CN104237393B - The detection method of impurity in a kind of Penequine hydrochloride - Google Patents
The detection method of impurity in a kind of Penequine hydrochloride Download PDFInfo
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Abstract
The present invention discloses 2 kinds of detection methods containing the impurity of rubane in a kind of Penequine hydrochloride, and the method adopts the content of vapor-phase chromatography detection 3-quininone and 3-quinine alcohol impurity. Measure time, Penequine hydrochloride sample alkali organic solvent is dissolved so that it is in all hydrochlorides be changed into free alkali, nitrogen blows dry, then adds dimethyl formamide and is mixed with need testing solution; Impurity reference substance same treatment, is mixed with impurity reference substance solution. Get need testing solution, impurity reference substance solution direct injection respectively, gather color atlas, by external standard method with calculated by peak area foreign matter content. The method of the present invention have easy and simple to handle, highly sensitive, can quantitative assay, accuracy height, favorable reproducibility feature, effectively to control the quality product of Penequine hydrochloride, ensure clinical application safe and effective.
Description
Technical field
The present invention relates to the detection method of impurity in medicine, relate to the detection method of 3-quininone and 3-quinine alcohol in Penequine hydrochloride specifically.
Background technology
Penequine hydrochloride, chemical name: 3-(2-cyclopentyl-2-hydroxyl-2-phenyl ethoxy) quinuclidine hydrochloride. Chemical formula is
This strain new selective anticholinergic drug, enters in brain by hemato encephalic barrier. Its energy blockage of acetylcholine is to the agonism of M-ChR in brain and nAChR; Therefore, can anti-organophosphorus toxic poisoning short of money causes preferably maincenter toxicity symptom, as fainted from fear, maincenter respiratory and circulatory failure and dysphoria etc. Meanwhile, also there is stronger blockage of acetylcholine in periphery to the agonism of m receptor; Thus, can the poisoning muscarinic toxicity symptom caused of anti-organophosphorus poisonous substance (agricultural chemicals) short of money preferably, as bronchial muscular spasm and secretory product increase, perspire, curtain coating, miosis and gastrointestinal smooth myospasm or contraction etc. It can also increase respiratory rate and respiratory flow, due to this product to M2 acceptor without obvious effect, therefore is had no significant effect by heart rate; To periphery n receptor without obvious antagonistic action.
Penequine hydrochloride is clinical in anaesthetizing front administration to suppress sialisterium and air flue glandular secretion and the treatment of organophosphorus poisonous substance (agricultural chemicals) poisoning first-aid and poisoning later stage or Pseudocholinesterase (ChE) aging rear maintenance coromegine. Due to the curative effect that Penequine hydrochloride is definite, this medicine is used widely in clinical, wide market.
In the preparation process of Penequine hydrochloride, 3-quininone II (hereinafter referred to as impurity II) and 3-quinine alcohol III (hereinafter referred to as impurity III) are raw material important in its preparation process and intermediate. Meanwhile, the degraded product of Penequine hydrochloride in storage process also comprises impurity III. For guaranteeing the safe and effective of clinical application, it is necessary to the degradation impurity III in the impurity II, III introduced in Penequine hydrochloride preparation technology and storage process is carried out strict control.
At present, the first-selected high performance liquid chromatography (HPLC) of the conventional detection method of impurity of the drug, but, 3-quininone II and 3-quinine alcohol III do not retain in conventional reversed phase high efficiency liquid phase chromatographic column, itself is without uv-absorbing simultaneously, adopts high performance liquid chromatography UV-detector to be difficult to detect, it may also be useful to when evaporation photodetector and differential refraction detector, the detection sensitivity of impurity II, III is low, poor reproducibility. National drug standards WS1-(X-026)-2004Z have employed tlc to Penequine hydrochloride in impurity III detect, but tlc detection exists affects more, poor reproducibility, the unconspicuous shortcoming of colour developing by temperature, humidity, reagent type, some sample technology etc., detected result can only be reached sxemiquantitative, and operate miss is bigger simultaneously. This standard regulation impurity III detection limit is only 0.25% simultaneously, can not meet the requirement strictly controlled by medicine impurity day by day improved. Therefore, urgently need to set up a kind of easy and simple to handle, highly sensitive, can quantitative assay, accuracy height, favorable reproducibility Penequine hydrochloride in the detection method of impurity II, III.
