CN105651900A - Method for separating and measuring process impurities in Clobetasone butyrate and preparation of Clobetasone butyrate - Google Patents
Method for separating and measuring process impurities in Clobetasone butyrate and preparation of Clobetasone butyrate Download PDFInfo
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- CN105651900A CN105651900A CN201610216909.XA CN201610216909A CN105651900A CN 105651900 A CN105651900 A CN 105651900A CN 201610216909 A CN201610216909 A CN 201610216909A CN 105651900 A CN105651900 A CN 105651900A
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- clobetasone butyrate
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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 belongs to the field of analytic chemistry and particularly relates to a method for separating and measuring process impurities in Clobetasone butyrate and a preparation of Clobetasone butyrate. According to the method, octadecylsilane chemically bonded silica is taken as a solid phase, a moving phase A and a moving phase B are taken as the moving phases for gradient elution and solid-liquid separation, and the process impurities in the preparation are one or more of A-G and I. With the adoption of the method, Clobetasone butyrate, A-G and I can be separated and detected simultaneously, the process impurities A-G and I in Clobetasone butyrate and the preparation of Clobetasone butyrate can be completely separated and detected within 44 min, the accuracy is high, and the sensitivity is good; the problem about separation and measurement of the 8 types of process impurities in Clobetasone butyrate and the preparation of Clobetasone butyrate is solved, so that controllable quality of Clobetasone butyrate and the preparation of Clobetasone butyrate is guaranteed, safety and effectiveness of a product are determined finally, and product quality is guaranteed fundamentally. By means of the method, the degree of separation is high, and the specificity is high; the method is simple to operate and has the advantage of convenience and rapidness.
Description
Technical field
The invention belongs to analytical chemistry field, be specifically related in a kind of separation determination clobetasone butyrate and preparation thereof the method for process contaminants.
Background technology
Clobetasone butyrate is to be developed by the GlaxoSmithKline PLC company of Britain, for short term therapy with control eczema and dermatitis, including atopic eczema, primary stimulus and allergic dermatitis. Listed in Britain early than 1975, after successively in Ireland, Canada, Belgium, Germany, Italy, Switzerland, Holland, Japan and other countries list, but not in U.S.'s listing. On May 5th, 2011, GLAXOWELLCOME drugmaker obtains import registration official written reply at home, and crude drug does not list at home, chloro-9 �� of clobetasone butyrate chemical name 21--fluoro-17 pregnant steroid-Isosorbide-5-Nitrae-diene-3 of Alpha-hydroxy-16 Beta-methyl, 11,20-triketone butyrate, molecular formula is C26H32ClFO5. Clobetasone butyrate structural formula is:
As a rule, a kind of impurity of the drug total content should be less than 1.0%, and single impurity content is less than 0.1%; For prepare in clobetasone butyrate process produce impurity or introducing have related substance, whether all need strictly to control in crude drug or preparation. At present in the method for disclosed separation determination clobetasone butyrate and related impurities thereof, wherein disclosed impurity A is identical with the impurity D structure in impurity list of the present invention with the impurity A in impurity list in the application, disclosed impurity F, all the other are all different, and in method, impurity A can not separate with impurity D completely with impurity F, impurity C, clobetasone butyrate main peak can not well separate with other impurities.
Therefore up to the present, the impurity of A-G and I in the application can be concurrently separated but without disclosed method report. Therefore developing and a kind of efficiently separate the method for 8 kinds of process contaminants in clobetasone butyrate and preparation thereof, quality control and degradation pathway research for medicine are all very meaningful.
Summary of the invention
In view of this, it is an object of the invention to provide process contaminants in a kind of separation determination clobetasone butyrate and preparation thereof, with process contaminants A-G and I in high efficiency liquid chromatography for separating and determining clobetasone butyrate and preparation thereof, separation and the detection of clobetasone butyrate and A-G and I can be realized simultaneously, the method separating degree is good, specificity is strong, highly sensitive;And simple to operate, there is simplicity, quick advantage.
