CN104330501A - Method for detecting rivastigmine tartrate optical isomer by high performance liquid chromatography - Google Patents
Method for detecting rivastigmine tartrate optical isomer by high performance liquid chromatography Download PDFInfo
- Publication number
- CN104330501A CN104330501A CN201410699941.9A CN201410699941A CN104330501A CN 104330501 A CN104330501 A CN 104330501A CN 201410699941 A CN201410699941 A CN 201410699941A CN 104330501 A CN104330501 A CN 104330501A
- Authority
- CN
- China
- Prior art keywords
- mobile phase
- rivastigmine
- solution
- liquid chromatography
- hydrogentartrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- WUZDAYZPSDJPEP-LBPRGKRZSA-N C[C@@H](c1cc(OCNC)ccc1)N(C)C(C)=C Chemical compound C[C@@H](c1cc(OCNC)ccc1)N(C)C(C)=C WUZDAYZPSDJPEP-LBPRGKRZSA-N 0.000 description 1
Landscapes
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention mainly provides a method for detecting a rivastigmine tartrate optical isomer by a high performance liquid chromatography. According to the method, alpha1-acid glycoprotein is bonded with silica gel to form a chiral column of fillers (CHIRAL-AGP 4.0*150mm); the alpha1-acid glycoprotein is in a particle state under testing conditions, and different hydrogen bond bonding effect, lyophobic effect and the like can be generated by the alpha1-acid glycoprotein and the rivastigmine isomer, so that the resolution effect is realized; and a water-containing flow phase is used as a solvent so that rivastigmine tartrate and the isomer thereof can be sufficiently dissolved out and the recycling rate of a main drug can be up to be 100%.
Description
Technical field
The present invention relates to the method being detected rivastigmine-hydrogentartrate optical isomer by high performance liquid chromatography.
Background technology
Rivastigmine is a kind of acetylcholinesteraseinhibitors inhibitors of carbamic acid class, promote that cholinergic nerve conducts by delaying the degraded of the acetylcholine of cholinergic neuron release, the cognition dysfunction of patients with Alzheimer disease choline mediation can be improved, be used for the treatment of light, the symptom of moderate DAT, with existing anticholinesterase as Tacrine, donepezils etc. are compared, Rivastigmine has height brain regioselectivity and double inhibition effect, and it significantly can improve the daily life self-care ability of dementia, curative effect in social activities ability is also slightly better than donepezil.Its chemistry is by name: N-ethyl-N-methyl-carbamic acid 3-[(S)-1-(dimethylamino) ethyl] phenyl ester, and its structural formula is:
Containing 1 asymmetric carbon atom in this compound, pharmaceutically use its S isomeride, therefore, strictly should control the R type isomer impurities produced in Rivastigmine preparation process.In prior art, isomeride in rivastigmine-hydrogentartrate raw material detects and adopts normal phase chromatography, the chromatographic column of positive phase system is chiral chromatographic column Chiralcel OD-H, mobile phase is normal hexane-isopropyl alcohol-trifluoracetic acid-diethylamine (80:20:0.2:0.2), common solvent is isopropyl alcohol, ethanol and methyl alcohol etc., but empirical tests finds no matter this method uses which kind of solvent of the prior art or its mixed liquor that the rivastigmine-hydrogentartrate in capsule and isomeride thereof all cannot be made fully to be dissolved out, thus cause isomeride testing result inaccurate, and the main ingredient recovery is also lower.
Summary of the invention
The object of this invention is to provide a kind of reversed-phased high performace liquid chromatographic, detect the rivastigmine-hydrogentartrate enantiomter in capsule, with the purity of Quality control.This method employing α 1-acidoglycoprotein bonded silica gel is the chiral column of filling agent (CHIRAL-AGP4.0*150mm), α 1-acidoglycoprotein in particle state, can produce different Hydrogenbond effect, hydrophobic effect etc. from Rivastigmine isomeride thus reach fractionation effect under test condition of the present invention; Adopt moisture mobile phase to make solvent, rivastigmine-hydrogentartrate and isomeride thereof can be made fully to be dissolved out, and the main ingredient recovery can reach 100%.