Summary of the invention
For the deficiencies in the prior art, it is an object of the invention to set up the detection method of impurity II, III in a kind of Penequine hydrochloride, effectively to control the quality product of Penequine hydrochloride, ensure the safe and effective of clinical application. The present invention adopts the content of vapor-phase chromatography (GC) checked for impurities II, III, easy and simple to handle, highly sensitive, accuracy height, favorable reproducibility, and can quantitatively record the content of impurity II, III, compensate for the deficiencies in the prior art.
The present inventor finds, adopts vapor-phase chromatography, and directly with organic solvent (such as dimethyl formamide, be called for short DMF) the laggard sample of sample dissolution, the chromatographic peak circulation ratio extreme difference of Penequine hydrochloride, impurity II, III, sensitivity is very low, and error is very big. We analyze reason, it may be that when preparing Penequine hydrochloride, and impurity II, III also creates corresponding hydrochloride. And the hydrochloride of Penequine hydrochloride and impurity II, III is not volatile substances, more difficult employing vapor-phase chromatography itself measures, but its free alkali is volatile substances, and vapor-phase chromatography can be adopted to carry out detection by quantitative. Therefore, the present inventor is groped by test of many times, establishes a kind of first processing sample, then adopts the analytical procedure of the content of impurity II, III in vapor-phase chromatography detection by quantitative Penequine hydrochloride. Proving through test, the method is highly sensitive, favorable reproducibility, can the content of impurity II, III in detection by quantitative Penequine hydrochloride.
Detection method of the present invention, first dissolves Penequine hydrochloride alkali organic solvent so that it is in all hydrochlorides be changed into free alkali, nitrogen blows dry, then adds DMF and is mixed with need testing solution; The reference substance then same treatment of impurity II, III, is mixed with impurity reference substance solution; Get need testing solution, impurity reference substance solution direct injection respectively, gather color atlas, by the content of external standard method with calculated by peak area impurity II, III. Get final product the content easy, sensitive, accurate, detection by quantitative goes out impurity II, III in Penequine hydrochloride.
Described alkali organic solvent is methyl alcohol or the ethanolic soln of sodium hydroxide or potassium hydroxide, and quality concentration of volume percent is 0.1 ~ 2%, it is preferable that 0.2%.
Concrete technical scheme of the present invention is as follows:
The gas-chromatography detection method of impurity II, III in Penequine hydrochloride of the present invention, its chromatographic condition is as follows:
Chromatographic column: the amino test column that 5% phenylbenzene/95% dimethyl polysiloxane Amine capillary chromatographic column or polarity are similar, as: Rtx-5Amine (30m �� 0.25mm, 0.5 ��m), TG-5MSAMINE (30m �� 0.25mm, 0.5 ��m).
Detector: flame ionization ditector (FID), temperature 280 DEG C-300 DEG C, it is preferable that 300 DEG C.
Injector temperature: 150 DEG C-230 DEG C, it is preferable that 190 DEG C. By the heat analysis data of amyl ethyl quin ether it will be seen that amyl ethyl quin ether volatilizees from 150 DEG C, start after 230 DEG C to decompose. If injector temperature is too low, sample cannot gasify completely, does not reach the object of detection by quantitative, and injection port also can be caused to remain simultaneously, and impact measures next time. The too high amyl ethyl quin ether of temperature cause detection inaccurate if can decomposite impurity. Preferably 190 DEG C.
