WO2019154131A1 - 测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法 - Google Patents
测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法 Download PDFInfo
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- WO2019154131A1 WO2019154131A1 PCT/CN2019/073225 CN2019073225W WO2019154131A1 WO 2019154131 A1 WO2019154131 A1 WO 2019154131A1 CN 2019073225 W CN2019073225 W CN 2019073225W WO 2019154131 A1 WO2019154131 A1 WO 2019154131A1
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- WIPO (PCT)
- Prior art keywords
- solution
- colloidal
- pectin
- ethanol
- colloidal pectin
- Prior art date
Links
- 239000001814 pectin Substances 0.000 title claims abstract description 182
- 235000010987 pectin Nutrition 0.000 title claims abstract description 182
- 229920001277 pectin Polymers 0.000 title claims abstract description 182
- 238000002360 preparation method Methods 0.000 title claims abstract description 71
- 238000000034 method Methods 0.000 title claims abstract description 56
- 229910052797 bismuth Inorganic materials 0.000 title abstract description 25
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 title abstract description 25
- 239000000243 solution Substances 0.000 claims abstract description 191
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 169
- 239000006228 supernatant Substances 0.000 claims abstract description 50
- 239000007864 aqueous solution Substances 0.000 claims abstract description 17
- 238000002798 spectrophotometry method Methods 0.000 claims abstract description 13
- 239000006185 dispersion Substances 0.000 claims abstract description 10
- 238000004448 titration Methods 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract 2
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 75
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 68
- 229910052712 strontium Inorganic materials 0.000 claims description 47
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 47
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 42
- 238000002835 absorbance Methods 0.000 claims description 35
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- 239000012088 reference solution Substances 0.000 claims description 31
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 29
- 229910017604 nitric acid Inorganic materials 0.000 claims description 29
- 239000011668 ascorbic acid Substances 0.000 claims description 21
- 229960005070 ascorbic acid Drugs 0.000 claims description 21
- 235000010323 ascorbic acid Nutrition 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 238000004090 dissolution Methods 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000004033 plastic Substances 0.000 claims description 11
- 229920003023 plastic Polymers 0.000 claims description 11
- 238000005119 centrifugation Methods 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 238000003926 complexometric titration Methods 0.000 claims description 4
- 238000000870 ultraviolet spectroscopy Methods 0.000 claims description 4
- 238000004040 coloring Methods 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- 238000005259 measurement Methods 0.000 abstract description 17
- 150000001621 bismuth Chemical class 0.000 abstract description 2
- 239000012085 test solution Substances 0.000 description 47
- 239000002775 capsule Substances 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 239000012490 blank solution Substances 0.000 description 34
- 239000012086 standard solution Substances 0.000 description 23
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 19
- 229910052707 ruthenium Inorganic materials 0.000 description 19
- 239000011550 stock solution Substances 0.000 description 18
- 206010036790 Productive cough Diseases 0.000 description 14
- 210000003802 sputum Anatomy 0.000 description 14
- 208000024794 sputum Diseases 0.000 description 14
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 10
- 238000010812 external standard method Methods 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 239000010453 quartz Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000011084 recovery Methods 0.000 description 8
- 239000004743 Polypropylene Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 239000004417 polycarbonate Substances 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- -1 cerium ions Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 159000000008 strontium salts Chemical class 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- KZFDVWZZYOPBQZ-UHFFFAOYSA-K bismuth;potassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KZFDVWZZYOPBQZ-UHFFFAOYSA-K 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 241001674044 Blattodea Species 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229910052792 caesium Inorganic materials 0.000 description 3
- 238000001246 colloidal dispersion Methods 0.000 description 3
- 239000000084 colloidal system Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007919 dispersible tablet Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000703 high-speed centrifugation Methods 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012353 t test Methods 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- KKMOSYLWYLMHAL-UHFFFAOYSA-N 2-bromo-6-nitroaniline Chemical compound NC1=C(Br)C=CC=C1[N+]([O-])=O KKMOSYLWYLMHAL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 150000000703 Cerium Chemical class 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 238000001879 gelation Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052758 niobium Inorganic materials 0.000 description 2
- 239000010955 niobium Substances 0.000 description 2
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 238000000184 acid digestion Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ZQUAVILLCXTKTF-UHFFFAOYSA-H bismuth;tripotassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ZQUAVILLCXTKTF-UHFFFAOYSA-H 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000007944 soluble tablet Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229910001427 strontium ion Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/33—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using ultraviolet light
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
- G01N21/79—Photometric titration
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
Definitions
- the invention belongs to the technical field of quality control of colloidal pectin, and relates to a method for determining free sputum in colloidal pectin or colloidal pectin preparation for controlling free sputum limit and improving medication safety.
- Colloidal pectin and its capsules are the first drugs of Shanxi Zhendong Ante Bio-Pharmaceutical Co., Ltd., the predecessor of Taiyuan Red Star Pharmaceutical Factory. The drug was first approved by the former Ministry of Health in July 1992 for the production and listing of Taixing Hongxing Pharmaceutical Factory.
- colloidal pectin capsules The active ingredient of colloidal pectin capsules is a yellow powder, which is insoluble in organic solvents such as ethanol, acetone and ether. It forms a stable colloidal dispersion in water and forms a gel in artificial gastric juice.
- Colloidal pectin and its capsules have been included in the 2015 edition of the Chinese Pharmacopoeia.
- the colloidal pectin content is from 14.0 to 16.0% in terms of bismuth (Bi). Take 50 mg of colloidal pectin, add 50 ml of water, shake, and the pH is 8.5 to 10.5.
- Colloidal pectin is a gastric mucosal protective agent, which forms a stable gel in the stomach acid environment, covering the mucosal surface, so that the erosion surface and the ulcer surface are separated from gastric acid and pepsin, which protects the damaged mucosa and promotes ulcer tissue. Repair and healing; can stimulate the production of endogenous prostaglandins and epidermal growth factor, accelerate the healing of ulcer surface and inflammation, and have a certain hemostasis.
- Colloidal pectin ⁇ acts on Helicobacter pylori, which is beneficial for eradication of Helicobacter pylori.
- Lu Wei-feng Choinese healthy adults bismuth absorption and pharmacokinetic studies [D] Beijing: China Union Medical College, 2001) reported that Andrew ® colloidal bismuth pectin capsules in healthy volunteers almost no absorption, colloidal bismuth subcitrate AUC 0-24hr sheet is 15.6 times Andrew ® colloidal bismuth pectin capsules.
- niobium is directly related to the size of niobium particles.
- colloidal pectin capsules absorb less than colloidal bismuth citrate tablets is mainly because the sputum particles of colloidal pectin are much larger than those of colloidal bismuth citrate.
- the cerium ions and small molecules have small strontium particles and are absorbed by the human body.
- the sputum particles of the macromolecules are large and the body absorbs less.
- Colloidal pectin is a complex composition of pectin and anthraquinone. Since the pectin molecule is a macromolecular substance and the molecular composition is indefinite, in the synthesis process of the colloidal pectin, there may be an incompletely synthesized hydrazine, and a small molecule hydrazine, collectively referred to as free hydrazine.
- cockroaches As a heavy metal, cockroaches, if excessively absorbed by the body, cause toxicity and damage to the kidneys, bones and joints, and the central nervous system.
- colloidal pectin 1(Bi), which should be 14.0-16.0%, but there is no difference between colloidal pectin and free cockroach. It is stipulated that the method of complex titration after nitric acid digestion can be used to determine the content of colloidal pectin, and it is also impossible to distinguish macromolecular colloidal pectin from free caries.
- CN 104880428B relates to a method for determining the content of strontium in colloidal pectin or colloidal pectin preparation, which is prepared by dispersing colloidal pectin or colloidal pectin preparation in water, adding protonic acid dissociating agent to make dispersion
- concentration of hydrogen ions in the medium reaches 0.8-1.2mol/L.
- the supernatant is separated, and the supernatant is separated.
- the chromogenic solution of citric acid or ascorbic acid and potassium iodide is added to obtain a test solution, which is at a wavelength of 380-470 nm.
- the absorbance was measured and compared with the absorbance of the known concentration of the reference solution under the same conditions, and the content of bismuth in the colloidal pectin or the colloidal pectin preparation was calculated.
- the method solves the problem that the macromolecular acid pectin has serious interference when the content of bismuth in the colloidal pectin or the colloidal pectin preparation is directly determined by spectrophotometry, and the measurement result has high accuracy and good repeatability, and can effectively control the colloidal fruit.
- the quality of the product of the capsule and its preparation is compared with the absorbance of the known concentration of the reference solution under the same conditions, and the content of bismuth in the colloidal pectin or the colloidal pectin preparation was calculated.
- the bismuth content of the colloidal pectin or the colloidal pectin preparation which is finally given by the method also contains the free strontium content, and it is still impossible to distinguish the macromolecular colloidal pectin from the free cockroach.
- Chinese Patent Application No. 201810000930.5 relates to a method for detecting free strontium in colloidal pectin or colloidal pectin preparation, which is to put colloidal pectin or colloidal pectin preparation in a plastic centrifuge tube and add water for no more than 1 min. Shake, obtain a colloidal solution with uniform dissolution, centrifuge the colloidal solution immediately, separate the supernatant, and detect the content of strontium in the supernatant by complexometric titration or ultraviolet spectrophotometry to calculate the colloidal pectin. Free strontium content in sputum or colloidal pectin preparations.
