CN104020230A - Method for detecting by-product in penehyclidine hydrochloride - Google Patents
Method for detecting by-product in penehyclidine hydrochloride Download PDFInfo
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Abstract
The invention discloses a method for detecting a by-product in penehyclidine hydrochloride. The detecting method comprises the following steps of detecting the content of the by-product in penehyclidine hydrochloride by using a high-efficiency liquid chromatography, wherein the by-product is 3-[2-cyclopentyl2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethyoxyl)-ethyoxyl]; preparing a test solution for later use, preparing a reference substance solution for later use, and measuring the test solution and the reference substance solution. The method provided by the invention has the advantages that the detection limit of the device can achieve 0.32mug/ml, 3-[2-cyclopentyl2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethyoxyl)-ethyoxyl]quinine naphthene hydrochloride which is higher than 0.03% in a hydrochloric acid penehyclidine hydrochloride original soup is detected, and a practical detecting effect is good.
Description
Technical field
The present invention is a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride, is specifically related to the quantitative detecting method of accessory substance in amyl ethyl quin ether hydrochloride bulk drug, belongs to drug test field.
Background technology
Amyl ethyl quin ether hydrochloride is the new drug with independent intellectual property right of China's development, the existing formulation of its bulk drug is mainly parenteral solution, be penehyclidine hydrochloride injection (long holder is peaceful), there is selectivity choline receptor antagonism, the bad reactions such as tachycardia that can not only effectively avoid atropine to produce, also there is drug effect long, the advantages such as bad reaction is few, its indication comprises: for preanesthetic medication to suppress salivary gland and air flue glandular secretion, maintain atropinization etc. after aging for organophosphorus poison (agricultural chemicals) poisoning first-aid treatment and poisoning later stage or cholinesterase (ChE).At present, this medicine has started application in the clinical fields such as preanesthetic medication, organic phosphorus pesticide poisoning rescue, shock, respiratory disease, angiocardiopathy and drug addiction treatment, the application of the amyl ethyl quin ether hydrochloride that the application of the amyl ethyl quin ether hydrochloride that a kind of medical compounds disclosing as: patent documentation CN02134118.4 and composition thereof and the application in pharmacy, patent documentation CN200510088052.X disclose in pharmacy and patent documentation CN200910058142.2 disclose in preparation treatment haemorrhagic shock medicine etc.
Existing situation is, along with China is to the increasingly stringent of impurity research requirement in drug research and development and clear and definite, especially the research of medicine accessory substance, catabolite etc. has been entered to the today in a brand-new stage, whether medicine can produce bad reaction in clinical use becomes more and more important.Certainly, we also clearly know, in actual clinical field, the bad reaction that medicine produces in clinical use procedure, except outside the Pass the pharmacologically active with medicine major component has, also with medicine in the impurity that exists have relation, in clinical trial, often the mode by medicine accessory substance exists, therefore, for improving constantly security and the validity of penehyclidine hydrochloride injection, the present invention has set up a kind of method that energy accurate quantitative analysis detects the accessory substance in amyl ethyl quin ether hydrochloride (as: amyl ethyl quin ether hydrochloride original liquid).
Summary of the invention
The object of the present invention is to provide a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride, this detection method is to adopt high performance liquid chromatography, with 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride in contrast product position, to 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] the quantitative detection carried out of quinuclidine hydrochloride, its specificity, quantitative limit and detectability, linear, precision, accuracy, stability of solution, the aspects such as durability are all through authentication in detail, and every the result all meets the requirement of relevant laws and regulations and governing principle, actual detection is respond well.