Post temperature: temperature programming, is then raised to final temperature 275-315 DEG C with every minute temperature rise rate of 3 DEG C-50 DEG C by initial temperature 70-150 DEG C, keeps final temperature to go out to the greatest extent to main peak. Substance to be measured is high boiling substance, and post initial temperature can not be too low, but the too high impurity of post initial temperature not easily separates, post initial temperature preferably 90 DEG C; Post final temperature is raised to 275-315 DEG C, is there is not post residual impact to measure to ensure principal constituent to go out peak completely next time. Make chromatographic column impaired to avoid post temperature too high, post final temperature preferably 300 DEG C; After determining the first gentle post final temperature of post, those of ordinary skill in the art according to the particular case adjustment heating schedule of gas chromatograph isochromatic spectrum hardware and temperature rise rate, can make the resolution of impurity II, III reach requirement.
The preferred initial temperature of whole temperature programming process 90 DEG C, the preferred initial temperature of whole temperature programming process 90 DEG C, keeps 1 minute, is warmed up to 300 DEG C with every minute temperature rise rate of 8 DEG C, keeps 8 minutes.
Column flow rate: 1.0-4.0ml/min, it is preferable that 2.5ml/min;
Splitting ratio: 10:1-1:1, it is preferable that 4:1;
Sample size: 2 �� l;
Wherein, column flow rate, splitting ratio, sample size can not be particularly limited, and those skilled in the art can adjust accordingly according to the difference of gas chromatograph.
The preparation of need testing solution: precision takes Penequine hydrochloride 40mg, adds 0.2% sodium hydrate methanol solution 4ml and dissolves, and nitrogen blows dry, precision adds 8mlDMF and dissolves, supersound extraction 15min, filters, and gets continuous filtrate and obtains the solution containing Penequine hydrochloride 5mg in every 1ml;
The preparation of impurity reference substance solution: get 3-quininone, 3-quinine alcohol impurity reference substance respectively appropriate, accurately weighed, the solution of 10 �� g/ml it is mixed with the sodium hydrate methanol solution of 0.2%, precision pipettes above-mentioned solution 4ml respectively, nitrogen blows dry, then adds 8mlDMF dissolving, supersound extraction 15min, filter, get continuous filtrate and obtain in every 1ml respectively containing the solution of 3-quininone or 3-quinine alcohol 5 �� g.
Assay method: get need testing solution, impurity reference substance solution 2 �� l direct injection respectively, gathers color atlas, by the content of external standard method with impurity in calculated by peak area this product II, III.
A in formulaAssortedFor the peak area of impurity in trial-product; ARightFor the peak area of impurity reference substance; CRightFor the concentration of impurity reference substance; CSupplyThe concentration of Penequine hydrochloride need testing solution.
Detection method of the present invention, can adopt conventional gas chromatograph, such as TRACEGC �� LTRA gas chromatograph.
Adopt detection method of the present invention to measure the content of the impurity II, III in Penequine hydrochloride, there is following advantage:
1, can the content of quantitative assay impurity II, III: the method adopting the present invention, after first sample being processed, and then detect by vapor-phase chromatography, tlc in national drug standards WS1-(X-026)-2004Z relatively at present, can directly record peak area, calculated the concrete content of impurity in Penequine hydrochloride by external standard method, add the controllability of drug quality, in Penequine hydrochloride, the detection of impurity provides more direct, stable analytical procedure;
2, highly sensitive, accuracy good: by repeatedly testing confirmation, detection method provided by the invention, the quantitative limit of impurity II, III can reach 1.4ng (0.7 �� g/ml) and 2.8ng (1.4 �� g/ml) respectively, substantially increases detection sensitivity; Through adding sample recovery test, the impurity meeting rate of recovery is between 90-110%, and the method is accurately controlled. For strictly controlling the quality of Penequine hydrochloride, it is to increase quality standard provides checks basis reliably.
