CN102109500B - Method for separating and measuring acitretin-related substances - Google Patents
Method for separating and measuring acitretin-related substances Download PDFInfo
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Abstract
The invention relates to a method for separating and quantitatively measuring acitretin-related substances, i.e. cis isomer and a 13-ethyl substitute. The method comprises the following steps: using octadecyl silane bonded silica gel as a fixed phase of a chromatographic column, using a mobile phase consisting of acetic acid aqueous solution and an organic solvent, and adopting the gradient elution. Therefore, the acitretin cis isomer and the 13-ethyl substitute can be separated and the contents of the acitretin cis isomer and the 13-ethyl substitute can be measured. The method is simple, convenient and feasible and has good reproducibility.
Description
Technical field:
The present invention relates to a kind of analytical approach of medicine, particularly use the separated Acitretin of high performance liquid chromatography and three cis-isomers and an ethyl substituent, and the method for carrying out quantitative measurement.
Background technology:
" related substance (related substances) " alleged in Pharmaceutical Analysis refers in certain drug it is not chief component thing, but the material relevant to composition.Therefore related substance detection is the important indicator of controlling drug quality.
Compound 9-(4-methoxyl-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nona tetraenoic acid) structure in there are a plurality of conjugated double bonds, therefore there is multiple cis-trans-isomer.
Alltrans 9-(4-methoxyl-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nona tetraenoic acid) commodity Acitretin by name, be a kind of skin disease medication, be used for the treatment of clinically severe psoriasis and dyskeratosis.
In the product of synthetic Acitretin, tend to produce multiple isomeride, as 11,13-di-cis, 11-cis and tri-kinds of isomeride of 13-cis simultaneously.In the synthetic product of Acitretin, also very easily produce ethyl substituent (13 are replaced formed impurity by ethyl) simultaneously.
When synthetic Acitretin, due to the complicacy of chemical reaction, when producing Acitretin, easily produce Acitretin related substance, as Acitretin cis-isomer, ethyl substituent.Due to the cis-isomer of Acitretin,, the structure of ethyl substituent and Acitretin are very close, separation is very difficult, is more difficult to quantitatively.
The analytical approach of European Pharmacopoeia is to use the chromatographic process of HPLC-cartridge PAH chromatographic column, there are many problems, ethyl substituent can not be separated with Acitretin main peak, although above-mentioned three kinds of cis-isomers can be separated with Acitretin main peak, between each cis-isomer because of completely overlapping can not be disconnected from each other.Therefore,, by the method for European Pharmacopoeia, cannot to each cis-isomer wherein existing respectively quantitatively, also cannot measure the wherein content of impurity ethyl substituent.
In the production of bulk drug, in order to ensure the quality of medicine, often not only need to measure the content of bulk drug main ingredient, but also need to control the amount of Drug-related.During the analysis of Acitretin is measured, alleged " related substance " is exactly above-mentioned cis-isomer and ethyl substituent.Therefore need to have a kind of good method, can carry out separation quantitative to " related substance " of Acitretin, this control to Acitretin quality has very important significance.
Summary of the invention
The object of this invention is to provide a kind of method that Acitretin and cis-isomer thereof and ethyl substituent are carried out to separated and quantitative measurement.
The inventor, through test of many times, has filtered out chromatographic column in suitable efficient liquid phase chromatographic analysis, the mobile condition that equates, has reached foregoing invention object.
The invention provides the separated also method of quantitative measurement of three kinds of cis-isomers of a kind of Acitretin and 13-ethyl substituent, it is characterized in that: adopt high performance liquid chromatography, chromatographic column filler is octadecylsilane chemically bonded silica, mobile phase is comprised of 0.2%～1.5% (V/V) acetic acid aqueous solution and organic solvent, and the ratio of described acetic acid aqueous solution and organic solvent (V/V) is: 10%～25%: 75%～90%; Adopt gradient elution, according to peak sequence can be by Acitretin with three kinds of cis-isomers and 13-ethyl substituent is separated and qualitative determination, peak 1 be 11,13-di-cis, peak 2 be 13-cis, peak 3 for 11-cis, peak 4 for Acitretin, peak 5 be 13-ethyl substituent.