The present invention is achieved through the following technical solutions: a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride, described detection method comprises the content that uses high performance liquid chromatography to detect accessory substance in amyl ethyl quin ether hydrochloride, described accessory substance is 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride, comprise following steps:
A: prepare need testing solution: get amyl ethyl quin ether hydrochloride and mobile phase is hybridly prepared into need testing solution, stand-by, in mass ratio, amyl ethyl quin ether hydrochloride: the ratio of mobile phase is (1～3): 1000;
B: preparation reference substance solution: 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy is provided) ethoxy] quinuclidine hydrochloride reference substance, by 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride reference substance and mobile phase be hybridly prepared into reference substance solution, stand-by, count in mass ratio, 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride reference substance: the ratio of mobile phase is (0.005～0.02): 1000,
C: measure: draw respectively reference substance solution and the need testing solution of equivalent, inject high performance liquid chromatograph and measure, the condition determination of described high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: mainly by methanol-water phase or acetonitrile-water phase composition;
Flow velocity: 0.5～1.5ml/min;
Column temperature: 20～40 ℃;
Detect wavelength: 205～216nm.
This method detectability reaches 0.62 μ g/ml, can detect in amyl ethyl quin ether hydrochloride the 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy higher than 0.03%) ethoxy] quinuclidine hydrochloride, practical.
For realizing better above-mentioned steps, further, in described steps A, the mass ratio of amyl ethyl quin ether hydrochloride and mobile phase is 2:1000; In described step B, 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] mass ratio of quinuclidine hydrochloride reference substance and mobile phase is 0.01:1000.
In the present invention, described mobile phase is: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that volume ratio is 80:20:0.5.
Further, described mobile phase is 4.0～6.0 by phosphoric acid solution adjusting pH value.
In actual testing process, for the high performance liquid chromatography adopting for the present invention, in its condition determination, each parameter is after suitably adjusting, all can accurately detect 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] content of quinuclidine hydrochloride, comprise flow phase pH value, flow velocity, column temperature and detect the adjustment that wavelength carries out, as follows:
(1), in described step C, in high effective liquid chromatography for measuring condition, the pH value of mobile phase is 4.0,5.0 or 6.0.
(2), in described step C, the flow velocity in high effective liquid chromatography for measuring condition is 0.5ml/min, 1.0ml/min or 1.5ml/min.
(3), in described step C, the column temperature in high effective liquid chromatography for measuring condition is 25 ℃, 35 ℃ or 40 ℃.
(4), in described step C, the detection wavelength in high effective liquid chromatography for measuring condition is 205 nm, 210 nm or 216 nm.
The present invention compared with prior art, has the following advantages and beneficial effect:
(1) the present invention is to accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] the quantitative detection of quinuclidine hydrochloride, principle is very simple, adopt high performance liquid chromatography, with 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride in contrast product position, its specificity, quantitative limit and detectability, linear, precision, accuracy, stability of solution, the aspects such as durability are all through authentication in detail, and every the result all meets the requirement of relevant laws and regulations and governing principle, actual detection is respond well.
(2) the present invention is practical, in actual testing process, its detectability can reach 0.62 μ g/ml, can detect in amyl ethyl quin ether hydrochloride the 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy higher than 0.03%) ethoxy] content of quinuclidine hydrochloride, testing process is simple, quick.
(3) high performance liquid chromatography of the present invention, the scope that its condition determination comprises is effective value, that is: in each parameter area, get after arbitrary value, also can accurately detect 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] content of quinuclidine hydrochloride, in actual testing process, be convenient to detection person to the adjustment of parameter and the impact of avoiding human error to produce testing result, suitablely extensively promote the use of.
Accompanying drawing explanation
Fig. 1 is the chemical formula of amyl ethyl quin ether hydrochloride of the present invention.
Fig. 2 is 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy of the present invention) ethoxy] chemical formula of quinuclidine hydrochloride.
Fig. 3 is the liquid chromatogram of reference substance solution of the present invention.
Fig. 4 is the liquid chromatogram of need testing solution of the present invention.
Embodiment
Below goal of the invention of the present invention, technical scheme and beneficial effect are described in further detail.
Should be noted that, it is all exemplary below describing in detail, be intended for the requested to provide further explanation of the invention, except as otherwise noted, all technology used herein and scientific terminology have the identical meanings of conventionally understanding with general technical staff of the technical field of the invention.