Accompanying drawing explanation
Fig. 1 is the gas chromatogram of DMF solvent in the embodiment of the present invention 1;
Fig. 2 is the gas chromatogram of 3-quininone reference substance solution in the embodiment of the present invention 1;
Fig. 3 is the gas chromatogram of 3-quinine alcohol reference substance solution in the embodiment of the present invention 1;
Fig. 4 is the gas chromatogram of the embodiment of the present invention 1 Penequine hydrochloride need testing solution;
Fig. 5 is 3-quininone linear relationship chart in the embodiment of the present invention 1;
Fig. 6 is 3-quinine alcohol linear relationship chart in the embodiment of the present invention 1.
Embodiment
Below by embodiment, the present invention is further illustrated, but embodiment does not limit the scope of the invention.
Embodiment 1
Main instrument and chromatographic condition:
TRACEGCULTRA gas chromatograph, joins flame ionization ditector (FID), temperature 300 DEG C, automatic sampler, Chromeleon chromatographic working station.
Chromatographic column: Rtx-5Amine (30m �� 0.25mm, 0.5 ��m)
Post temperature: initial temperature 90 DEG C, keeps 1 minute, is warmed up to 300 DEG C with every minute temperature rise rate of 8 DEG C, keeps 8 minutes.
Column flow rate: 2.5ml/min;
Injector temperature: 190 DEG C;
Splitting ratio: 4:1;
Sample size: 2ul.
Penequine hydrochloride is provided by Chongqing Xian Yang Pharmaceutical Technology Co., Ltd, lot number: 110900.
Impurity II reference substance is provided by Chongqing Xian Yang Pharmaceutical Technology Co., Ltd, lot number 110601.
Impurity III reference substance is purchased from Sigma, lot number MKBF3377V.
The preparation of need testing solution: precision takes Penequine hydrochloride, and (lot number: 110900) 40mg, adds 0.2% sodium hydrate methanol solution 4ml and dissolve, and nitrogen blows dry, precision adds 8mlDMF and dissolves, supersound extraction 15min, filters, gets continuous filtrate as need testing solution;
The preparation of impurity reference substance solution: get impurity II, III reference substance respectively appropriate, accurately weighed, the solution of 10 �� g/ml it is mixed with the sodium hydrate methanol solution of 0.2%, precision pipettes above-mentioned solution 4ml respectively, nitrogen blows dry, then adds 8mlDMF dissolving, supersound extraction 15min, filter, get continuous filtrate as impurity reference substance solution;
Get DMF, need testing solution, impurity reference substance solution 2 �� l direct injection respectively, gather color atlas (such as Fig. 1,2,3,4), by external standard method with calculated by peak area result.
Wherein Fig. 1 is solvent DMF color atlas; Fig. 2, Fig. 3 are impurity II, III reference substance solution color atlas, and the retention time of impurity II, III is respectively 5.117min and 5.551min as can be seen. Determine that impurity exists according to the retention time of impurity peaks in need testing solution color atlas; The content (Fig. 4) going out impurity in calculated by peak area trial-product according to impurity.
Embodiment 2
According to above chromatographic condition and working method, respectively the specificity of the method, precision, linear, detectability and quantitative limit, average recovery, stability having been carried out Method validation, result is as follows:
(1) specificity:
Get the mixing solutions of solvent DMF, need testing solution, impurity reference substance II solution, impurity reference substance III solution, need testing solution and impurity reference substance II, III solution respectively, enter sample successively. Result shows, solvent time of withing a hook at the end is the peak of 1.370min, 2.565min, 2.939min, 3.331min, impurity II retention time is 5.113min, impurity III retention time is 5.557min, amyl ethyl quin ether retention time is 14.948min, showing that solvent and impurity reference substance resolution are good, amyl ethyl quin ether and impurity reference substance do not produce interference, and this method specificity is strong.
(2) precision:
Get impurity reference substance solution and enter sample 6 times in accordance with the law, gather color atlas, the results are shown in Table 1:
Table 1 precision measurement result
Result shows, enter under same concentration sample 6 times the RSD% of each impurity peaks is all less than 10%, meet external standard method calculation requirement, therefore under this chromatographic condition, precision is good.
