CN110243971A - The method for detecting Cyclen and its derivative content using HPLC-ELSD - Google Patents
The method for detecting Cyclen and its derivative content using HPLC-ELSD Download PDFInfo
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- CN110243971A CN110243971A CN201910583611.6A CN201910583611A CN110243971A CN 110243971 A CN110243971 A CN 110243971A CN 201910583611 A CN201910583611 A CN 201910583611A CN 110243971 A CN110243971 A CN 110243971A
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- cyclen
- butoxycarbonylmethyl
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/38—Flow patterns
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/38—Flow patterns
- G01N2030/388—Elution in two different directions on one stationary phase
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Abstract
The invention discloses a kind of methods for detecting Cyclen (Cyclen) and its derivative content using HPLC-ELSD.Method includes the following steps: 1) the HPLC-ELSD condition that setting detects: HPLC condition: mobile phase acetonitrile: water=30 ~ 50:50 ~ 70, isocratic elution；ELSD condition: drift tube temperature is 75 ~ 105 DEG C, N2Air pressure 0.4 ~ 0.6 M pa, N2Flow velocity is 1.6 ~ 2.2 L/min, gain: 2-4, not shunt mode；2) standard curve is drawn；3) sample size of Cyclen and its derivative measures.Cyclen is detected using HPLC-ELSD and its derivative content, specificity, repeatability, precision, the rate of recovery are good.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of to detect Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanes using HPLC-ELSD
The method of dodecane and its derivative content.
Background technique
The hot spot of big cyclic amine compound research is Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanands (Cyclen) and its derivative,
Since they and metal ion have very strong coordination ability, and biomolecule can be covalently attached to after complexing of metal ion
On.Cyclen and its derivative are one of common intermediates of lanthanide series specificity chelating agent, are mainly used for diagnosing and control
Treat the compound in drug (e.g., for the paramagnetism lanthanide chelate of MRI).Cyclen is alternatively arranged as intermediate progress
N- alkylation, forming multiple compounds can be used for molecular recognition and Coordinative Chemistry.Liquid phase about Cyclen and its derivative contains
It measures fixed aspect to have not been reported, since Cyclen and its derivative do not have ultraviolet and fluorescent absorption, and Composition distribution is sensitive
Spend low, the demand based on market, it would be highly desirable to easy to operate, high sensitivity, fast and accurately detection method are developed, to push
The research and development of Cyclen and its derivative.
Summary of the invention
The purpose of the present invention is intended to provide a kind of method for measuring Cyclen and its derivative content using HPLC-ELSD.
In order to realize following purposes, the invention adopts the following technical scheme:
A kind of utilization HPLC-ELSD detection Isosorbide-5-Nitrae, the method for 7,10- tetraazacyclododecanands and its derivative content, including
Following steps:
1) testing conditions are set
HPLC condition: mobile phase acetonitrile: water=30~50:50~70, isocratic elution；
ELSD condition: drift tube temperature is 75~105 DEG C, N20.4~0.6M of air pressure pa, N2Flow velocity is 1.6~2.2L/
Min, gain: 2-4, not shunt mode；
2) standard curve is drawn
Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4 are prepared respectively,
The standard sample of 7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen
Product are detected under conditions of step 1) using methanol as solvent, obtain corresponding peak area, are with the logarithm of peak area
Ordinate makes standard curve using the logarithm of respective substance content as abscissa；
3) sample is tested and analyzed under conditions of step 1), the mark made according to the peak area and step 2) of acquisition
Directrix curve calculates separately out Cyclen in sample, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, 7- tri--(uncle N-
Butoxycarbonylmethyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen content.
Preferably, mobile phase acetonitrile: water=50:50.
Preferably, N2Flow velocity is 2.0L/min.
Preferably, drift tube temperature is 90 DEG C.
Preferably, chromatographic column is Super C18 column, and partial size is 5 μm, internal diameter 4.6mm, column length 250mm.
Beneficial effects of the present invention:
1) mobile phase ratio of the present invention is acetonitrile: water=30~50:50~70, and isocratic elution is convenient for operation,
The damage since acid or buffer salt etc. is added to chromatographic column can be reduced, avoid the elution time occurred when gradient elution long and
The unfavorable problems such as peak coincidence；
2) chromatographic column used is Super C18, compared to common C18 column, Super C18 in the present invention to Isosorbide-5-Nitrae,
The assay of 7,10- tetraazacyclododecanand and its derivative shows shorter appearance time and more preferably peak type；
3) drift tube temperature is 75~105 DEG C, N20.4~0.6M of air pressure pa, N2Flow velocity is 1.6~2.2L/min, herein
Under the method for evaporative light scattering detector, Isosorbide-5-Nitrae, the assay of 7,10- tetraazacyclododecanands and its derivative, specificity,
Repeatability, precision, the rate of recovery are good.
Detailed description of the invention
Fig. 1 is the HPLC-ELSD chromatogram of Cyclen standard items.
Fig. 2 is the HPLC-ELSD chromatogram of 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen standard items.
Fig. 3 is the HPLC-ELSD chromatogram of 1,4,7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen standard items.