For achieving the above object, the technical scheme is that
The method of process contaminants in separation determination clobetasone butyrate and preparation thereof, with octadecylsilane chemically bonded silica for fixing phase, solid-liquid separation is carried out for eluent gradient eluting with mobile phase A and Mobile phase B, in described preparation, process contaminants is one or more of A-G and I, and concrete structure formula is as follows:
Described mobile phase A is inorganic phase, and described Mobile phase B is organic solvent.
At present in the method for disclosed separation determination clobetasone butyrate and related impurities thereof, wherein disclosed impurity A is identical with the impurity D structure in impurity list of the present invention with the impurity A in impurity list in the application, disclosed impurity F, all the other are all different, and in method, impurity A can not separate with impurity D completely with impurity F, impurity C, clobetasone butyrate main peak can not well separate with other impurities. Method in the application successfully solves the problem that efficiently separates of process contaminants A-G and I in clobetasone butyrate and preparation thereof, and then achieves impurity and effectively control, and fundamentally ensure that product quality.
Further, described gradient elution is provided that
Described mobile phase A is water, and described Mobile phase B is acetonitrile.
Preferred as one, described gradient elution is provided that
The two of the purpose of the present invention are in that providing a kind of utilizes the method for process contaminants in high efficiency liquid chromatography for separating and determining clobetasone butyrate and preparation thereof, the chromatographic column adopted is with octadecylsilane chemically bonded silica for filler, carry out gradient elution with mobile phase A and Mobile phase B for mobile phase, enter detector and detect; Described mobile phase A is water, and described Mobile phase B is acetonitrile; In described preparation, process contaminants includes one or more of A-G and I.
Further, in described preparation, process contaminants is A-G and I, and concrete grammar comprises the following steps:
1) reference substance of process contaminants A-G and I in testing sample clobetasone butyrate and preparation thereof is taken respectively, dissolve with diluent and make testing sample and the reference substance solution of described each impurity, take testing sample clobetasone butyrate and each process contaminants reference substance solution sample introduction thereof respectively, carry out efficient liquid phase chromatographic analysis, it is determined that the retention time of testing sample clobetasone butyrate and each impurity thereof;
2) take test sample to add diluent and make need testing solution, take diluent again as blank solution, take need testing solution and blank solution sample introduction respectively, carry out efficient liquid phase chromatographic analysis, record chromatogram, by limit method according to need testing solution and the peak area ratio of the impurity content compared with impurity A-G and I in reference substance solution.
Result of determination: if there being the chromatographic peak consistent with retention time in reference substance solution record chromatogram in need testing solution record chromatogram, its peak area cannot be greater than the peak area of corresponding impurity in reference substance solution, then be judged to and meet regulation.
Preferred as one, specifically can realize according to following steps:
(1) take clobetasone butyrate appropriate, use acetonitrile sample dissolution, be configured to every 1ml sample solution containing clobetasone butyrate 1.0-3.0mg;
(2) selecting model is the chromatograph of Shimadzu LC-2010AHT, and chromatographic column model is YMC-PackODS-A (150 �� 4.6mm, 3 ��m), and mobile phase A is water; Mobile phase B is acetonitrile; The sample solution 10 �� l taking step (1) injects in chromatograph of liquid, arranging flow rate of mobile phase is 1.5ml/min, detection wavelength is 241nm, chromatographic column post case temperature is 40 DEG C, data shown according to the form below 1 carry out linear gradient elution, and completing clobetasone butyrate has separation and the mensuration of related substance.
Table 1 carries out the volume of linear gradient elution mobile phase A and Mobile phase B
Preferred as one, what described chromatographic column selected is YMC-PackODS-A chromatographic column.
Further, before separation determination, adopting acetonitrile to dissolve testing sample, the testing sample concentration of preparation is: 1.0mg/ml-3.0mg/ml.
Further, it is characterised in that the specification of described chromatographic column is 150 �� 4.6mm, 3 ��m.
