CN117890496A - Method for detecting related substances of compound preparation of novel oral solution of guaifenesin - Google Patents
Method for detecting related substances of compound preparation of novel oral solution of guaifenesin Download PDFInfo
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- CN117890496A CN117890496A CN202311738379.1A CN202311738379A CN117890496A CN 117890496 A CN117890496 A CN 117890496A CN 202311738379 A CN202311738379 A CN 202311738379A CN 117890496 A CN117890496 A CN 117890496A
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- guaifenesin
- related substances
- compound preparation
- oral solution
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- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960002146 guaifenesin Drugs 0.000 title claims abstract description 76
- 229940100688 oral solution Drugs 0.000 title claims abstract description 57
- 239000000126 substance Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 150000001875 compounds Chemical class 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 42
- 239000012535 impurity Substances 0.000 claims abstract description 62
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960002335 bromhexine hydrochloride Drugs 0.000 claims abstract description 21
- 238000001514 detection method Methods 0.000 claims abstract description 21
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims abstract description 11
- 235000019796 monopotassium phosphate Nutrition 0.000 claims abstract description 11
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010828 elution Methods 0.000 claims abstract description 9
- 238000010606 normalization Methods 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 28
- 239000012085 test solution Substances 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- 239000003643 water by type Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 19
- 239000000463 material Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000000049 pigment Substances 0.000 abstract description 4
- 229940059084 guaifenesin oral solution Drugs 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000012216 screening Methods 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 235000013305 food Nutrition 0.000 description 6
- 238000007689 inspection Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical class OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for detecting related substances of a compound preparation of a new oral solution of guaifenesin, which belongs to the technical field of drug detection and comprises the steps of adopting a high performance liquid chromatography, taking a potassium dihydrogen phosphate solution as a mobile phase A, taking acetonitrile as a mobile phase B to carry out gradient elution to detect the related substances of the compound preparation of the new oral solution of guaifenesin, and calculating the content of the related substances in the compound preparation of the new oral solution of guaifenesin according to an area normalization method. The method can effectively eliminate the interference of auxiliary materials such as essence, pigment, bacteriostat and the like, and simultaneously detects the impurities introduced by the guaifenesin and bromhexine hydrochloride serving as two active components, thereby providing a solution for related substances of the compound preparation guaifenesin oral solution, improving the quality control level of medicines and reducing the safety risk of the medicines.
Description
Technical Field
The invention belongs to the technical field of medicine detection, and in particular relates to a method for detecting related substances of a compound preparation of a novel oral solution of guaifenesin.
Background
The oral solution of the guaifenesin is a compound preparation, which contains two active ingredients of guaifenesin and bromhexine hydrochloride, wherein each 10ml contains 200mg of guaifenesin and 8mg of bromhexine hydrochloride. The product is used for treating acute and chronic upper airway infection (such as common cold), acute and chronic bronchitis, and bronchiectasis caused by viscous phlegm, excessive phlegm, and difficult expectoration.
Impurities are key quality attributes of medicines, are important research contents of medicine research and development and quality control, and insufficient research of the impurities can potentially influence the safety and effectiveness of the medicines. The impurities in the quality standard of the medicine refer to the impurities brought by the production process or raw materials or the impurities generated in the storage process in the medicine produced according to the process and raw materials approved by the national medicine supervision and management department according to the legal examination.
At present, related substances of the novel oral solution of the guaifenesin are not carried in pharmacopoeias of various countries. The detection method of the related substances in guaifenesin and bromhexine hydrochloride quality standards carried in the pharmacopoeia of each country is only suitable for single-prescription preparations, separation and detection of two active ingredients and related impurities cannot be simultaneously considered, and the detection of the related substances can be interfered by adding essence, pigment and bacteriostat into the guaifenesin and bromhexine hydrochloride quality standards, and the detection method of the related substances of the compound preparation is reported in the prior art.
