CN106483202A - A kind of separation and the method measuring alitretinoin and isomer - Google Patents
A kind of separation and the method measuring alitretinoin and isomer Download PDFInfo
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Abstract
A kind of high efficiency liquid chromatography for separating and determining alitretinoin and its method for 5 kinds of isomers, chromatographic column with octadecane bonded silica gel as filler, with the mixed liquor of sour methanol solution and ether solvent as mobile phase.This method can carry out separation detection to any one or more isomer in alitretinoin and its 5 kinds of isomers simultaneously.Compared with prior art, alitretinoin is separated with Isomers all preferably, and improves separation detection efficiency.This method is applied to various preparations containing alitretinoin and its isomer, various biological sample, the detection of various cosmetics and quality control.
Description
Technical field：
The invention belongs to analytical chemistry field, it is related to a kind of method separating alitretinoin and isomer；This method further relates to survey
The method determining tretinoin and its isomer or the identical structural material adding in cosmetics.
Background technology：
Alitretinoin is a kind of endogenouss retinoic acid, is now used for the invalid chronic hand eczema of the potent glucocorticoid of local topical
Patient, is also used for treating skin kaposi's sarcoma.
Alitretinoin is easy to isomerization occur and mutual phase transformation with other isomers such as tretinoins, in synthesis and placement process
In all may be converted into other isomers：
Existing document is mainly tretinoin, the assay method of isotretinoin, but its tretinoin is reached not with the separating degree of alitretinoin
To 1.5, and the retention time of alitretinoin reaches more than 30min, all can not meet requirement to analytical effect and efficiency.
After the present inventor's contrast tretinoin, isotretinoin, find that in prior art, the relevant substance-measuring method about isotretinoin all can not
Separate alitretinoin and tretinoin very well.See as follows：
Table 1 prior art isotretinoin assay method
At present, Retinoids are applied not only to multiple dermatosis and cancer prevention and treatment, also have repeatly and send out
Give birth to bad enterprise or businessman adds the situation of tretinoin medicines in cosmetics.Therefore, research by alitretinoin and its
Isomer separation, and carry out the method for detection by quantitative and have very much realistic meaning.
Content of the invention
It is an object of the invention to provide a kind of height efficiently separating and measuring that can be used in alitretinoin and its 5 kinds of isomers
Effect liquid phase chromatogram method, and improve the efficiency of separation detection.
The technical scheme is that：
A kind of high efficiency liquid chromatography for separating and determining alitretinoin and its method for 5 kinds of isomers, are reversed phase liquid chromatography,
Chromatographic column filler is octadecyl or eight alkyl linked silica gel, purple with adopting after the mobile phase eluting containing methanol and the mixed liquor of acid
External detector is detected, it is characterized in that：T-butyl methyl ether is also contained, content accounts for mobile phase cumulative volume in mobile phase
15%-35%.
The described volume ratio of mixed liquor containing methanol and acid is：Acid:Water:Methanol=0.2～2:30～70:70～30；
Described acid is selected from one or more of phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, preferably acetic acid.
Preferably octadecyl silane grain diameter is 3.5 μm, and column length is preferably 250mm.
Other analysis conditions：
The column temperature scope that chromatographic column is suitable for is 20-40 DEG C, preferably 30 DEG C.
The flow velocity of mobile phase is 0.2-2.0ml/min, preferably 0.5-1.5ml/min, more preferably 1.0ml/min.
The Detection wavelength of UV-detector is 350nm, and detector models do not limit, and such as can use DAD or VWD detector.
In one specific embodiment of the present invention, chromatographic column is the chromatographic column (Thermo of filler for octadecyl silane
Hypersil 250×4.6mm,5μm).T-butyl methyl ether：Methanol：1% glacial acetic acid=15：60：25(v/v/v)；
Operational approach is：Take alitretinoin, isomer 1, isomer 2, isomer 3, isomer 4, isomer 5 reference substance
Each appropriate, with methanol dissolving, be configured to every 1ml contain alitretinoin 200 μ g, isomer 1, isomer 2, isomer 3,
Isomer 4, the system suitability solution of each 2 μ g of isomer 5.
Injection chromatograph of liquid, by chromatographic condition of the present invention, (chromatographic column filler is octadecyl silane, and column length is
250mm, Detection wavelength is 350nm, with t-butyl methyl ether：Methanol：1% glacial acetic acid=15：60：25 (v/v/v)) enter
Row eluting, the flow velocity of mobile phase is 1.0ml/min, and chromatographic column column oven temperature is 30 DEG C, and sampling volume is measured for 20 μ l.