- the method is characterized in that the colloidal pectin or the colloidal pectin preparation is dispersed in water and centrifuged to separate the macromolecular colloidal pectin from the free clam, and the free clam content is highly accurate, and the colloidal fruit can be effectively controlled.
- the quality of the product of the capsule and its preparation is characterized in that the colloidal pectin or the colloidal pectin preparation is dispersed in water and centrifuged to separate the macromolecular colloidal pectin from the free clam, and the free clam content is highly accurate, and the colloidal fruit can be effectively controlled.
- the quality of the product of the capsule and its preparation is characterized in that the colloidal pectin or the colloidal pectin preparation is dispersed in water and centrifuged to separate the macromolecular colloidal pectin from the free clam, and the free clam content is highly accurate, and the colloidal fruit can be effectively controlled. The quality of the product of the capsule and its preparation.
- the colloidal pectin After the colloidal pectin is dispersed in water to form a colloidal solution, it is affected by the binding force between the cerium salt and the pectin in the molecular structure of the colloidal pectin, and the colloidal pectin has a dynamic release of the cerium salt. Therefore, when the free hydrazine content in colloidal pectin mash is determined by the aqueous solution method, the measurement results are related to time. If the colloidal pectin solution has a long standing time, the obtained free hydrazine measurement results not only include the inherent free strontium content, but also the dynamic release of strontium salt content due to prolonged time. Can not represent the true free strontium content.
- the object of the present invention is to overcome the problem that the colloidal pectin colloidal solution is allowed to release free sputum, and to provide a method for determining free strontium in colloidal pectin or colloidal pectin preparation, thereby simplifying the determination method and improving free sputum.
- the reproducibility of the assay is to overcome the problem that the colloidal pectin colloidal solution is allowed to release free sputum, and to provide a method for determining free strontium in colloidal pectin or colloidal pectin preparation, thereby simplifying the determination method and improving free sputum. The reproducibility of the assay.
- the invention utilizes colloidal pectin to form a stable colloidal dispersion with certain gelation in an aqueous solution containing ethanol, and a molecular weight difference between the colloidal pectin and the small molecule free anthracene, and the colloidal pectin is separated by high speed centrifugation.
- the ruthenium is separated from the free ruthenium to precisely measure the content of free ruthenium.
- the method for determining free sputum in the colloidal pectin or colloidal pectin preparation is: placing the colloidal pectin or the colloidal pectin preparation in a plastic centrifuge tube, adding a volume concentration of 7 to 20%. The aqueous solution of ethanol is shaken to make the solution uniform, and a colloidal solution is obtained. The supernatant is centrifuged, and the content of strontium in the supernatant is determined by complexometric titration or ultraviolet spectrophotometry to calculate colloidal pectin or colloid. Free strontium content in pectin sputum preparations.
- volume concentration of the aqueous ethanol solution is preferably from 10 to 16%.
- the suitable concentration of ethanol aqueous solution can not only make the colloidal pectin molecule easily disperse evenly, completely dissolve the free ruthenium in the colloidal pectin mash, and ethanol has a certain gelation effect on the colloidal pectin oxime molecule, so that the colloidal pectin is made.
- the stability of the ruthenium molecule is enhanced, and the water is resolved to release the strontium salt. Therefore, by using the above method of the invention to dissolve the colloidal pectin, it is not necessary to strictly control the dissolution time, and a relatively stable colloidal solution can be obtained, and then the macromolecular colloidal pectin can be obtained by centrifugation. The required, undisturbed supernatant is used for the determination of free hydrazine.
- the present invention can also determine the free strontium content in the colloidal pectin or the colloidal pectin preparation by the following method, and can also ensure the freeness. Rapid dissolution of hydrazine and stabilization of colloidal pectin ⁇ molecules.
- the colloidal pectin or the colloidal pectin preparation is placed in a plastic centrifuge tube, and an ethanol aqueous solution having a volume concentration of not more than 5% is added, shaken and dispersed, and then ethanol is added to adjust the volume concentration of the ethanol in the dispersion to 30 to 50%. Shake to dissolve evenly, obtain a colloidal solution, centrifuge to take the supernatant, determine the content of strontium in the supernatant by complexometric titration or ultraviolet spectrophotometry, and calculate colloidal pectin or colloidal pectin. Free strontium content in the formulation.
- volume concentration of ethanol in the dispersion is preferably from 30 to 40%.
- the above method of the invention firstly adds a lower concentration of ethanol solution, and only shakes and disperses, rapidly dissolves the free hydrazine, does not require uniform dispersion, and then increases the concentration of ethanol to form a gel to increase the stability of the colloidal pectin molecule. To prevent its decomposition and release of barium salts.
- Colloidal pectin has a certain gelatinity in ethanol.
- the experiment proves that the aqueous solution of ethanol used in the above two methods of the invention not only has good solubility to free ruthenium, but also can block the colloidal pectin molecule to a certain extent, and effectively prevents the dynamic release of the bismuth salt of the colloidal pectin.
- the colloidal pectin can be fully dispersed by using a certain concentration of aqueous ethanol solution.
- the free hydrazine content tends to be stable within a certain period of time, and does not change with the change of the solution standing time.
- the free hydrazine and the colloidal pectin ⁇ colloidal solution reach a certain balance.
- the measurement result of free cesium is more accurate and reliable, closer to the true free strontium content, and is conducive to the reproducibility of the experimental results.
- the colloidal pectin molecules were substantially larger than 0.1 ⁇ m.
- direct filtration is very difficult due to the high viscosity of the colloidal dispersion of colloidal pectin in aqueous ethanol solution. Therefore, the high-molecular colloidal pectin solution dispersed in the aqueous solution of ethanol can be completely settled under the high-speed centrifugation of the colloidal solution of the present invention at a speed of 10,000 rpm or more for not less than 5 minutes. The required, undisturbed supernatant was tested for free enthalpy determination.
- the most preferred centrifugation conditions of the present invention are high speed centrifugation at 12,000 rpm for 30 min.
- the colloidal solution may be firstly centrifuged at a speed of 7000 to 10,000 rpm for at least 5 minutes, and then the centrate is filtered through a filter of 0.1 ⁇ m or less, and the same can be obtained.
- the most preferred centrifugation conditions in the above method were centrifuged at 8000 rpm for 10 min.
- the invention can also centrifuge the colloidal solution at a speed of 3000-7000 rpm for not less than 10 min, mix the centrate and the low-carbon alcohol, and then centrifuge at a speed of 5000-7000 rpm. At 10 minutes, the supernatant for free sputum detection without interference was obtained.
- the most preferred centrifugation condition is to centrifuge two centrifugations at 6000 rpm for 10 min.
- the colloidal solution may be first centrifuged at 3000-7000 rpm for not less than 10 minutes, and the centrate is mixed with the lower alcohol, and then at 3000-7000 rpm. After the centrifugation of min is not less than 10 min, the centrate is filtered through a membrane of 0.1 ⁇ m or less, and the obtained supernatant can also satisfy the detection requirement of free hydrazine.
- the lower alcohol is a conventional alcohol organic solvent such as ethanol, methanol or isopropanol.
- Colloidal pectin is characterized by strong colloidal properties, high viscosity, and easy adhesion to the surface of the object.
- the colloidal pectin colloidal solution is prepared, if it is dissolved in a glass material container with a high surface energy, the colloidal pectin can easily form a gel to adhere to the surface of the glass container, and is not easily dispersed and dispersed. Uniform, requires constant strong shaking. Therefore, in the present invention, a plastic material container such as PP (polypropylene), PC (polycarbonate), or PE (polyethylene) having a small surface energy is preferably used to facilitate the rapid dispersion of the colloidal pectin.
- PP polypropylene
- PC polycarbonate
- PE polyethylene
- the colloidal pectin or the colloidal pectin preparation and the aqueous ethanol solution are preferably formulated into a uniformly dispersed solution containing colloidal pectin ⁇ 0.03 to 3 mg/ml.
- the present invention uses ultraviolet spectrophotometry to determine the free strontium content in the colloidal pectin or colloidal pectin preparation, that is, the supernatant is colored with an acid coloring solution of citric acid or ascorbic acid and potassium iodide.
- the absorbance of the solution was measured at a wavelength of 380 to 470 nm, and compared with the absorbance of the known concentration of the reference solution under the same conditions, the free strontium content in the colloidal pectin or the colloidal pectin preparation was calculated.
- the solution for measuring the absorbance should be diluted to a concentration of 0.1 to 50 ⁇ g/ml in the solution.
- concentration of ruthenium in the assay solution is 2 to 20 ⁇ g/ml. More preferably, the enthalpy concentration of the assay solution is 5 to 12 ⁇ g/ml.
- the color developing solution is an aqueous solution or a 0.2 to 2 mol/L nitric acid or acetic acid solution, and contains 0.5 to 10% by weight of citric acid or ascorbic acid and 2.5 to 25% by weight of potassium iodide.
- the color developing solution is an aqueous solution or a 1 mol/L nitric acid or acetic acid solution, and contains 2.5% by weight of citric acid or ascorbic acid and 12.5% by weight of potassium iodide.
- the single-wavelength method can be used to measure the free ruthenium content, or the two-wavelength method can be used to better eliminate the interference.
- the single wavelength method uses a wavelength in the range of 380 to 470 nm, preferably 399 nm, 433 nm, and 463 nm; the dual wavelength method may use a combination of 398 nm and 433 nm or 433 nm and 463 nm, preferably a combination of 433 nm and 463 nm.