In summary, no effective detection method for related substances of the novel oral solution of the guaifenesin exists at present, the impurity condition in the novel oral solution of the guaifenesin cannot be effectively monitored, the product quality of the novel oral solution of the guaifenesin is ensured, and the development of the impurity detection method suitable for the variety is particularly important and urgent.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
Disclosure of Invention
The invention aims to solve the problems, and aims to provide a related substance detection method of a compound preparation of a novel oral solution of guaifenesin, which adopts high performance liquid chromatography to effectively separate known impurities in the compound preparation, can eliminate the interference of auxiliary materials such as essence, pigment, bacteriostat and the like, and calculates the content of each impurity according to an area normalization method.
The invention provides a method for detecting related substances of a compound preparation of a novel oral solution of guaifenesin, which has the characteristics that: detecting related substances of the compound preparation of the novel oral solution of the guaifenesin by adopting a high performance liquid chromatography, and calculating the content of the related substances in the compound preparation of the novel oral solution of the guaifenesin according to an area normalization method, wherein the related substances are impurities YFX-impA, YFX-impB, YFX-impC, YFX-impD, YFX-impE, YFX-impF, YFX-impG, YFX-impH, YFX-impI, YFX-imp II, YFX-impII and YFX-impIV; the chromatographic conditions of the high performance liquid chromatography are as follows: taking potassium dihydrogen phosphate solution as a mobile phase A and acetonitrile as a mobile phase B for gradient elution; the gradient elution procedure was:
| time (minutes) | Mobile phase a (vol%) | Mobile phaseB (vol%) |
| 0 | 95 | 5 |
| 3 | 95 | 5 |
| 10 | 70 | 30 |
| 20 | 20 | 80 |
| 35 | 20 | 80 |
| 35.1 | 95 | 5 |
| 45 | 95 | 5 |
。
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein, the chemical names and structural formulas of the related substances are as follows:
the method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein, the concentration of the potassium dihydrogen phosphate solution in the mobile phase A is 0.001mol/L to 0.010mol/L, and the pH value is 5.0 to 7.0.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein the flow rate of the mobile phase in the high performance liquid chromatography is 0.8-1.2 mL/min.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein, the chromatographic column of the high performance liquid chromatography uses octadecylsilane chemically bonded silica as filler.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: the model of the chromatographic column of the high performance liquid chromatography is Waters XB ridge C18, 4.6X105 mm,3.5um.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein the column temperature of the chromatographic column of the high performance liquid chromatography is 25-35 ℃.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein the detector of the high performance liquid chromatography is an ultraviolet detector.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein the detection wavelength of the detector is 246-250 nm and 273-279 nm.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin can also have the following characteristics: wherein, the concentration of guaifenesin in the test solution in the high performance liquid chromatography is 0.8-1.2 mg/mL, and the concentration of bromhexine hydrochloride is 0.032-0.048 mg/mL.
Effects and effects of the invention
The invention provides a method for detecting related substances in a compound preparation of a new oral solution of guaifenesin, which adopts High Performance Liquid Chromatography (HPLC), takes monopotassium phosphate solution as a mobile phase A and acetonitrile as a mobile phase B to carry out gradient elution to detect the related substances in the compound preparation, and calculates the content of the related substances in the compound preparation of the new oral solution of guaifenesin according to an area normalization method. According to the method disclosed by the invention, related substances of the novel oral solution of the guaifenesin are detected, the interference of auxiliary materials such as essence, pigment, bacteriostat and the like can be effectively eliminated, and simultaneously, the impurities introduced by the guaifenesin and the bromhexine hydrochloride serving as two active components are detected, so that a solution is provided for the related substances of the novel oral solution of the guaifenesin in a compound preparation, the quality control level of a medicine is improved, and the safety risk of the medicine is reduced.
