compound (I) | Linear Range (μ g/ml) | Linear equation of equations | Regression coefficient |
| Pidotimod | 0.0552～4.6040 | y＝85041x-154.06 | r＝0.9990 |
| Impurity A | 0.0300～0.3747 | y＝84318x+2133.6 | r＝0.9994 |
| Impurity B | 0.0676～1.6892 | y＝89039x-258.24 | r＝0.9994 |
| Impurity C | 0.0469～1.1730 | y＝82257x+2560.1 | r＝0.9995 |
| Impurity E | 0.0764～1.9088 | y＝88327x+4196.1 | r＝0.9992 |
| Impurity X | 0.0648～4.8600 | y＝55028x+845.44 | r＝0.9992 |
| Impurity Y | 0.0918～4.3020 | y＝66421x-3834.6 | r＝0.9993 |
| L-pyroglutamic acid | 0.0977～4.9840 | y＝20102x-1439.1 | r＝0.9993 |
The results show that: under the method, the pidotimod and the 7 related substances thereof can show good linear relation within a certain concentration range.
4. Accuracy of
Precisely measuring an appropriate amount of pidotimod oral solution, diluting with a phosphate buffer solution (1.3 g of monopotassium phosphate and 1.55g of disodium hydrogen phosphate (anhydrous substance)) with the pH value of 6.8, dissolving with water, diluting to 1000ml, and adjusting the pH value to 6.80 with phosphoric acid to prepare 9 parts of a solution with the pidotimod concentration of 0.57mg/ml, wherein three parts are taken as one group, and appropriate amounts of related substances are respectively added into the three groups, so that the concentrations of the related substances in the three groups of solutions are respectively the quantitative limit concentration, 50% of the relative limit and 100% of the relative limit. And (5) injecting and recording a chromatogram, and calculating the recovery rate, wherein the result is shown in a table 4.
TABLE 4 accuracy test results
| Compound (I) | Quantitative limiting concentration | Limit concentration of 50% | Limit concentration of 100% |
| Impurity A | 100.0 | 86.6 | 90.7 |
| Impurity B | 111.7 | 106.8 | 98.5 |
| Impurity C | 111.1 | 110.7 | 100.8 |
| Impurity E | 108.3 | 106.0 | 108.4 |
| Impurity X | 95.8 | 96.4 | 96.7 |
| Impurity Y | 106.3 | 108.9 | 110.5 |
| L-pyroglutamic acid | 88.0 | 83.7 | 100.1 |
The results show that: the method has good accuracy.
5. Destructive testing
Precisely measuring an appropriate amount of pidotimod oral solution, respectively carrying out a damage test on the pidotimod oral solution under the conditions of strong acid, strong base, high temperature, illumination, oxidation and the like, carrying out sample injection and recording a chromatogram, and counting the damaged impurity conditions, wherein the results are shown in table 5.
TABLE 5 destructive testing results
The results show that: the method can well detect the degradation products generated by the pidotimod destructive test, the material balance rate is between 90 and 110 percent, the separation degree of the degraded impurities and the main peak meets the requirement, and the spectral purity of the main peak also meets the requirement. Therefore, the chromatographic system can be used for determining related substances and degradation products thereof in the pidotimod oral solution.
Example 2
In this example, six batches of pidotimod oral solution pilot drugs are taken as examples, and relevant substances are measured.
Precisely measuring 1ml of each of 6 batches of pidotimod oral solutions, respectively placing the pidotimod oral solutions into a 100ml measuring flask, diluting the pidotimod oral solutions to a scale with a phosphate buffer solution with the pH value of 6.8 (1.3 g of monopotassium phosphate and 1.55g of disodium hydrogen phosphate (anhydrous substance) by dissolving the pidotimod oral solutions with water and diluting the pidotimod oral solutions to 1000ml, adjusting the pH value of the pidotimod oral solutions to 6.80 by using phosphoric acid, and shaking the pidotimod oral solutions uniformly to obtain a; appropriate amounts of pidotimod reference substance, levo-pyroglutamic acid reference substance, impurity X reference substance and impurity Y reference substance are taken, and dissolved and diluted by phosphate buffer solution with pH6.8 to prepare solution containing about 2.5 mu g of each impurity per 1ml, so as to obtain reference substance solution.
