CN107132297B - A kind of analyzing detecting method of pramiconazole optical isomer - Google Patents
A kind of analyzing detecting method of pramiconazole optical isomer Download PDFInfo
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- CN107132297B CN107132297B CN201710520143.9A CN201710520143A CN107132297B CN 107132297 B CN107132297 B CN 107132297B CN 201710520143 A CN201710520143 A CN 201710520143A CN 107132297 B CN107132297 B CN 107132297B
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Abstract
The invention discloses a kind of analyzing detecting methods of pramiconazole optical isomer, using liquid chromatography, the stationary phase of liquid chromatography is octadecylsilane chemically bonded silica, mobile phase is acetonitrile solution, acetonitrile concentration expressed in percentage by volume is 30-50%, 4- tert. butyl cyclohexanol in the acetonitrile solution containing effective concentration, and 4- tert. butyl cyclohexanol is cis-trans-isomer mixture.Efficiently separating for pramiconazole optical isomer can be realized in common C18 chromatographic column using method provided by the invention, application cost significantly reduces, and can save a large amount of chromatographic column consumptive material expenses.
Description
Technical field
The invention belongs to Pharmaceutical Analysis fields, and in particular to a kind of analyzing detecting method of pramiconazole optical isomer.
Background technique
Pramiconazole (Pramiconazole, SR type), chemical name 1- (4- { 4- [4- ({ (2S, 4R) -4- (2,4- difluorobenzenes
Base) -4- [(1H-1,2,4- triazol-1-yl) methyl] -1,3- dioxolanes -2- base } methoxyl group) phenyl] piperazine -1- base } benzene
Base) -3- (propane -2- base) imidazolidinone -2- alkane is one developed by Belgian BarrierTherapeutics company
Kind of Novel triazole antifungal, was still in for II a clinical trial phase stage in European Union at present, not yet lists, have it is curative for effect,
The characteristics of tolerance is good, adverse reaction lesser extent is a kind of more promising broad-spectrum antifungal medicine.
There are 2 chiral carbons in pramiconazole structure, 4 kinds of optical isomers may be generated in the synthesis process, in addition to mesh
It marks outside compound pramiconazole SR type, there are also RS type isomers, RR type isomers and SS type isomers.According to research and development alloisomerism
The associated specifications of body new drug, it is necessary to establish a set of perfect analysis method to the optical isomer impurity of pramiconazole into
The control of row quality and Product Quality Evaluation.Isomers chemical structural formula is as follows:
Zheng Xizi provide four kinds of optical isomers in a kind of pramiconazole HPLC measuring method (Chinese Medicine Leader,
In April, 2016), but this method is using chiral chromatographic column (DaicelChiralpakIC chiral column).It is well known that hand
Property chromatographic column costly, and service life is short, the liquid phase analysis method application with higher for using chiral chromatographic column to develop
Cost.
Summary of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide one kind to measure pula based on common C18 chromatographic column
The liquid phase analysis method of four kinds of optical isomers in health azoles saves development costs to reduce chromatography consumptive material expenditure.
The present invention is achieved by following technical solution:
A kind of analyzing detecting method of pramiconazole optical isomer, using liquid chromatography, the fixation of liquid chromatography
It is mutually octadecylsilane chemically bonded silica, mobile phase is acetonitrile solution, and acetonitrile concentration expressed in percentage by volume is 30-50%, the acetonitrile
4- tert. butyl cyclohexanol in aqueous solution containing effective concentration, and 4- tert. butyl cyclohexanol is cis-trans-isomer mixture.
Preferably, in the mobile phase, the effective concentration of 4- tert. butyl cyclohexanol refers to that mass-volume concentration is 1-2g/L.
Preferably, the analyzing detecting method includes following chromatographic parameter:
Chromatographic column: octadecylsilane chemically bonded silica (C18) chromatographic column；
Mobile phase A phase: 30% acetonitrile solution, the mass-volume concentration of 4- tert. butyl cyclohexanol are 1.5g/L；
Mobile phase B phase: 50% acetonitrile solution, the mass-volume concentration of 4- tert. butyl cyclohexanol are 1.5g/L；
Elution program: 0-3min, 0%B phase；3-5min, 0% → 50%B phase；5-10min, 50%B phase；
Flow velocity: 0.8-1.2mL/min；
Column temperature: 28-32 DEG C；
Detection wavelength: 208-212nm.
Preferably, flow velocity 1.0mL/min.
Preferably, column temperature is 30 DEG C.
Preferably, Detection wavelength 210nm.