- the method for determining the free strontium content provided by the invention is suitable for the colloidal pectin mash raw material prepared by various methods, and any single or compound preparation containing colloidal pectin, including common tablets, capsules, dispersible tablets and granules. , dry suspension, powder, enteric-coated tablets, colon-soluble tablets, enteric-coated capsules, colon-soluble capsules and other suitable dosage forms.
- the method for determining free ruthenium in colloidal pectin or colloidal pectin preparation prepared by the invention has strong specificity, and is simpler and easier to operate than the patent application method of 201810000930.5, and improves the reproducibility of free sputum determination.
- Example 1 Determination of free strontium content in colloidal pectin mash bulk drug.
- color developing solution take about 2.5g of ascorbic acid, about 12.5g of potassium iodide, put it in a 200ml volumetric flask, add about 100ml of water, shake to dissolve, add 25ml of 1mol/L nitric acid solution, dilute with water and dilute to volume.
- a solution containing 1.25% ascorbic acid and 6.25% potassium iodide was prepared.
- ⁇ reference solution Take about 250mg of metal ruthenium, accurately weigh it, put it into a 100ml volumetric flask, add 6.4ml of nitric acid to dissolve, dilute to the mark with water, as a standard stock solution. 1 ml of the standard stock solution was accurately weighed, placed in a 50 ml volumetric flask, and diluted with a 1 mol/L nitric acid solution to a mark to prepare a solution containing about 50 ⁇ g of hydrazine per 1 ml as a standard solution for hydrazine. Precisely measure 5 ml of the standard solution, place it in a 50 ml volumetric flask, dilute to the mark with a developer, shake it up, and use it as a reference solution.
- test solution Take about 15mg of colloidal pectin mash powder in PC centrifuge tube, accurately weighed, accurately add 6ml of 10% ethanol solution, shake to make the solution even.
- the PC centrifuge tube was placed in a high speed centrifuge and centrifuged at 16,000 rpm for 20 min. Precisely take 2 ml of the supernatant, place it in a 10 ml volumetric flask, dilute to the mark with a developer, and shake it to obtain the test solution 1.
- blank solution accurately measure 5 ml of 10% ethanol solution, place it in a 25 ml volumetric flask, dilute to the mark with a color developing solution, shake well, and use as blank solution 1.
- Determination take the reference solution and the test solution 1 and the test solution 2, respectively, using the blank solution 1 and the blank solution 2 as a reference, according to the ultraviolet-visible spectrophotometry, using a 1 cm quartz cuvette, The absorbance was measured at a wavelength of 463 nm, and the free ruthenium content in the drug substance was calculated by an external standard method. The average value of the test solution 1 was 0.62%, and the average value of the test solution 2 was 0.63%.
- Example 2 The free strontium content in a colloidal pectin capsule (specification 40 mg, in decim) was determined.
- test solution Take the content of colloidal pectin ⁇ capsule about 10mg in PP centrifuge tube, accurately weighed, accurately add 2.63ml of 1% ethanol, shake and disperse, add 1.37ml of absolute ethanol, shake to make Dissolved evenly. It was placed in a high speed centrifuge and centrifuged at 12,000 rpm for 30 min. Precisely take 2 ml of the supernatant, place it in a 10 ml volumetric flask, dilute to the mark with a developer, and shake it to prepare a test solution.
- Example 3 The free strontium content in a colloidal pectin capsule (specification 50 mg, in decim) was determined.
- test solution Take about 10mg of colloidal pectin capsule content in PE centrifuge tube, accurately weighed, accurately add 4ml of 12% ethanol solution, shake to make the dissolution even. Place in a high speed centrifuge and centrifuge at 18,000 rpm for 15 min. Precisely take 5 ml of the supernatant, place it in a 25 ml volumetric flask, dilute to the mark with a developer, and shake it to obtain the test solution 1. Take about 10mg of colloidal pectin capsule content in PE centrifuge tube, accurately weighed, accurately added 2.65ml of 2% ethanol solution, shake and disperse, add 1.35ml of absolute ethanol, shake to make the solution even.
- blank solution accurately measure 5 ml of 12% ethanol solution, place it in a 25 ml volumetric flask, dilute to the mark with a color developing solution, shake well, and use as blank solution 1. Accurately measure 5 ml of 35% ethanol solution, place it in a 25 ml volumetric flask, dilute to the mark with a color developing solution, and shake well to obtain a blank solution 2.
- Determination take the reference solution and the test solution 1 and the test solution 2, respectively, using the blank solution 1 and the blank solution 2 as a reference, according to the ultraviolet-visible spectrophotometry, using a 1 cm quartz cuvette The absorbance was measured at a wavelength of 463 nm, and the free enthalpy was calculated as a percentage of the labeled amount by an external standard method. The average value of the test solution 1 was 6.25%, and the average value of the test solution 2 was 6.24%.
- Example 4 The free strontium content in a colloidal pectin capsule (specification 100 mg, in decim) was determined.
- ⁇ reference solution Take 275mg of metal ruthenium, accurately weigh it, put it into a 100ml volumetric flask, add 6.4ml of nitric acid to dissolve, dilute with water to the mark, as a standard stock solution. 1.5 ml of the standard stock solution was accurately weighed, placed in a 100 ml volumetric flask, and diluted to a mark with a 0.5 mol/L nitric acid solution to prepare a solution containing about 41.25 ⁇ g per 1 ml as a standard solution. Precisely measure 2 ml of the standard solution, place it in a 25 ml volumetric flask, dilute to the mark with a developer, shake it up, and use it as a reference solution.
- test solution Take about 30mg of colloidal pectin capsule content in PP centrifuge tube, accurately weighed, precisely add 10ml of 11% ethanol solution, shake to make the dissolution even. It was placed in a high speed centrifuge and centrifuged at 12,000 rpm for 30 min. The supernatant was accurately weighed to 10 ml, placed in a 50 ml volumetric flask, diluted to the mark with a developer, and shaken to obtain a test solution 1.
- blank solution accurately measure 5 ml of 11% ethanol solution, place it in a 25 ml volumetric flask, dilute to the mark with a color developing solution, shake well, and use as blank solution 1. Accurately measure 5 ml of 32% ethanol solution, place it in a 25 ml volumetric flask, dilute to the mark with a color developing solution, and shake well to obtain a blank solution 2.
- Determination take the reference solution and the test solution 1 and the test solution 2, respectively, using the blank solution 1 and the blank solution 2 as a reference, according to the ultraviolet-visible spectrophotometry, using a 1 cm quartz cuvette The absorbance was measured at a wavelength of 463 nm, and the free enthalpy contained in each 100 mg of lanthanum was calculated as a percentage of the labeled amount by an external standard method. The average value of the test solution 1 was 5.75%, and the average value of the test solution 2 was 5.72%.
- Example 5 The free hydrazine content in a colloidal pectin mash dispersible tablet (specification 50 mg, in decim) was determined.
- ⁇ reference solution Take 275mg of metal ruthenium, accurately weigh it, put it into a 100ml volumetric flask, add 6.4ml of nitric acid to dissolve, dilute with water to the mark, as a standard stock solution. 1.2 ml of a standard stock solution was accurately weighed, placed in a 100 ml volumetric flask, and diluted to a mark with a 0.8 mol/L nitric acid solution to prepare a solution containing about 33 ⁇ g of hydrazine per 1 ml as a standard solution for hydrazine. Precisely measure 5 ml of the standard solution, place it in a 25 ml volumetric flask, dilute to the mark with a developer, shake it up, and use it as a reference solution.
- test solution Take 20 pieces of colloidal pectin ⁇ dispersible tablets, grind finely, take about 60mg of powder in PE centrifuge tube, accurately weigh, accurately add 12.5ml of 4% ethanol solution, shake and disperse, add no Water ethanol 7.5ml to make the dissolution even. Place in a centrifuge and centrifuge at 8000 rpm for 10 min. The supernatant was taken, filtered with a 0.1 ⁇ m microporous membrane, and 2 ml of the filtrate was accurately weighed, placed in a 10 ml volumetric flask, diluted to the mark with a developer, and shaken to obtain a test solution.
- Example 6 The free hydrazine content of colloidal pectin mash particles (specification 150 mg, in decim) was determined.
- color developing solution take 10g of ascorbic acid, 30g of potassium iodide, place it in a 200ml volumetric flask, add 100ml of water, shake to dissolve, add 25ml of 1mol/L nitric acid solution, dilute with water and dilute to the mark to make 5% ascorbic acid. , 15% color developing solution of potassium iodide.
- test solution Take colloidal pectin granules, grind finely, take about 30mg of powder in PP centrifuge tube, accurately weigh, precisely add 4ml of 16% ethanol solution, shake to make the dissolution even. Centrifuge at 6000 rpm for 30 min. 5 ml of the supernatant was accurately weighed, 5 ml of ethanol was added, shaken, and centrifuged at 6000 rpm for 30 min. Precisely take 2 ml of the supernatant, place it in a 10 ml volumetric flask, dilute to the mark with a developer, and shake it to prepare a test solution.
- Example 7 The free colloid content in a compound colloidal pectin capsule (composed of colloidal pectin, metronidazole, tetracycline hydrochloride, wherein each capsule contains colloidal pectin in an amount of 35 mg).
