CN104678017A - Method for detecting organic-solvent residues in dabigatran etexilate - Google Patents
Method for detecting organic-solvent residues in dabigatran etexilate Download PDFInfo
- Publication number
- CN104678017A CN104678017A CN201510078256.9A CN201510078256A CN104678017A CN 104678017 A CN104678017 A CN 104678017A CN 201510078256 A CN201510078256 A CN 201510078256A CN 104678017 A CN104678017 A CN 104678017A
- Authority
- CN
- China
- Prior art keywords
- acetone
- ethyl acetate
- ethanol
- tetrahydrofuran
- reference substance
- 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.)
- Pending
Links
Landscapes
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention relates to a method for detecting organic-solvent residues in dabigatran etexilate, and particularly relates to a method for simultaneously detecting residues of alcohol, acetone, ethyl acetate and tetrahydrofuran in dabigatran etexilate by gas chromatography. An external standard method is adopted for simultaneously detecting the amount of the residues of four types of organic solvents in the dabigatran etexilate, and the chromatographic conditions are as follows: a chromatographic column is in the type of Agilent DB-1301 (30m*0.32mm*0.25microns), the column temperature is increased by programming, the initial temperature is 40 DEG C, the maintaining time is 6 minutes, then the temperature is increased to be 180 DEG C at a speed of 50 DEG C/min and is maintained for 10 minutes, the temperature of a sample inlet is 200 DEG C, the detection temperature is 250 DEG C, carrier gas is N2, the flow is 2ml/min, a headspace sampling method is adopted, the balance time is 30 minutes and the balance temperature is 90 DEG C. The method is high in sensitivity, good in repeatability and high in accuracy, and is suitable for detecting the organic-solvent residues in the dabigatran etexilate.
Description
Technical field
The present invention relates to a kind of method detecting organic solvent residual in dabigatran etcxilate, especially relate to and detect the residual method of ethanol in dabigatran etcxilate, acetone, ethyl acetate, tetrahydrofuran by gas chromatography simultaneously, belong to Pharmaceutical Analysis detection field.
Background technology
Dabigatran etcxilate (dabigatran etexilate), commodity are called Pradaxa, it is the novel anticoagulation medicine with various features developed by German Boehringer Ingelheim company, dabigatran etcxilate is the pro-drug of dabigatran, be converted into activated dabigatran in vivo, the latter plays anticoagulation effect by direct Trombin inhibiting.Dabigatran etcxilate can be used for the secondary prevention of knee joint and the prevention of deep venous thrombosis after primary hip replacement surgery embolism, DVT embolotherapy, auricular fibrillation, coronary events, has fixed dosage administration and without the need to multinomial advantages such as Laboratory Monitorings.
Residual solvent in medicine refer to bulk drug, preparation produce in use the organic solvent but do not removed completely.If the residual organic solvent concentration contained in medicine is higher than safety value, after patient takes, harm can be produced to human body.In the governing principle of International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use (ICH), the solvent commonly used in pharmaceutical production is divided into 4 classes according to the extent of injury, and defines the limit value of often kind of solvent.China's version pharmacopeia in 2010 also specify in " project that should check with duration of storage Mass Control in process of production ", need to check harmful organic solvent limit, be respectively not higher than 0.5% to ethanol, acetone, ethyl acetate, tetrahydrofuran bound requirements, 0.5%, 0.5%, 0.072%.
The present invention is directed in dabigatran etcxilate, the ethanol introduced by synthesis technique, acetone, ethyl acetate, tetrahydrofuran 4 kinds of organic solvent residuals, utilize vapor-phase chromatography, and select the content simultaneously detecting these four kinds of organic solvents under suitable chromatographic condition.
Summary of the invention
Technical matters to be solved by this invention is, a kind of method detecting organic solvent residual in dabigatran etcxilate is provided, utilize vapor-phase chromatography easy, detect the ethanol be present in dabigatran etcxilate, acetone, ethyl acetate, tetrahydrofuran 4 kinds of Determination of Residual Organic Solvents fast and accurately simultaneously.
The present invention is solved the problems of the technologies described above by following technical proposal.
