CN105758971B - The method of quality control of Policresulen bolt - Google Patents
The method of quality control of Policresulen bolt Download PDFInfo
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- CN105758971B CN105758971B CN201610333415.XA CN201610333415A CN105758971B CN 105758971 B CN105758971 B CN 105758971B CN 201610333415 A CN201610333415 A CN 201610333415A CN 105758971 B CN105758971 B CN 105758971B
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- CN
- China
- Prior art keywords
- cresol
- policresulen
- suppository
- sulfonic acid
- mobile phase
- Prior art date
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- ACZKMKGNTMOPBD-UHFFFAOYSA-N policresulen Chemical compound CC1=CC(O)=C(S(O)(=O)=O)C=C1CC1=CC(S(O)(=O)=O)=C(O)C(CC=2C(=CC(O)=C(C=2)S(O)(=O)=O)C)=C1C ACZKMKGNTMOPBD-UHFFFAOYSA-N 0.000 title claims abstract description 154
- 229920001607 Policresulen Polymers 0.000 title claims abstract description 87
- 229960002954 policresulen Drugs 0.000 title claims abstract description 87
- 238000000034 method Methods 0.000 title claims abstract description 71
- 238000003908 quality control method Methods 0.000 title abstract description 9
- 239000000829 suppository Substances 0.000 claims abstract description 153
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 35
- 239000002253 acid Substances 0.000 claims abstract description 11
- GCFPFWRHYINTRX-UHFFFAOYSA-N 2-hydroxy-4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C(O)=C1 GCFPFWRHYINTRX-UHFFFAOYSA-N 0.000 claims description 88
- VXBOGQDATFKUAM-UHFFFAOYSA-N 4-hydroxy-6-methylbenzene-1,3-disulfonic acid Chemical compound CC1=CC(O)=C(S(O)(=O)=O)C=C1S(O)(=O)=O VXBOGQDATFKUAM-UHFFFAOYSA-N 0.000 claims description 85
- 239000000243 solution Substances 0.000 claims description 77
- PYPXOMYXFFYJIF-UHFFFAOYSA-N 4-hydroxy-2-methylbenzenesulfonic acid Chemical compound CC1=CC(O)=CC=C1S(O)(=O)=O PYPXOMYXFFYJIF-UHFFFAOYSA-N 0.000 claims description 76
- 238000005303 weighing Methods 0.000 claims description 72
- 238000000926 separation method Methods 0.000 claims description 49
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 48
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 36
- 239000005695 Ammonium acetate Substances 0.000 claims description 36
- 229940043376 ammonium acetate Drugs 0.000 claims description 36
- 235000019257 ammonium acetate Nutrition 0.000 claims description 36
- 239000013558 reference substance Substances 0.000 claims description 36
- 238000012360 testing method Methods 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000008187 granular material Substances 0.000 claims description 28
- 239000007788 liquid Substances 0.000 claims description 28
- -1 ammonium policresulen dimer Chemical class 0.000 claims description 26
- 238000002844 melting Methods 0.000 claims description 26
- 230000008018 melting Effects 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 25
- 238000001816 cooling Methods 0.000 claims description 24
- 238000005520 cutting process Methods 0.000 claims description 24
- 238000001514 detection method Methods 0.000 claims description 24
- 238000007865 diluting Methods 0.000 claims description 24
- 238000010812 external standard method Methods 0.000 claims description 24
- 239000000945 filler Substances 0.000 claims description 24
- 239000000706 filtrate Substances 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000002156 mixing Methods 0.000 claims description 24
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 24
- 230000002829 reductive effect Effects 0.000 claims description 24
- 239000000377 silicon dioxide Substances 0.000 claims description 24
- 239000012088 reference solution Substances 0.000 claims description 12
- 229930003836 cresol Natural products 0.000 claims description 11
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims 3
- 239000011259 mixed solution Substances 0.000 claims 2
- 239000012488 sample solution Substances 0.000 claims 2
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 claims 1
- 239000000539 dimer Substances 0.000 claims 1
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 abstract description 5
- 229940100630 metacresol Drugs 0.000 abstract 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 abstract 2
- 238000003556 assay Methods 0.000 abstract 2
- 239000012085 test solution Substances 0.000 description 22
- 239000003814 drug Substances 0.000 description 16
- 238000005259 measurement Methods 0.000 description 13
- GFAJOMHUNNCCJQ-UHFFFAOYSA-N 1,3-dioxetane Chemical compound C1OCO1 GFAJOMHUNNCCJQ-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 210000001215 vagina Anatomy 0.000 description 6
- 238000005345 coagulation Methods 0.000 description 5
- 230000015271 coagulation Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- RVRCFVVLDHTFFA-UHFFFAOYSA-N heptasodium;tungsten;nonatriacontahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W] RVRCFVVLDHTFFA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000008350 Pruritus Vulvae Diseases 0.000 description 2