The present invention mainly provides a kind of high performance liquid chromatography to detect the method for rivastigmine-hydrogentartrate optical isomer, specific as follows:
1) chromatographic condition: chromatographic column CHIRAL-AGP adopts α 1-acidoglycoprotein bonded silica gel to be filling agent; Adopting concentration to be 1-30mmol mixture of acetonitrile-phosphate buffer is mobile phase, and its ratio is 70 ~ 99: 30 ~ 1; Determined wavelength is 200nm ~ 240nm; Column temperature is 20 ~ 40 DEG C; Flow rate of mobile phase is 0.3 ~ 1.0ml/min;
2) preparation of sample solution: under getting assay item, content is appropriate, is placed in measuring bottle, and add mobile phase appropriate, the ultrasonic rivastigmine-hydrogentartrate that makes dissolves, and is diluted to scale, shakes up with mobile phase, filters, gets subsequent filtrate as need testing solution;
3) measure: precision measures need testing solution injection liquid chromatography, record chromatogram.
1-30mmol phosphate buffer described above is phosphate sodium dihydrogen buffer solution, and pH is 4.5-6.5, adopts 0.2M sodium hydroxide solution to carry out pH adjustment.
Described mobile phase phosphate sodium dihydrogen buffer solution-acetonitrile ratio is 85 ~ 99: 15 ~ 1, preferably 95 ~ 99: 5 ~ 1.
Described determined wavelength is 210nm ~ 220nm, preferred 214nm.
Described column temperature is 20 ~ 30 DEG C, preferably 25 DEG C.
Described flow rate of mobile phase is 0.4 ~ 0.6ml/min, preferred 0.5ml/min.
Technical scheme provided by the invention, in invention research process, shows the clear superiority of rivastigmine-hydrogentartrate isomeride detection side's science of law aspect in capsule.
The chromatographic condition that above-mentioned experiment draws by inventor has carried out Method validation.
1) specificity experiment
Location test: get raceme reference substance appropriate, adds mobile phase of the present invention and dissolves and quantitatively dilute the solution making about 0.1mg/ml.Separately get rivastigmine-hydrogentartrate capsule 's content appropriate, add the ultrasonic main ingredient that makes of mobile phase to dissolve, filter, getting subsequent filtrate dilution makes about containing the solution of Rivastigmine 0.5 μ g/ml, precision measures 10 μ l injection liquid chromatographies respectively, and result shows, and enantiomter peak and Rivastigmine peak flow out successively, the two degree of separation is greater than 2, and meet the requirements (table 1).
Table 1 location test result
Known impurities interference test: get raceme reference substance, tartrate reference substance, initiation material, intermediate 1, intermediate 2, intermediate 3, intermediate 4 (impurity D), impurity A, impurity B and impurity C respectively appropriate, add mobile phase dissolve respectively and dilute the solution making about 1.0mg/ml, precision measures each solution 10 μ l, injection liquid chromatography, under testing result is presented at this chromatographic condition, tartrate and each known impurities all do not disturb the mensuration (table 2) of enantiomter.
Table 2 location test result
| Sample | Retention time t R(min) |
| Impurity A | 3.784 |
| Impurity B | 15.604 |
| Impurity C | 4.957 |
| Impurity D | 8.302 |
| Impurity E | 7.566 |
| Impurity F | 8.602 |
| Impurity G | 8.337/10.943 |
| Impurity H | 2.947/3.604 |
| Tartrate | 5.073 |
| Enantiomter | 6.147 |
| Rivastigmine | 7.336 |
2) Linear Experiment result
Respectively with the sample size of isomeride and Rivastigmine for X-axis, peak area is Y-axis, and both linear relationships are as follows:
Rivastigmine isomeride: within the scope of 0-1.75ng, isomeride peak area (Y) and its quality (X, ng) are directly proportional, and linear equation is Y=5.828X+0.1, and related coefficient is 0.997, and linear relationship is good.