Further, described flow rate of mobile phase is 0.5-2.0ml/min.
Further, described detector is UV-detector, and the detection wavelength of described detector is 210-280nm.
Further, described chromatographic column post case temperature is 25-45 DEG C.
Further, described diluent is acetonitrile.
The beneficial effects of the present invention is: the method for process contaminants in separation determination clobetasone butyrate provided by the invention and preparation thereof, adopt high performance liquid chromatography that process contaminants A-G and I in clobetasone butyrate and preparation thereof is easily separated and is detected, in 44 minutes, process contaminants A-G and I in clobetasone butyrate and preparation thereof can be kept completely separate and detects, this chromatographic system can by all for sample impurity and alkali, illumination violent degradation condition under the impurity that produces all can separate very well, it was shown that the sensitivity of this method and specificity are good. The invention solves the separation determination problem of 8 kinds of process contaminants of clobetasone butyrate and preparation thereof, ensure that the quality controllable of clobetasone butyrate and preparation thereof, and finally determine the safe and effective of product, fundamentally ensure that product quality. The method separating degree is good, and accuracy is high; And simple to operate, there is simplicity, quick advantage.
Accompanying drawing explanation
Fig. 1 is the high-efficient liquid phase chromatogram of blank solvent.
Fig. 2 is the mixed solution high-efficient liquid phase chromatogram of clobetasone butyrate and impurity A-G and I.
Fig. 3 is the high-efficient liquid phase chromatogram of clobetasone butyrate contrast test.
Fig. 4 is the high-efficient liquid phase chromatogram of clobetasone butyrate emulsifiable paste blank auxiliary.
Fig. 5 is the high-efficient liquid phase chromatogram of clobetasone butyrate emulsifiable paste.
Fig. 6 is the high-efficient liquid phase chromatogram of clobetasone butyrate alkaline degradation.
Fig. 7 is the photodegradative high-efficient liquid phase chromatogram of clobetasone butyrate.
Detailed description of the invention
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail. The experimental technique of unreceipted actual conditions in preferred embodiment, generally conventionally condition, illustrated embodiment is to better present disclosure be illustrated, but is not that present disclosure is only limitted to illustrated embodiment. So embodiment is carried out nonessential improvement and adjustment according to foregoing invention content by those of ordinary skill in the art, still fall within protection scope of the present invention.
In following example, instrument and the chromatographic condition of employing are as follows:
High performance liquid chromatograph: Shimadzu LC-2010AHT
Chromatographic column: YMC-PackODS-A (150 �� 4.6mm, 3 ��m)
Mobile phase: mobile phase A: water;
Mobile phase B: acetonitrile.
Mobile phase A and Mobile phase B according to the form below carry out linear gradient elution:
Detector detection wavelength: 241nm
Flow rate of mobile phase: 1.5ml/min
Chromatographic column post box column temperature: 40 DEG C
Sample size: 10 �� l
Diluent (dissolves the solvent of reference substance and testing sample): acetonitrile.
The chromatogram of 8 kinds of process contaminants in embodiment 1 clobetasone butyrate preparation
The preparation of impurity A-G and I reference substance solution: take impurity A-G respectively and I reference substance is about 65mg, put in 25ml measuring bottle, add acetonitrile and dissolve and be diluted to scale, shake up, obtain impurity A-G and I storing solution.Precision measures storing solution 1.0ml and puts in 100ml measuring bottle again, adds dilution in acetonitrile to scale, shakes up, and obtains impurity A-G and reference substance mixed liquor that I concentration is 26 �� g/ml.
The preparation of mixed solution: weigh test sample and be about 26mg, puts in 10ml measuring bottle, and precision pipettes impurity A-G and I reference substance mixed solution makes solution in right amount and is quantitatively diluted to scale, shakes up, to obtain final product.
Taking diluent and mixed solution respectively by above-mentioned chromatographic condition sample introduction, record chromatogram, measurement result is in Table 2. Result is shown in Fig. 1, Fig. 2.