For constantly improving security and the validity of amyl ethyl quin ether hydrochloride medicine, the present invention proposes a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride, mainly to accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] the quantitative detection of quinuclidine hydrochloride, the method is through detailed methodology checking, there is good use value, its checking content includes: specificity, quantitative limit and detectability, linear, precision, accuracy, stability of solution, durability etc., and every the result all meets the requirement of relevant laws and regulations and governing principle.In actual testing process, the detectability of this method can reach 0.62 μ g/ml, can detect in amyl ethyl quin ether hydrochloride the 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy higher than 0.03%) ethoxy] quinuclidine hydrochloride, actual detect respond well.
Below further describing technical solution of the present invention:
This detection method is to use high performance liquid chromatography to accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] the quantitative detection of quinuclidine hydrochloride, wherein, amyl ethyl quin ether hydrochloride and accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] chemical formula of quinuclidine hydrochloride is respectively as Fig. 1, shown in Fig. 2, the high performance liquid chromatography that the present invention uses is to adopt 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride in contrast product position, to the 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] quinuclidine hydrochloride detects, concrete operation step can be summarized as follows:
A: prepare need testing solution: get amyl ethyl quin ether hydrochloride and mobile phase is hybridly prepared into need testing solution, stand-by, in mass ratio, and amyl ethyl quin ether hydrochloride: the ratio of mobile phase is (1～3): 1000, optimization, its ratio is 2:1000;
B: preparation reference substance solution: 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy is provided) ethoxy] quinuclidine hydrochloride reference substance, by 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride reference substance and mobile phase be hybridly prepared into reference substance solution, stand-by, count in mass ratio, 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride reference substance: the ratio of mobile phase is (0.005～0.02): 1000, optimize, its ratio is 0.01:1000,
C: measure: draw respectively reference substance solution and the need testing solution of equivalent, inject high performance liquid chromatograph and measure, the condition determination of described high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: mainly by methanol-water phase or acetonitrile-water phase composition;
Flow velocity: 0.5～1.5ml/min;
Column temperature: 20～40 ℃;
Detect wavelength: 205～216nm.
In actual testing process, for the high performance liquid chromatography adopting for the present invention, in its condition determination, each parameter is after suitably adjusting, all can accurately detect 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] content of quinuclidine hydrochloride, comprise flow phase pH value, flow velocity, the adjustment that column temperature and detection wavelength carry out etc., therefore, with nine exemplary embodiments, enumerate explanation the specific embodiment of the present invention below, the amyl ethyl quin ether hydrochloride that each embodiment all chooses different lot numbers detects, certainly, protection scope of the present invention is not limited to following examples.
Embodiment 1:
Choose lot number and be 080601 amyl ethyl quin ether hydrochloride, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride detects, as follows:
A: prepare need testing solution: add methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that 25ml pH value 5.0, volume ratio are 80:20:0.5 in the amyl ethyl quin ether hydrochloride of 50mg, its mass ratio is 2:1000, after mixing, be mixed with the solution of the hydrochloric amyl ethyl quin ether 2mg of every 1ml, as need testing solution, stand-by;
B: preparation reference substance solution: at 100 μ g 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxys) ethoxy] add methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that 10ml pH value 5.0, volume ratio are 80:20:0.5 in quinuclidine hydrochloride reference substance, its mass ratio 0.01:1000, after mixing, be mixed with every 1ml containing the solution of 10.0 μ g, product solution, stand-by in contrast;
C: measure: draw respectively each 10 μ l of reference substance solution and need testing solution, injecting high performance liquid chromatograph measures, Fig. 3 and Fig. 4 are respectively 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy of the present invention) ethoxy] liquid chromatogram of quinuclidine hydrochloride reference substance solution and amyl ethyl quin ether hydrochloride need testing solution, wherein, the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value 5.0, volume ratio are 80:20:0.5;
Flow velocity: 1.0ml/min;
Column temperature: 35 ℃;
Detect wavelength: 210nm.