Chromatographic conditions are as follows: using Shimadzu high performance liquid chromatograph, ultraviolet detector, octadecylsilane chemically bonded silica (model 250mm × 4.6mm × 5 μm); taking 0.01M sodium dihydrogen phosphate aqueous solution (pH value is adjusted to 2.5 by phosphoric acid) as a mobile phase A, taking acetonitrile-isopropanol (6:1) as a mobile phase B, carrying out gradient elution for 0-10 min, wherein the proportion of the mobile phase B is changed from 2% to 5% and 10-20 min, the proportion of the mobile phase B is changed from 5% to 15% and 20-40 min, the proportion of the mobile phase B is 15% and 40-40.1 min, and the proportion of the mobile phase B is changed from 15% to 2%; 40.1-50 min, wherein the proportion of the mobile phase B is 2%; the detection wavelength is 210 nm; the flow rate is 1.0 ml/min; precisely measuring 20 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, injecting and recording chromatogram, and calculating the content of each related substance by using an external standard method, wherein the result is shown in Table 6.
TABLE 6 comparison of the results of the assay for six batches of pidotimod oral solution pilot drug
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by one of ordinary skill in the art and related arts based on the embodiments of the present invention without any creative effort, shall fall within the protection scope of the present invention. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by one of ordinary skill in the art and related arts based on the embodiments of the present invention without any creative effort, shall fall within the protection scope of the present invention.
Claims (8)
1. A method for analyzing substances related to pidotimod oral solution is characterized by comprising the following steps: the method adopts high performance liquid chromatography, uses octadecylsilane chemically bonded silica as chromatographic column filler, adopts an ultraviolet detector, selects proper organic solvent and buffer solution as mobile phase, and performs gradient elution.
2. The method for analyzing substances related to pidotimod oral solution according to claim 1, wherein: the organic solvent is acetonitrile-isopropanol (6:1), the buffer solution is sodium dihydrogen phosphate aqueous solution, the concentration of the sodium dihydrogen phosphate is 0.01-0.02M, and the pH value is adjusted to 2.0-4.0 by using phosphoric acid.
3. The method for analyzing substances related to pidotimod oral solution according to claim 2, wherein: the gradient elution procedure is 0-10 min, and the proportion of acetonitrile-isopropanol (6:1) is changed from 2% to 5%; the proportion of acetonitrile-isopropanol (6:1) is changed from 5% to 15% for 10-20 min; 20-40 min, wherein the proportion of acetonitrile-isopropanol (6:1) is 15%; 40-40.1 min, wherein the proportion of acetonitrile-isopropanol (6:1) is changed from 15% to 2%; 40.1-50 min, and the proportion of acetonitrile-isopropanol (6:1) is 2%.
4. The method for analyzing substances related to pidotimod oral solution according to claim 2, wherein: detection conditions are as follows: the detection wavelength is 205 nm-215 nm; the flow rate is 0.9-1.1 ml/min; the sample injection amount is 10-50 mu l; the concentration of the sodium dihydrogen phosphate in the buffer solution is 0.01-0.02M, and the pH value is 2.0-4.0.
5. The method for analyzing substances related to pidotimod oral solution according to claim 4, wherein: the detection wavelength is 210 nm; the flow rate is 1.0 ml/min; the sample injection amount is 20 mu l; the concentration of the sodium dihydrogen phosphate aqueous solution in the buffer solution was 0.01M, and the pH was 2.5.
6. The method for analyzing substances related to pidotimod oral solution according to claim 2, wherein: the sample configuration method comprises the following steps: precisely measuring a proper amount of the pidotimod oral solution, diluting the pidotimod oral solution with a phosphate buffer solution with the pH value of 6.8, and preparing the solution with the pidotimod concentration of 0.50-0.70 mg/ml.
7. The method for analyzing substances related to pidotimod oral solution according to claim 6, wherein: the concentration of the solution containing the pidotimod is 0.57 mg/ml.
8. The method for analyzing substances related to pidotimod oral solution according to any one of claims 1 to 7, wherein: the related substances are impurity A, impurity B, impurity C, impurity E, impurity X, impurity Y and L-pyroglutamic acid.
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| MADHURI BAGHEL, SADHANA J. RAJPUT: "HPLC SEPARATION OF PIDOTIMOD ENANTIOMERS USING BETA-CYCLODEXTRIN BASED CHIRAL STATIONARY PHASE" * |
| 国家食品药品监督管理局: "匹多莫德", 《国家食品药品监督管理局 国家药品标准》 * |
| 孙兰真等: "HPLC 法测定匹多莫德原料药中 7 种有关物质", 《沈 阳 药 科 大 学 学 报》 * |
| 方克忠等: "HPLC 法测定匹多莫德中的有关物质", 《沈 阳 药 科 大 学 学 报》 * |
| 朱永琴等: "HPLC法测定匹多莫德含量及其有关物质", 《河南科技大学学报(医学版)》 * |
| 毛 柯等: "匹多莫德口服液中有关物质的 HPLC 法测定", 《中国医药工业杂志》 * |
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| CN113063882B (en) | 2023-03-21 |
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