CN106018584A - Detection method for dezocine related substances - Google Patents
Detection method for dezocine related substances Download PDFInfo
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- CN106018584A CN106018584A CN201610312659.XA CN201610312659A CN106018584A CN 106018584 A CN106018584 A CN 106018584A CN 201610312659 A CN201610312659 A CN 201610312659A CN 106018584 A CN106018584 A CN 106018584A
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- dezocine
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- triethylamine
- acetonitrile
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Abstract
The invention provides a detection method for dezocine related substances. Octadecyl silane bonded silica gel is adopted as a chromatographic column of a filling agent, and an acetonitrile-triethylamine solution is adopted as a mobile phase, wherein the acetonitrile-triethylamine solution is obtained by taking 1000 ml of water, adding 5 ml of triethylamine and 2 ml of a tetrabutyl ammonium hydroxide water solution, and adjusting pH to 3.2 through diluted phosphoric acid (1-5), and the ratio of acetonitrile to triethylamine is 200:800; the flow rate is 0.6 ml per min, and the detection wavelength is 281 nanometers. According to the detection method for dezocine related substances, the concentration of buffer salts is increased, elution is enhanced, an ion-pairing agent is added, the peak shape is improved, and the problems that due to the fact that the number of theoretical plates of an original method is small and a main peak cannot be rapidly eluted, the peak width is large and trailing is serious are solved.
Description
Technical field
The present invention relates to a kind of dezocine and have the detection method of related substance, belong to pharmaceutical chemistry analysis technical field.
Background technology
Dezocine belongs to a kind of (Dezocine) and belongs to a kind of typical opium alkaloids bases analgesic, Astra company of Sweden develop.Dezocine is the mixed type opiate receptor agonistic-antagonistic of synthetic, produces alleviating pain effect when steady plasma-drug concentration reaches 5-9 μ g/L, and its analgesic effect is 5-9 times of Pethidine, suitable with morphine.It is the most exciting to К receptor, produces definite analgesic activity, and partial agonist μ receptor the most again makes the incidence rate of respiration inhibition and addiction reduce, and dezocine is the most weak to delta opiate receptor activity, does not produce irritated Anxiety.Therefore, it is put into the category of non-narcotic product, is widely used in clinical Postoperative Analgesia After.Be applicable to treat Post operation medium to having an intense pain, internal organs angor and the pain of patient with advanced cancer.Owing to dezocine has good toleration and safety, become the medicine clinically with good development prospect.
Dezocine is white or off-white color crystalline powder, and odorless dissolves in methanol, ethanol or glacial acetic acid, the most molten in acetone, ethyl acetate or chloroform, the most insoluble in water, the most sensitive to the environment such as high temperature, oxidation.
At present, dezocine has the general method using standard No. YBH09172006 (the dezocine quality standard of Yangzijiang Pharmaceutical Group Co., Ltd) of related substance detection: about substance detecting method, use reverse-phase chromatography, it is filler with octadecylsilane key silica gel, detection wavelength is 281nm, with triethylamine solution, [water intaking 1000ml adds 2.5ml triethylamine, with phosphoric acid,diluted (1 5) regulation pH value to 3.2] flow based on acetonitrile (80:20) and study mutually, concentration is 1.4mg/ml.From spectrumFigureUnderstanding, number of theoretical plate is relatively low, peak width can not be caused wider by rapid eluting and hangover is serious mainly due to main peak, therefore has related substance detection needs to make further improvements；It is thus desirable to the detection method that exploitation is sensitiveer, more robust.
Summary of the invention
It is an object of the invention to overcome the deficiency of existing detection method, it is provided that a kind of dezocine has the detection method of related substance, detection dezocine sensitiveer, more effective can have related substance.