Fig. 4 is the HPLC-ELSD chromatogram of 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen standard items.
Specific embodiment
The present invention is described in detail combined with specific embodiments below
1) testing conditions are set
HPLC condition:
Chromatograph: Ultimate3000 high performance liquid chromatograph (Thermo company)
Chromatographic column: ACE 4.6mm × 250mm, 5 μm of partial size, Super C18 chromatographic column；
Mobile phase: mobile phase A is acetonitrile, and Mobile phase B is water；
Isocratic elution:
Acetonitrile: water=50:50
Flow velocity: 1.0mL/min；
ELSD condition:
Using 2000ES ELSD detector (Aeltech company)
Drift tube temperature is 90 DEG C, nitrogen pressure 0.4M pa, gas flow rate (N2) it is 2.0L/min, Gain:2, it does not shunt
Mode
2) standard curve is drawn
1. drawing the standard curve of Cyclen
I, five groups of Cyclen standard items (Ti Xiai chemical conversion industry Development Co., Ltd, purity > 99%) is weighed, with methanol point
Other constant volume is diluted in volumetric flask, is configured to the Cyclen methanol that cyclen content is 10,20,50,100,500 μ g/mL respectively
The testing conditions of five groups of Cyclen methanol solution steps 1) are detected, obtain the peak area of five groups of Cyclen by solution；
II, using the logarithm of the peak area of Cyclen as ordinate, using the logarithm of Cyclen content as abscissa, according to each group
The data of detection are drawn, and the standard curve of Cyclen is obtained after fitting, obtain the function of standard curve according to standard curve
Relational expression y=1.933x+18.388, R2=0.9996；
2. drawing the standard curve of 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen
I, weighing five groups of 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen standard items, (the limited public affairs of people's biotechnology are thought by Austria
Department, purity > 99%), with methanol, constant volume is diluted in volumetric flask respectively, prepares Isosorbide-5-Nitrae, 7,10- tetra--(N- tertbutyloxycarbonyls respectively
Methyl)-Cyclen content be 10,20,50,100,500 μ g/mL 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen methanol
Solution is examined the testing conditions of five groups of 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen methanol solution step 1)
It surveys, obtains the peak area of five groups of 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen；
II, with the logarithm of the peak area of 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen for ordinate, with 1,7- bis--
The logarithm of (N- tert-Butoxycarbonylmethyl)-Cyclen content is abscissa, is drawn according to the data that each group detects, after fitting
The standard curve of 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen is obtained, the function of standard curve is obtained according to standard curve
Relational expression y=2.979x+7.5814, R2=0.9996；
3. drawing the standard curve of 1,4,7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen
I, weighing five groups of 1,4,7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen standard items, (it is limited that people's biotechnology is thought by Austria
Company, purity > 99%), with methanol, constant volume is diluted in volumetric flask respectively, prepares Isosorbide-5-Nitrae, 7- tri--(N- tertbutyloxycarbonyl first respectively
Base)-Cyclen content be 10,20,50,100,500 μ g/mL 1,4,7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen methanol
Solution is examined the testing conditions of five groups of Isosorbide-5-Nitraes, 7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen methanol solution step 1)
It surveys, obtains five groups of Isosorbide-5-Nitraes, the peak area of 7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen；
II, with Isosorbide-5-Nitrae, the logarithm of the peak area of 7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen is ordinate, with Isosorbide-5-Nitrae,
The logarithm of 7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen content is abscissa, is drawn according to the data that each group detects,
Isosorbide-5-Nitrae is obtained after fitting, the standard curve of 7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen obtains standard song according to standard curve
The functional relation y=3.175x+7.7535, R of line2=0.9994；
4. drawing the standard curve of 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen
I, weighing five groups of 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen standard items, (people's biotechnology is thought by Austria
Co., Ltd, purity > 99%), with methanol, constant volume is diluted in volumetric flask respectively, is configured to Isosorbide-5-Nitrae, 7,10- tetra--(uncle N- respectively
Butoxycarbonylmethyl) the Isosorbide-5-Nitrae of-Cyclen content for 5,10,25,50,100 μ g/mL, 7,10- tetra--(N- tertbutyloxycarbonyl first
Base)-Cyclen methanol solution, by five groups of Isosorbide-5-Nitraes, 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen methanol solution steps
1) testing conditions are detected, and five groups of Isosorbide-5-Nitraes, the peak area of 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen are obtained；
II, with Isosorbide-5-Nitrae, the logarithm of the peak area of 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen is ordinate, with 1,
The logarithm of 4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen contents is abscissa, is carried out according to the data of each group detection
It draws, Isosorbide-5-Nitrae is obtained after fitting, the standard curve of 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen is obtained according to standard curve
To the functional relation y=3.3066x+26.77, R of standard curve2=0.9977.
By Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7- tri--(N- tertbutyloxycarbonyl first
Base)-Cyclen, Isosorbide-5-Nitrae, the standard curve of 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen can be seen that Cyclen, 1,
7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen and 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen is 5~100
Linear relationship is good in μ g range.