Rivastigmine: within the scope of 0-1.75ng, Rivastigmine peak area (Y) and its quality (X, ng) are directly proportional, and linear equation is Y=5.453X+0.128, and related coefficient is 0.998, and linear relationship is good.
3) detection line, quantitative limit
Get raceme reference substance solution, progressively dilute sample introduction, with signal to noise ratio (S/N ratio) (S/N) 3:1 for detectability, 10:1 is quantitative limit.Detection is limited to 0.15ng (being equivalent to 0.03% of need testing solution concentration), is less than reporting limit 0.05%; Quantitatively be limited to for 0.5 (being equivalent to 0.1% of need testing solution concentration), meet the requirements.
4) precision test
Get raceme reference substance appropriate, add mobile phase dissolve and dilute the solution making 5.6 μ g/ml, precision measures 10 μ l injection liquid chromatographies, record chromatogram, repeat sample introduction 6 times, result display raceme reference substance continuous sample introduction 6 times, isomeride peak and Rivastigmine peak-to-peak area RSD are all less than 2%, and this law precision better (table 3).
Table 3 sample introduction Precision test result
| Sample introduction | Isomeride peak area | Rivastigmine peak area |
| 1 | 89.069 | 86.653 |
| 2 | 89.250 | 88.597 |
| 3 | 89.212 | 90.273 |
| 4 | 89.461 | 91.610 |
| 5 | 88.720 | 90.001 |
| 6 | 89.865 | 90.284 |
| Average peak area | 89.263 | 89.570 |
| RSD(％) | 0.4％ | 1.9％ |
5) study on the stability result
Get the capsule sample content appropriate (about containing Rivastigmine 5mg) of 1.5mg, 3.0mg and 4.5mg tri-specifications respectively, put in 100ml measuring bottle, add mobile phase ultrasonic make main ingredient dissolve after be quantitatively diluted to scale, get subsequent filtrate as need testing solution, respectively at 0,1,2,4,8 and 12 hour sample introduction, observe content of isomer change.Result shows, and solution to be measured is in 12 hours, and significant change does not occur content of isomer, and need testing solution stablized (table 4) in 12 hours.
Table 4 need testing solution stability result
| Specification | 0hr | 1hr | 2hr | 4hr | 8hr | 12hr | Mean value |
| 1.5mg | 0.11 | 0.09 | 0.10 | 0.10 | 0.11 | 0.10 | 0.10 |
| 3.0mg | 0.09 | 0.09 | 0.09 | 0.11 | 0.11 | 0.10 | 0.10 |
| 4.5mg | 0.09 | 0.09 | 0.09 | 0.10 | 0.10 | 0.10 | 0.10 |
6) system robustness experiment
Get system suitability solution, parameter in suitable adjustment chromatographic system, as flow velocity, column temperature and mobile phase ratio, investigate the separation case after chromatographic condition change, after result display chromatographic condition small variations, isomeride peak and Rivastigmine peak degree of separation are all greater than 2, meet the requirements, and this method good tolerance (table 5) is described.
Table 5 system robustness test findings
This chromatographic process, has good specificity, linear, precision, stability and system robustness.
HPLC detection method of the present invention, fast, accurately can detect the rivastigmine-hydrogentartrate enantiomter in capsule on the one hand, improve the recovery, substantially increase the accuracy of detection, shorten analysis time, ensure that the quality controllable of Rivastigmine; On the other hand, the method has methodology meaning, and lower being convenient to of cost is promoted.