The inventive method is applied to separation and the mensure of alitretinoin and 5 kinds of isomers, can be used for individually detecting a certain isomery
Body, also can concurrently separate and detect this 5 kinds of isomers.Can be used for alitretinoin crude drug and alitretinoin soft capsule, Ah
The detection of alitretinoin and its isomer and quality control in sharp tretinoin emulsifiable paste, alitretinoin gel, various cosmetics,
Can be additionally used in detecting the biological metabolite in person's body of taking alitretinoin.
Alitretinoin in example 1 Fig. 1 is separated with tretinoin and reaches 2.67, alitretinoin theoretical cam curve 12067, A Li
Tretinoin retention time is 8.831min, and the peak purity of retention time 8.831min is 0.999, the peak pair of retention time 8.831min
The factor is called 1.02；And alitretinoin is separated with tretinoin and substantially cannot separate in comparative example example 1 Fig. 2, theoretical cam curve 5678,
Alitretinoin retention time is 39.856min, and retention time is the peak purity of 39.856min is 0.825, retention time
The peak symmetrical factor of 8.831min is 1.38；By comparison example 1 and comparative example 1, draw the present invention has following helpful effect
Really.
The beneficial effects of the present invention is：
1st, preferably, specificity is strong for alitretinoin and isomer separation.
Art methods, in comparative example 1, can separate very well between other isomers, but alitretinoin is divided with tretinoin
Do not reach separation requirement from degree, in method of the present invention embodiment 1, not only can separate very well between other isomers, and
And alitretinoin is separated with tretinoin and reaches 2.67；In art methods comparative example 1, the theoretical cam curve of alitretinoin
5678, in method of the present invention embodiment 1, the theoretical cam curve of alitretinoin is 12067；Art methods comparative example 1
In, alitretinoin peak peak symmetrical factor be 1.38, peak purity be 0.825；In method of the present invention embodiment 1, A Li
Tretinoin peak peak symmetrical factor be 1.02, peak purity be 0.999.Comparative example and embodiment, Isomers peak sequence one
Cause, prior art can not be separated with tretinoin to alitretinoin, and the inventive method can be complete with tretinoin by alitretinoin
Separately, when carrying out separating alitretinoin with tretinoin, specificity is higher.
2nd, the used time is short, improves efficiency.
Art methods, in comparative example 1, Isomers are all strong than the reservation of embodiments of the invention, alitretinoin and dimension
A acid retention time is 39.856min, and the method alitretinoin in the embodiment of the present invention 1 and tretinoin retention time are respectively
8.831min being 9.995min；The present invention is higher than the separation efficiency of prior art.
3rd, result is more accurate.
The present invention due to detached specificity higher after, when carrying out assay, would not be by alitretinoin and tretinoin one
Rise and carry out content and the calculating about material as alitretinoin or tretinoin, thus more accurate than art methods.
Note：Prior art described above, refers to relevant mensure isotretinoin A in " EP7.5 version isotretinoin crude drug quality standard "
Acid and its standard method of preparation.And the former column's length 150mm of chromatographic column is changed to separation preferably long chromatographic column
250mm.
Table 2 the inventive method is contrasted with art methods
Note：
Each comparative example adopts art methods to measure, and refers specifically to rule in " EP7.5 version isotretinoin crude drug quality standard "
Fixed method, and the former column's length 150mm that standard is specified is changed to separation preferably long chromatographic column 250mm.
Each embodiment adopts the method for the present invention to detect.
Brief description
Fig. 1 be using the method for the present invention detect alitretinoin mixed isomers chromatogram, each peak from left to right, according to
Secondary it is：Isomer 4, isomer 5, isomer 2, isomer 3, alitretinoin, isomer 1；
Fig. 2 be using EP7.5 isotretinoin method measure alitretinoin mixed isomers chromatogram, each peak from a left side to
The right side, is followed successively by：Isomer 4, isomer 5, isomer 2, isomer 3, alitretinoin.(can be seen that A Liwei A
Acid and isomer 1 are not separately)；
Fig. 3 be using the method for the present invention detect alitretinoin light degradation impurity chromatogram, each peak from left to right, according to
Secondary it is：Isomer 2, alitretinoin, isomer 1, unknown impuritie 1, unknown impuritie 2；
Fig. 4 be using EP7.5 method detect alitretinoin light degradation impurity chromatogram, each peak from left to right, successively
For：Isomer 2, alitretinoin, unknown impuritie 1, unknown impuritie 2.(can be seen that alitretinoin and isomer 1
Not separately)；
Fig. 5 is the chromatogram detecting alitretinoin soft capsule using the method for the present invention, and each peak from left to right, is followed successively by
Alitretinoin, tretinoin；
Fig. 6 is chromatograph Fig. 2 detecting alitretinoin soft capsule using the method for the present invention, and each peak from left to right, is followed successively by
Alitretinoin, tretinoin.