(3) linear:
Getting II impurity reference substance storing solution and be diluted to 0.7 �� g/ml successively, the serial solution of 2 �� g/ml, 3 �� g/ml, 4 �� g/ml, 5 �� g/ml, 6 �� g/ml, 7 �� g/ml concentration, enters sample in accordance with the law, records concentration linear relationship, see Fig. 5.
Getting III impurity reference substance storing solution and be diluted to 1.4 �� g/ml successively, the serial solution of 2 �� g/ml, 3 �� g/ml, 4 �� g/ml, 5 �� g/ml, 6 �� g/ml, 7 �� g/ml concentration, enters sample in accordance with the law, records concentration linear relationship, see Fig. 6.
Conclusion:
When impurity II is in 0.7��7 �� g/ml concentration range, linear relationship is good, and relation conefficient is 0.9943.
When impurity III is in 1.4��7 �� g/ml concentration ranges, linear relationship is good, and relation conefficient is 0.9934.
(4) detectability and quantitative limit:
Get impurity reference substance solution DMF respectively and it is diluted to series concentration solution successively, test in accordance with the law:
Impurity II detection is limited to 0.6ng (0.3 �� g/ml), is quantitatively limited to 1.4ng (0.7 �� g/ml).
Impurity III detection is limited to 1.4ng (0.7 �� g/ml), is quantitatively limited to 2.8ng (1.4 �� g/ml).
(5) average recovery:
In Penequine hydrochloride need testing solution, add the impurity reference substance of basic, normal, high quality respectively, be mixed with the solution containing impurity 0.08%, 0.1%, 0.12%, measure in accordance with the law, the results are shown in Table 2, table 3:
Table 2 impurity II determination of recovery rates result
Table 3 impurity III determination of recovery rates result
Result shows, and records average recovery all 90%��110%, meet gas phase rate of recovery calculation requirement, demonstrate the method accurately controlled under three kinds of concentration.
(6) stability:
Get impurity II, III reference substance solution to place and get sample determination in Different periods respectively in 12 hours, the results are shown in Table 4:
Table 4 stability of solution measurement result
By result it will be seen that impurity II reference substance solution stability RSD% is 3.0%, solution is stablized for 12 hours; Impurity III reference substance solution stability RSD% is 2.7%, and solution is stablized for 12 hours. (7) sample determination:
Measure many batches of Penequine hydrochlorides with aforesaid method, the results are shown in Table 5:
The assay result of impurity II, III in table 5 sample
Above result shows, present method is highly sensitive, favorable reproducibility, and real result is reliable, can accurately determine the content of impurity II, III in Penequine hydrochloride.
Embodiment 3
With reference to the method for embodiment 1, injector temperature is investigated. The results are shown in Table 6:
Table 6 injector temperature investigates result
Above result shows, injector temperature measures within the scope of 150-230 DEG C, and impurity II, III are separated good, can realize accurately mensuration.
Embodiment 4
With reference to the method for embodiment 1, different post temperature condition is investigated. The results are shown in Table 7:
Different post temperature condition is investigated by table 7
Result shows, when post temperature initial temperature is lower, temperature rise rate can be suitably quicker, and when initial temperature is higher, temperature rise rate can be suitably slow, and impurity II, III resolution can reach requirement. When post temperature final temperature changes, the measurement result no significant difference of post final temperature between 275-315 DEG C.
Embodiment 5
With reference to the method for embodiment 1, alkali organic solvent kind, alkali concn are investigated. The results are shown in Table 8:
Table 8 alkali organic solvent
Result shows, impurity detection by quantitative is had no significant effect by the potassium hydroxide of 0.1 ~ 2% or the methyl alcohol of sodium hydroxide or ethanolic soln. Methyl alcohol boiling point, lower than ethanol, is saved the time when nitrogen blows dry relatively, therefore solvent particular methanol; If inorganic paper mill wastewater comparison is low, the corresponding increase of required solvent volume, blows the increase consuming time of dry solvent, excessive concentration, and alkali solubleness in a solvent is undesirable, therefore mineral alkali concentration preferably 0.2%.