Technical solution of the present invention is as follows: a kind of dezocine has the detection method of related substance, use the chromatographic column with octadecylsilane chemically bonded silica as filler, [1000ml water is taken with acetonitrile-triethylamine solution, add 5ml triethylamine and 2ml TBAH aqueous solution, be transferred to pH3.2 with phosphoric acid,diluted (1 5)] (200:800) for flowing phase；Flow velocity is 0.6ml per minute, detects wavelength 281nm, and number of theoretical plate is calculated by dezocine peak should be not less than 3000.The separating degree at dezocine peak and other impurities peak should meet the requirements.
Assay method: take dezocine about 35mg, accurately weighed, put in 25ml measuring bottle, add acetonitrile 5ml, put in hot bath heat shaking a little and make dissolving, [take 1000ml water with triethylamine solution, add 5ml triethylamine and 2ml TBAH aqueous solution, it is transferred to pH3.2 with phosphoric acid,diluted (1 5)] it is diluted to scale, shake up, as need testing solution；Measure need testing solution 1ml, put in 100ml volumetric flask, with flowing phase dilution to scale, as contrast solution.Measuring contrast solution 20 μ l, inject chromatograph of liquid, regulation detection sensitivity makes main composition peak height be about the 10～20% of monitor full scale.Precision measures need testing solution, each 20 μ l of contrast solution again, injects chromatograph of liquid, records chromatographFigureTo main composition peak retention time 2 times.Need testing solution chromatographIn figureIf any impurity peaks, the area of single impurity peaks cannot be greater than the 1/10 (0.1%) of contrast solution main composition peak area, measures the sum of each impurity peak area, cannot be greater than contrast solution main composition peak area (1.0%).
The relevant substance detecting method of dezocine of the present invention has the advantages that
(1) increase buffer salinity, strengthen triethylamine concentration, strengthen eluting power；
(2) increase ion-pairing agent TBAH, improve peak shape；
(3) overcoming former theoretical method plate number relatively low, main peak by rapid eluting, and can not cause peak width wider and the problem such as hangover is serious.
Accompanying drawing explanation
Figure 1For using YBH09172006 method to detect relevant substance method spectrumFigure。
Figure 2For using the inventive method to detect relevant substance method spectrumFigure。
Figure 3Dezocine linear relationship data is detected for the inventive methodFigure (N=10).
Detailed description of the invention
In order to make those skilled in the art be more fully understood that the present invention program, below in conjunction with detailed description of the invention, the present invention is described in further detail.
Embodiment 1.YBH09172006 detection method is tested
The relevant substance detecting method of employing YBH09172006 (the dezocine quality standard of Yangzijiang Pharmaceutical Group Co., Ltd) dezocine raw material:
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are filler；With acetonitrile-triethylamine solution [take 1000ml water, add 2.5ml triethylamine, be transferred to pH3.2 with phosphoric acid,diluted (1 5)] (200:800) for flowing phase；Flow velocity is 0.6ml per minute, detects wavelength 281nm, and number of theoretical plate is calculated by dezocine peak should be not less than 3000.The separating degree at dezocine peak and other impurities peak should meet the requirements.
Algoscopy takes this product about 35mg, accurately weighed, puts in 25ml measuring bottle, adds acetonitrile 5ml, puts in hot bath heat shaking a little and makes dissolving, is diluted to scale with triethylamine solution, shakes up, as need testing solution；Measure need testing solution 1ml, put in 100ml volumetric flask, with flowing phase dilution to scale, as contrast solution.Measuring contrast solution 20 μ l, inject chromatograph of liquid, regulation detection sensitivity makes main composition peak height be about the 10～20% of monitor full scale.Precision measures need testing solution, each 20 μ l of contrast solution again, injects chromatograph of liquid, records chromatographFigureTo main composition peak retention time 2 times.Need testing solution chromatographIn figureIf any impurity peaks, the area of single impurity peaks cannot be greater than the 1/10 (0.1%) of contrast solution main composition peak area, measures the sum of each impurity peak area, cannot be greater than contrast solution main composition peak area (1.0%).
Table
1
From spectrumFigure ( Figure 1) understand, number of theoretical plate is relatively low, peak width can not be caused wider by rapid eluting and hangover is serious mainly due to main peak.