Drawings
FIG. 1 is an HPLC chart of chromatographic condition 1 in screening example 1;
FIG. 2 is an enlarged view of 0 to 10min in FIG. 1;
FIG. 3 is an HPLC chromatogram of chromatographic condition 2 in screening example 1;
FIG. 4 is an HPLC chart of chromatographic condition 3 in screening example 1;
FIG. 5 is an HPLC chromatogram of chromatographic condition 4 in screening example 1;
FIG. 6 is an enlarged view of 9-25 min in FIG. 5;
FIG. 7 is an HPLC chart (276 nm) of a blank adjuvant solution of a proprietary middle-guaifenesin oral solution of example 1;
FIG. 8 is an HPLC chart (248 nm) of a blank adjuvant solution of a proprietary middle-guaifenesin oral solution of example 1;
FIG. 9 is a HPLC chart (276 nm) of a sample solution of a proprietary novel oral solution of guaifenesin of example 1;
FIG. 10 is a HPLC chart (248 nm) of a sample solution of a proprietary novel oral solution of guaifenesin in example 1.
Detailed Description
In order to make the technical means, creation characteristics, achievement purposes and effects of the compound preparation easy to understand, the following describes a related substance detection method of the compound preparation of the novel oral solution of the guaifenesin in detail by combining the examples and the attached drawings.
Unless otherwise indicated, reagents and pharmaceuticals for use in the present invention are commercially available. All the test standards not mentioned are national standards.
1. Reagents and materials
Potassium dihydrogen phosphate, phosphoric acid, acetonitrile, methanol and water.
Guaifenesin (source: china food and drug inspection institute, lot number: 100528-201303, content: 99.6%);
bromhexine hydrochloride (source: china food and drug inspection institute, lot number: 100427-202204, content: 100.0%);
impurity YFXX-impA (source: SINCO, lot number: 18-07-1403, content: 91.18%)
Impurity YFXX-impB (source: SINCO, lot number: 22-12-0506, content: 98.81%)
Impurity YFXX-impC (source: china food and drug inspection institute, lot number: 101417-201601, content: 100%)
Impurity YFXX-impD (source: china food and drug inspection institute, lot number: 101418-201601, content: 100%)
Impurity YFXX-impE (source: SINCO, lot number: 21-04-6047, content: 95.49%)
Impurity YFXX-impF (source: china food and drug inspection institute, lot number: 101419-201601, content: 100%)
Impurity YFXX-impG (source: china food and drug inspection institute, lot number: 101387-202102, content: 100%)
Impurity YFXX-impH (source: SINCO, lot number: 22-07-1207, content: 98.20%)
Impurity YFXX-impI (source: SINCO, lot number: 22-08-2614, content: 97.53%)
Impurity YFXX-impII (source: SINCO, lot number: 22-06-0114, content: 99.13%)
Impurity YFXX-impIII (source: SINCO, lot number: 22-08-0574, content: 96.73%)
Impurity YFXX-impIV (source: SINCO, lot number: 21-04-1901, content: 98.65%)
The composition of the oral solution (source: homemade) of the guaifenesin is shown in the following table:
blank auxiliary materials (source: homemade); wherein, the blank auxiliary materials are solutions prepared by mixing according to a prescription of a compound preparation of the novel oral solution of the guaifenesin, and the compositions are shown in the following table:
| component (A) | Content (mg/ml) |
| Sodium benzoate | 1.00 |
| Saccharin sodium salt | 1.00 |
| Sorbitol | 350.00 |
| Povidone | 25.00 |
| Maltol | 0.80 |
| Alluring red | 0.12 |
| Cherry essence | 0.22 |
| Vanilla essence | 2.00 |
| Citric acid | 9.5 |
| Purified water | Constant volume to 1mL |
2. Main instrument
Thermo U3000 high performance liquid chromatograph.
The method for detecting the related substances of the compound preparation of the novel oral solution of the guaifenesin adopts a high performance liquid chromatography to detect the related substances of the compound preparation of the novel oral solution of the guaifenesin, and calculates the content of the related substances in the compound preparation of the novel oral solution of the guaifenesin according to an area normalization method. The method comprises the following steps: preparing a test solution, taking a proper amount of the test solution, injecting the test solution into a liquid chromatograph, recording a chromatogram, and calculating the content of related substances in the compound preparation, namely the new oral solution of the guaifenesin according to an area normalization method.