Accompanying drawing explanation
The testing result of optical isomer in rivastigmine-hydrogentartrate raw material under accompanying drawing 1 normal-phase chromatography condition
The testing result of optical isomer in rivastigmine-hydrogentartrate capsule under accompanying drawing 2 normal-phase chromatography condition
The testing result of rivastigmine-hydrogentartrate raw material light middle school isomeride under accompanying drawing 3 reverse-phase chromatography condition
The testing result of optical isomer in rivastigmine-hydrogentartrate capsule under accompanying drawing 4 reverse-phase chromatography condition
Embodiment
The detection of rivastigmine-hydrogentartrate optical isomer under embodiment 1 normal-phase chromatography condition
Chromatographic condition:
High performance liquid chromatograph: Shimadzu LC-20AB
Mobile phase: normal hexane-isopropyl alcohol-trifluoracetic acid-diethylamine (80:20:0.2:0.2)
Chromatographic column: chiral chromatographic column Chiralcel OD-H (0.46cm*25cm)
Determined wavelength: 214nm
Flow velocity: 0.5ml/min
Column temperature: 25 DEG C
Sample size: 10 μ l
Experimental procedure:
1) take rivastigmine-hydrogentartrate raw material 16mg, be placed in 10ml measuring bottle, it is appropriate to add isopropyl alcohol (or ethanol/methyl alcohol etc.), ultrasonic make main ingredient dissolve after, add mobile phase and be settled to scale, shake up, centrifugal, get supernatant as need testing solution 1.
2) rivastigmine-hydrogentartrate capsule 's content appropriate (about containing rivastigmine-hydrogentartrate raw material 16mg) is taken, be placed in 10ml measuring bottle, add isopropyl alcohol (or ethanol/methyl alcohol etc.) appropriate, ultrasonic make main ingredient dissolve after, add mobile phase and be settled to scale, shake up, centrifugal, get supernatant as need testing solution 2.
3) by test sample 1 and 2 (sampling amount ratio is 1:1) injection liquid chromatography, record testing result.
Testing result:
When isopropyl alcohol is as solvent, the main peak peak area of raw material and preparation is respectively 44474039 (Fig. 1) and 18609897 (Fig. 2).Therefore, when isopropyl alcohol is as solvent, 42% is only for the main ingredient extraction ratio in capsule 's content.
The detection of rivastigmine-hydrogentartrate optical isomer under embodiment 2 reverse-phase chromatography condition
Chromatographic condition:
High performance liquid chromatograph: Agilent 1260
Mobile phase: 20mM phosphate sodium dihydrogen buffer solution (adjusting pH to 5.0 with 0.1M sodium hydroxide solution)-acetonitrile (98:2)
Chromatographic column: CHIRAL AGP (0.4cm*15cm)
Determined wavelength: 214nm
Flow velocity: 0.5ml/min
Column temperature: 25 DEG C
Sample size: 10 μ l
Experimental procedure:
1) get rivastigmine-hydrogentartrate raw material and be about 10mg (being about equivalent to containing Rivastigmine raw material 6mg), put in 100ml measuring bottle, be dissolved in water and be quantitatively diluted to scale, shaking up, as need testing solution 1.
2) get capsule 's content appropriate (being about equivalent to containing Rivastigmine raw material 5mg), put in 100ml measuring bottle, add water appropriate, ultrasonic main ingredient is dissolved after, add water and be settled to scale, shake up, centrifugal, get supernatant as need testing solution 2.
3) need testing solution 1 and 2 (sampling amount ratio is 1.2) is got respectively, injection liquid chromatography, record chromatogram.
Testing result:
In need testing solution 1 and 2, main peak peak area is respectively 2801 (Fig. 3) and 2324 (Fig. 4), and peak area ratio is 1.2, consistent with sampling amount ratio, therefore under reverse-phase chromatography condition, the main ingredient extraction ratio in capsule 's content is 100%.
Claims (9)
1. high performance liquid chromatography detects a method for rivastigmine-hydrogentartrate optical isomer, it is characterized by:
1) chromatographic condition: chromatographic column CHIRAL-AGP adopts α 1-acidoglycoprotein bonded silica gel to be filling agent; Adopting concentration to be 1-30mmol mixture of acetonitrile-phosphate buffer is mobile phase, and its ratio is 70 ~ 99: 30 ~ 1; Determined wavelength is 200nm ~ 240nm; Column temperature is 20 ~ 40 DEG C; Flow rate of mobile phase is 0.3 ~ 1.0ml/min;
2) preparation of sample solution: under getting assay item, content is appropriate, puts in measuring bottle, and add mobile phase appropriate, the ultrasonic rivastigmine-hydrogentartrate that makes dissolves, with mobile phase dilution, shakes up, filters, get subsequent filtrate as need testing solution;
3) measure: precision measures need testing solution injection liquid chromatography, record chromatogram.