Table 2 test determination result
Conclusion: plain dilution agent not disturbed specimen measures; Main peak and the contiguous peak-to-peak separating degree of impurity are more than 1.5; The peak-to-peak separating degree of each known impurities is more than 1.5; Above-mentioned it have been experienced that main peak separates well with impurity peaks, specificity is strong.
Comparative example
In this comparative example, except the mobile phase A adopted, B difference, all the other conditions are all identical with embodiment 1.
Mobile phase A: inorganic phase: 0.1% aqueous formic acid
Mobile phase B: organic facies: 0.1% formic acid acetonitrile solution.
In this comparative example, have employed 0.1% aqueous formic acid is mobile phase A, and with 0.1% formic acid acetonitrile solution for Mobile phase B, chromatographic column adopts WatersRP183.5um, all the other conditions are all identical with embodiment 1, and according to the form below Gradient program carries out eluting:
| Time (min) | 0 | 3 | 26 |
| Mobile phase A (%) | 57 | 57 | 43 |
| Mobile phase B (%) | 43 | 43 | 57 |
Mixed solution sample introduction in Example 1, records chromatogram, and result is shown in Fig. 3.
Conclusion: under the chromatographic condition in comparative example, impurity A can not efficiently separate with impurity F, impurity C and impurity D, and clobetasone butyrate main peak can not well separate with other impurities. Comparative example's result shows: the present invention can 8 kinds of process contaminants in separation detection clobetasone butyrate and preparation thereof better.
The impact that clobetasone butyrate is measured by embodiment 2 clobetasone butyrate emulsifiable paste adjuvant
Take clobetasone butyrate emulsifiable paste 1 (containing clobetasone butyrate 7.5mg), as need testing solution.
Taking need testing solution, by above-mentioned chromatographic condition sample introduction, record chromatogram, and carry out blank auxiliary test with method, result is shown in Fig. 4, Fig. 5.
Conclusion: blank auxiliary does not disturb the mensuration of this product, illustrates that the method for the present invention may be used for the quality testing of clobetasone butyrate emulsifiable paste.
Embodiment 3 adds a small amount of acid reagent in mobile phase and clobetasone butyrate and 8 kinds of process contaminants is easily separated
Adding the formic acid (or phosphoric acid) of 0.1% in mobile phase, other chromatographic conditions are same with embodiment 1, and mixed solution sample introduction in Example 1 records chromatogram, and result of the test is as follows:
Table 3 adds the measurement result of mixed solution when acid reagent in mobile phase
Conclusion: add acid reagent (formic acid, phosphoric acid) in mobile phase and all can well separate process contaminants in clobetasone butyrate and 8.
The mensuration of embodiment 4 clobetasone butyrate catabolite
Take this product 65mg, accurately weighed, it is placed in 25ml measuring bottle, adding the sodium hydroxide 0.4ml adding 0.1mol/l after 5ml acetonitrile makes dissolving, after placing 3 minutes, the hydrochloric acid 0.4ml adding 0.1mol/l neutralizes, add diluent and be diluted to scale, shake up, as alkaline degradation product mensuration solution.
Take this product appropriate, put in the lighting box that intensity is 4500Lx �� 500Lx about 30cm place, place 15 days (total illumination > 1.2 �� 106Lx) and sample 65.38mg afterwards, accurately weighed, put in 25ml measuring bottle, add acetonitrile dissolve and be diluted to scale with diluent, shake up, as Photodegradation Products mensuration solution.
Take above-mentioned catabolite mensuration solution sample introduction, record chromatogram, do blank assay simultaneously, record chromatogram, as shown in Figure 6, Figure 7, calculate each impurity content by area normalization method, and analyze result of the test.
Conclusion: this chromatographic system can by all for sample impurity and alkali, illumination violent degradation condition under the impurity that produces all can separate very well, it was shown that the sensitivity of this method and specificity are good.