Fig. 7 be using the method for the present invention detect alitretinoin soft capsule biological metabolism chromatogram, each peak from left to right,
It is followed successively by acitretin, alitretinoin, tretinoin.
Specific embodiment
Following illustrated embodiment is to more clearly illustrate to present disclosure, but present disclosure not only limiting
Lifted in embodiment.So, those of ordinary skill in the art carry out non-intrinsically safe according to foregoing invention content to embodiment
Improvement and adjustment, still fall within protection scope of the present invention.
Except special instruction, the condition such as the instrument of following examples and comparative example employing and chromatographic column is as follows：
Japanese Shimadzu SHIMADZU LC-20AT chromatograph of liquid, detector：UV；Chromatographic work station：LCsolution,
Chromatographic column：Octadecyl silane or eight alkyl linked silica gel, flow velocity：1.0ml/min；Chromatographic column column oven temperature is
30℃.
Embodiment 1 the inventive method detects 6 kinds of mixed isomers of alitretinoin
Take alitretinoin, isomer 1, isomer 2, isomer 3, isomer 4, isomer 5 standard substance co-dissolve in
Methanol, is configured to every 1ml and contains alitretinoin, isomer 1, isomer 2, isomer 3, isomer 4, each 2 μ g of isomer 5
System suitability solution.
Take 20 μ l injection chromatograph of liquid；
Chromatographic condition：Chromatographic column：ODS post (Thermo Hypersil 250mm × 4.6mm, 3.5 μm), Detection wavelength is
350nm, with t-butyl methyl ether：Methanol：1% acetic acid=15：60：25 (v/v/v) carry out eluting, record chromatogram.
Obtaining Fig. 1 is the chromatogram detecting 6 kinds of mixed isomers of alitretinoin using the method for the present invention.
Comparative example 1 EP7.5 isotretinoin method measures 6 kinds of mixed isomers of alitretinoin
Using instrument and chromatographic column and system suitability solution with embodiment 1.
The testing sample solution 20 μ l injection chromatograph of liquid of Example 1, by the chromatographic process of EP7.5 isotretinoin, with first
Alcohol-water-glacial acetic acid (770:225:5) carry out eluting, record chromatogram.
Obtaining Fig. 2 is the chromatogram measuring alitretinoin mixed isomers using EP7.5 isotretinoin method.
Embodiment 2 the inventive method detects alitretinoin light degradation impurity
Due to tretinoin medicines, light degradation solution isomerization, therefore alitretinoin is carried out obtaining after light forced degradation
Light degradation material is measured.
By alitretinoin crude drug, 10 hours samples under the conditions of illumination 5000XL, become 600 μ g's with methanol dilution
Sample solution, takes 10 μ l injection chromatograph of liquid；
Chromatographic condition：Chromatographic column：ODS post (Thermo Hypersil 250mm × 4.6mm, 3.5 μm), Detection wavelength
For 355nm, with t-butyl methyl ether：Methanol：2% formic acid=25：45：30 (v/v/v) carry out eluting, record chromatogram.
Obtaining Fig. 3 adopts the method for the present invention to detect the chromatogram of alitretinoin light degradation impurity.
Comparative example 2 EP7.5 method detects alitretinoin light degradation impurity
The testing sample solution 20 μ l injection chromatograph of liquid of Example 2；
Chromatographic column：ODS post (Thermo Hypersil 250mm × 4.6mm, 3.5 μm), Detection wavelength is 355nm,
Sample size is 10 μ l；Flow velocity：1.5ml/min, by the chromatographic process of EP7.5 isotretinoin, with methanol-water-glacial acetic acid
(770:225:5) carry out eluting, record chromatogram.