Embodiment 2. uses the relevant substance detecting method of dezocine raw material of the present invention:
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are filler；With acetonitrile-triethylamine solution [taking 1000ml water, add 5ml triethylamine and 2ml TBAH aqueous solution, be transferred to pH3.2 with phosphoric acid,diluted (1 5)] (200:800) for flowing phase；Flow velocity is 0.6ml per minute, detects wavelength 281nm, and number of theoretical plate is calculated by dezocine peak should be not less than 3000.The separating degree at dezocine peak and other impurities peak should meet the requirements.
Algoscopy takes this product about 35mg, accurately weighed, puts in 25ml measuring bottle, adds acetonitrile 5ml, puts in hot bath heat shaking a little and makes dissolving, is diluted to scale with triethylamine solution, shakes up, as need testing solution；Measure need testing solution 1ml, put in 100ml volumetric flask, with flowing phase dilution to scale, as contrast solution.Measuring contrast solution 20 μ l, inject chromatograph of liquid, regulation detection sensitivity makes main composition peak height be about the 10～20% of monitor full scale.Precision measures need testing solution, each 20 μ l of contrast solution again, injects chromatograph of liquid, records chromatographFigureTo main composition peak retention time 2 times.Need testing solution chromatographIn figureIf any impurity peaks, the area of single impurity peaks cannot be greater than the 1/10 (0.1%) of contrast solution main composition peak area, measures the sum of each impurity peak area, cannot be greater than contrast solution main composition peak area (1.0%).
Table
2
Table
3
| Time (min) | A (%) | B (%) | Flow velocity |
| 0 | 80 | 20 | 0.6 |
| 12 | 80 | 20 | 0.6 |
| 15 | 80 | 20 | 1.2 |
| 28 | 50 | 50 | 1.2 |
| 50 | 50 | 50 | 1.2 |
| 55 | 80 | 20 | 1.2 |
| 58 | 80 | 20 | 0.6 |
| 60 | 80 | 20 | 0.6 |
From spectrumFigure 2Understand, the number of theoretical plate of this product substantially meets relevant substance method and analyzes requirement, main peak retention time is 8.389 minutes, and the relative retention time of impurity A and impurity B is 3.1 and 5.9, illustrates that the present invention analyzes method and can be used for dezocine and injection has the detection of related substance.
The checking of embodiment 3. Related substance of the present invention method
1, specificity test
(1), separating degree test
To the initiation material in synthesis and each main intermediate, and carrying out separating degree experimental study with issuable known impurities, experimental result is shown inFollowing table,
Table 4Dezocine has related substance separating degree experimental resultTable
Learnt by above-mentioned data, at thisLight colourUnder spectral condition, dezocine with wherein may deposit intermediate and known impurities etc. and all can preferably be separated, separating degree is all higher than 1.5.
(2), Degrading experiment is forced
Taking dezocine sample appropriate, carry out acid, alkali, illumination, high temperature and Oxidative demage respectively, investigate this chromatographic condition to the detection of catabolite and separating power, test operation process is shown inTable 5, experimental result is shown inTable ,6。
Table 5Dezocine forces degraded testing programTable
Table 6Dezocine forces degraded result of the testTable
Result understands, and dezocine has a large amount of degraded under the conditions of Oxidative demage, slightly degrades under basic conditions；The most slightly degrading, destroy being hardly degraded under high light and hot conditions, the degradation impurity produced under each degradation condition all can have preferable separating degree with product main peak；Result of the test shows that the degradation impurity produced in destructive testing effectively can be detected under this chromatographic condition simultaneously.
By specificity experimental study, use thisLight colourSpectral condition can measure known impurities and catabolite or unknown impuritie present in this product, and separating degree is preferably and detection is not disturbed by impurity.
(3), Peak homogeneity
Need testing solution: take dezocine fine work, crude product about 35mg respectively, accurately weighed, put in 25ml measuring bottle, add acetonitrile 5ml, put in hot water heat shaking a little and make dissolving, be diluted to scale with triethylamine solution, shake up, to obtain final product.