Known after testing, lot number is accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in 080601 batch of amyl ethyl quin ether hydrochloride) ethoxy] content of quinuclidine hydrochloride is 0.162%.
Embodiment 2:
The present embodiment is only from the difference of embodiment 1: in chromatographic condition, the parameter of flow velocity and the amyl ethyl quin ether hydrochloride lot number chosen are different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 090901, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 5.0, volume ratio is 80:20:0.5;
Flow velocity: 1.5ml/min;
Column temperature: 35 ℃;
Detect wavelength: 210nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in the amyl ethyl quin ether hydrochloride that lot number is 090901) ethoxy] content of quinuclidine hydrochloride is 0.188%.
Embodiment 3:
The present embodiment is only from the difference of embodiment 1: in chromatographic condition, the parameter of flow velocity and the amyl ethyl quin ether hydrochloride lot number chosen are different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 100701, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 5.0, volume ratio is 80:20:0.5;
Flow velocity: 0.5ml/min;
Column temperature: 35 ℃;
Detect wavelength: 210nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in the amyl ethyl quin ether hydrochloride that lot number is 100701) ethoxy] content of quinuclidine hydrochloride is 0.080%.
Embodiment 4:
The present embodiment is from the difference of embodiment 1: in chromatographic condition, the parameter of column temperature and the amyl ethyl quin ether hydrochloride lot number chosen are different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 111101, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 5.0, volume ratio is 80:20:0.5;
Flow velocity: 1.0ml/min;
Column temperature: 25 ℃;
Detect wavelength: 210nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in the amyl ethyl quin ether hydrochloride that lot number is 111101) ethoxy] content of quinuclidine hydrochloride is 0.071%.
Embodiment 5:
The present embodiment is from the difference of embodiment 1: in chromatographic condition, the parameter of column temperature and the amyl ethyl quin ether hydrochloride lot number chosen are different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 120201, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 5.0, volume ratio is 80:20:0.5;
Flow velocity: 1.0ml/min;
Column temperature: 40 ℃;
Detect wavelength: 210nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in the amyl ethyl quin ether hydrochloride that lot number is 120201) ethoxy] content of quinuclidine hydrochloride is 0.134%.
Embodiment 6:
The present embodiment is from the difference of embodiment 1: in chromatographic condition, the pH value of mobile phase and the amyl ethyl quin ether hydrochloride lot number chosen are different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 120901, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 4.0, volume ratio is 80:20:0.5;
Flow velocity: 1.0ml/min;
Column temperature: 40 ℃;
Detect wavelength: 210nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in the amyl ethyl quin ether hydrochloride that lot number is 120901) ethoxy] content of quinuclidine hydrochloride is 0.065%.
Embodiment 7:
The present embodiment is from the difference of embodiment 1: in chromatographic condition, the pH value of mobile phase and the amyl ethyl quin ether hydrochloride lot number chosen are different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 130701, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 6.0, volume ratio is 80:20:0.5;
Flow velocity: 1.0ml/min;
Column temperature: 40 ℃;
Detect wavelength: 210nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in the amyl ethyl quin ether hydrochloride that lot number is 130701) ethoxy] content of quinuclidine hydrochloride is 0.0%.
Embodiment 8:
The present embodiment is from the difference of embodiment 1: in chromatographic condition, detect the parameter of wavelength and the amyl ethyl quin ether hydrochloride lot number chosen different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 131101, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 5.0, volume ratio is 80:20:0.5;
Flow velocity: 1.0ml/min;
Column temperature: 40 ℃;
Detect wavelength: 205nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in the amyl ethyl quin ether hydrochloride that lot number is 131101) ethoxy] content of quinuclidine hydrochloride is 0.044%.
Embodiment 9:
The present embodiment is from the difference of embodiment 8: the parameter that detects wavelength in chromatographic condition is different.
In the present embodiment, the amyl ethyl quin ether hydrochloride lot number of choosing is 131101, to its accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] content of quinuclidine hydrochloride is when detect, and the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that pH value is 5.0, volume ratio is 80:20:0.5;
Flow velocity: 1.0ml/min;
Column temperature: 40 ℃;
Detect wavelength: 216nm.