Obtaining Fig. 4 adopts EP7.5 method to detect the chromatogram of alitretinoin light degradation impurity.
Embodiment 3 the inventive method detection alitretinoin soft capsule (one)
Take alitretinoin soft capsule, cut off, with 10ml dichloromethane by contents melting, be subsequently adding methanol and mix and determine
Hold to 100ml, filter, obtain final product the test liquid containing about alitretinoin about 100ug/ml；Take test liquid 10 μ l；
Chromatographic condition：Eight alkyl linked silica gel chromatographic columns (Boston Green C84.6mm × 250mm, 5 μm), detection
Wavelength is 350nm, with t-butyl methyl ether：Methanol：0.5% acetic acid=35：30：35 (v/v/v) carry out eluting, record
Chromatogram.
Obtaining chromatogram is Fig. 5.
Embodiment 4 the inventive method detection alitretinoin soft capsule (two)
Except mobile phase is different, remaining is identical with embodiment 3 experiment content.
Mobile phase is：T-butyl methyl ether：Methanol：0.3% phosphoric acid=20：40：40(v/v/v).
Obtaining chromatogram is Fig. 6.
Embodiment 5 the inventive method detects alitretinoin soft capsule biological metabolite
Internal standard working solution：Take appropriate acitretin, obtain the internal standard working solution of 40 μ g/ml with methanol dilution.
Take the blood 0.5ml having taken alitretinoin soft capsule, add 4.0ug/mL internal standard acitretin acid solution 50 μ L,
The concussion 30s that is vortexed mixes, and add diethyl ether 5mL, and be vortexed concussion 3min, and 4000rpm is centrifuged 5min, shifts upper organic phase
In another point bottom test tube, put logical nitrogen stream in 40 DEG C of water-baths and volatilize.Residue is dissolved in 100 μ l methanol：DMF(1:1v/v),
Vibration 30s, 13000rpm are centrifuged 3min, take supernatant sample introduction 40 μ l；
With t-butyl methyl ether：Methanol：2% trifluoroacetic acid=23：47：30 (v/v/v) carry out eluting, record chromatogram.
Obtaining chromatogram is Fig. 7.
Claims (8)
1. a kind of employing high performance liquid chromatography separation and the method measuring alitretinoin and its 5 kinds of isomers, are reverse phase liquid color
Spectrometry, chromatographic column filler is octadecyl or eight alkyl linked silica gel, is adopted with after the mobile phase eluting containing methanol and the mixed liquor of acid
Detected with UV-detector；
Described alitretinoin and its 5 kinds of isomers are specific as follows：
Described separation and mensure, including being separately separated and detecting a certain isomer, also include concurrently separating and detect above-mentioned 6 kinds
Several or whole in isomer；
It is characterized in that：T-butyl methyl ether is also contained, content accounts for the 15%-35% of mobile phase cumulative volume in mobile phase.
2. the method described in claim 1, described mensure, including quantitative determination alitretinoin crude drug, alitretinoin system
Contained alitretinoin and its 5 kinds of isomers in agent and biological sample.
3. the method described in claim 1, described alitretinoin preparation, including alitretinoin hard capsule or soft capsule, Ah
Sharp tretinoin emulsifiable paste or alitretinoin gel, also include the cosmetics containing alitretinoin and its isomer；Described biological sample bag
Include the biological metabolite in person's body of taking alitretinoin.
4. the method described in claim 1, the described volume ratio of mixed liquor containing methanol and acid is：Acid:Water:Methanol=
0.2～2:30～70:70～30；Described acid is selected from one or more of phosphoric acid, formic acid, acetic acid, trifluoroacetic acid.
5. the method described in claim 4, described acid is acetic acid.
6. the method described in claim 1, described octadecyl silane grain diameter is 3.5 μm, and column length is 250mm.
7. the method described in claim 1, analysis condition is：The column temperature scope that chromatographic column is suitable for is 20-40 DEG C；Mobile phase
Flow velocity is 0.2-2.0ml/min；The Detection wavelength of UV-detector is 350nm.
8. the method described in claim 7, the column temperature scope that described chromatographic column is suitable for is 30 DEG C；The flow velocity of mobile phase is
0.5-1.5ml/min.
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| CN114814051A (en) * | 2022-04-02 | 2022-07-29 | 重庆市妇幼保健院(重庆市妇产科医院、重庆市遗传与生殖研究所) | Method for quantitatively detecting retinoic acid isomer |
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