- 241001502500 Trichomonadida Species 0.000 description 2
- 241000224526 Trichomonas Species 0.000 description 2
- 206010046914 Vaginal infection Diseases 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 206010056530 Vulvovaginal pruritus Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- ODLIHNXQTJXBDT-UHFFFAOYSA-N 2-hydroxy-6-methylbenzenesulfonic acid Chemical compound CC1=CC=CC(O)=C1S(O)(=O)=O ODLIHNXQTJXBDT-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000207202 Gardnerella Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000186783 Lactobacillus vaginalis Species 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- YPZUZOLGGMJZJO-UHFFFAOYSA-N ambrofix Natural products C1CC2C(C)(C)CCCC2(C)C2C1(C)OCC2 YPZUZOLGGMJZJO-UHFFFAOYSA-N 0.000 description 1
- YPZUZOLGGMJZJO-LQKXBSAESA-N ambroxan Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C)[C@@H]1[C@]2(C)OCC1 YPZUZOLGGMJZJO-LQKXBSAESA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 210000004177 elastic tissue Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
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
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
- G01N2030/885—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds involving polymers
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to the method for quality control of Policresulen bolt.Specifically, the present invention relates to the method that quality control is carried out to Policresulen suppository, this method includes the use of the step of high performance liquid chromatography carries out assay to 4 sulfonic acid of metacresol, 6 sulfonic acid of metacresol, 4,6 disulfonic acid of metacresol in suppository.The step of the invention further relates to high performance liquid chromatography is used to carry out assay to the Policresulen dimer in suppository.The method of the present invention can effectively control product quality.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a policresulen suppository, in particular to a quality control method of a policresulen suppository.
Background
Policresulen (policresulen) and its formulation were originally developed by the pharmaceutical factory of becton, germany and were imported in 1993, and the ambrox has been accepted as the primary drug in our country. Policresulen is a kind of local hemostatic and bactericidal agent, has powerful pathogen killing effect, is used mainly in gynecology, surgery, dermatology, ear, nose and throat department clinically and has the advantage of no damage to normal tissue.
The policresulen is a strong acid substance, and the action mechanism of the policresulen is to kill various pathogenic microorganisms such as bacteria, trichomonas, mould and the like through the coagulation action of strong acid and protein; can selectively act on the pathological epithelial cells and ectopic columnar epithelia to solidify, denature and shed the pathological epithelial cells and the ectopic columnar epithelia, promote tissue repair, cause vasoconstriction and plasma protein coagulation to stop bleeding, and do not affect normal squamous epithelia. In the gynecological medicine, the acidic environment of the vagina can be restored, excessive reproduction of pathogenic bacteria is not facilitated, the reproduction of physiological flora is facilitated, and uncomfortable symptoms such as pruritus vulvae, leukorrhagia and the like can be relieved.
From the analysis of treatment results, the policresulen for treating various vaginitis has the characteristics of broad spectrum, high efficiency, safety and convenience, has obvious effects of improving local symptoms and reducing vaginal secretion, is favorable for regeneration of necrotic or pathological tissues and re-covering of epithelia, has no damage to healthy tissues, has no adverse reaction after administration, is a good novel medicine for treating gynecological inflammation, and is worthy of clinical popularization and use.
The current clinically common policresulen preparation is pessary, 36% solution or gel. However, the existing suppository has the defects of easy melting and flowing out, greasy feeling and burning feeling after administration; the concentrated solution can be used after being diluted by water, the accuracy of the concentration of the solution is difficult to ensure in the dilution process, and the sanitary problem that clothes and bedding are easy to be polluted exists; the gel needs to be coated on the inner surface of the vagina by a coating device, and although the preparation has good adhesiveness on the surface of the vagina mucosa, the preparation is difficult to ensure uniform coating, is easy to have dead corners (such as the fornix part of the vagina) for administration, and is more critical to the inconvenience of administration.