Precision measures need testing solution and dezocine forces each 20ul of solution under degraded experimental condition, injects chromatograph of liquid, carries out all-wave long 3D detection at 200nm-400nm, and result is shown inTable 7。
Table 7Peak purity testing resultTable
FromUpper tableResult understands: a, the purity factor are all higher than purity threshold value, illustrate that this product has related substance to compose at thisIn figureThe purity of main peak meets Related substance requirement.
B, this product maximum absorbance wavelength under this chromatographic condition is 281nm.
2, replica test
Confirm with this instrument system run dezocine have related substance method of testing verify whether meet the requirements.
Take this product appropriate, add acetonitrile 5ml, put in hot water heat shaking a little and make dissolving, the solution containing 1.4mg in every 1ml is made with triethylamine solution dilution, as need testing solution, under above-mentioned chromatographic condition, repeat continuous sample introduction 6 times, calculate total impurities and single maximum contaminant by areas of peak normalization method, and calculate the quantity of total impurities.Result is shown inTable 8,
Acceptable standard: impurity peaks should meet the requirements with the separating degree at dezocine peak.Number of theoretical plate is calculated by dezocine peak and is not less than 2000, repeats sample introduction 6 pin, calculates total impurities and the amount of single maximum contaminant by areas of peak normalization method, and RSD all should be less than 10.0%, and the RSD of retention time should be less than 2.0%.
Table 8Replica test result
Result shows, the relative standard deviation of total impurities, single maximum contaminant and amount of impurities, retention time that repetition sample introduction is 6 times is respectively less than 10%, illustrates that this method measures dezocine and has related substance repeatability good.
3, detection limit and quantitative limit
(1), the detection limit of dezocine and quantitative limit
Determine under dezocine has related substance chromatographic condition, the bottom line that dezocine can be detected and can be by the bottom line of accurate quantitative analysis.
The sample solution of concentration known being diluted to the sample of low concentration, the signal measured compares with the signal (baseline voice) of blank space, and detection limit is in terms of signal to noise ratio S/N=2～3 times；Quantitative limit is in terms of signal to noise ratio S/N=10.Result is shown inTable 9。
Table 9Dezocine has related substance detection limited amount limit
| Title | Sample introduction concentration | Sample size | Signal-noise ratio |
| Detection limit | 1.20672ug/ml | 2ul | 2.9 |
| Quantitative limit | 0.40224ug/ml | 20ul | 10.1 |
Being computed, the detection of dezocine is limited to 2.41ng；Dezocine be quantitatively limited to 8.04ng
4, linear and scope
(1), dezocine is linear and scope
nullPrecision weighs reference substance 25.02mg，Put in 25ml measuring bottle，Add acetonitrile 5ml，Put in hot water heat shaking a little and make dissolving，It is diluted to scale with triethylamine solution，Shake up，Precision measures 4ml and is placed in 100ml measuring bottle，The solution containing dezocine 40.032 μ g in every 1ml is made with triethylamine solution-acetonitrile (80:20) dilution，Precision measures 4.5ml the most respectively、3.5ml、3ml、2.5ml、2ml、1.5ml、1ml、0.4ml、0.35ml、It is placed in 10ml measuring bottle with 0.3ml，The μ g Han dezocine 18.0144 it is diluted in every 1ml respectively again with triethylamine solution-acetonitrile (80:20)、14.0112μg、12.0096μg、10.008μg、8.0064μg、6.0048μg、4.0032μg、1.60128μg、The solution of 1.40112 μ g and 1.20096ug，During precision measures each 20 μ l injection chromatograph of liquid of above-mentioned 10 kinds of solution respectively，Record chromatographFigure, measure peak area, with concentration as abscissa, peak area is that vertical coordinate carries out linear regression, and measurement result is shown inTable 10,Figure 3。
Table 10 dezocine linear relationship dataTable (N=10)
Result shows, dezocine equation of linear regression in the range of 1.20096 μ g/ml (0.12%)～18.0144 μ g/ml (1.8%) is: A=18.04 × C-4.7284, correlation coefficient is 0.9997, illustrates that this product is linear good in the range of 1.20096 μ g/ml (0.12%)～18.0144 μ g/ml (1.8%).
Conclusion: this product impurity response value under this chromatographic condition and this product response value quite or consistent in the case of, be accurately to detect in the impurity ranges of 0.12%～1.8%.
6, precision test
(1) Intermediate precision
Taking technique three batches of products of checking batch, related substance chromatographic condition is had according to dezocine, by different personnel on different time and different instrument, detect by different chromatographic columns, investigate the combined influence that relevant substance method is detected by instrument, personnel, time and chromatographic column, calculating and have the difference between related substance testing result, result is shown inTable 11。
Table 11 dezocine has related substance Intermediate precision conditionTable
Table 12 dezocines have related substance Intermediate precision experimental resultTable
Testing result shows, the impurity number of sample, the amount of impurity and impurity ownership are all consistent, and the Intermediate precision of illustration method is good.
7, the stability test of solution
Dezocine relevant substance-measuring solution, after room temperature places certain time, assesses the affected degree of testing result.
Need testing solution: take dezocine about 35mg, accurately weighed, to put in 25ml measuring bottle, add acetonitrile 5ml, put in hot water hot a little, shaking makes dissolving, is diluted to scale with triethylamine solution, shakes up, to obtain final product.
Being placed at ambient temperature by need testing solution, detect respectively at sampling in 0,1,2,3,4,5,8 hours, result of the test is shown inTable 13。
Table 1The solution stability testing result of 3 dezocine Related substance methodsTable
Result shows: need testing solution is placed 8 hours at ambient temperature, and the amount of impurity number and impurity is basically identical, has related substance testing result without significant change, illustrates that need testing solution is stable in placing at ambient temperature 8 hours.
8, method ruggedness
When in dezocine is about substance method, the parameter of the chromatographic condition variation of little scope (chromatographic column, the flowing ratio of phase, chromatographic column, flow velocity, sample size, wavelength and column temperature carry out) has small variations, the assessment affected degree of measurement result, the reliability of result when determining the method for there being related substance to detect.
(1), need testing solution
Take dezocine 35mg, accurately weighed, to put in 25ml measuring bottle, add acetonitrile 5ml, put in hot water hot a little, shaking makes dissolving, is diluted to scale with triethylamine solution, shakes up, to obtain final product.
(2), the change of chromatographic condition
A) flow velocity is changed: other conditions of detection method are constant, and flow velocity is changed into 0.58ml/min and 0.62ml/min
B) change column temperature: other conditions of detection method are constant, column temperature is changed into 39 DEG C and 41 DEG C
C) wavelength is changed: other conditions of detection method are constant, are 280nm and 282nm by wavelength shift
D) sample size is changed: other conditions of detection method are constant, and sample size is changed into 18ul and 22ul
E) chromatographic column is changed: other conditions of detection method are constant, change identical filler, the chromatographic column of different manufacturers
(3), acceptable standard
Main peak is adjacent impurity peaks can reach good separation, and under different condition, system suitability result meets the requirements, and detects impurity number, maximum single miscellaneous and total miscellaneous RSD ＜ 10%.
(4), precision measure need testing solution 20 μ l inject chromatograph of liquid, record the chromatograph under the conditions of eachFigure, method serviceability test result is shown inTable 14。
Table 1The serviceability test result of 4 dezocine Related substance methods
Note: chromatographic column changes sees Intermediate precision
Result of the test shows: this product is in sample size, flow velocity, wavelength, column temperature, mobile phase ratio have suitable excursion, retention time, maximum single miscellaneous and total impurities RSD are respectively 1.58%, 1.49%, 1.49% and are respectively less than 2.0%, have the impact of related substance result inconspicuous on this product；By suitably changing the parameters such as chromatographic column model, flow velocity, wavelength, sample size, mobile phase ratio and column temperature, testing conditions all can meet the testing requirement of related substance, illustrates that the ruggedness of this method is preferable.
In this product quality standard, the Related substance method under check item is through the checking of methodological study, illustrates that the inventive method can detect related impurities exactly.
Claims (2)
1. dezocine has a detection method for related substance, it is characterized in that, uses with octadecylsilane chemically bonded silica as filler
Chromatographic column, with acetonitrile-triethylamine solution [take 1000ml water, add 5ml triethylamine and 2ml TBAH aqueous solution,
Be transferred to pH3.2 with phosphoric acid,diluted (1 5)] (200:800) for flowing phase；Flow velocity is 0.6ml per minute, detects wavelength 281nm.
2. dezocine as claimed in claim 1 has the detection method of related substance, it is characterized in that, assay method specifically, takes ground
Help pungent 35mg, accurately weighed, put in 25ml measuring bottle, add acetonitrile 5ml, put in hot bath heat shaking a little and make dissolving, use three second
Amine aqueous solution is diluted to scale, shakes up, as need testing solution；Measure need testing solution 1ml, put in 100ml volumetric flask, with stream
Dynamic phase dilution is to scale, as contrast solution；Measuring contrast solution 20 μ l, inject chromatograph of liquid, regulation detection sensitivity makes
Main composition peak height is about the 10～20% of monitor full scale；Precision measures need testing solution, each 20 μ l of contrast solution again, injects
Chromatograph of liquid, 2 times of record chromatogram to main composition peak retention time.
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| CN108444984A (en) * | 2018-04-11 | 2018-08-24 | 南京明捷生物医药检测有限公司 | The remaining assay method of palladium metal in a kind of dezocine bulk pharmaceutical chemicals |
| CN108611278A (en) * | 2018-05-02 | 2018-10-02 | 北京师范大学 | A kind of method and its bacterial strain preparing phenazocine by microbial fermentation |
| CN109142551A (en) * | 2017-06-15 | 2019-01-04 | 北京挑战生物技术有限公司 | A kind of quick accurate detecting method that enzyme activity in enzyme industrialization production is quenched |
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| CN111170886A (en) * | 2020-01-03 | 2020-05-19 | 扬子江药业集团有限公司 | Preparation method of dezocine impurity |
| CN115124435A (en) * | 2021-03-25 | 2022-09-30 | 扬子江药业集团有限公司 | Opium compound and preparation method and application thereof |
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| CN109142551A (en) * | 2017-06-15 | 2019-01-04 | 北京挑战生物技术有限公司 | A kind of quick accurate detecting method that enzyme activity in enzyme industrialization production is quenched |
| CN108444984A (en) * | 2018-04-11 | 2018-08-24 | 南京明捷生物医药检测有限公司 | The remaining assay method of palladium metal in a kind of dezocine bulk pharmaceutical chemicals |
| CN108611278A (en) * | 2018-05-02 | 2018-10-02 | 北京师范大学 | A kind of method and its bacterial strain preparing phenazocine by microbial fermentation |
| CN108611278B (en) * | 2018-05-02 | 2021-09-28 | 北京师范大学 | Method for preparing phenazocine through microbial fermentation and bacterial strain thereof |
| CN110483315A (en) * | 2018-05-15 | 2019-11-22 | 扬子江药业集团有限公司 | A kind of preparation method of dezocine impurity C |
| CN110483315B (en) * | 2018-05-15 | 2021-11-09 | 扬子江药业集团有限公司 | Preparation method of dezocine impurity C |
| CN111170886A (en) * | 2020-01-03 | 2020-05-19 | 扬子江药业集团有限公司 | Preparation method of dezocine impurity |
| CN111170886B (en) * | 2020-01-03 | 2021-11-09 | 扬子江药业集团有限公司 | Preparation method of dezocine impurity |
| CN115124435A (en) * | 2021-03-25 | 2022-09-30 | 扬子江药业集团有限公司 | Opium compound and preparation method and application thereof |
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