The related substances comprise an impurity YFX-impA related to bromhexine hydrochloride, an impurity YFX-impB, an impurity YFX-impC, an impurity YFX-impD, an impurity YFX-impE, an impurity YFX-impF, an impurity YFX-impG, an impurity YFX-impH, an impurity YFX-impI related to guaifenesin, an impurity YFX-impII, an impurity YFX-impIII and an impurity YFX-impIV.
The specific structural information of the impurities is as follows:
the conditions of the high performance liquid chromatography are as follows: taking potassium dihydrogen phosphate solution as a mobile phase A and acetonitrile as a mobile phase B for gradient elution; the gradient elution procedure was:
| time minutes | Mobile phase a (vol%) | Mobile phase B (vol%) |
| 0 | 95 | 5 |
| 3 | 95 | 5 |
| 10 | 70 | 30 |
| 20 | 20 | 80 |
| 35 | 20 | 80 |
| 35.1 | 95 | 5 |
| 45 | 95 | 5 |
The concentration of the potassium dihydrogen phosphate solution in the mobile phase A is preferably 0.001mol/L to 0.010mol/L, more preferably 0.004mol/L to 0.006mol/L, and even more preferably 0.005mol/L; the pH of the potassium dihydrogen phosphate solution in mobile phase A is preferably 5.0 to 7.0, more preferably 5.5 to 6.5, and even more preferably 6.0. The flow rate of the mobile phase is preferably 0.8 to 1.2mL/min, more preferably 0.9 to 1.1mL/min, and still more preferably 1.0mL/min.
In the present invention, the column is preferably octadecylsilane chemically bonded silica as a packing material. The chromatographic column is preferably Waters XBiridge C18, 4.6X105 mm,3.5um. The temperature of the column is preferably 25 to 35 ℃, more preferably 28 to 32 ℃, and still more preferably 30 ℃.
In the present invention, the detector in the high performance liquid chromatography is preferably an ultraviolet detector. The detection wavelength of the ultraviolet detector is preferably 246 to 250nm and 273 to 279nm, more preferably 247 to 249nm and 275 to 277nm, and still more preferably 248nm and 276nm.
In the invention, the test solution in the high performance liquid chromatography is a solution obtained by mixing a new oral solution of the guaifenesin with a diluent (a mixed solvent of methanol and water, wherein the volume ratio of the methanol to the water is 50:50); the concentration of guaifenesin in the test solution is 0.8-1.2 mg/mL, more preferably 0.9-1.1 mg/mL, and even more preferably 1.0mg/mL; the bromhexine hydrochloride concentration in the test solution is 0.032 to 0.048mg/mL, more preferably 0.036 to 0.044mg/mL, still more preferably 0.04mg/mL.
In the embodiment of the invention, the conditions of the high performance liquid chromatography are selected as follows:
chromatographic column: octadecylsilane chemically bonded silica is used as a filler;
detection wavelength: 248nm &276nm;
column temperature: 30 ℃;
flow rate: 1.0mL/min;
sample injection amount: 10 μl;
mobile phase a:0.005mol/L potassium dihydrogen phosphate solution, and regulating the pH value to 6.0+/-0.05 by phosphoric acid;
mobile phase B: acetonitrile
The diluent is a methanol-water mixed solvent, and the volume ratio of methanol to water is 50:50.
screening example 1: development process of method
In the screening example, the sample injection is an impurity mixed solution, and the preparation method is as follows:
precisely weighing the reference substances of guaifenesin, bromhexine hydrochloride and a proper amount of each known impurity, and adding a release agent to dissolve and dilute the mixture to prepare mixed solutions containing 1mg of guaifenesin, 0.04mg of bromhexine hydrochloride and 5 mug of each known impurity per 1 mL.