Detect a method for organic solvent residual in dabigatran etcxilate, detect ethanol in dabigatran etcxilate, acetone, ethyl acetate, tetrahydrofuran 4 kinds of Determination of Residual Organic Solvents by gas chromatography, its step is specific as follows simultaneously.
1. chromatographic condition
Chromatographic column: Agilent DB-1301 (30m × 0.32mm × 0.25 μm); Column temperature: temperature programme, initial temperature is 40 DEG C, and keep 6min, then temperature is with 50 DEG C/min ramp to 180 DEG C, keeps 10min; Injector temperature: 200 DEG C; Detected temperatures: 250 DEG C; Carrier gas: N
2, flow 2ml/min; Input mode: headspace injection method; Equilibration time: 30min; Equilibrium temperature: 90 DEG C.
2. sample determination, adopt external standard method, its concrete steps are as follows.
(1) system suitability
Get ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution and four mixing reference substance solution, respectively sample introduction, draws collection of illustrative plates.
(2) precision test
Get ethanol respectively, acetone, ethyl acetate, tetrahydrofuran reference substance stock solution insert same measuring bottle, after DMF dilution, continuous sample introduction 6 times, records the relative standard deviation RSD of each reference substance peak area.
(3) linear test
Get ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution respectively, after equal proportion dilution, sample introduction, with the peak area of ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance for ordinate, with four concentration for horizontal ordinate sets up linear regression curves.
(4) recovery test
Get dabigatran etcxilate appropriate, precision weighing, adds ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution respectively as recovery sample solution, sample introduction, and record chromatogram, calculates the recovery.
Recovery %=(measured amount-sample size)/addition × 100%
(5) detectability and quantitative limit test
Use DMF alcohol,diluted, acetone, ethyl acetate, tetrahydrofuran reference substance solution successively respectively, calculate detectability with signal to noise ratio (S/N ratio) S/N=3, limit with signal to noise ratio (S/N ratio) S/N=10 calculation in quantity.
(6) sample survey
Get dabigatran etcxilate appropriate, precision weighing, add N, dinethylformamide dissolves makes need testing solution, ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution and need testing solution be sample introduction respectively, record chromatogram, by external standard method with the content of ethanol, acetone, ethyl acetate, tetrahydrofuran in calculated by peak area dabigatran etcxilate.
The invention has the advantages that:
(1) adopt vapor-phase chromatography to detect ethanol, acetone, ethyl acetate, content of tetrahydrofuran, highly sensitive, reproducible, precision is high simultaneously.
(2) the inventive method is applicable to the residual detection of ethanol in dabigatran etcxilate, acetone, ethyl acetate, tetrahydrofuran.
Accompanying drawing explanation
Fig. 1 Ethanol System compatibility test gas chromatogram (1. ethanol; 2.N, dinethylformamide)
Fig. 2 acetone system suitability test gas chromatogram (1. acetone; 2.N, dinethylformamide)
Fig. 3 ethyl acetate system suitability test gas chromatogram (1. ethyl acetate; 2.N, dinethylformamide)
Fig. 4 tetrahydrofuran system suitability test gas chromatogram (1. tetrahydrofuran; 2.N, dinethylformamide)
Fig. 5 ethanol, acetone, ethyl acetate, tetrahydrofuran commingled system compatibility test gas chromatogram (1. ethanol; 2. acetone; 3. ethyl acetate; 4. tetrahydrofuran; 5.N, dinethylformamide)
Embodiment
Embodiment
1. instrument and reagent
Instrument: Agilent6890 gas chromatograph, detecting device FID; Agilent chromatographic work station; Reagent: agents useful for same is chromatographically pure.
2. chromatographic condition
Chromatographic column: Agilent DB-1301 (30m × 0.32mm × 0.25 μm); Column temperature: temperature programme, initial temperature is 40 DEG C, and keep 6min, then temperature is with 50 DEG C/min ramp to 180 DEG C, keeps 10min; Injector temperature: 200 DEG C; Detected temperatures: 250 DEG C; Carrier gas: N
2, flow 2ml/min; Input mode: headspace injection method; Equilibration time: 30min; Equilibrium temperature: 90 DEG C.