3) methodological study is tested
1. detection limit and quantitative limit
Each standard items working curve minimum concentration is taken gradually to dilute, 20 μ L of sample introduction is with signal and signal-to-noise ratio (S/N) respectively
3:1 and 10:1 is as quantitative limit and detection limit, Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, 7- tri--
(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen detection limit be respectively
0.3,0.8,0.7,0.4 μ g/mL, Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, 7- tri--(the tertiary fourth of N-
Oxygen carbonyl methyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen be quantitatively limited to 1.5,3.5,3.0,
2.0μg/mL。
2. instrument precision is tested
Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7- tri--(N- tertbutyloxycarbonyl are taken respectively
Methyl)-Cyclen, Isosorbide-5-Nitrae, 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen sample, 50 μ g/mL, 20 μ L of sample introduction, divides respectively
Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, 7- are not continuously obtained with calculated by peak area into 6 needles
Three-(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen RSD be respectively
0.1%, 1.8%, 2.1%, 1.9%, show that instrument precision is good.
3. repeated experiment
Take Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7- tri--(N- tertbutyloxycarbonyl first
Base)-Cyclen, Isosorbide-5-Nitrae, 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen sample, 50 μ g/mL, parallel 6 parts respectively, sample introduction
20 μ L, with calculated by peak area, Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, 7- tri--(the tertiary fourth oxygen of N-
Carbonvlmethyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen RSD be respectively 2.5%, 1.5%,
1.9%, 0.8%, RSD < 3% shows that this method has good reproduction.
4. stability test
Take Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7- tri--(N- tertbutyloxycarbonyl first
Base)-Cyclen, Isosorbide-5-Nitrae, 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen sample, 50 μ g/mL respectively 0,2,4,8,12,
24,48h sample introduction, 20 μ L obtains Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae with calculated by peak area,
The RSD difference of 7- tri--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen
For 1.2%, 0.6%, 2.0%, 1.7%, RSD < 3%, illustrate that sample stability is good.
5. recovery test
Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, the 1,4,7- tri--(N- of 2mg synthesis are weighed respectively
Tert-Butoxycarbonylmethyl)-Cyclen, 6 parts of-Cyclen sample of 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl) be in 10mL capacity
In bottle, it is separately added into 1mg/mLCyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, 7- tri--(the tertiary fourth oxygen of N-
Carbonvlmethyl)-Cyclen, Isosorbide-5-Nitrae, 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen standard solution 1mL are diluted to quarter
Degree shakes up, 20 μ L of sample introduction, with calculated by peak area, brings respective standard curve into, calculate average recovery rate be respectively 100%.28,
98.61%, 95.22%, 97.56%, RSD is respectively 2.90%, 1.98%, 2.85%, 2.75%, RSD < 3%, illustrates to recycle
Rate is good.
1 recovery test result of table
4) influence that testing conditions measure Cyclen and its derivative
2 mobile phase ratio of table influences Cyclen and its derivative retention time
3 gas flow rate (N of table2) Cyclen and its derivative detection limit are influenced
4 drift tube temperature of table influences Cyclen and its derivative detection limit
Pass through mobile phase, gas flow rate (N2), drift tube temperature influence that Cyclen and its derivative are measured, preferably go out
The determination condition of Cyclen and its derivative: mobile phase: acetonitrile: water=50:50；Drift tube temperature is 90 DEG C, gas flow rate
(N2) it is 2.0L/min.
Claims (5)
1. a kind of detect Isosorbide-5-Nitrae, the method for 7,10- tetraazacyclododecanands and its derivative content, feature using HPLC-ELSD
It is, includes the following steps:
1) testing conditions are set
HPLC condition: mobile phase acetonitrile: water=30~50:50~70, isocratic elution；
ELSD condition: drift tube temperature is 75~105 DEG C, N2Air pressure 0.4~0.6Mpa, N2Flow velocity is 1.6~2.2L/min, is increased
Benefit: 2-4, not shunt mode；
2) standard curve is drawn
Cyclen, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, 1,4,7- are prepared respectively
Three-(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, the standard sample of 7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen,
It using methanol as solvent, is detected under conditions of step 1), obtains corresponding peak area, be vertical sit with the logarithm of peak area
Mark makes standard curve using the logarithm of respective substance content as abscissa；
3) sample is tested and analyzed under conditions of step 1), the standard according to the production of the peak area and step 2) of acquisition is bent
Line calculates separately out Cyclen in sample, 1,7- bis--(N- tert-Butoxycarbonylmethyl)-Cyclen, Isosorbide-5-Nitrae, 7- tri--(the tertiary fourth oxygen of N-
Carbonvlmethyl)-Cyclen, 1,4,7,10- tetra--(N- tert-Butoxycarbonylmethyl)-Cyclen content.
2. the method according to claim 1, wherein mobile phase acetonitrile: water=50:50.
3. the method according to claim 1, wherein N2Flow velocity is 2.0L/min.
4. the method according to claim 1, wherein drift tube temperature is 90 DEG C.
5. method according to claim 1 to 4, which is characterized in that chromatographic column is Super C18 column, partial size
It is 5 μm, internal diameter 4.6mm, column length 250mm.
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