Claims (7)
1. the detection method of 3-quininone and 3-quinine alcohol impurity in a Penequine hydrochloride, it is characterized in that adopting vapor-phase chromatography to detect, first use alkali organic solvent sample dissolution, all hydrochlorides wherein are made to be changed into free alkali, nitrogen blows dry, then adds dimethyl formamide and is mixed with need testing solution; Impurity 3-quininone and 3-quinine alcohol reference substance then same treatment, be mixed with impurity reference substance solution; Get need testing solution, impurity reference substance solution direct injection respectively, gather color atlas, by external standard method with the content of calculated by peak area 3-quininone and 3-quinine alcohol impurity;
Described alkali organic solvent is methyl alcohol or the ethanolic soln of sodium hydroxide, or the methyl alcohol of potassium hydroxide or ethanolic soln;
The chromatographic condition of described vapor-phase chromatography is as follows:
Chromatographic column: 5% phenylbenzene/95% dimethyl polysiloxane amino capillary chromatographic column;
Detector: flame ionization ditector, temperature 280 DEG C-300 DEG C;
Injector temperature: 150 DEG C-230 DEG C;
Post temperature: temperature programming, initial temperature 70-150 DEG C, final temperature 275-315 DEG C, temperature rise rate be every minute 3-25 DEG C;
Column flow rate is 2.5ml/min, and splitting ratio is 4:1, and sample size is 2 �� l.
2. detection method as claimed in claim 1, it is characterised in that the quality concentration of volume percent of described alkali organic solvent is 0.1-2%.
3. detection method as claimed in claim 1 or 2, it is characterised in that:
The preparation of need testing solution: precision takes Penequine hydrochloride 40mg, adds 0.2% sodium hydrate methanol solution 4ml and dissolves, and nitrogen blows dry, precision adds 8ml dimethyl formamide and dissolves, supersound extraction 15min, filters, and gets continuous filtrate and obtains the solution containing Penequine hydrochloride 5mg in every 1ml;
The preparation of impurity reference substance solution: get 3-quininone, 3-quinine alcohol impurity reference substance respectively appropriate, accurately weighed, the solution of 10 �� g/ml it is mixed with the sodium hydrate methanol solution of 0.2%, precision pipettes above-mentioned solution 4ml respectively, nitrogen blows dry, then adds the dissolving of 8ml dimethyl formamide, supersound extraction 15min, filter, get continuous filtrate and obtain in every 1ml respectively containing the solution of 3-quininone or 3-quinine alcohol 5 �� g.
4. detection method as claimed in claim 1, it is characterised in that described injector temperature is 190 DEG C.
5. detection method as claimed in claim 1, it is characterised in that in described post temperature, temperature programming, initial temperature is 90 DEG C.
6. detection method as claimed in claim 1, it is characterised in that in described post temperature, temperature programming, final temperature is 300 DEG C.
7. detection method as claimed in claim 1, it is characterised in that in described post temperature, temperature programming, initial temperature 90 DEG C, keeps 1 minute, be warmed up to 300 DEG C with every minute temperature rise rate of 8 DEG C, keeps 8 minutes.
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| Determination of penehyclidine by gas chromatographic–mass spectrometry and its application to pharmacokinetics in humans, rabbits and mice;Ming Xue et al.;《Journal of Chromatography B》;20061231;第843卷;第234-239页 * |
| HPLC-MS/MS 测定大鼠血浆及组织中盐酸戊乙奎醚浓度;余勤等;《四川大学学报》;20101231;第41卷(第1期);第153-157页 * |
| Structural elucidation of in vivo metabolites of penehyclidine in rats by the method of liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry and isotope ion cluster;Ying Liu et al.;《Journal of Chromatography B》;20081231;第873卷;第41-50页 * |
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