3. solution preparation
Precision takes ethanol, acetone, ethyl acetate, tetrahydrofuran each 500mg, 500mg, 500mg, 72mg, add N, dinethylformamide is dissolved in 100ml measuring bottle, making concentration is respectively containing ethanol 5mg, acetone 5mg, ethyl acetate 5mg, tetrahydrofuran 0.72mg solution in every 1ml, as the reference substance stock solution of ethanol, acetone, ethyl acetate, tetrahydrofuran.
Precision measures above-mentioned stock solution 10ml and inserts 100ml measuring bottle, add N, dinethylformamide is to scale, shake up, making concentration is respectively containing ethanol 0.5mg, acetone 0.5mg, ethyl acetate 0.5mg, tetrahydrofuran 0.072mg solution in every 1ml, as ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution.
Get ethanol, acetone, ethyl acetate, each 10ml of tetrahydrofuran reference substance stock solution, mix the mixing reference substance solution making four.
4. sample determination
(1) system suitability
Precision measures ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution, mixing reference substance solution, respectively gets 5ml, headspace sampling.
Under above-mentioned chromatographic condition, each component can be separated preferably, and each component retention time and degree of separation are in table 1, and accompanying drawing 1 ~ 5 is shown in by system suitability collection of illustrative plates.
The each component retention time of table 1 and degree of separation measurement result
(2) precision test
Precision measures ethanol, acetone, ethyl acetate, each 10ml of tetrahydrofuran reference substance stock solution insert same 100ml measuring bottle, adds DMF to scale, shakes up, get 5ml headspace sampling.Continuous sample introduction 6 pin, the RSD of each reference substance peak area of compute is in table 2.Result shows, RSD is all within 5%.
Table 2 precision test data result (n=6)
(3) linear test
Precision measures ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance stock solution, and get 5ml respectively, 7.5ml, 12.5ml, 15ml insert 100mL measuring bottle, add DMF to scale, shake up, as a series of linear test solution.Headspace sampling, each solution continuous sample introduction 2 times.With reference substance peak area for ordinate, ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance concentration are that horizontal ordinate sets up linear regression line.Measurement result is in table 3.
Table 3 linear test measurement result
(4) recovery test
Precision weighing dabigatran etcxilate 500mg totally 9 parts, add respectively ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance stock solution 8,10,12ml inserts 100ml measuring bottle, adds N, dinethylformamide is to scale, shake up, as recovery sample solution, get 5ml headspace sampling.Record chromatogram, calculates the recovery by measured amount and addition.The acceptable recovery should at 90% ~ 110% (100% ± 10%).Measurement result is in table 4.
Recovery %=(measured amount-sample size)/addition × 100%
Table 4 recovery test measurement result
(5) detectability and quantitative limit test
Calculate detectability with signal to noise ratio (S/N ratio) S/N=3, with signal to noise ratio (S/N ratio) S/N=10 calculation in quantity limit, use the reference substance stock solution of DMF alcohol,diluted, acetone, ethyl acetate, tetrahydrofuran successively respectively.Get 5ml headspace sampling.Record chromatogram, detectability and quantitative limit measurement result are in table 5.
Table 5 ethanol, acetone, ethyl acetate, tetrahydrofuran detectability, quantitative limit result
(6) sample survey result
Get dabigatran etcxilate, accurately weighed, add DMF and dissolve and make containing 100mg solution in every 1ml, as need testing solution.Accurate absorption ethanol, acetone, ethyl acetate, each 10ml of tetrahydrofuran reference substance stock solution, add DMF and be settled to 100ml measuring bottle, in contrast product solution.Accurate draw test sample and each 5ml of reference substance solution, headspace sampling, record chromatogram, by external standard method with calculated by peak area, 0.5% must not be crossed containing ethanol, acetone must not cross 0.5%, ethyl acetate must not cross 0.5%, tetrahydrofuran must not cross 0.072%.
The residual solvent of sample is detected, ethanol 0%, acetone 0.03%, ethyl acetate 0%, tetrahydrofuran 0% according to said method.
Claims (3)
1. one kind is detected the method for organic solvent residual in dabigatran etcxilate, detect with GC-External Standard method, it is characterized in that, detect ethanol in dabigatran etcxilate, acetone, ethyl acetate, tetrahydrofuran 4 kinds of Determination of Residual Organic Solvents simultaneously, wherein, chromatographic condition is: mm × 0.25 μm, chromatographic column Agilent DB-1301(30 m × 0.32), column temperature program heats up, initial temperature 40 DEG C, keeps 6 min, and then temperature is with 50 DEG C/min ramp to 180 DEG C, keep 10 min, injector temperature 200 DEG C, detected temperatures 250 DEG C, carrier gas N
2, flow 2 ml/min, adopts the input mode of headspace injection method, equilibration time 30 min, equilibrium temperature 90 DEG C; The step of sample determination is:
Get ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution and four mixing reference substance solution, respectively sample introduction, draws collection of illustrative plates;
Get ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution respectively, after equal proportion dilution, sample introduction, with the peak area of ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance for ordinate, with four concentration for horizontal ordinate sets up linear regression curves;
Get dabigatran etcxilate appropriate, precision weighing, adds ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution respectively as recovery sample solution, sample introduction, and record chromatogram, calculates the recovery;
Recovery %=(measured amount-sample size)/addition × 100%
Detectability and quantitative limit test, use successively respectively
n,
n-dimethyl formamide alcohol,diluted, acetone, ethyl acetate, tetrahydrofuran reference substance solution, calculate detectability with signal to noise ratio (S/N ratio) S/N=3, limit with signal to noise ratio (S/N ratio) S/N=10 calculation in quantity;
Get dabigatran etcxilate appropriate, precision weighing, adds
n,
n-dimethyl formamide dissolves makes need testing solution, ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution and need testing solution be sample introduction respectively, record chromatogram, by external standard method with the content of ethanol, acetone, ethyl acetate, tetrahydrofuran in calculated by peak area dabigatran etcxilate.
2. the method for organic solvent residual in detection dabigatran etcxilate according to claim 1, it is characterized in that, dabigatran etcxilate is sample; Ethanol described in preparation, acetone, ethyl acetate, tetrahydrofuran reference substance solution, get ethanol, acetone, ethyl acetate, each 500 mg of tetrahydrofuran, 500 mg, 500 mg, 72 mg, add
n,
n-dimethyl formamide is dissolved in 100 ml measuring bottles, in contrast product stock solution; Precision measures above-mentioned stock solution 10 ml and inserts 100 ml measuring bottles, adds
n,
n-dimethyl formamide, to scale, shakes up, and making concentration is respectively containing the solution of ethanol 0.5 mg, acetone 0.5 mg, ethyl acetate 0.5 mg, tetrahydrofuran 0.072 mg in every 1 ml, as ethanol, acetone, ethyl acetate, tetrahydrofuran reference substance solution.
3. the method for organic solvent residual in detection dabigatran etcxilate according to claim 1, it is characterized in that the preparation of the mixing reference substance solution of described ethanol, acetone, ethyl acetate, tetrahydrofuran, get ethanol, acetone, ethyl acetate, each 10 ml of tetrahydrofuran reference substance stock solution respectively, mix the mixing reference substance solution making four.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510078256.9A CN104678017A (en) | 2015-02-12 | 2015-02-12 | Method for detecting organic-solvent residues in dabigatran etexilate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510078256.9A CN104678017A (en) | 2015-02-12 | 2015-02-12 | Method for detecting organic-solvent residues in dabigatran etexilate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104678017A true CN104678017A (en) | 2015-06-03 |
Family
ID=53313363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510078256.9A Pending CN104678017A (en) | 2015-02-12 | 2015-02-12 | Method for detecting organic-solvent residues in dabigatran etexilate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104678017A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105067724A (en) * | 2015-08-05 | 2015-11-18 | 山东省药学科学院 | Method for detecting organic solvent residue in Cetilistat |
