CN101320014A - Analytical method for measuring raw medicine content of thiohydroxylamine tropine by non-aqueous titrimetry - Google Patents
Analytical method for measuring raw medicine content of thiohydroxylamine tropine by non-aqueous titrimetry Download PDFInfo
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- CN101320014A CN101320014A CN 200810022165 CN200810022165A CN101320014A CN 101320014 A CN101320014 A CN 101320014A CN 200810022165 CN200810022165 CN 200810022165 CN 200810022165 A CN200810022165 A CN 200810022165A CN 101320014 A CN101320014 A CN 101320014A
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- tropine
- titration
- hydroxamamide
- content
- thiohydroxylamine
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- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 title claims abstract description 28
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 title claims abstract description 28
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 title claims abstract description 28
- 238000004448 titration Methods 0.000 title claims abstract description 28
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 19
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 title claims description 23
- 238000004458 analytical method Methods 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Substances CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003918 potentiometric titration Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 34
- 238000013459 approach Methods 0.000 claims description 6
- 239000012086 standard solution Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 abstract description 9
- 238000003908 quality control method Methods 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- HZLFSOZSLFKJKA-JSXRDJHFSA-N 2-[2-[[(1s,3s,4r,5r)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-4-yl]methyl-(2-sulfanylethyl)amino]ethylamino]ethanethiol Chemical compound C1([C@@H]2[C@H](CN(CCS)CCNCCS)[C@H]3CC[C@@H](C2)N3C)=CC=C(Cl)C=C1 HZLFSOZSLFKJKA-JSXRDJHFSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000000954 titration curve Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- -1 (2-mercapto ethyl) ethylene diamin Chemical compound 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 206010068100 Vascular parkinsonism Diseases 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 1
- 229930004006 tropane Natural products 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention discloses an analysis method for determining the hydroxamamide tropine raw drug content through a non-aqueous titration method and relates to the hydroxamamide tropine raw drug quality control technology field. The method for determining the content of hydroxamamide tropine is provided, the process of which is as follows: glacial acetic acid-acetic oxide is used as a solvent for the quantitative dissolution of the hydroxamamide tropine. Then, perrchloric acid titrating solution is sued as titrant, and a potentiometric titration method is adopted for the titration. The method has the advantages of small sample amount, simple operation, good precision, and the like, and can be applied to the routine analysis and the quality control of hydroxamamide tropine raw drugs.
Description
Technical field
A kind of analytical approach of measuring raw medicine content of thiohydroxylamine tropine by non-aqueous titrimetry relates to mercapto amine tropine bulk drug Quality Control Technology field.
Background technology
Technetium [
99mTc] mercapto amine tropine (
99mTc-TRODAT-1, the chinesization formal name used at school: technetium [
99mTc]-2 β-[N, N '-two (2-mercapto ethyl) ethylene diamin(e) base] methyl-3 β-(4-chlorphenyl) tropane is the radiopharmaceutical that last century, the nineties was succeeded in developing, it and dopamine transporter (DAT) have high specific and selectivity (Kung HF, et al., Eur J Nucl Med 1996,23:1527-30; Kung MP, et al., Eur J Nucl Med 1997,24:372-80), with this medicine is developer, in conjunction with widely used single photon emission computed tomography (SPECT) technology clinically, can provide valuable information for the diagnosis and the research of the spiritual class disease of many nerves.Vast amount of clinical is found both at home and abroad, uses
99mTc-TRODAT-1 carries out human brain DAT video picture, can be for providing the Clinics and Practices information of clinical value with dopaminergic system pathology diseases associated.As, to Parkinson's (PD) patient carry out video picture analysis clearly and diagnosis (Mozley PD, et al., J Nucl Med 2000,41:584-9); Can carry out early stage even subclinical phase diagnosis (Huang WS, et al., J Nucl Med 2001,42:1303-8 to PD; Chou KL, et al., Parkinsonism Relat Disord 2004,10:375-9); Can from video picture figure, distinguish the PD disease similar to PD intuitively with some other clinical symptoms, as vascular parkinsonism (Tzen KY, et al., J Nucl Med 2001,42:408-13), (Wang J such as essential tremor, et al., Acta Neurol Scand 2005,112:380-5; Kanyo B, et al., Ideggyogy Sz 2003,56:231-40); In addition,
99mTc-TRODAT-1 can be used for research and application (Krause KH, et al., Neurosci Biobehav Rev 2003, the 27:605-13 to diseases such as attention deficit hyperkinetic syndrome, Wilson diseases; Huang CC, et al., Can J Neurol Sci 2003,30:163-7).Safety research shows that this medicine is to people fool proof (Mozley PD, et al., J Nucl Med 1998,39:2069-76; Fang P, et al., NuclMed Biol 2000,27:69-75).
In view of
99mGood clinical value and the application prospect of Tc-TRODAT-1, all attach great importance to the research and the market development both at home and abroad to this medicine, clinical research before external GE company is going on the market to this medicine, China Taiwan Province has obtained listing permission, and area, domestic continent is the research work before stepping up to go on the market also.
Mercapto amine tropine (TRODAT-1) be used to prepare technetium [
99mTc] bulk drug of mercapto amine tropine, its purity to technetium [
99mTc] quality of mercapto amine tropine has crucial influence, TRODAT-1 carried out purity analysis also be
99mTherefore the routine work that must carry out when Tc-TRODAT-1 applies need set up a kind of method of fast and accurately analyzing bulk drug TRODAT-1 content.So far, domestic also do not have a bibliographical information to this.
Summary of the invention
The method that the purpose of this invention is to provide a kind of quick and accurate analysis bulk drug mercapto amine tropine content.In order in actual production the bulk drug mercapto amine tropine to be carried out quality control, we have set up a kind of method of measuring mercapto amine tropine content.
Technical scheme of the present invention: a kind of analytical approach of measuring raw medicine content of thiohydroxylamine tropine by non-aqueous titrimetry, analytic process is: with glacial acetic acid-acetic anhydride is solvent, quantitatively dissolve mercapto amine tropine, be titrant with the perchloric acid standard solution again, adopt potentiometric titration to carry out titration, graphing method is determined titration end-point, and calculates content.
The volume ratio that is used to dissolve the solvent acetic acid-acetic anhydride of mercapto amine tropine is 1: 9.
The concentration that is used for the perchloric acid standard solution of titration mercapto amine tropine is 0.02mol/L.
Beneficial effect of the present invention: the present invention provides a kind of method of measuring mercapto amine tropine content first, can be used for mercapto amine tropine is carried out conventional quality control, is domestic and international reported first.
Description of drawings
Fig. 1 titration curve.
Fig. 2 is used for determining the titration curve first order derivative figure of titration end-point.
Embodiment
Embodiment 1
0.02mol/L the preparation of perchloric acid titration liquid: get anhydrous glacial acetic acid 750mL, add perchloric acid (70~72%) 1.7mL, shake up, at room temperature slowly drip acetic anhydride 15.4mL, the limit edged shakes, and jolting is even again after adding, put cold, add anhydrous glacial acetic acid and make into 1000mL in right amount, shake up, place 24 hours standby.
The demarcation of perchloric acid titration liquid: be taken at 105 ℃ of about 32.0mg of benchmark Potassium Hydrogen Phthalate that are dried to constant weight, the accurate title, decide, add glacial acetic acid 2mL, heating makes dissolving, put cold, add acetic anhydride 18mL, decide with the perchloric acid titration drop, and titration results is proofreaied and correct with blank test according to potentiometric titration (two appendix VIIA of Chinese Pharmacopoeia version in 2005).Every 1mL perchloric acid titration liquid (0.02mol/L) is equivalent to the Potassium Hydrogen Phthalate of 4.084mg.According to the amount of taking of the consumption and the Potassium Hydrogen Phthalate of this liquid, the concentration of calculating this liquid promptly.
C=W/204 (V
Sample-V
Empty)
Wherein: V
SampleConsume the volume number (mL) of perchloric acid to terminal the time for the titration Potassium Hydrogen Phthalate; V
EmptyThe perchloric acid volume number (mL) that consumes to terminal the time for the titration blank; C is the concentration (mol/L) of perchloric acid; W is the Potassium Hydrogen Phthalate amount (mg) that takes by weighing.
Embodiment 3
The titration of mercapto amine tropine bulk drug: get the about 20.0mg of homemade TRODAT-1 hydrochloride (preparation method's reference: Fang Ping, et al., Chinese Journal of Pharmaceuticals 2000,31:244-247), the accurate title, decide, and adds glacial acetic acid 2mL, the stirring at normal temperature dissolving, add acetic anhydride 18mL, decide with the perchloric acid titration drop, and titration results is proofreaied and correct (two appendix VIIA of Chinese Pharmacopoeia version in 2005) with blank test according to potentiometric titration (two appendix VIIA of Chinese Pharmacopoeia version in 2005).Every 1mL perchloric acid titration liquid (0.02mol/L) is equivalent to the C of 3.58mg
21H
34ClN
3S
23HCl.
Content %=(the V of TRODAT-1
Sample-V
Empty) * C * 537/3W * 100%
Titration curve adopts the first order derivative method to determine titration end-point, as shown in Figure 2 as shown in Figure 1.
Wherein: V
SampleConsume the volume number (mL) of perchloric acid to terminal the time for the titration sample; V
EmptyThe perchloric acid volume number (mL) that consumes to terminal the time for the titration blank; C is the concentration (mol/L) of perchloric acid; W is the sample size (mg) that takes by weighing.
The precision test: precision takes by weighing equivalent TRODAT-1 hydrochloride, and METHOD FOR CONTINUOUS DETERMINATION 5 times, measurement result are that the content mean value of TRODAT-1 hydrochloride is 98.5%, and relative standard deviation (RSD) is 0.29%.See Table 1.Test findings shows, this method favorable reproducibility, and the precision height meets the quality control requirement of assay fully.
Table 1 mercapto amine tropine content is measured Precision test result
Claims (3)
1, a kind of analytical approach of measuring raw medicine content of thiohydroxylamine tropine by non-aqueous titrimetry, it is characterized in that analytic process is: with glacial acetic acid-acetic anhydride is solvent, quantitatively dissolve mercapto amine tropine, be titrant with the perchloric acid standard solution again, adopt potentiometric titration to carry out titration, graphing method is determined titration end-point, and calculates content.
2, analytical approach according to claim 1, the volume ratio that it is characterized in that being used to dissolving the solvent acetic acid-acetic anhydride of mercapto amine tropine is 1: 9.
3, analytical approach according to claim 1, the concentration that it is characterized in that being used for the perchloric acid standard solution of titration mercapto amine tropine is 0.02mol/L.
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CN1314456C (en) * | 2005-09-27 | 2007-05-09 | 江苏省原子医学研究所 | Medicament box of 2beta-[N,N'-di(2-mercaptoethyl) ethylene diamine] methyl-3 beta-(4- chlorphenyl) tropane |
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CN113884618A (en) * | 2021-08-04 | 2022-01-04 | 广东省科学院测试分析研究所(中国广州分析测试中心) | Method for determining content of organic alkali hydrohalite compound by non-aqueous titration method |
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