(1) Screening and optimization of chromatographic conditions
(1) Chromatographic condition 1 (refer to the method of bromhexine hydrochloride related substances in the 2020 edition of Chinese pharmacopoeia)
Conclusion: under the chromatographic condition, bromhexine hydrochloride has good peak shape, but guaifenesin and corresponding impurities are not reserved (the retention time is 1-2 min), and the graphs are shown in fig. 1 and 2.
(2) Chromatographic condition 2
Conclusion: after the gradient elution is adjusted, the retention time of guaifenesin and bromhexine hydrochloride is proper and the peak shape is good, but the retention time of the impurity YFX-impH and YFX-impA are coincident, and the separation degree does not meet the requirement; the map is shown in figure 3.
(3) Chromatographic condition 3
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Conclusion: after the buffer salt concentration and gradient program are adjusted, guaifenesin, bromhexine hydrochloride and known impurities have good peak shapes, but the separation degree of the impurities YFX-impH and YFX-impA is less than 1.5, and the baseline separation is still not satisfied; the map is shown in figure 4.
(4) Chromatographic condition 4
Conclusion: when the column temperature is reduced to 30 ℃, guaifenesin, bromhexine hydrochloride and known impurities have good peak shapes, the separation degree is more than 1.5, and blank auxiliary materials do not interfere with detection; the patterns are shown in fig. 5 and 6.
(2) Method of determination
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Example 1: methodological verification
(1) Specialization of
Impurity localization solution: taking proper amounts of impurities YFX-impA, YFX-impB, YFX-impC, YFX-impD, YFX-impE, YFX-impF, YFX-impG, YFX-impH, YFX-impI, YFX-impII, YFX-impIII and YFX-impIV, placing into different volumetric flasks, adding a diluent (methanol-water mixed solvent, the volume ratio of methanol to water is 50:50) to dissolve and dilute the mixture into a positioning solution containing 200 mug of impurities per 1 mL.
Mixing a control solution: precisely weighing guaifenesin and bromhexine hydrochloride as reference substances, placing into a same volumetric flask, adding appropriate amount of the impurity locating solution, and adding a release agent to dissolve and dilute to obtain mixed reference solution containing guaifenesin 1mg, bromhexine hydrochloride 0.04mg and known impurities 5 μg per 1 mL.
Blank auxiliary material solution: precisely measuring 1mL of blank auxiliary materials, placing into a 20mL measuring flask, adding a diluent, shaking a proper amount to dissolve and dilute to a scale, and shaking uniformly to obtain the product.
Test solution: precisely measuring 1mL of the new oral solution of the guaifenesin, placing the new oral solution of the guaifenesin in a 20mL measuring flask, adding a diluent, shaking to dissolve and dilute the solution to a scale, and shaking uniformly to obtain the oral solution of the guaifenesin.
And (3) respectively precisely measuring 10 mu L of each positioning solution, mixed control solution, blank auxiliary material solution and test sample solution, injecting into a liquid chromatograph, and carrying out sample injection analysis under the chromatographic conditions of the determined method in the screening example 1. The results are shown in Table 1.
TABLE 1 results of various chromatographic peaks for the mixed control solutions
| Name of the name | Retention time (min) | Degree of separation |
| YFXX-impI | 10.070 | 7.96 |
| Guaifenesin | 10.757 | 12.09 |
| YFXX-impII | 12.027 | 3.63 |
| YFXX-impC | 12.477 | 26.07 |
| YFXX-impE | 15.520 | 3.38 |
| YFXX-impIII | 15.847 | 2.62 |
| YFXX-impH | 16.080 | 3.56 |
| YFXX-impA | 16.420 | 7.05 |
| YFXX-impIV | 17.083 | 21.14 |
| YFXX-impB | 19.157 | 12.94 |
| YFXX-impD | 20.957 | 2.46 |
| YFXX-impF | 21.300 | 42.39 |
| YFXX-impG | 30.703 | 4.09 |
| Bromhexine hydrochloride | 32.160 | N/A |
Conclusion: the components sequentially show peaks, and the separation degree among the peaks is more than 1.5; the blank auxiliary materials do not interfere with the determination of known impurities, the specificity is good, and the chromatograms of the mixed control solution and the solution of the test sample are shown in figures 7-10.