| CN107966498A (en) * | 2016-10-18 | 2018-04-27 | 湖北生物医药产业技术研究院有限公司 | It is a kind of to detect method of the Chinese mugwort for Larry dissolvent residual in this |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040076387A (en) * | 2003-02-25 | 2004-09-01 | 한국과학기술연구원 | Improved solid phase microextraction fiber, preparation method thereof and determination method of alkylphenols and bisphenol-a in water samples with the spme fiber |
| CA2565224A1 (en) * | 2004-05-06 | 2005-11-17 | Chiron Corporation | Methods and systems for detection of macrolides |
-
2015
- 2015-02-12 CN CN201510078256.9A patent/CN104678017A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040076387A (en) * | 2003-02-25 | 2004-09-01 | 한국과학기술연구원 | Improved solid phase microextraction fiber, preparation method thereof and determination method of alkylphenols and bisphenol-a in water samples with the spme fiber |
| CA2565224A1 (en) * | 2004-05-06 | 2005-11-17 | Chiron Corporation | Methods and systems for detection of macrolides |
Non-Patent Citations (4)
| Title |
|---|
| 冯光玲等: "毛细管气相色谱法测定依诺昔酮原料药中6种有机溶剂残留量", 《中国药房》 * |
| 叶琳: "顶空气相色谱法测定盐酸纳美芬的残留溶剂", 《中国生化药物杂志》 * |
| 游飞明: "顶空气相色谱法测定头抱曲松钠中多种溶剂残留量", 《福建分析测试》 * |
| 陆烨等: "毛细管气相色谱法测定13种有机溶剂残留", 《复旦学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105067724A (en) * | 2015-08-05 | 2015-11-18 | 山东省药学科学院 | Method for detecting organic solvent residue in Cetilistat |
| CN107966498A (en) * | 2016-10-18 | 2018-04-27 | 湖北生物医药产业技术研究院有限公司 | It is a kind of to detect method of the Chinese mugwort for Larry dissolvent residual in this |
| CN107966498B (en) * | 2016-10-18 | 2021-06-22 | 湖北生物医药产业技术研究院有限公司 | Method for detecting solvent residue in Idelalis |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104655751B (en) | A kind of detect the method for organic solvent residual in dapoxetine | |
| CN105067724B (en) | A kind of detect the method for organic solvent residual in Cetilistat | |
| CN105717230B (en) | A kind of method of organic solvent residual in detection Favipiravir | |
| CN105203658B (en) | The detection method of residual solvent in a kind of Ezetimibe | |
| CN106018586A (en) | Method for simultaneously detecting seven sleep chemical medicines | |
| CN106706785A (en) | Method for detecting related substances in irbesartan hydrochlorothiazide tablets by adopting high performance liquid chromatography | |
| CN104865336B (en) | Method for detecting related substances in aprepitant by high performance liquid chromatography | |
| CN107860826A (en) | The method that residual solvent in Ezetimibe bulk drug is determined using headspace gas chromatography | |
| CN103698424B (en) | Detecting method of detecting organic solvent in slightly-soluble aluminum salt drug | |
| CN111521698B (en) | Method for detecting residual solvent in setastine hydrochloride raw material medicine | |
| CN105388223B (en) | The assay method of residual solvent in a kind of Decitabine intermediate | |
| CN113791148A (en) | Gas chromatography for determining residual quantity of organic solvent in parecoxib sodium raw material medicine | |
| CN106146332A (en) | Separate and measure Linezolid raw material X3 and the method for process contaminants X2 thereof | |
| CN103115969A (en) | Method for determining residual quantities of organic solvents in temozolomide hexyl ester | |
| CN105929045A (en) | Method for detecting residual organic solvent in cis-atracurium besilate | |
| CN104678017A (en) | Method for detecting organic-solvent residues in dabigatran etexilate | |
| CN106198819B (en) | The method of residual solvent in Headspace Gas Chromatography Xi Gelieting bulk pharmaceutical chemicals | |
| CN108593818A (en) | A kind of measurement efficient liquid-phase chromatography method of the Nicergoline in relation to substance | |
| CN104849388B (en) | Method for determining residual organic solvent content in arbidol hydrochloride crude drug | |
| CN106546689A (en) | A kind of HPLC analysis methods of amber love song Ge Lieting bulk drugs and its preparation enantiomter | |
| CN108760951A (en) | A method of a variety of residual organic solvents in detection Bioabsorbable Polyesters film | |
| CN105823845B (en) | The measure of capecitabine and its application | |
| CN113092640B (en) | Method for detecting benzyl alcohol and benzaldehyde in heparin sodium injection | |
| CN107917965A (en) | A kind of LC MS detection methods of 9 acrylic adenine | |
| CN108344811A (en) | The detection method of organic solvent residual in a kind of Injectable liposomal |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150603 |