Preferably, the specification of octadecylsilane chemically bonded silica chromatographic column is long 250mm, internal diameter 4.6mm, 5 μ of packing material size
m。
Preferably, the preferred Thermo of octadecylsilane chemically bonded silica chromatographic column
ScientificTMAcclaimTM120C18。
Advantages of the present invention:
The effective of pramiconazole optical isomer can be realized in common C18 chromatographic column using method provided by the invention
Separation, application cost significantly reduce, and can save a large amount of chromatographic column consumptive material expenses.
Detailed description of the invention
Fig. 1 is that the chemical structural formula of four kinds of optical isomers of pramiconazole compares；
Fig. 2 is the HPLC chromatogram of four kinds of optical isomer mixed reference substance solutions of pramiconazole；
Fig. 3 is chromatogram of the test solution under chromatographic condition of the present invention；
Fig. 4 is chromatogram of the mixed reference substance solution in the case where comparing chromatographic condition.
Specific embodiment
It is further described technical solution of the present invention combined with specific embodiments below.
The separation and measurement of 1 pramiconazole optical isomer of embodiment
One, experimental material
Shimadzu LC-20A high performance liquid chromatograph；
CPA225D electronic balance (Beijing Sai Duolisi instrument system Co., Ltd)；
Chromatographic column: Thermo ScientificTMAcclaimTM120C18；
The self-control of pramiconazole bulk pharmaceutical chemicals, pramiconazole, RS type isomers, RR type isomers and SS type isomer control product are certainly
System (purity is greater than 98.5%), the chemical structural formula of pramiconazole and its isomers is as shown in Figure 1；
4- tert. butyl cyclohexanol (CAS 98-52-2, cis-trans-isomer mixture, lark prestige science and technology, product number
107223)；
Acetonitrile is chromatographically pure, and water is deionized water, remaining reagent is that analysis is pure.
Two, experimental method and result
1, solution is prepared
Reference substance and test sample dilution: the mass-volume concentration of 30% acetonitrile solution, 4- tert. butyl cyclohexanol is
1.5g/L。
Reference substance solution: precision weighs 4 kinds of isomers standard items of pramiconazole respectively about 10mg respectively, is respectively placed in 100mL amount
It in bottle, in addition stating dilution dissolves and be settled to scale, shakes up, the reference substance solution for being 100 μ g/mL as concentration.
Mixed reference substance solution: 4 kinds of isomer control product solution are mixed in equal volume, are configured to 4 kinds of isomer concentrations point
Not Yue Wei 25 μ g/mL mixed reference substance solution.
Test solution: precision weighs pramiconazole sample 100mg, is placed in 100mL measuring bottle, in addition stating dilution dissolution
And it is settled to scale, it shakes up, the test solution for being 1mg/mL as concentration.
2, chromatographic condition
Chromatographic column: Thermo ScientificTMAcclaimTM120C18；
Mobile phase A phase: 30% acetonitrile solution, the mass-volume concentration of 4- tert. butyl cyclohexanol are 1.5g/L；
Mobile phase B phase: 50% acetonitrile solution, the mass-volume concentration of 4- tert. butyl cyclohexanol are 1.5g/L；
Elution program: 0-3min, 0%B phase；3-5min, 0% → 50%B phase；5-10min, 50%B phase；
Flow velocity: 1.0mL/min；
Column temperature: 30 DEG C；
Detection wavelength: 210nm.
3, separating degree is investigated
Pramiconazole 4 kinds of isomer control product solution, mixed reference substance solutions are taken, respectively sample introduction measurement, the results showed that, 4
The peak sequence of kind isomers is followed successively by RR type isomers, SR type isomers, RS type isomers, SS isomer form, pramiconazole
And its optical isomer baseline reaches and is kept completely separate, separating degree is all larger than 1.5, and number of theoretical plate is all larger than 10000, and tailing factor is equal
Less than 1.15, solvent peak not interference measurement.Chromatogram is shown in Fig. 2.
4, linear test
It is appropriate to weigh 4 kinds of isomer control product for precision respectively, adds dilution to dissolve and shakes up dilution, be configured to about 0.5,5,
10, the series of concentrations solution of 20,50,80,100,120 μ g/mL, sample introduction measurement, maps to concentration with peak area, is linearly returned
Return, respectively obtain the regression equation of 4 kinds of isomers, linear relationship is good, R2> 0.9998.
5, sensitivity is investigated
Precision weighs that 4 kinds of isomer control product are each appropriate, and adding dilution to dissolve and being diluted to 4 kinds of isomers peak heights is about base
3 times of line noise.As a result the minimum detectability of Isomers is each about 1.2 × 10-3μ g, high sensitivity.
6, sample recovery rate is tested
Determination of recovery rates solution is prepared according to a conventional method, calculates the rate of recovery of Isomers, as a result proves 4 kinds of pramiconazole
The rate of recovery of isomers (RSD < 1.5%, n=3) between 98-102%, meets the requirements.