Known after testing, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] content of quinuclidine hydrochloride is 0.045%.
Testing result to above-described embodiment 1～9 is added up, as shown in table 1:
Table 1
| Numbering | Amyl ethyl quin ether hydrochloride lot number | The content (%) of impurity 3-quinuclidinol |
| 1 | 080601 | 0.162 |
| 2 | 090901 | 0.188 |
| 3 | 100701 | 0.080 |
| 4 | 111101 | 0.071 |
| 5 | 120201 | 0.134 |
| 6 | 120901 | 0.065 |
| 7 | 130701 | 0.0 |
| 8 | 131101 | 0.044 |
| 9 | 131101 | 0.045 |
From above-mentioned table 1, accessory substance 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy in amyl ethyl quin ether hydrochloride) ethoxy] in the quantitative testing process of quinuclidine hydrochloride, suitable each parameter to chromatographic condition, as: after the pH value of mobile phase, flow velocity, column temperature and detection wavelength are adjusted, its testing result is all effectively, and its measurement result is accurately.
The above, be only preferred embodiment of the present invention, not the present invention done to any pro forma restriction, and any simple modification, equivalent variations that every foundation technical spirit of the present invention is done above embodiment, within all falling into protection scope of the present invention.
Claims (9)
1. the method for detection of accessory substance in amyl ethyl quin ether hydrochloride, it is characterized in that: described detection method comprises the content that uses high performance liquid chromatography to detect accessory substance in amyl ethyl quin ether hydrochloride, described accessory substance is 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride, comprise following steps:
A: prepare need testing solution: get amyl ethyl quin ether hydrochloride and mobile phase is hybridly prepared into need testing solution, stand-by, in mass ratio, amyl ethyl quin ether hydrochloride: the ratio of mobile phase is (1～3): 1000;
B: preparation reference substance solution: 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy is provided) ethoxy] quinuclidine hydrochloride reference substance, by 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride reference substance and mobile phase be hybridly prepared into reference substance solution, stand-by, count in mass ratio, 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] quinuclidine hydrochloride reference substance: the ratio of mobile phase is (0.005～0.02): 1000,
C: measure: draw respectively reference substance solution and the need testing solution of equivalent, inject high performance liquid chromatograph and measure, the condition determination of described high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as filling agent;
Mobile phase: mainly by methanol-water phase or acetonitrile-water phase composition;
Flow velocity: 0.5～1.5ml/min;
Column temperature: 20～40 ℃;
Detect wavelength: 205～216nm.
2. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 1, is characterized in that: in described steps A, the mass ratio of amyl ethyl quin ether hydrochloride and mobile phase is 2:1000.
3. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 1, it is characterized in that: in described step B, 3-[2-cyclopentyl 2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy) ethoxy] mass ratio of quinuclidine hydrochloride reference substance and mobile phase is 0.01:1000.
4. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 1, is characterized in that: described mobile phase is: methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine that volume ratio is 80:20:0.5.
5. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 4, is characterized in that: it is 4.0～6.0 that described mobile phase regulates pH value with phosphoric acid solution.
6. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 5, is characterized in that: in described step C, in high effective liquid chromatography for measuring condition, the pH value of mobile phase is 4.0,5.0 or 6.0.
7. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 1, is characterized in that: in described step C, the flow velocity in high effective liquid chromatography for measuring condition is 0.5ml/min, 1.0ml/min or 1.5ml/min.
8. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 1, is characterized in that: in described step C, the column temperature in high effective liquid chromatography for measuring condition is 25 ℃, 35 ℃ or 40 ℃.
9. a kind of method for detection of accessory substance in amyl ethyl quin ether hydrochloride according to claim 1, is characterized in that: in described step C, the detection wavelength in high effective liquid chromatography for measuring condition is 205 nm, 210 nm or 216 nm.
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