- test solution Take about 60mg of compound colloidal pectin capsule content in PE centrifuge tube, accurately weighed, accurately add 12.53ml of 1% ethanol solution, shake and disperse, add 7.47ml of absolute ethanol, vibrate Shake to dissolve evenly. Centrifuge at 7000 rpm for 20 min. Precisely take 5ml of the supernatant, add 5ml of isopropanol, shake, and then centrifuge at 7000 rev / min for 20min, take the supernatant, filter with 0.1 ⁇ m needle filter, accurately measure the filtrate 2ml, set In a 10 ml volumetric flask, dilute to the mark with a developer and shake well to serve as a test solution.
- Example 8 The free strontium content in colloidal pectin (specification 150 mg, in decim) was determined.
- test solution Take about 35mg of colloidal pectin in PC centrifuge tube, accurately weighed, accurately add 10.71ml of 2% ethanol solution, shake and disperse, add 4.29ml of absolute ethanol, shake to dissolve Evenly. Centrifuge at 8000 rpm for 30 min. Precisely take 5ml of supernatant, add 5ml of methanol, shake, and then centrifuge at 8000 rev / min for 20min, take the supernatant, filter with 0.1 ⁇ m needle filter, accurately measure 2ml of filtrate, set 10ml capacity In the bottle, dilute to the mark with a developer, shake it, and use it as a test solution.
- Example 9 Determination of free strontium content in colloidal pectin ⁇ dry suspension (specification 150 mg, in decimated form).
- ⁇ reference solution Take 275mg of metal ruthenium, accurately weigh it, put it into a 100ml volumetric flask, add 6.4ml of nitric acid to dissolve, dilute with water to the mark, as a standard stock solution. 1 ml of the standard stock solution was accurately weighed, placed in a 100 ml volumetric flask, and diluted to a mark with a 1 mol/L nitric acid solution to prepare a solution containing about 27.5 ⁇ g of hydrazine per 1 ml as a standard solution for hydrazine. Accurately measure 4 ml of the standard solution, place it in a 10 ml volumetric flask, dilute to the mark with a color developing solution, and use it as a reference solution.
- test solution Take about 15mg of colloidal pectin and dry suspension in PP centrifuge tube, accurately weighed, precision added 10ml of 13% ethanol solution, shake to make the dissolution even. Centrifuge at 16000 rpm for 20 min. Accurately measure 2 ml of the supernatant, place it in a 10 ml volumetric flask, dilute to the mark with a color developing solution, and shake well to serve as a test solution.
- Example 10 Effect of different centrifugation conditions on the determination of free strontium content.
- the reference solution was taken and the absorbance was measured at a wavelength of 463 nm. The measurement was repeated 6 times.
- the absorbance values were 0.3204, 0.3206, 0.3207, 0.3209, 0.3203, 0.3201, and the relative standard deviation RSD was 0.09%. The precision of the instrument was good.
- Example 12 Limit of detection and limit of quantitation.
- the detection limit and the limit of quantitation were calculated according to the requirements of the International Union of Pure and Applied Chemistry (IUPAC) for detection limits.
- test solution of colloidal pectin ⁇ raw material drug, colloidal pectin ⁇ capsule (specification 100 mg) and colloidal pectin ⁇ capsule (specification 50 mg) was prepared according to the following method, and the absorbance was measured to calculate the free strontium content. The specific measurement results are shown in Tables 1 to 3.
- colloidal pectin ⁇ raw material drug colloidal pectin ⁇ capsule (specification 100mg) content about 10mg, accurately weighed, placed in a plastic centrifuge tube, precision added 4ml ethanol solution 4ml, shake to make the dissolution even, to 12000 Centrifuge at /min for 30 min or more. Accurately measure 2 ml of the supernatant, place it in a 10 ml volumetric flask, dilute to the mark with a color developing solution, and shake well to serve as a test solution.
- colloidal pectin capsule (specification 50mg) content about 10mg, accurately weighed, placed in a plastic centrifuge tube, accurately added 2.95ml of 5% ethanol solution, shake and disperse, add 1.05ml of absolute ethanol, shake to dissolve Evenly. Centrifuge at 12000 rpm for 30 min or more. Accurately measure 2 ml of the supernatant, place it in a 10 ml volumetric flask, dilute to the mark with a color developing solution, and shake well to serve as a test solution.
- colloidal pectin capsule (50mg specification) The content is about 10mg, accurately weighed, placed in plastic centrifuge tube, accurately added 2.95ml of 5% ethanol solution, shake and disperse, add 1.05ml of absolute ethanol, shake and dissolve evenly Mix and centrifuge at 12000 rpm for 30 min or more. Precisely take 2ml of the supernatant, then accurately add 2ml of the standard solution, place it in a 10ml volumetric flask, dilute to the mark with the color developing solution, shake it up, and use it as the test solution. A total of 6 parts were prepared, the absorbance was measured, and the recovery was calculated. The results are shown in Table 6.
- the measurement results show that the method of the invention has a good recovery rate and good measurement accuracy.