Embodiment 5 chromatographic system is to the detection limit of clobetasone butyrate and impurity A-G and I, quantitative limit basic research
Quantitative limit solution: precision weighs each impurity reference substance, is made into certain density solution, and stepwise dilution obtains quantitative limit solution, as shown in table 4.
Detection limit solution: precision pipettes quantitative limit solution 7.0ml, puts in 20ml measuring bottle, adds diluent and is diluted to scale, shakes up, must detect limit solution, as shown in table 5.
Assay method:
Take above-mentioned quantitative limit solution continuous sample introduction 3 times, detection limit solution continuous sample introduction 2 times, calculate the ratio (signal to noise ratio) of main peak peak height and noise. Record chromatogram, result of the test is in Table 4 and table 5.
Table 4 quantitative limit measurement result
Table 5 detection limit measurement result
Conclusion: from upper watch test data it can be seen that under this chromatographic system, the detection limit of clobetasone butyrate and impurity A-G and I, quantitative limit correspond with requirement.
What finally illustrate is, above example is only in order to illustrate technical scheme and unrestricted, although the present invention being described in detail with reference to preferred embodiment, it will be understood by those within the art that, technical scheme can be modified or equivalent replacement, without deviating from objective and the scope of technical solution of the present invention, it all should be encompassed in the middle of scope of the presently claimed invention.
Claims (10)
1. the method for process contaminants in separation determination clobetasone butyrate and preparation thereof, it is characterized in that, with octadecylsilane chemically bonded silica for fixing phase, solid-liquid separation is carried out for eluent gradient eluting with mobile phase A and Mobile phase B, in described preparation, process contaminants is one or more of A-G and I, and concrete structure formula is as follows:
Described mobile phase A is inorganic phase, and described Mobile phase B is organic solvent.
2. method according to claim 1, it is characterised in that described gradient elution is provided that
Described mobile phase A is water, and described Mobile phase B is acetonitrile.
3. utilize the method for process contaminants in high efficiency liquid chromatography for separating and determining clobetasone butyrate and preparation thereof, it is characterized in that, the chromatographic column adopted is with octadecylsilane chemically bonded silica for filler, carries out gradient elution with mobile phase A and Mobile phase B for mobile phase, enters detector and detects; Described mobile phase A is water, and described Mobile phase B is acetonitrile; In described preparation, process contaminants includes one or more of A-G and I.
4. method according to claim 3, it is characterised in that in described preparation, process contaminants is A-G and I, comprises the following steps:
1) reference substance of process contaminants A-G and I in testing sample clobetasone butyrate and preparation thereof is taken respectively, dissolve with diluent and make testing sample and the reference substance solution of described each impurity, take testing sample clobetasone butyrate and each process contaminants reference substance solution sample introduction thereof respectively, carry out efficient liquid phase chromatographic analysis, it is determined that the retention time of testing sample clobetasone butyrate and each impurity thereof;
2) take test sample to add diluent and make need testing solution, take diluent again as blank solution, take need testing solution and blank solution sample introduction respectively, carry out efficient liquid phase chromatographic analysis, record chromatogram, by limit method according to need testing solution and the peak area ratio of the impurity content compared with impurity A-G and I in reference substance solution.
5. the method according to claim 1 or 3, it is characterised in that before separation determination, adopts acetonitrile to dissolve testing sample, and the testing sample concentration of preparation is: 1.0mg/ml-3.0mg/ml.
6. method according to claim 3, it is characterised in that the specification of described chromatographic column is 150 �� 4.6mm, 3 ��m.
7. method according to claim 3, it is characterised in that described flow rate of mobile phase is 0.5-2.0ml/min.
8. method according to claim 3, it is characterised in that described detector is UV-detector, the detection wavelength of described detector is 210-280nm.
9. method according to claim 3, it is characterised in that described chromatographic column post case temperature is 25-45 DEG C.
10. method according to claim 4, it is characterised in that described diluent is acetonitrile.
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Application publication date: 20160608 |