2. method according to claim 1, it is characterized in that described 1-30mmol phosphate buffer is phosphate sodium dihydrogen buffer solution, pH is 4.5-6.5, adopts 0.2M sodium hydroxide solution to regulate.
3. method according to claim 2, is characterized in that described mobile phase phosphate sodium dihydrogen buffer solution-acetonitrile ratio is 85 ~ 99: 15 ~ 1.
4. method according to claim 3, is characterized in that described mobile phase phosphate sodium dihydrogen buffer solution-acetonitrile ratio is 95 ~ 99: 5 ~ 1.
5. method according to claim 1, is characterized in that determined wavelength is 210nm ~ 220nm.
6. method according to claim 5, is characterized in that determined wavelength is 214nm.
7. method according to claim 1, is characterized in that column temperature is 20 ~ 30 DEG C, preferably 25 DEG C.
8. method according to claim 1, is characterized in that flow rate of mobile phase is 0.4 ~ 0.6ml/min.
9. method according to claim 8, is characterized in that flow rate of mobile phase is 0.5ml/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410699941.9A CN104330501B (en) | 2014-11-27 | 2014-11-27 | A kind of high performance liquid chromatography detects the method for rivastigmine-hydrogentartrate optical isomer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410699941.9A CN104330501B (en) | 2014-11-27 | 2014-11-27 | A kind of high performance liquid chromatography detects the method for rivastigmine-hydrogentartrate optical isomer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104330501A true CN104330501A (en) | 2015-02-04 |
| CN104330501B CN104330501B (en) | 2016-01-20 |
Family
ID=52405269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410699941.9A Active CN104330501B (en) | 2014-11-27 | 2014-11-27 | A kind of high performance liquid chromatography detects the method for rivastigmine-hydrogentartrate optical isomer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104330501B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105116062A (en) * | 2015-06-27 | 2015-12-02 | 万特制药(海南)有限公司 | Method for separation determination of impurity content in rivastigmine tartrate |
| CN108226319A (en) * | 2016-12-22 | 2018-06-29 | 亚宝药业集团股份有限公司 | A kind of method for detecting optical isomer in Rivastigmine patch |
-
2014
- 2014-11-27 CN CN201410699941.9A patent/CN104330501B/en active Active
Non-Patent Citations (5)
| Title |
|---|
| ANDREA KAVALIROVA等: "Enantiomeric analysis of rivastigmine in pharmaceuticals by cyclodextrin-modified capillary zone electrophoresis", 《ANALYTICA CHIMICA ACTA》, vol. 525, 3 September 2004 (2004-09-03), pages 43 - 51, XP 004594305, DOI: doi:10.1016/j.aca.2004.08.026 * |
| M.K. SRINIVASU等: "A validated chiral liquid chromatographic method for the enantiomeric separation of Rivastigmine hydrogen tartarate, a cholinesterase inhibitor", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》, vol. 38, 2 February 2005 (2005-02-02), pages 320 - 325 * |
| SAADET DERMIş: "Voltammetric Behaviour of Rivastigmine Hydrogen Tartrate and its Determination in Capsule Dosage Form", 《HACETTEPE UNIVERSITY JOURNAL OF THE FACULTY OF PHARMACY》, vol. 26, no. 1, 31 January 2006 (2006-01-31), pages 1 - 12 * |
| 刘敏等: "重酒石酸卡巴拉汀和其消旋体的合成,及HPLC法拆分", 《海南省药学会2009年学术会议论文集》, 1 October 2009 (2009-10-01), pages 67 - 71 * |
| 王芳侠等: "HPLC法测定重酒石酸卡巴拉汀片含量", 《中国新药杂志》, vol. 17, no. 19, 31 December 2008 (2008-12-31), pages 1700 - 1702 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105116062A (en) * | 2015-06-27 | 2015-12-02 | 万特制药(海南)有限公司 | Method for separation determination of impurity content in rivastigmine tartrate |
| CN108226319A (en) * | 2016-12-22 | 2018-06-29 | 亚宝药业集团股份有限公司 | A kind of method for detecting optical isomer in Rivastigmine patch |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104330501B (en) | 2016-01-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021217887A1 (en) | Testing method for potential mutagenic impurities in pitavastatin calcium tablet | |