- Example 16 Effect of different standing times on the results of determination of free hydrazine content of colloidal pectin mash.
- the measurement results show that the results of the three methods are basically the same within 1 min of the control time.
- water used as the dispersion medium
- the amount of free strontium content measured increases with the extension of the colloidal solution.
- the value of free strontium content changes slowly with the standing time of the colloidal solution, which proves that the colloidal stability increases, and the determination result of free strontium content is more accurate and reliable, close to the true free strontium content, which is beneficial to the experiment.
- the reproducibility of the results are basically the same within 1 min of the control time.
- Example 17 Effect of different standing time on the results of determination of free strontium content of colloidal pectin capsules (specification 100 mg, in terms of hydrazine).
- colloidal pectin capsules Take the content of colloidal pectin capsules about 0.5g, accurately weighed, set in a 200ml volumetric flask, add 147.37ml of 5% ethanol solution to shake and disperse, add absolute ethanol to the scale, shake vigorously, and evenly disperse into
- the colloidal solution was taken at 1 min, 10 min, 20 min, 40 min, 60 min, 90 min, 120 min, respectively, and 4 ml of the above colloidal solution was taken, and centrifuged at a speed of 12,000 rpm for 30 min at high speed, and then 2 ml of the supernatant was accurately weighed, and a volume of 10 ml was set.
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Abstract
本发明提供了一种测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法，是在胶体果胶铋或含胶体果胶铋制剂中加入体积浓度7～20%的乙醇水溶液，振摇使溶散均匀，或者加入体积浓度不超过5%的乙醇水溶液振摇分散，再加入乙醇至分散液中乙醇体积浓度为30～50%，振摇使溶散均匀，以得到胶态溶液，离心取上清液，以络合滴定法或紫外分光光度法测定，计算出胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。乙醇水溶液不仅对游离铋有较好的溶解性，而且能在一定程度上封闭胶体果胶铋分子，有效防止胶体果胶铋的动态释放铋盐过程，本发明使用乙醇水溶液分散胶体果胶铋进行游离铋的测定，游离铋测定结果更准确可靠。
Description
本发明属于胶体果胶铋质量控制技术领域，涉及一种胶体果胶铋或含胶体果胶铋制剂中的游离铋测定方法，以用于控制游离铋限度，提升用药安全性。
胶体果胶铋及其胶囊是山西振东安特生物制药有限公司前身太原市红星制药厂的首创药品。该药品于1992年7月经原国家卫生部首先批准太原市红星制药厂生产上市。
胶体果胶铋胶囊的活性成分胶体果胶铋为黄色粉末，不溶于乙醇、丙酮、乙醚等有机溶剂，在水中可形成稳定的胶体分散系，在人工胃液中可形成凝胶。胶体果胶铋及其胶囊剂已收载于《中国药典》2015年版二部。胶体果胶铋含量以铋(Bi)计为14.0～16.0%。取胶体果胶铋50mg，加水50ml，振摇，pH值为8.5～10.5。取胶体果胶铋0.25g，置100ml具塞量筒中，加水至100ml，强力振摇1min，使成胶态溶液，静置1hr，胶态物的顶面不得下降至97ml刻度以下。
胶体果胶铋为胃粘膜保护剂，在胃酸环境中形成稳定凝胶体，覆盖在黏膜表面，使糜烂面和溃疡灶与胃酸及胃蛋白酶隔离，对受损黏膜起到保护作用，促进溃疡组织修复和愈合；可刺激内源性前列腺素和表皮生长因子产生，加速溃疡面愈合和炎症消失，同时具有一定的止血作用。胶体果胶铋作用于幽门螺旋杆菌，有利于根除胃幽门螺杆菌。
于学敏等(维敏胶囊各项试验研究结论概述[J]. 中国新药杂志, 1993, 2(3): 34-36)研究表明，安特
®胶体果胶铋胶囊在人工胃液中的特性黏数为126，胶体次枸橼酸铋钾的特性黏数为17，前者为后者的7.4倍。鲁巍峰(中国健康成人铋剂的吸收与药代动力学研究[D]. 北京: 中国协和医科大学, 2001)报道安特
®胶体果胶铋胶囊人体几乎不吸收，胶体次枸橼酸铋片的AUC
0-24hr是安特
®胶体果胶铋胶囊的15.6倍。
进一步研究表明，铋的吸收与铋颗粒的大小有着直接关系。胶体果胶铋胶囊之所以比胶体次枸橼酸铋片吸收少，主要是由于胶体果胶铋的铋颗粒远远大于胶体次枸橼酸铋的铋颗粒。铋离子、小分子铋的铋颗粒小，人体吸收多；反之，大分子铋的铋颗粒大，人体吸收少。
胶体果胶铋是由果胶与铋形成的组成不定的复合物。由于果胶分子为大分子物质，且分子组成不定，因此，在胶体果胶铋的合成过程中，可能会存在未完全合成上去的铋，以及小分子铋，统称游离铋。
铋作为一种重金属，一旦过多被人体吸收，将会导致毒性反应，出现肾脏、骨关节以及中枢神经系统等的损害。
国家食品药品监督管理总局《关于胃肠道局部作用药物、电解质平衡用药仿制药质量和疗效一致性评价及特殊药品生物等效性试验申请有关事宜的意见（征求意见稿）》将铋剂，包括枸橼酸铋钾颗粒、枸橼酸铋钾胶囊、枸橼酸铋钾片和胶体果胶铋胶囊列为首批选取的10个一致性评价品种，并强调鉴于过量铋盐已知的毒副作用，应在现有原料药和制剂的质量标准中增加游离铋盐的限度控制。
《中国药典》2015年版二部中，胶体果胶铋含量以铋(Bi)计，应为14.0～16.0%，但并未区别胶体果胶铋和游离铋，未对游离铋的含量做出相关规定，且采用硝酸消解后络合滴定的方法测定胶体果胶铋含量，也无法将大分子胶体果胶铋与游离铋区分开来。
CN 104880428B涉及一种胶体果胶铋或含胶体果胶铋制剂中铋含量的测定方法，是将胶体果胶铋或含胶体果胶铋制剂分散于水中，加入质子酸解离剂，使分散液中氢离子浓度达到0.8～1.2mol/L，解离完全后离心，分离出上清液，加入柠檬酸或抗坏血酸与碘化钾的显色溶液显色，得到供试品溶液，在380～470nm波长处测定吸光度，与相同条件下已知浓度铋对照品溶液的吸光度比较，计算胶体果胶铋或含胶体果胶铋制剂中的铋含量。该方法解决了直接采用分光光度法测定胶体果胶铋或含胶体果胶铋制剂中铋含量时高分子酸根果胶干扰严重的问题，测定结果准确度高，重复性好，可以有效控制胶体果胶铋及其制剂的产品质量。
然而，该方法最终给出的胶体果胶铋或含胶体果胶铋制剂中的铋含量中同样包含了游离铋含量，依然无法将大分子胶体果胶铋与游离铋区分开来。
中国专利申请201810000930.5涉及一种胶体果胶铋或含胶体果胶铋制剂中游离铋的检测方法，是将胶体果胶铋或含胶体果胶铋制剂置于塑料离心管中，加水进行不超过1min的振摇，得到溶散均匀的胶态溶液，将胶态溶液立即离心，分离出上清液，以络合滴定法或紫外分光光度法检测上清液中的铋含量，计算出胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。该方法通过将胶体果胶铋或含胶体果胶铋制剂分散于水中并离心分离，使大分子胶体果胶铋与游离铋区分开来，游离铋含量测定结果准确度高，可以有效控制胶体果胶铋及其制剂的产品质量。
胶体果胶铋分散于水中形成胶态溶液后，受胶体果胶铋分子结构中铋盐与果胶之间的结合作用力影响，胶体果胶铋存在一个动态释放铋盐的过程。因此，采用水溶液法测定胶体果胶铋中游离铋含量时，其测定结果与时间相关。如果胶体果胶铋胶态溶液的静置时间过长，所得到的游离铋测定结果中不仅包括了固有的游离铋含量，还会包括随时间延长导致的动态释放出的铋盐含量，测定结果不能表示真实的游离铋含量。所以201810000930.5专利申请严格控制加水后的振摇时间不超过1min，且分散均匀后立即离心。这无疑给实验操作带来了一定的难度，且由于每次实验的振摇时间和离心时间不可能控制完全一致，不可避免会导致测定结果的重现性较差。
本发明的目的是克服胶体果胶铋胶态溶液静置释放游离铋的问题，提供一种测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法，以简化测定方法，提高游离铋测定的重现性。
本发明利用胶体果胶铋能够在含有乙醇的水溶液中形成具有一定胶凝性的稳定胶体分散系，及胶体果胶铋与小分子游离铋存在分子量差异的特性，通过高速离心手段将胶体果胶铋与游离铋分离，从而精密测定游离铋的含量。
本发明所述的测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法是：将胶体果胶铋或含胶体果胶铋制剂置于塑料离心管中，加入体积浓度7～20%的乙醇水溶液，振摇使溶散均匀，得到胶态溶液，离心取上清液，以络合滴定法或紫外分光光度法测定上清液中的铋含量，计算出胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。
进一步地，所述乙醇水溶液的体积浓度优选为10～16%。
适合浓度的乙醇水溶液不仅能够使胶体果胶铋分子容易地分散均匀，将胶体果胶铋中的游离铋完全溶出，且乙醇对胶体果胶铋分子又有一定的胶凝作用，使胶体果胶铋分子的稳定性增强，延缓其水解析出释放铋盐。因此，使用本发明上述方法溶散胶体果胶铋，不需要对溶散时间进行严格控制，能够获得比较稳定的胶态溶液，再经离心处理使大分子胶体果胶铋沉降后，即可获得符合要求的、没有干扰的上清液用于游离铋的测定。
然而，如果乙醇水溶液的浓度过大，虽然能更好地阻止胶体果胶铋分子的分解释放铋盐行为，但也会阻碍游离铋的快速溶出，导致测定结果可能偏低。因此，本发明除了可以选择合适的乙醇水溶液浓度对胶体果胶铋进行溶散外，还可以通过下述方法测定胶体果胶铋或含胶体果胶铋制剂中的游离铋含量，同样能够保证游离铋的快速溶出以及胶体果胶铋分子的稳定。
将胶体果胶铋或含胶体果胶铋制剂置于塑料离心管中，加入体积浓度不超过5%的乙醇水溶液，振摇分散，再加入乙醇调整分散液中乙醇的体积浓度为30～50%，振摇使溶散均匀，得到胶态溶液，离心取上清液，以络合滴定法或紫外分光光度法测定上清液中的铋含量，计算出胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。
进一步地，所述分散液中乙醇的体积浓度优选为30～40%。
本发明上述方法先加入较低浓度的乙醇溶液，并只振摇分散，将游离铋快速溶出，不要求分散均匀，随后再提高乙醇的浓度，以形成凝胶增加胶体果胶铋分子的稳定性，阻止其分解释放铋盐的行为。
胶体果胶铋在乙醇中具有一定的胶凝性。实验证明，本发明上述两种方法采用的乙醇水溶液不仅对游离铋有较好的溶解性，而且能在一定程度上封闭胶体果胶铋分子，有效防止胶体果胶铋的动态释放铋盐过程。使用一定浓度的乙醇水溶液可以使胶体果胶铋充分分散，游离铋含量在一定时间内趋于稳定，不随溶液静置时间的变化而改变，游离铋与胶体果胶铋胶态溶液达到一定的平衡，使得游离铋的测定结果更加准确可靠，更接近真实的游离铋含量，并有利于实验结果的重现性。
根据胶体果胶铋在乙醇水溶液中形成分散体系的粒度分布结果分析，胶体果胶铋分子基本上均大于0.1μm。但是，由于胶体果胶铋在乙醇水溶液中形成的稳定胶体分散系黏度大，直接过滤非常困难。因此，将本发明所述溶散均匀的胶态溶液以10000转/min以上的转速高速离心不少于5min，就能够使分散于乙醇水溶液中的大分子胶体果胶铋完全沉降下来，获得符合检测要求的、没有干扰的上清液用于游离铋的测定。
本发明最优选的离心条件是以12000转/min的转速高速离心30min。
进而，本发明也可以将所述胶态溶液先以7000～10000转/min的转速高速离心不少于5min，再将离心液以0.1μm以下的滤膜过滤，同样能够获得符合检测要求的、没有干扰的游离铋检测用上清液。
上述方法中最优选的离心条件是以8000转/min的转速离心10min。
本发明还可以将所述胶态溶液先以3000～7000转/min的转速离心不少于10min，取离心液与低碳醇等比例混合，再以5000～7000转/min的转速离心不少于10min，依然能获得符合检测要求的、没有干扰的游离铋检测用上清液。
上述方法中，最优选的离心条件是将两次离心均以6000转/min的转速离心10min。
进而，更进一步地，本发明还可以将所述胶态溶液先以3000～7000转/min的转速离心不少于10min，将离心液与低碳醇等比例混合，再以3000～7000转/min的转速离心不少于10min后，将离心液以0.1μm以下的滤膜过滤，所获得的上清液同样能够满足游离铋的检测要求。
其中，所述的低碳醇是乙醇、甲醇或异丙醇等常规醇类有机溶剂。
胶体果胶铋的特点是胶体特性强，黏度大，容易粘附于物体表面。制备胶体果胶铋胶态溶液时，如果将其置于表面能较高的玻璃材质容器中进行溶散，则胶体果胶铋很容易形成胶状物粘附于玻璃容器表面，不容易分散分散均匀，需要持续的强烈振摇。因此，本发明优选使用表面能较小的PP(聚丙烯)、PC(聚碳酸酯)、PE(聚乙烯)等塑料材质容器，以助于胶体果胶铋能够快速分散。
进而，本发明优选将胶体果胶铋或含胶体果胶铋制剂加乙醇水溶液配制成含胶体果胶铋0.03～3mg/ml的均匀分散溶液。
优选地，本发明是采用紫外分光光度法测定检测胶体果胶铋或含胶体果胶铋制剂中的游离铋含量，即将上清液以柠檬酸或抗坏血酸与碘化钾的酸性显色溶液显色，在380～470nm波长处测定溶液的吸光度，与相同条件下已知浓度铋对照品溶液的吸光度比较，计算胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。
本发明上述测定方法中，所述用于测定吸光度的溶液，包括供试品溶液或铋对照品溶液，应稀释至溶液中的铋浓度为0.1～50μg/ml。优选地，所述测定溶液中的铋浓度为2～20μg/ml。更优选地，测定溶液的铋浓度为5～12μg/ml。
上述测定方法中，所述的显色溶液为水溶液或0.2～2mol/L硝酸或醋酸溶液，并含有柠檬酸或抗坏血酸0.5～10wt%，碘化钾2.5～25wt%。
进一步地，所述显色溶液为水溶液或1mol/L的硝酸或醋酸溶液，并含有柠檬酸或抗坏血酸2.5wt%，碘化钾12.5wt%。
上述测定方法中，可以采用单波长法测定游离铋含量，也可以采用双波长法，以更好的消除干扰。
其中，单波长法是采用380～470nm范围内的波长，优选采用399nm、433nm、463nm的波长；双波长法则可以采用398nm与433nm或433nm与463nm的组合，优选采用433nm与463nm的组合。
本发明所提供的游离铋含量测定方法适合于以各种方法制备的胶体果胶铋原料药，以及任何含胶体果胶铋的单方或复方制剂，包括普通片剂、胶囊、分散片、颗粒剂、干混悬剂、散剂、肠溶片、结肠溶片、肠溶胶囊、结肠溶胶囊等一切适宜的剂型。
本发明建立的测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法专属性强，较201810000930.5专利申请方法更加简单，容易操作，提高了游离铋测定的重现性。
下述实施例仅为本发明的优选技术方案，并不用于对本发明进行任何限制。对于本领域技术人员而言，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
实施例1：测定胶体果胶铋原料药中的游离铋含量。
1)显色溶液制备：取抗坏血酸约2.5g，碘化钾约12.5g，置200ml容量瓶中，加水约100ml，振摇使溶解，加1mol/L的硝酸溶液25ml，用水稀释并定容至刻度，制成含抗坏血酸1.25%、碘化钾6.25%的溶液。
2)铋对照品溶液制备：取金属铋约250mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液1ml，置50ml容量瓶中，加1mol/L的硝酸溶液稀释至刻度，制成每1ml约含铋50μg的溶液，作为铋标准溶液。精密量取铋标准溶液5ml，置50ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋粉末约15mg于PC离心管中，精密称定，精密加入10%乙醇溶液6ml，振摇使溶散均匀。将PC离心管置于高速离心机中，以16000转/min的转速离心20min。精密量取上清液2ml，置10ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液1。取胶体果胶铋粉末约15mg于PC离心管中，精密称定，精密加入1%乙醇溶液4.42ml，振摇分散，加入无水乙醇1.58ml，振摇使溶散均匀。将PC离心管置于高速离心机中，以16000转/min的转速离心20min。精密量取上清液2ml，置10ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液2。
4)空白溶液制备：精密量取10%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液1。精密量取30%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液2。
5)测定：取铋对照品溶液与供试品溶液1和供试品溶液2，分别以空白溶液1和空白溶液2作参比，照紫外-可见分光光度法，用1cm石英比色皿，在463nm波长处测定得到吸光度，以外标法计算出原料药中的游离铋含量。其中，供试品溶液1的测定平均值为0.62%，供试品溶液2的测定平均值为0.63%。
6)对上述两组数据进行t检验分析，结果P=0.66，R-Sq=2.00%，证明两种溶散方式无显著差异。
实施例2：测定胶体果胶铋胶囊(规格40mg，以铋计)中的游离铋含量。
1)显色溶液制备：取抗坏血酸5g，碘化钾12.5g，置200ml容量瓶中，加水100ml，振摇使溶解，加1mol/L硝酸溶液25ml，用水稀释并定容至刻度，制成含抗坏血酸2.5%、碘化钾6.25%的显色溶液。
2)铋对照品溶液制备：取金属铋约275mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液2ml，置100ml容量瓶中，加0.8mol/L的硝酸溶液稀释至刻度，制成每1ml约含铋55μg的溶液，作为铋标准溶液。精密量取铋标准溶液5ml，置50ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋胶囊内容物约10mg于PP离心管中，精密称定，精密加入1%乙醇2.63ml，振摇分散，加入无水乙醇1.37ml，振摇使溶散均匀。置于高速离心机中，以12000转/min的转速离心30min。精密量取上清液2ml，置10ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液。
4)空白溶液制备：精密量取35%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液。
5)测定：取铋对照品溶液与供试品溶液，以空白溶液做参比，照紫外-可见分光光度法，用1cm的石英比色皿，在463nm的波长处测定吸光度，以外标法计算，每40mg铋含游离铋2.73mg，相当于标示量的6.83%。
实施例3：测定胶体果胶铋胶囊(规格50mg，以铋计)中的游离铋含量。
1)显色溶液制备：取抗坏血酸20g，碘化钾50g，置200ml容量瓶中，加水100ml，振摇使溶解，加1mol/L醋酸溶液25ml，用水稀释并定容至刻度，制成含抗坏血酸10%、碘化钾25%的显色溶液。
2)铋对照品溶液制备：取金属铋约275mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液1ml，置100ml容量瓶中，加1mol/L的硝酸溶液稀释至刻度，制成每1ml约含铋27.5μg的溶液，作为铋标准溶液。精密量取铋标准溶液5ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋胶囊内容物约10mg于PE离心管中，精密称定，精密加入12%乙醇溶液4ml，振摇使溶散均匀。置于高速离心机中，以18000转/min的转速离心15min。精密量取上清液5ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液1。取胶体果胶铋胶囊内容物约10mg于PE离心管中，精密称定，精密加入2%乙醇溶液2.65ml，振摇分散，加入无水乙醇1.35ml，振摇使溶散均匀。置于高速离心机中，以18000转/min的转速离心15min。精密量取上清液5ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液2。
4)空白溶液制备：精密量取12%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液1。精密量取35%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液2。
5)测定：取铋对照品溶液与供试品溶液1和供试品溶液2，分别以空白溶液1和空白溶液2做参比，照紫外-可见分光光度法，用1cm的石英比色皿，在463nm的波长处测定吸光度，以外标法计算出游离铋相当于标示量的百分数。其中，供试品溶液1的测定平均值为6.25%，供试品溶液2的测定平均值为6.24%。
6)对上述两组数据进行t检验分析，结果P=0.75，R-Sq=1.07%，证明两种溶散方式无显著差异。
实施例4：测定胶体果胶铋胶囊(规格100mg，以铋计)中的游离铋含量。
1)显色溶液制备：取柠檬酸4g，碘化钾20g，置200ml容量瓶中，加水100ml，振摇使溶解，用水稀释并定容至刻度，制成含柠檬酸2%、碘化钾10%的显色溶液。
2)铋对照品溶液制备：取金属铋275mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液1.5ml，置100ml容量瓶中，以0.5mol/L硝酸溶液稀释至刻度，制成每1ml约含铋41.25μg的溶液，作为铋标准溶液。精密量取铋标准溶液2ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋胶囊内容物约30mg于PP离心管中，精密称定，精密加11%乙醇溶液10ml，振摇使溶散均匀。置于高速离心机中，以12000转/min的转速离心30min。精密量取上清液10ml，置50ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液1。取胶体果胶铋胶囊内容物约30mg于PP离心管中，精密称定，精密加入1%乙醇溶液6.87ml，振摇分散，加入无水乙醇3.13ml，振摇使溶散均匀。置于高速离心机中，以12000转/min的转速离心30min。精密量取上清液10ml，置50ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液2。
4)空白溶液制备：精密量取11%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液1。精密量取32%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液2。
5)测定：取铋对照品溶液与供试品溶液1和供试品溶液2，分别以空白溶液1和空白溶液2做参比，照紫外-可见分光光度法，用1cm的石英比色皿，在463nm的波长处测定吸光度，以外标法计算出每100mg铋中含有的游离铋相当于标示量的百分数。其中，供试品溶液1的测定平均值为5.75%，供试品溶液2的测定平均值为5.72%。
6)对上述两组数据进行t检验分析，结果P=0.66，R-Sq=1.96%，证明两种溶散方式无显著差异。
实施例5：测定胶体果胶铋分散片(规格50mg，以铋计)中的游离铋含量。
1)显色溶液制备：取柠檬酸20g，碘化钾25g，置200ml容量瓶中，加水100ml，振摇使溶解，加5mol/L硝酸溶液25ml，用水稀释并定容至刻度，制成含柠檬酸10%、碘化钾12.5%的显色溶液。
2)铋对照品溶液制备：取金属铋275mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液1.2ml，置100ml容量瓶中，以0.8mol/L硝酸溶液稀释至刻度，制成每1ml约含铋33μg的溶液，作为铋标准溶液。精密量取铋标准溶液5ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋分散片20片，研细，取粉末约60mg于PE离心管中，精密称定，精密加入4%乙醇溶液12.5ml，振摇分散，加入无水乙醇7.5ml，使溶散均匀。置于离心机中，以8000转/min的转速离心10min。取上清液，用0.1μm的微孔滤膜抽滤，精密量取续滤液2ml，置10ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液。
4)空白溶液制备：精密量取40%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液。
5)测定：取铋对照品溶液与供试品溶液，以空白溶液做参比，照紫外-可见分光光度法，用1cm的石英比色皿，在463nm的波长处测定吸光度，以外标法计算，每50mg铋含游离铋3.17mg，相当于标示量的6.34%。
实施例6：测定胶体果胶铋颗粒(规格150mg，以铋计)中的游离铋含量。
1)显色溶液制备：取抗坏血酸10g，碘化钾30g，置200ml容量瓶中，加水100ml，振摇使溶解，加1mol/L硝酸溶液25ml，用水稀释并定容至刻度，制成含抗坏血酸5%、碘化钾15%的显色溶液。
2)铋对照品溶液制备：取金属铋50mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液1ml，置25ml容量瓶中，以1.1mol/L硝酸溶液稀释至刻度，制成每1ml约含铋20μg的溶液，作为铋标准溶液。精密量取铋标准溶液5ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋颗粒，研细，取粉末约30mg于PP离心管中，精密称定，精密加16%乙醇溶液4ml，振摇使溶散均匀。以6000转/min的转速离心30min。精密量取上清液5ml，加入乙醇5ml，振摇，再以6000转/min的转速离心30min。精密量取上清液2ml，置10ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液。
4)空白溶液制备：精密量取16%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液。
5)测定：取铋对照品溶液与供试品溶液，以空白溶液做参比，照紫外-可见分光光度法，用1cm的石英比色皿，在463nm的波长处测定吸光度，以外标法计算，每150mg铋含游离铋8.43mg，相当于标示量的5.62%。
实施例7：测定复方胶体果胶铋胶囊(由胶体果胶铋、甲硝唑、盐酸四环素组成，其中每粒胶囊含胶体果胶铋以铋计35mg)中的游离铋含量。
1)显色溶液制备：取抗坏血酸20g，碘化钾40g，置200ml容量瓶中，加水100ml，振摇使溶解，加1mol/L硝酸溶液25ml，用水稀释并定容至刻度，制成含抗坏血酸10%、碘化钾20%的显色溶液。
2)铋对照品溶液制备：取金属铋80mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液2ml，置50ml容量瓶中，以0.7mol/L硝酸溶液稀释至刻度，制成每1ml约含铋32μg的溶液，作为铋标准溶液。精密量取铋标准溶液5ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取复方胶体果胶铋胶囊内容物约60mg于PE离心管中，精密称定，精密加入1%乙醇溶液12.53ml，振摇分散，加入无水乙醇7.47ml，振摇使溶散均匀。以7000转/min的转速离心20min。精密量取上清液5ml，加入异丙醇5ml，振摇，再以7000转/min的转速离心20min，取上清液，用0.1μm的针头过滤器过滤，精密量取续滤液2ml，置10ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液。
4)空白溶液制备：精密量取38%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液。
5)测定：取铋对照品溶液与供试品溶液，以空白溶液做参比，照紫外-可见分光光度法，用1cm的石英比色皿，在463nm的波长处测定吸光度，以外标法计算，每35mg铋含游离铋2.28mg，相当于标示量的6.52%。
实施例8：测定胶体果胶铋散(规格150mg，以铋计)中的游离铋含量。
1)显色溶液制备：取抗坏血酸1g，碘化钾5g，置200ml容量瓶中，加水100ml，振摇使溶解，加5mol/L醋酸溶液25ml，用水稀释并定容至刻度，制成含抗坏血酸0.5%、碘化钾2.5%的显色溶液。
2)铋对照品溶液制备：取金属铋120mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液1ml，置100ml容量瓶中，以1mol/L硝酸溶液稀释至刻度，制成每1ml约含铋12μg的溶液，作为铋标准溶液。精密量取铋标准溶液5ml，置25ml容量瓶中，用显色剂稀释至刻度，摇匀，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋约35mg于PC离心管中，精密称定，精密加入2%乙醇溶液10.71ml，振摇分散，加入无水乙醇4.29ml，振摇使溶散均匀。以8000转/min的转速离心30min。精密量取上清液5ml，加入甲醇5ml，振摇，再以8000转/min的转速离心20min，取上清液，用0.1μm的针头过滤器过滤，精密量取续滤液2ml，置10ml容量瓶中，用显色剂稀释至刻度，摇匀，作为供试品溶液。
4)空白溶液制备：精密量取30%乙醇溶液5ml，置25ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液。
5)测定：取铋对照品溶液与供试品溶液，以空白溶液做参比，照紫外-可见分光光度法，用1cm的石英比色皿，在463nm的波长处测定吸光度，以外标法计算，每150mg铋含游离铋10.66mg，相当于标示量的7.11%。
实施例9：测定胶体果胶铋干混悬剂(规格150mg，以铋计)中的游离铋含量。
1)显色溶液制备：取抗坏血酸10g，碘化钾25g，置200ml容量瓶中，加水100ml，振摇使溶解，加1mol/L硝酸溶液25ml，用水稀释并定容至刻度，制成含抗坏血酸5%、碘化钾12.5%的显色溶液。
2)铋对照品溶液制备：取金属铋275mg，精密称定，置100ml容量瓶中，加硝酸6.4ml使溶解，用水稀释至刻度，作为铋标准储备液。精密量取铋标准储备液1ml，置100ml容量瓶中，以1mol/L硝酸溶液稀释至刻度，制成每1ml约含铋27.5μg的溶液，作为铋标准溶液。精密量取铋标准溶液4ml，置10ml容量瓶中，用显色溶液稀释至刻度，作为铋对照品溶液。
3)供试品溶液制备：取胶体果胶铋干混悬剂约15mg于PP离心管中，精密称定，精密加13%乙醇溶液10ml，振摇使溶散均匀。以16000转/min的转速离心20min。精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为供试品溶液。
4)空白溶液制备：精密量取13%乙醇溶液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为空白溶液。
5)测定：取铋对照品溶液与供试品溶液，以空白溶液作参比，照紫外-可见分光光度法，用1cm石英比色皿，在463nm波长处测定吸光度，以外标法计算，每150mg胶体果胶铋中含游离铋10.27mg，相当于标示量的6.85%。
实施例10：不同离心分离条件对游离铋含量测定结果的影响。
取胶体果胶铋胶囊内容物约0.5g，精密称定，置200ml容量瓶中，加10%乙醇溶液至刻度，强力振摇，使均匀分散成胶态溶液。以下述三种分离处理方式得到上清液，测定游离铋含量。
1、取上述胶态溶液4ml，以12000转/min的转速高速离心30min，再精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋含量。共测定6次，测定平均值相当于标示量的6.46%。
2、取上述胶态溶液8ml，以8000转/min的转速离心10min。取上清液，用0.1μm滤膜过滤，精密量取续滤液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋含量。共测定6次，测定平均值相当于标示量的6.45%。
3、取上述胶态溶液8ml，以6000转/min的转速离心10min。精密量取上清液5ml，加入乙醇5ml，振摇，再以6000转/min的转速离心10min。精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋含量。共测定6次，测定平均值相当于标示量的6.48%。
对以上三组数据进行单因素方差分析，结果R-Sq=0.72%，R-Sq(调整)=0.00%，可见三种分离处理方式无显著差异。
实施例11：仪器精密度试验。
取铋对照品溶液，在463nm波长下测定吸光度，重复测定6次，吸光度值依次为0.3204，0.3206，0.3207，0.3209，0.3203，0.3201，相对标准偏差RSD为0.09%，仪器精密度良好。
实施例12：检出限与定量限。
制备21份空白溶液，在463nm波长下测定吸光度，分别为0.0065，0.0020，0.0030，0.0027，0.0003，0.0154，0.0031，0.0040，0.0011，0.0190，0.0086，0.0116，0.0035，0.0095，0.0139，0.0087，0.0093，0.0031，0.0012，0.0033，0.0007，计算标准偏差SD=0.005317。
根据国际纯粹和应用化学联合会(IUPAC)对检出限的规定计算检出限和定量限，检出限=3×0.005317=0.01595，相当于0.3μg/ml铋对照品溶液中的铋离子浓度，定量限=10×0.005317=0.05317，相当于0.9μg/ml铋对照品溶液中的铋离子浓度。
实施例13：线性范围。
精密量取铋标准溶液(27.5μg/ml) 10.0ml、5.0ml、2.5ml、1.0ml、0.5ml、0.25ml，分别置于25ml容量瓶中，用显色溶液稀释至刻度，在463nm波长下测定吸光度。以最小二乘法对吸光度与铋标准溶液浓度进行线性回归，回归方程A=0.0576C+0.0098，相关系数R
2=0.9997，线性关系良好。
实施例14：重复性试验。
按照下述方法分别制备胶体果胶铋原料药、胶体果胶铋胶囊(规格100mg)、胶体果胶铋胶囊(规格50mg)的供试品溶液各6份，测定吸光度，计算游离铋含量。具体测定结果见表1～表3。
分别取胶体果胶铋原料药、胶体果胶铋胶囊(规格100mg)内容物约10mg，精密称定，置塑料离心管中，精密加10%乙醇溶液4ml，振摇使溶散均匀，以12000转/min的转速离心30min以上。精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为供试品溶液。
取胶体果胶铋胶囊(规格50mg)内容物约10mg，精密称定，置塑料离心管中，精密加入5%乙醇溶液2.95ml，振摇分散，加入无水乙醇1.05ml，振摇使溶散均匀。以12000转/min的转速离心30min以上。精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为供试品溶液。
表1 胶体果胶铋原料药重复性测定结果
表2 胶体果胶铋胶囊(100mg规格)重复性测定结果
表3 胶体果胶铋胶囊(50mg规格)重复性测定结果
结果：胶体果胶铋原料药及不同规格胶体果胶铋胶囊各6份样品测定结果的RSD均不大于2.0%，方法重复性良好。
实施例15：回收率试验。
取胶体果胶铋粉末约10mg，精密称定，置塑料离心管中，精密加10%乙醇溶液4ml，振摇使溶散均匀，以12000转/min的转速离心30min以上。精密量取上清液2ml，再精密加入铋标准溶液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为供试品溶液。共制备6份，测定吸光度，计算回收率，结果见表4。
表4 胶体果胶铋原料回收率测定结果
取胶体果胶铋胶囊(100mg规格)内容物约10mg，精密称定，置塑料离心管中，精密加10%乙醇溶液4ml，振摇使溶散均匀，以12000转/min的转速离心30min以上。精密量取上清液2ml，再精密加入铋标准溶液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为供试品溶液。共制备6份，测定吸光度，计算回收率，结果见表5。
表5 胶体果胶铋胶囊(100mg规格)回收率测定结果
取胶体果胶铋胶囊(50mg规格) 内容物约10mg，精密称定，置塑料离心管中，精密加入5%乙醇溶液2.95ml，振摇分散，加入无水乙醇1.05ml，振摇溶散均匀混匀，以12000转/min的转速离心30min以上。精密量取上清液2ml，再精密加入铋标准溶液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，作为供试品溶液。共制备6份，测定吸光度，计算回收率，结果见表6。
表6 胶体果胶铋胶囊(50mg规格)回收率测定结果
测定结果显示本发明方法回收率较好，测定准确性良好。
实施例16：不同静置时间对胶体果胶铋原料游离铋含量测定结果的影响。
1、取胶体果胶铋粉末约0.5g，精密称定，置200ml容量瓶中，加水至刻度，强力振摇，使均匀分散成胶态溶液，分别于1min、10min、20min、40min、60min、90min、120min取上述胶态溶液4ml，以12000转/min的转速高速离心30min，再精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋含量，其值分别为0.71%、0.81%、0.95%、1.02%、1.13%、1.21%、1.23%。
2、取胶体果胶铋粉末约0.5g，精密称定，置200ml容量瓶中，加10%乙醇溶液至刻度，强力振摇，使均匀分散成胶态溶液，分别于1min、10min、20min、40min、60min、90min、120min取上述胶态溶液4ml，以12000转/min的转速高速离心30min，再精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋含量，其值分别为0.69%、0.70%、0.72%、0.75%、0.76%、0.79%、0.81%。
3、取胶体果胶铋粉末约0.5g，精密称定，置200ml容量瓶中，加5%乙醇溶液147.37ml振摇分散，加无水乙醇至刻度，强力振摇，使均匀分散成胶态溶液，分别于1min、10min、20min、40min、60min、90min、120min取上述胶态溶液4ml，以12000转/min的转速高速离心30min，再精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋含量，其值分别为0.70%、0.72%、0.76%、0.79%、0.80%、0.81%、0.82%。
测定结果显示：在控制时间1min以内，三种方法的测定结果基本一致。但以水为分散介质时，随着胶态溶液静置时间的延长，测定出的游离铋含量数值随之增大。而以乙醇水溶液作为分散介质时，游离铋含量数值随胶态溶液的静置时间变化缓慢，证明其胶体稳定性增加，游离铋含量的测定结果更加准确可靠，接近真实游离铋含量，有利于实验结果的重现性。
实施例17：不同静置时间对胶体果胶铋胶囊(规格100mg，以铋计)游离铋含量测定结果的影响。
1、取胶体果胶铋胶囊内容物约0.5g，精密称定，置200ml容量瓶中，加水至刻度，强力振摇，使均匀分散成胶态溶液，分别于1min、10min、20min、40min、60min、90min、120min取上述胶态溶液4ml，以12000转/min的转速高速离心30min，再精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋占标示量百分数，其值分别为4.92%、5.56%、6.26%、7.13%、7.54%、8.25%、8.46%。
2、取胶体果胶铋胶囊内容物约0.5g，精密称定，置200ml容量瓶中，加10%乙醇溶液至刻度，强力振摇，使均匀分散成胶态溶液，分别于1min、10min、20min、40min、60min、90min、120min取上述胶态溶液4ml，以12000转/min的转速高速离心30min，再精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋占标示量百分数，其值分别为4.73%、4.78%、4.84%、4.98%、5.23%、5.48%、5.55%。
3、取胶体果胶铋胶囊内容物约0.5g，精密称定，置200ml容量瓶中，加5%乙醇溶液147.37ml振摇分散，加无水乙醇至刻度，强力振摇，使均匀分散成胶态溶液，分别于1min、10min、20min、40min、60min、90min、120min取取上述胶态溶液4ml，以12000转/min的转速高速离心30min，再精密量取上清液2ml，置10ml容量瓶中，用显色溶液稀释至刻度，摇匀，在463nm波长处测定吸光度，计算游离铋占标示量百分数，其值分别为4.88%、4.92%、4.96%、5.17%、5.39%、5.62%、5.83%。
Claims (18)
- 一种测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法，是将胶体果胶铋或含胶体果胶铋制剂置于塑料离心管中，加入体积浓度7～20%的乙醇水溶液，振摇使溶散均匀，得到胶态溶液，离心取上清液，以络合滴定法或紫外分光光度法测定上清液中的铋含量，计算出胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。
- 根据权利要求1所述的方法，其特征是所述乙醇水溶液的体积浓度为10～16%。
- 一种测定胶体果胶铋或含胶体果胶铋制剂中游离铋的方法，是将胶体果胶铋或含胶体果胶铋制剂置于塑料离心管中，加入体积浓度不超过5%的乙醇水溶液振摇分散，再加入乙醇至分散液中乙醇体积浓度为30～50%，振摇使溶散均匀，得到胶态溶液，离心取上清液，以络合滴定法或紫外分光光度法测定上清液中的铋含量，计算出胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。
- 根据权利要求3所述的方法，其特征是所述分散液中乙醇的体积浓度为30～40%。
- 根据权利要求1～4任一所述的方法，其特征是将所述溶散均匀的胶态溶液以10000转/min以上的转速高速离心不少于5min。
- 根据权利要求5所述的方法，其特征是将所述胶态溶液以12000转/min的转速高速离心30min。
- 根据权利要求1～4任一所述的方法，其特征是将所述胶态溶液先以7000～10000转/min的转速高速离心不少于5min，再将离心液以0.1μm以下的滤膜过滤。
- 根据权利要求7所述的方法，其特征是将所述胶态溶液以8000转/min的转速离心10min。
- 根据权利要求1～4任一所述的方法，其特征是将所述胶态溶液先以3000～7000转/min的转速离心不少于10min，取离心液与低碳醇等比例混合，再以5000～7000转/min的转速离心不少于10min。
- 根据权利要求9所述的方法，其特征是所述两次离心均以6000转/min的转速离心10min。
- 根据权利要求9或10所述的方法，其特征是所述的低碳醇是乙醇、甲醇或异丙醇。
- 根据权利要求1～4任一所述的方法，其特征是将所述胶态溶液先以3000～7000转/min的转速离心不少于10min，将离心液与低碳醇等比例混合，再以3000～7000转/min的转速离心不少于10min，将离心液以0.1μm以下的滤膜过滤。
- 根据权利要求12所述的方法，其特征是所述的低碳醇是乙醇、甲醇或异丙醇。
- 根据权利要求1～4任一所述的方法，其特征是将胶体果胶铋或含胶体果胶铋制剂加一定乙醇水溶液制成含胶体果胶铋0.03～3mg/ml的胶态溶液。
- 根据权利要求1～4任一所述的方法，其特征是将上清液以柠檬酸或抗坏血酸与碘化钾的酸性显色溶液显色，在380～470nm波长处测定溶液的吸光度，与相同条件下已知浓度铋对照品溶液的吸光度比较，计算胶体果胶铋或含胶体果胶铋制剂中的游离铋含量。
- 根据权利要求15所述的方法，其特征是将所述用于测定吸光度的溶液稀释至溶液中的铋浓度为0.1～50μg/ml。
- 根据权利要求15所述的方法，其特征是所述的显色溶液为水溶液或0.2～2mol/L硝酸或醋酸溶液，并含有柠檬酸或抗坏血酸0.5～10wt%，碘化钾2.5～25wt%。
- 根据权利要求15所述的方法，其特征是所述的显色溶液为水溶液或1mol/L的硝酸或醋酸溶液，并含有柠檬酸或抗坏血酸2.5wt%，碘化钾12.5wt%。
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| CN114129532B (zh) * | 2021-12-10 | 2023-09-19 | 丽珠集团丽珠制药厂 | 一种枸橼酸铋钾制剂 |
| CN115739800A (zh) * | 2022-11-16 | 2023-03-07 | 中广核研究院有限公司 | 材料表面凝固铅铋的清洗装置和清洗方法 |
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| CN110146500A (zh) | 2019-08-20 |
| JP6942263B2 (ja) | 2021-09-29 |
| AU2019218185B2 (en) | 2021-11-25 |
| JP2021513079A (ja) | 2021-05-20 |
| CN110146500B (zh) | 2021-07-23 |
| AU2019218185A1 (en) | 2020-09-24 |
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