7, precision and stability test
Above-mentioned mixed reference substance solution and test solution are taken, continuous sample introduction 6 times respectively, records chromatogram.As a result RSD is equal
Less than 2.0% (n=6), show that this method precision is good.
Take above-mentioned mixed reference substance solution and test solution respectively, in being placed at room temperature for, respectively at 0,4,8,12, for 24 hours into
Sample measurement, records chromatogram.As a result the peak area of 4 kinds of isomers of pramiconazole is respectively less than 2.0% (n=5) in RSD interior for 24 hours,
It is stable for 24 hours to show that mixed reference substance solution is placed at room temperature for.
8, content of isomer measures in raw material
It takes sample appropriate, prepares mixed reference substance solution and test solution according to the above method, respectively sample introduction measurement, record
Chromatogram.If any identical miscellaneous with Isomers retention time in mixed reference substance solution chromatogram in test solution chromatogram
Mass peak, by external standard method with the content of calculated by peak area Isomers.Test solution chromatogram is as shown in Figure 3.
Content of the RR type isomers in three batches of samples is respectively 0.02%, 0.03%, 0.02%；
Content of the RS type isomers in three batches of samples is respectively 0.03%, 0.02%, 0.02%；
Content of the SS type isomers in three batches of samples is respectively 0.03%, 0.02%, 0.03%.
2 comparative example of embodiment uses common acetonitrile water elution
One, experimental material
Shimadzu LC-20A high performance liquid chromatograph；
CPA225D electronic balance (Beijing Sai Duolisi instrument system Co., Ltd)；
Chromatographic column: Thermo ScientificTMAcclaimTM120C18；
The self-control of pramiconazole bulk pharmaceutical chemicals, pramiconazole, RS type isomers, RR type isomers and SS type isomer control product are certainly
System (purity is greater than 98.5%), the chemical structural formula of pramiconazole and its isomers is as shown in Figure 1；
Acetonitrile is chromatographically pure, and water is deionized water, remaining reagent is that analysis is pure.
Two, experimental method and result
1, solution is prepared
Reference substance and test sample dilution: 30% acetonitrile solution.
Reference substance solution: precision weighs 4 kinds of isomers standard items of pramiconazole respectively about 10mg respectively, is respectively placed in 100mL amount
It in bottle, in addition stating dilution dissolves and be settled to scale, shakes up, the reference substance solution for being 100 μ g/mL as concentration.
Mixed reference substance solution: 4 kinds of isomer control product solution are mixed in equal volume, are configured to 4 kinds of isomer concentrations point
Not Yue Wei 25 μ g/mL mixed reference substance solution.
2, chromatographic condition
Chromatographic column: Thermo ScientificTMAcclaimTM120C18；
Mobile phase A phase: 30% acetonitrile solution；
Mobile phase B phase: 50% acetonitrile solution；
Elution program: 0-3min, 0%B phase；3-5min, 0% → 50%B phase；5-10min, 50%B phase；
Flow velocity: 1.0mL/min；
Column temperature: 30 DEG C；
Detection wavelength: 210nm.
3, separating degree is investigated
Pramiconazole mixed reference substance solution sample introduction is taken to measure, as a result 4 kinds of isomers cannot achieve under the chromatographic condition
It separates two-by-two.Chromatogram of the mixed reference substance solution under the chromatographic condition is shown in Fig. 4.
The effective of pramiconazole optical isomer can be realized in common C18 chromatographic column using method provided by the invention
Separation, application cost significantly reduce, and can save a large amount of chromatographic column consumptive material expenses.
Claims (2)
1. a kind of analyzing detecting method of pramiconazole optical isomer, which is characterized in that including following chromatographic parameter:
Chromatographic column: octadecylsilane chemically bonded silica chromatographic column, specification are long 250mm, 4.6 mm of internal diameter, 5 μm of packing material size；
Mobile phase A phase: 30% acetonitrile solution, and the 4- tert. butyl cyclohexanol containing 1.5g/L；
Mobile phase B phase: 50% acetonitrile solution, and the 4- tert. butyl cyclohexanol containing 1.5g/L；
Elution program: 0-3min, 0% B phase；3-5min, 0% → 50% B phase；5-10min, 50% B phase；
Flow velocity: 1.0 mL/min；
Column temperature: 30 DEG C；
Detection wavelength: 210nm.
2. analyzing detecting method according to claim 1, it is characterised in that: the octadecylsilane chemically bonded silica chromatography
Column is 120 C18 chromatographic column of Thermo Scientific Acclaim.
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| CN110672753B (en) * | 2019-11-04 | 2022-05-20 | 青海省农林科学院 | Method for splitting and detecting fluorochloridone isomer |
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