| CN103353491B (en) | A method of with liquid chromatography for separating and determining alogliptin benzoate raw material and its preparation | |
| CN104391058B (en) | Ah method replaces the detection method of Buddhist nun and isomeride thereof | |
| CN106841413B (en) | Ticagrelor enantiomer and diastereoisomer separation and detection method | |
| CN104330501B (en) | A kind of high performance liquid chromatography detects the method for rivastigmine-hydrogentartrate optical isomer | |
| US10047068B2 (en) | Optical resolution method of lenalidomide | |
| CN110501441A (en) | Detection method in relation to substance in a kind of paracetamol tablets | |
| CN104777243B (en) | It is a kind of at the same determine the tuber of pinellia in organic acid, nucleosides and ephedrine HPLC methods | |
| US9856207B2 (en) | Process for the production of ralfinamide salts substantially free from impurities having genotoxic effects | |
| WO2015178460A1 (en) | Method for pretreatment and method for analysis of lenalidomide in biological sample | |
| CN107941970A (en) | The method for separating and detecting of D D-pHPGs and its enantiomter | |
| CN105301159A (en) | High performance liquid chromatography analysis method of sirolimus | |
| CN108318610A (en) | Analysis method in relation to substance in a kind of alogliptin benzoate raw material and its preparation | |
| CN109655544B (en) | Quality control method of metformin hydrochloride and preparation thereof | |
| CN102961378B (en) | A kind of compound a-ketone acid sheet and its preparation method and detection method | |
| CN110927279B (en) | Method for separating imidapril hydrochloride related substances | |
| CN101609069A (en) | A kind of method of measuring Entecavir and Pharmaceutical composition related substance thereof with the HPLC method | |
| CN107219312B (en) | A method of detection Tedizolid Phosphate isomer impurities | |
| CN109557218B (en) | Chromatographic analysis method of AHU377 and isomers thereof | |
| CN103512968A (en) | Method for separating and measuring L-arginine levo-nadifloxacin and optical isomer thereof through liquid chromatography | |
| CN104458945A (en) | Separation and measurement method of besifloxacin hydrochloride and isomer of besifloxacin hydrochloride | |
| CN107870211A (en) | A kind of liquid-phase chromatography method of separation determination palonosetron Hcl | |
| CN106153756B (en) | High performance liquid chromatography for detecting rapamycin in everolimus | |
| CN106045901B (en) | The chiral separation method and compound paracetamol and amantadine hydrochloride preparations of chlorphenamine | |
| CN113740476A (en) | Method for detecting content of impurity L-2-aminobutanamide hydrochloride in brivaracetam drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: Cheng Wei Road Nanjing city Jiangsu province 210046 No. 9 Jiangsu Xianlin University Life Science and Technology Innovation Park F6 8 storey building in Jiangsu Zhengda Fenghai Pharmaceutical Co. Ltd. Patentee after: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd. Address before: Cheng Wei Road Nanjing city Jiangsu province 210046 No. 9 Jiangsu Xianlin University Life Science and Technology Innovation Park Patentee before: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd. |
|
| CP02 | Change in the address of a patent holder |
Address after: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd., No. 266, Nanxiang West Road, Dafeng District, Yancheng City, Jiangsu Province, 210046 Patentee after: JIANGSU CHIA TAI FENGHAI PHARMACEUTICAL Co.,Ltd. Address before: Cheng Wei Road Nanjing city Jiangsu province 210046 No. 9 Jiangsu Xianlin University Life Science and Technology Innovation Park F6 8 storey building in Jiangsu Zhengda Fenghai Pharmaceutical Co. Ltd. Patentee before: JIANGSU CHIA TAI FENGHAI PHARMACEUTICAL Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder |