CN106018054A - Pretreatment method for testing residual palladium in bendamustine hydrochloride sample with graphite furnace atomic absorption spectrophotometry - Google Patents
Pretreatment method for testing residual palladium in bendamustine hydrochloride sample with graphite furnace atomic absorption spectrophotometry Download PDFInfo
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- CN106018054A CN106018054A CN201610328515.3A CN201610328515A CN106018054A CN 106018054 A CN106018054 A CN 106018054A CN 201610328515 A CN201610328515 A CN 201610328515A CN 106018054 A CN106018054 A CN 106018054A
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- bendamustine hydrochloride
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N1/44—Sample treatment involving radiation, e.g. heat
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Abstract
The invention discloses a pretreatment method for testing residual palladium in a bendamustine hydrochloride sample with graphite furnace atomic absorption spectrophotometry. 0.18-0.22 g of bendamustine hydrochloride is taken and mixed with 8 mL of water, and the mixture is heated and shaken for 10-30 min in a water bath at the temperature of 70-100 DEG C, mixed with 0.2-1 mL of acid liquor with the volume fraction being 10%, cooled to the room temperature, diluted with water until the volume of the mixture reaches 10 mL and uniformly mixed through shaking. Bendamustine hydrochloride mixed with water is heated and constantly shaken in a high-temperature water bath to be degraded into a monohydroxy substitution product and a dyhydroxy substitution product, the solubility of bendamustine hydrochloride is improved, and accordingly, a solution with high concentration can be prepared for detection of the amount of extremely little residual palladium in bendamustine hydrochloride. The method is simple and convenient to operate, low in analysis cost, high in specificity and suitable for detection and monitoring of residual palladium in bendamustine hydrochloride.
Description
Technical field
The invention belongs to analytical chemistry detection field, relate to a kind of graphite furnace atomic absorption spectrometry and measure hydrochloric acid
The pre-treating method of residual palladium in bendamustine sample.
Background technology
In recent years, the harm of human body is increasingly come into one's own by heavy metal, but urges use in crude drug building-up process
The attention degree of agent is the most relatively low, especially with the catalyst of palladium, if the palladium content of drug residue is too high, can to the heart,
Liver, kidney cause damage, and produce haemolysis.Therefore, the palladium residual quantity in crude drug need to be controlled.
Bendamustine hydrochloride is the dual-functional group alkanisation antineoplastic agent developed by Merck company, in October, 2003
Listing in Germany, its pharmacological action is to make DNA strand and double-strand cross-link by alkanisation, the function of interference DNA and DNA's
Synthesis, thus play antineoplastic action.Can be clinically used for treating Hodgkin, non Hodgkin lymphoma, multiple bone marrow
The Several Kinds of Malignancies such as tumor, chronic lymphocytic leukemia (CLL) and breast carcinoma.European Medicines Agency (EMA) people medication committee member
Palladium is defined as 2B level, if this principle is pointed out in the ICH element impurity guideline that in December, 2014 is adopted by meeting (CHMP)
The production process of the raw material of medicine, adjuvant or other drug composition employs palladium, tackles it and carry out risk assessment.Hydrochloric acid benzene reaches
Mo Siting employs palladium in building-up process, has no the detection report of residual palladium in bendamustine hydrochloride at present.Test proves,
To the strict residual quantity controlling palladium so that it is 2/1000000ths must not be crossed, it is contemplated that the detection limit of instrument and quantitative limit, then for examination
The concentration of product should be 20mg/mL, and under room temperature, the solution using direct dissolution method to configure this concentration cannot make sample reach the most molten
Solving, test also proves that Microwave Digestion is not suitable for the pre-treatment of this product, and the blazing method of high temperature is suitable for but operating process is the most loaded down with trivial details,
Therefore, during residual palladium is studied in bendamustine hydrochloride, set up a kind of new sample-pretreating method, with
The needs meeting inspection and supervision are necessary.
Summary of the invention
For achieving the above object, the present invention proposes a kind of bendamustine hydrochloride sample-pretreating method, can be used for graphite
Residual palladium in stove atomic absorption spectroscopy determination bendamustine hydrochloride sample.
Technical solution of the present invention is as follows:
A kind of graphite furnace atomic absorption spectrometry measures the pre-treating method of residual palladium in bendamustine hydrochloride sample, step
Suddenly it is:
Taking bendamustine hydrochloride 0.18～0.22g, add water 8mL, shakes 10～30min in 70～100 DEG C of heating in water bath, then adds
Enter the acid solution 0.2～1mL of volume fraction 10%, be cooled to room temperature, be finally diluted with water to 10mL, shake up.
The preferred 0.2g of described bendamustine hydrochloride.
Described heating in water bath, temperature preferably 85 DEG C, time preferred 20min.
Described acid solution is nitric acid-aqueous solution or hydrochloric acid-aqueous solution, preferably nitric acid-aqueous solution.
The described preferred 0.5mL of acid solution consumption.
Bendamustine hydrochloride chemistry entitled 4-[5-[double (2-chloroethyl) amino]-1-tolimidazole-2-base] fourth
Acid hydrochloride, molecular formula is C16H22Cl3N3O2, molecular weight is 394.72, and structural formula is as shown in formula I:
Take bendamustine hydrochloride, respectively with water, dilute hydrochloric acid solution, dilute salpeter solution and nitric acid as solvent, compound concentration
It is about 20mg ml-1Solution, result all can not be completely dissolved；Also using nitric acid to carry out micro-wave digestion process, result is the most not
Satisfied.But bendamustine hydrochloride heats in water and easily hydrolyzes, generate its monohydroxy substituent and dihydroxy substituent, knot
Structure formula is as shown in formula II, formula III:
According to bendamustine hydrochloride These characteristics, the present invention uses with water as solvent, under high temperature heating conditions, makes hydrochloric acid benzene reach
Mo Siting is decomposed into its monohydroxy substituent and dihydroxy substituent, adds its dissolubility in water, makes sample the most molten
Solve, then add a certain amount of acid solution, when making the later stage use Atomic Absorption to be measured, there is higher sensitivity.
The present invention compared with prior art, has the beneficial effect that: heavy metal analysis pretreatment mode master in existing medicine
There are following three kinds: directly dissolution method, Microwave Digestion and sample is carried out the method that high temperature is blazing.Wherein direct dissolution method
Simply, quickly, but be of limited application；Microwave Digestion and the blazing method of high temperature are applicable to most sample, but complex operation,
Energy consumption is high, produces waste gas and easily causes environmental pollution and experimenter's health is caused murder by poisoning.Test proves, to strictly control palladium
Residual quantity so that it is must not cross 2/1000000ths, then directly dissolution method and Microwave Digestion are not suitable for the pre-treatment of this product, high
The blazing method of temperature is the most loaded down with trivial details, and the present invention during residual palladium is studied in bendamustine hydrochloride, establishes one
New sample-pretreating method, the method reagent consumes less, energy consumption is low, pollution-free, be beneficial to environmental protection, easy and simple to handle quick, basic
On the health of experimenter will not be caused murder by poisoning, make the detection of residual palladium in bendamustine hydrochloride more quick and easy.
Detailed description of the invention
The present invention is further described below in conjunction with specific embodiment, without departing from the idea case in the present invention described above,
The various replacements made according to ordinary skill knowledge and customary means or change, be included within the scope of the present invention.
Embodiment 1
Sample pre-treatments: taking bendamustine hydrochloride 3 batches, each 0.2g, accurately weighed, add water 8mL, then adds in 85 DEG C of water-baths
Heat shaking 20min, takes out, adds the aqueous solution of nitric acid 0.5mL that volume fraction is 10%, let cool to room temperature, last dilute
To 10mL, shake up.
Using atomic absorption spectroscopy determination, by standard curve method, (linear equation is A=0.00777C+0.0200, r
=0.9984) calculate palladium content in bendamustine hydrochloride, 3 batch sample measurement results be followed successively by 0.58ppm, 0.62ppm and
0.67ppm。
Result verification: taking above-mentioned 3 batches of bendamustine hydrochloride samples, each 0.2g, accurately weighed, the employing blazing method of high temperature is entered
The pre-treatment that row bendamustine hydrochloride measures, after process, adds 0.5% aqueous solution of nitric acid and dissolves and be diluted to 10mL, take this solution
Using atomic absorption spectroscopy determination, 3 batch sample measurement results are followed successively by 0.59ppm, 0.61ppm and 0.66ppm.Can
Seeing, measurement result is basically identical with the inventive method.
Embodiment 2
Sample pre-treatments: taking bendamustine hydrochloride 9 parts, every part of 0.2g, accurately weighed, every 3 parts is one group, and first group of precision adds
Entering concentration is 1000 ng mL-1Standard palladium solution 0.3mL, second group adds 0.4 mL, and the 3rd group adds 0.5 mL, add respectively
Water 8mL, then heats 20min in 85 DEG C of water-baths, and shakes constantly, take out, add 10% aqueous solution of nitric acid 0.5mL, let cool
To room temperature, finally it is diluted with water to 10mL, shakes up.
Use atomic absorption spectroscopy determination, calculate the response rate, measurement result is respectively 104.33%, 103.67%,
105.67%, 102.25%, 102.25%, 104.00%, 99.80%, 102.00% and 101.80%, mark-on recovery test averagely reclaims
Rate is 102.9%, and RSD is 1.7%, shows the sample after the inventive method process, uses atomic absorption spectroscopy determination
Accuracy is high.Under the conditions of above-mentioned, the detection recorded is limited to 2ng mL-1, quantitatively it is limited to 7 ng mL-1。
Embodiment 3
Compared with Example 1, in sample pretreatment process, the acid solution of addition changes the aqueous hydrochloric acid solution of 10% into, other conditions one
Cause, take the solution for preparing and use atomic absorption spectroscopy determination, 3 batch sample measurement results be followed successively by 0.56ppm,
0.61ppm and 0.65ppm.
Embodiment 4
Compared with Example 1, in sample pretreatment process, controlling water bath heating temperature is 70 DEG C, and the time of heating in water bath controls
For 10min, 10% aqueous solution of nitric acid of addition is 0.2 mL, takes the solution prepared and uses atomic absorption spectroscopy determination,
3 batch sample measurement results are followed successively by 0.57ppm, 0.61ppm and 0.67ppm.
Embodiment 5
Compared with Example 1, in sample pretreatment process, controlling water bath heating temperature is 100 DEG C, and the time of heating in water bath controls
For 30min, 10% aqueous solution of nitric acid of addition is 1mL, takes the solution for preparing and uses atomic absorption spectroscopy determination, 3 batches
Sample determination result is followed successively by 0.58ppm, 0.63ppm and 0.66ppm.
Embodiment 6
Compared with Example 1, in sample pretreatment process, the bendamustine hydrochloride of addition changes 0.18g into, other conditions one
Cause, take the solution for preparing and use atomic absorption spectroscopy determination, 3 batch sample measurement results be followed successively by 0.59ppm, 0.61
Ppm and 0.67ppm.
Embodiment 7
Compared with Example 1, in sample pretreatment process, the bendamustine hydrochloride of addition changes 0.22g into, other conditions one
Cause, take the solution for preparing and use atomic absorption spectroscopy determination, 3 batch sample measurement results be followed successively by 0.57ppm, 0.60
Ppm and 0.68ppm.
Comparative example 1
Compared with Example 1, in sample pretreatment process, controlling water bath heating temperature is 50 DEG C, after heating, bendamustine hydrochloride
Spit of fland can not be completely dissolved, acid adding, cooling, is settled to 10mL, uses atomic absorption spectroscopy determination after taking this solution centrifugal,
3 batch sample measurement results are followed successively by 0.40ppm, 0.42ppm and 0.41ppm, the knot that measurement result records significantly lower than embodiment 1
Really.
Comparative example 2
Compared with Example 1, in sample pretreatment process, the concentration adding aqueous solution of nitric acid changes 25% into, and addition changes into
1.5mL, after addition, cooling, with the reduction of temperature, constantly there is solid to separate out, be settled to 10mL, use former after taking this solution centrifugal
Sub-absorptiometry measures, and 3 batch sample measurement results are followed successively by 0.38ppm, 0.40ppm and 0.39ppm, and measurement result is bright
The aobvious result recorded less than embodiment 1.
Comparative example 3
3 batches of bendamustine hydrochloride samples of Example 1, each 0.2g, accurately weighed, add nitric acid 8mL, after micro-wave digestion, catch up with
Except unnecessary nitric acid, after adding 0.5% aqueous solution of nitric acid, there is solid to separate out, be settled to 10mL, after taking this solution centrifugal, use atom
Absorptiometry measures, and 3 batch sample measurement results are followed successively by 0.40ppm, 0.41ppm and 0.38ppm, and measurement result is obvious
The result recorded less than embodiment 1.
Claims (7)
1. a pre-treating method for residual palladium during graphite furnace atomic absorption spectrometry measures bendamustine hydrochloride sample,
It is characterized in that, step is: taking bendamustine hydrochloride 0.18～0.22g, add water 8mL, shakes in 70～100 DEG C of heating in water bath
Shake 10～30min, add the acid solution 0.2～1mL of volume fraction 10%, be cooled to room temperature, be finally diluted with water to 10mL, shake
Even.
Pre-treating method the most according to claim 1, it is characterised in that: described bendamustine hydrochloride is 0.2g.
Pre-treating method the most according to claim 1, it is characterised in that: described heating in water bath, temperature is 85 DEG C.
Pre-treating method the most according to claim 1, it is characterised in that: described heating in water bath, the time is 20min.
Pre-treating method the most according to claim 1, it is characterised in that: described acid solution be nitric acid-aqueous solution or hydrochloric acid-
Aqueous solution.
Pre-treating method the most according to claim 5, it is characterised in that: described acid solution is nitric acid-aqueous solution.
7. want the pre-treating method described in 1 or 5 or 6 according to right, it is characterised in that: described acid solution consumption is 0.5mL.
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Citations (4)
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|---|---|---|---|---|
| CN101196472A (en) * | 2007-05-25 | 2008-06-11 | 中国石化扬子石油化工有限公司 | Method for measuring palladium content in palladium carbon catalyzer by microwave clearing ICP method |
| CN101735277A (en) * | 2010-01-15 | 2010-06-16 | 大连理工大学 | Fluorescent probe compounds, preparation method and use thereof |
| CN103896850A (en) * | 2014-03-24 | 2014-07-02 | 东南大学 | Preparation method of bendamustine hydrochloride dimerization impurities |
| CN104402738A (en) * | 2014-10-31 | 2015-03-11 | 南京大学 | Selective reduction method for nitro |
-
2016
- 2016-05-18 CN CN201610328515.3A patent/CN106018054A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101196472A (en) * | 2007-05-25 | 2008-06-11 | 中国石化扬子石油化工有限公司 | Method for measuring palladium content in palladium carbon catalyzer by microwave clearing ICP method |
| CN101735277A (en) * | 2010-01-15 | 2010-06-16 | 大连理工大学 | Fluorescent probe compounds, preparation method and use thereof |
| CN103896850A (en) * | 2014-03-24 | 2014-07-02 | 东南大学 | Preparation method of bendamustine hydrochloride dimerization impurities |
| CN104402738A (en) * | 2014-10-31 | 2015-03-11 | 南京大学 | Selective reduction method for nitro |
Non-Patent Citations (5)
| Title |
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| 刘珍仁等: "盐酸苯达莫司汀临床给药过程中的降解产物及其结构确证", 《中国新药与临床杂志》 * |
| 潘英等: "盐酸苯达莫司汀的合成工艺研究", 《国外医药抗生素分册》 * |
| 王湘波等: "石墨炉原子吸收法测定替加环素中钯的残留量", 《中南药学》 * |
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