(2) Quantitative limit and detection limit
To ensure that the sensitivity of the method meets the requirements of routine testing, the impurity localization solution described above is gradually diluted with a diluent to determine the limit of detection (LOD) and limit of quantification (LOQ) solution concentrations. For known impurities, the limit of detection (LOD) and limit of quantification (LOQ) are determined by a signal-to-noise ratio method, i.e., a signal measured from a known low concentration sample is compared with a signal measured from a blank sample to dilute a stock solution of known concentration of impurities to a low concentration sample, and the measured signal is compared with the signal at the blank (baseline noise) typically at a signal-to-noise ratio of 3:1, determining a detection limit according to the corresponding concentration, wherein the signal to noise ratio is 10:1, determining a quantitative limit according to the corresponding concentration. The results are shown in Table 2.
TABLE 2 limit of detection and quantitative limit results
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(3) Repeatability of
The impurity control of the compound preparation is very important for the attribution of each impurity, the screening of the detected known impurities is carried out, the attribution is calculated under the corresponding main component items, and the judgment of the influence on the product quality caused by the confusion of the impurity control is avoided.
The reproducibility test is carried out by preparing 6 sample solutions and performing the test, and the Relative Standard Deviation (RSD) of the impurity variation amount of the 6 data results is required to be not more than 10%.
Test solution: precisely weighing 1mL of the new oral solution of the guaifenesin, placing the new oral solution of the guaifenesin in a 20mL measuring flask, adding a diluting agent, shaking to dissolve and dilute the new oral solution to a scale, and shaking uniformly to obtain the oral solution of the guaifenesin. 6 parts of the mixture were prepared in the same manner. The results are shown in Table 3.
TABLE 3 results of repeatability experiments
Conclusion: as shown by the repeatability test results, the RSD of the detection results of the impurities of the 6 sample solutions is less than 10%, and the repeatability meets the requirements.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. The method for detecting related substances of the compound preparation, namely the novel oral solution of the guaifenesin is characterized by comprising the following steps:
detecting related substances of the compound preparation of the new oral solution of the guaifenesin by adopting a high performance liquid chromatography method, calculating the content of the related substances in the compound preparation of the new oral solution of the guaifenesin according to an area normalization method,
wherein the related substances are impurities YFX-impA, YFX-impB, YFX-impC, YFX-impD, YFX-impE, YFX-impF, YFX-impG, YFX-impH, YFX-impI, YFX-impII and YFX-impIV;
the chromatographic conditions of the high performance liquid chromatography are as follows: taking potassium dihydrogen phosphate solution as a mobile phase A and acetonitrile as a mobile phase B for gradient elution;
the gradient elution procedure was:
。
2. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein the chemical names and structural formulas of the related substances are as follows:
3. the method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein the concentration of the potassium dihydrogen phosphate solution in the mobile phase A is 0.001mol/L to 0.010mol/L, and the pH value is 5.0 to 7.0.
4. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein the flow rate of the mobile phase in the high performance liquid chromatography is 0.8-1.2 mL/min.
5. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein, the chromatographic column of the high performance liquid chromatography uses octadecylsilane chemically bonded silica as filler.
6. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
the chromatographic column of the high performance liquid chromatography is of the model of Waters XB ridge C18, 4.6X105 mm and 3.5um.
7. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein the column temperature of the chromatographic column of the high performance liquid chromatography is 25-35 ℃.
8. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein the detector of the high performance liquid chromatography is an ultraviolet detector.
9. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein the detection wavelength of the detector is 246-250 nm and 273-279 nm.
10. The method for detecting related substances of the compound preparation of the novel oral solution of the guaifenesin, which is characterized in that:
wherein the concentration of guaifenesin in the test solution in the high performance liquid chromatography is 0.8-1.2 mg/mL, and the concentration of bromhexine hydrochloride is 0.032-0.048 mg/mL.
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