CN102824358A discloses a policresulen compound suppository, which adopts soybean lecithin and mixed fatty acid glyceride as suppository base materials, has a low melting point, is easy to flow out of a body after being melted, and is inconvenient to take.
CN101919807A discloses a suppository composition with improved properties, which uses high molecular weight polyoxyethylene as the matrix, but needs other aliphatic matrix and alcohols to be used in combination, and when filling with high molecular weight polyoxyethylene alone, the filling is inconvenient because of the sticky matrix.
CN1771989A discloses a compound preparation for treating gynecological inflammation, which adopts glycerogelatin, polyethylene glycol, polyoxyethylene 40 stearate and cocoa butter as suppository base, but the compound preparation brings inconvenience to the administration of some allergic patients as main ingredients and the corresponding side effects are increased.
CN103181889A and CN103520087A disclose the preparation technology of the polymetaphenesulfonic acid sodium expandable suppository, the medicine-containing matrix of the expandable suppository is fully contacted with the inner wall of the vagina, the bioavailability of active medicines is improved, but the expandable material absorbs water to physically expand, the water absorption expansion is slow and a large amount of liquid medicine can be absorbed; the swelling material absorbs water and swells, so that the vagina is dry and astringent, uncomfortable and the foreign body sensation is enhanced. The expansion value is difficult to control, and the problem of outflow of the liquid medicine is difficult to avoid. Even if the method of blocking the tail end is adopted in CN103520087A, the expansion of the expansion cotton sliver and other elastic fibers is irregular and can not be well attached to vaginal epithelium and mucosa, thus solving the problem of undesirable side leakage effect of the liquid medicine. The tail end of the expansion bolt is pulled, so that discomfort is brought to a patient.
Although the prior art discloses a plurality of technologies for preparing policresulen suppository, the products produced by the technologies still cannot be successfully applied to clinic for various reasons, and the clinically used policresulen suppository using mixed PEG as a matrix still is used at present.
The policresulen is an aqueous solution of m-cresol sulfonic acid and formaldehyde polymer. Policresulen is a red brown viscous liquid, is strongly acidic, can be mixed with water or ethanol, and is insoluble in chloroform or diethyl ether.
It is known that the policresulen has more impurities and the control of related substances is more difficult. For example, the polymethine sulfoaldehyde collected by national drug Standard WS1- (X-013) -2007Z of the State food and drug administration of China, involves the separation and analysis of the amounts of m-cresol-4, 6-disulfonic acid peak, m-cresol-4-sulfonic acid peak, m-cresol-6-sulfonic acid peak, dimelamine peak, etc., and the amount of polysulfonic acid in the raw drug substances by high performance liquid chromatography using gradient elution.
In addition, the commercially available policresulen solution is an aqueous solution of policresulen, and is a policresulen solution collected by national drug standard WS1- (X-023) -2007Z of the national food and drug administration, in which the separation and analysis of the amounts of m-cresol-4, 6-disulfonic acid peak, m-cresol-4-sulfonic acid peak, m-cresol-6-sulfonic acid peak, dimesylate peak, and the like, and the amount of polysulfonic acid in the raw drug substances is also involved in using high performance liquid chromatography of gradient elution.
Commercially available policresulen suppositories are also examined for substances involved, including, for example, the amount of m-cresol-4, 6-disulfonic acid peak, m-cresol-4-sulfonic acid peak, m-cresol-6-sulfonic acid peak, bismethanesulfonic acid peak, etc., and the amount of polysulfonic acid. In addition, commercially available policresulen suppositories also usually require examination of policresulen dimers therein.
However, the present inventors have found that the prior art quality control of policresulen suppositories by reversed-phase high performance liquid chromatography may result in insufficient separation of certain chromatographic peaks from their neighboring peaks, possibly due to the presence of a large amount of polymer matrix in the suppository. This is disadvantageous for accurate calculation of the chromatographic analysis.
Therefore, there is still a need in the art for new methods for quality control of policresulen suppository, and for example, these methods are expected to have excellent chromatographic properties for m-cresol-4, 6-disulfonic acid, m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, and policresulen dimer when quality control of policresulen suppository is performed.
Disclosure of Invention
The present invention aims to provide a novel method for quality control of policresulen suppository, which is expected to have excellent chromatographic properties for policresulen suppository, for example, m-cresol-4, 6-disulfonic acid, m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, and policresulen dimer. It has been surprisingly found that the use of the method of the present invention exhibits superior properties in at least one aspect.
Therefore, the invention provides a method for controlling the quality of policresulen suppository, which comprises the step of measuring the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository by using high performance liquid chromatography.
The method of the invention comprises the following steps of measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository by using high performance liquid chromatography:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 0.5% -1.5% of ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
The method of the invention, wherein the concentration of the ammonium acetate solution in the mobile phase is 0.75% -1.25%.
The process according to the invention, wherein the concentration of the ammonium acetate solution in the mobile phase is 1%.
Typically, commercially available policresulen suppositories contain 90mg of policresulen per suppository, in which case the art generally requires that per suppository: the amount of the m-cresol-4-sulfonic acid is less than 30.6mg, the amount of the m-cresol-6-sulfonic acid is less than 12.6mg, and the amount of the m-cresol-4, 6-disulfonic acid is less than 2.7 mg; this limitation requirement may also be referred to as a standard specification in this disclosure.
The method further comprises the step of measuring the content of the policresulen dimer in the suppository by using high performance liquid chromatography.
The method of the invention, wherein the step of measuring the content of the policresulen dimer in the suppository by using high performance liquid chromatography, comprises the following operations:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 0.5% -1.5% of ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
The method of the invention, wherein the concentration of the ammonium acetate solution in the mobile phase is 0.75% -1.25%.
The process according to the invention, wherein the concentration of the ammonium acetate solution in the mobile phase is 1%.
Typically, commercially available policresulen suppositories contain 90mg of policresulen per suppository, in which case the art generally requires that per suppository: the amount of the policresulen dimer is not less than 3.6 mg; this limitation requirement may also be referred to as a standard specification in this disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
In examples 1 to 10 below, although the measurement method can satisfy the requirements in various aspects, it has been found that, when the contents of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid are measured, an unknown impurity peak is often preceded and not well separated from the m-cresol-4, 6-disulfonic acid peak (the separation of the m-cresol-4, 6-disulfonic acid peak from the unknown impurity peak in each example is usually 0.9 to 1.1), although relatively small (the peak area is usually about 5 to 10% of that of m-cresol-4, 6-disulfonic acid), and although it is not usually necessary to consider this unknown impurity in the standard, the impurity greatly affects the calculation of the contents of m-cresol-4, 6-disulfonic acid, for example, for the same sample, after the measurement is repeated for 6 times, the content of the m-cresol-4, 6-disulfonic acid is calculated, and the relative standard deviation of 6 data is as high as 2.73 percent; in supplementary experiments, the inventors surprisingly found that, when the contents of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid are measured, 0.1% of tartaric acid is added into each of the ten mobile phases of examples 1 to 10, and then found that in 10 examples, the unknown impurity affecting the measurement of the content of m-cresol-4, 6-disulfonic acid can reach a separation degree of 1.9 or more from the m-cresol-4, 6-disulfonic acid peak area without affecting the calculation of the m-cresol-4, 6-disulfonic acid peak area; in 10 cases, the content of m-cresol-4, 6-disulfonic acid is calculated after 6 times of repeated measurement, and the relative standard deviation of 6 data is less than 0.75 percent; therefore, in one embodiment of the present invention, when the contents of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid, and m-cresol-4, 6-disulfonic acid are measured, 0.1% tartaric acid is added to the ammonium acetate solution in which the mobile phase is prepared. In addition, in examples 1 to 10 below, although the measurement method can satisfy the requirements in various aspects, it has been found that, in measuring the content of policresulen dimer, the symmetry of policresulen dimer peak is not ideal, and the tailing factor T for evaluating the symmetry of chromatographic peak is in the range of 1.07 to 1.12, which is obviously not ideal; in supplementary experiments, the inventors surprisingly found that, when 0.05% tartaric acid was added to each of the ten mobile phases of examples 1 to 10 in the determination of the content of policresulen dimer, the tailing factor T of the policresulen dimer peak was found to be in the range of 0.99 to 1.04 in 10 examples, and the tailing factor T was significantly improved (generally, the tailing factor T in the HPLC method should be in the range of 0.95 to 1.05); therefore, in one embodiment of the present invention, when determining the content of the policresulen dimer peak, 0.05% tartaric acid is added to the ammonium acetate solution in which the mobile phase is prepared.
The policresulen suppository is light brown to light red brown suppository, and the main component of the policresulen suppository is policresulen which is a polymer of m-cresol sulfoaldehyde and formaldehyde. The policresulen suppository is used for treating cervical erosion, cervicitis, various vaginal infections (such as leucorrhea increase caused by bacteria, trichomonad and mould), pruritus vulvae, and pressure ulcer caused by using pessary.
Each granule of policresulen suppository is 90mg/3 g. Policresulen can only be applied topically, and because of the inability to exclude interactions with other drugs, the use of more than two drugs at the same site is avoided. The action mechanism of policresulen is to kill bacteria, fungi and trichomonad by strong acid and protein coagulation. Selectively causing necrosis or degeneration of diseased tissue and columnar epithelial proteins. Causing vasoconstriction and coagulation of plasma proteins to stop bleeding. Policresulen has a broad spectrum of antimicrobial action, including common gram-positive bacteria, gram-negative bacteria, fungi and certain viruses, to which Gardnerella vaginata, anaerobacter trichomonas and candida are particularly sensitive. But Doderlein Vaginailflore (Lactobacillus vaginalis) is not substantially affected. At present, no report of drug resistance is reported. Policresulen has selective coagulation on necrotic or diseased tissue, and can promote tissue regeneration and epithelial recoating.
The method/product provided by the invention has excellent properties.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it.
Example 1 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in the market (national standard H20044373, Rongchang pharmaceutical Co., Ltd.)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 1% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 1% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 2 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in the market (national standard H20044373, Rongchang pharmaceutical Co., Ltd.)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 0.75% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 1.25% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of a polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 3 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in the market (national standard H20044373, Rongchang pharmaceutical Co., Ltd.)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 1.25% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 0.75% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 4 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in the market (national standard H20044373, Rongchang pharmaceutical Co., Ltd.)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 0.5% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 1.5% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of a polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 5 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in the market (national standard H20044373, Rongchang pharmaceutical Co., Ltd.)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 1.5% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 0.5% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 6 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository is available (H20# #30, available from Shandong, a company, the reference number of the national drug and the manufacturer are implicit or abbreviated, the same applies below)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 0.75% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 1% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 7 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in market (H20# #59, produced by Yunnan)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 1% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 1% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 8 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in market (H20# #09, produced by Hebei)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 0.75% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 1% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 9 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: policresulen suppository (H20# #85, manufactured by Hubei company)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 1% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 0.75% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
Example 10 measurement of the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid, m-cresol-4, 6-disulfonic acid, and the content of cresol furfural dimer in suppository
A) And (3) testing the sample: the policresulen suppository sold in market (H20# #13, produced by Liaoning)
B) The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filler, 1.25% ammonium acetate solution-methanol (85:15) is used as a mobile phase, the detection filter length is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, dissolving with mobile phase, and diluting to obtain solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; and (3) calculating by peak area according to an external standard method, and multiplying the results by 0.9171, 0.9171 and 0.8874 respectively to obtain the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository.
C) The method for measuring the content of the policresulen dimer in the suppository comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia is measured;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 1% ammonium acetate solution-methanol (57:43) is used as a mobile phase, the detection filter length is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymethylphenol formaldehyde dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, uniformly mixing, precisely weighing about 2.5g, putting into a 100ml measuring flask, adding a mobile phase to the scale, putting into a 40 ℃ water bath for complete melting, cooling, filtering, and taking the subsequent filtrate as a test solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving, and diluting to obtain solution containing about 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; and (4) calculating by using a peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of the policresulen dimer in the suppository.
D) As a result:
the contents of the m-cresol-4-sulfonic acid, the m-cresol-6-sulfonic acid and the m-cresol-4, 6-disulfonic acid in the suppository all meet the standard specification; the content of policresulen dimer in the suppository meets the standard specification.
The separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid are all more than 3, and the separation degrees of policresulen dimer and other substance peaks are all more than 2.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (6)
1. The method for measuring the content of m-cresol-6-sulfonic acid, m-cresol-4-sulfonic acid and m-cresol-4, 6-disulfonic acid in the policresulen suppository by using the high performance liquid chromatography comprises the following operation steps:
(1) the determination is carried out according to the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 0.5-1.5% ammonium acetate solution-methanol mixed solution with the volume ratio of 85:15 is used as a mobile phase, the detection wavelength is 265nm, and the number of theoretical plates is not less than 2000 in terms of m-cresol-6-sulfonic acid peak; the separation degrees of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid meet the requirement; wherein 0.1% tartaric acid is added into the ammonium acetate solution for preparing the mobile phase;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, mixing, precisely weighing about 2.5g, placing in a 100ml measuring flask, adding mobile phase to scale, placing in 40 deg.C water bath for completely melting, cooling, filtering, and taking the filtrate as sample solution; respectively precisely weighing appropriate amount of m-cresol-4-ammonium sulfonate, m-cresol-6-ammonium sulfonate and m-cresol-4, 6-ammonium disulfonate reference substances which are dried at 60 ℃ under reduced pressure to constant weight, adding mobile phase for dissolving and diluting to prepare solutions containing 0.33mg, 0.14mg and 0.03mg in each 1ml as reference substance solutions; precisely measuring 20 μ l of each solution, respectively injecting into a liquid chromatograph, and recording chromatogram; calculating by peak area according to an external standard method, and multiplying the result by 0.9171, 0.9171 and 0.8874 respectively to obtain the content of m-cresol-4-sulfonic acid, m-cresol-6-sulfonic acid and m-cresol-4, 6-disulfonic acid in the suppository;
wherein,
the policresulen contained in each granule of the policresulen suppository is 90mg,
the amount of the cresol-4-sulfonic acid in each particle of the policresulen suppository is less than 30.6mg,
the amount of the cresol-6-sulfonic acid in each particle of the policresulen suppository is less than 12.6mg,
the amount of the cresol-4, 6-disulfonic acid in each intermediate cresol particle of the policresulen suppository is less than 2.7 mg.
2. The method according to claim 1, wherein the concentration of the ammonium acetate solution in the mobile phase is between 0.75% and 1.25%.
3. The process according to claim 1, wherein the concentration of the ammonium acetate solution in the mobile phase is 1%.
4. The method for measuring the content of the policresulen dimer in the policresulen suppository by using the high performance liquid chromatography comprises the following operation steps:
(1) the determination is carried out according to the specification of the high performance liquid chromatography carried in the appendix VD of the second part of the 2010 edition of the Chinese pharmacopoeia;
(2) chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, 0.5-1.5% ammonium acetate solution-methanol mixed solution with the volume ratio of 85:15 is used as a mobile phase, the detection wavelength is 280nm, and the number of theoretical plates is not less than 2000 according to the peak of the polymetaphenesulfonic acid dimer; the separation degree between the policresulen dimer and other substance peaks is in accordance with the requirement; wherein 0.05 percent of tartaric acid is added into the ammonium acetate solution for preparing the mobile phase;
(3) the determination method comprises the following steps: taking 10 granules of policresulen suppository, precisely weighing, cutting, mixing, precisely weighing 2.5g, placing in a 100ml measuring flask, adding mobile phase to scale, placing in 40 deg.C water bath for completely melting, cooling, filtering, and taking the subsequent filtrate as sample solution; accurately weighing appropriate amount of ammonium policresulen dimer reference substance dried at 60 deg.C under reduced pressure to constant weight, adding mobile phase for dissolving and diluting to obtain solution containing 40 μ g per 1ml as reference solution; precisely measuring the two solutions by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram; calculating by peak area according to an external standard method, and multiplying the result by 0.9195 to obtain the content of policresulen dimer in the suppository;
wherein,
the policresulen contained in each granule of the policresulen suppository is 90mg,
the amount of policresulen dimer in each granule of the policresulen suppository is not less than 3.6 mg.
5. The method according to claim 4, wherein the concentration of the ammonium acetate solution in the mobile phase is between 0.75% and 1.25%.
6. The process according to claim 4, wherein the concentration of the ammonium acetate solution in the mobile phase is 1%.
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| CN105758971A (en) | 2016-07-13 |
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