Described organic solvent is lower alcohol or rudimentary nitrile, one or more in particular methanol, acetonitrile, ethanol.
Described acetic acid aqueous solution preferred concentration is 0.2%～0.5%.
In an example of the present invention, with octadecylsilane chemically bonded silica, be filling agent (chromatographic column ZORBAX ODS 4.6 * 250mm 5 μ m); Take 0.5% acetic acid aqueous solution: methyl alcohol (17: 83) is mobile phase; Detection wavelength is 360nm.Get 11,13-di-cis, 11-cis, 13-cis Acitretin isomeride is appropriate, adds the solution that a small amount of tetrahydrofuran dissolves and be diluted to methyl alcohol the about 0.1mg of every 1ml; Get 13-ethyl substituent appropriate, add the solution that a small amount of tetrahydrofuran dissolves and be diluted to methyl alcohol the about 0.2mg of every 1ml; After getting respectively above-mentioned two kinds of solution and mixing with Acitretin solution in right amount, by above-mentioned chromatographic condition sample introduction 20 μ l, record chromatogram.Press peak sequence, peak 1 is that 11,13-di-cis, peak 2 are that 13-cis, peak 3 are that 11-cis, peak 4 are that Acitretin, peak 5 are 13-ethyl substituent.Number of theoretical plate calculates and is not less than 5000 by Acitretin peak, and the degree of separation of Acitretin main peak and adjacent cis-isomer and 13-ethyl substituent is not less than 1.5.
By method of the present invention, not only three kinds of cis-isomers of Acitretin and ethyl substituent can be carried out to effective separation, can also its three kinds of cis-isomers 11 of quantitative measurement, the content of the content of 13-di-cis, 11-cis and 13-cis and 13-ethyl substituent.
Table 1 the inventive method and the contrast of European Pharmacopoeia method measurement result
From following examples result, can find out, this method is simple and feasible, favorable reproducibility.
Effective constituent Acitretin and three kinds of cis-isomers and ethyl substituent method for quantitatively determining thereof are, by above-mentioned high performance liquid chromatography, measure, record chromatogram, measure each cis-isomer peak area and ethyl substituent peak area, by external standard method, calculate the content of cis-isomer and ethyl substituent in Acitretin.
From embodiment 2 and embodiment 3, can find out, this quantivative approach is highly sensitive, linear relationship good.
Accompanying drawing explanation:
Figure 111, the high-efficient liquid phase chromatogram of 13-di-cis Acitretin (embodiment 1)
The high-efficient liquid phase chromatogram of Figure 21 1-cis Acitretin (embodiment 1)
The high-efficient liquid phase chromatogram of Figure 31 3-cis Acitretin (embodiment 1)
The high-efficient liquid phase chromatogram (embodiment 1) of Figure 41 3-ethyl Acitretin
The high-efficient liquid phase chromatogram of Fig. 5 Acitretin (embodiment 1)
Figure 61 1,13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent, the high-efficient liquid phase chromatogram (embodiment 1) that Acitretin mixes
Fig. 7 11, the high-efficient liquid phase chromatogram of 13-di-cis Acitretin (embodiment 2)
The high-efficient liquid phase chromatogram of Fig. 8 11-cis Acitretin (embodiment 2)
The high-efficient liquid phase chromatogram of Fig. 9 13-cis Acitretin (embodiment 2)
The high-efficient liquid phase chromatogram (embodiment 2) of Figure 10 13-ethyl Acitretin
The high-efficient liquid phase chromatogram of Figure 11 Acitretin (embodiment 2)
Figure 12 11,13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent, the high-efficient liquid phase chromatogram (embodiment 2) that Acitretin mixes
Figure 13 11,13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent, the high-efficient liquid phase chromatogram (embodiment 4) that Acitretin mixes
Figure 14 11,13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent, the high-efficient liquid phase chromatogram (embodiment 5) that Acitretin mixes
Figure 15 11,13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent, the high-efficient liquid phase chromatogram (embodiment 6) that Acitretin mixes
Figure 16 11,13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent, the high-efficient liquid phase chromatogram (embodiment 7) that Acitretin mixes
Figure 17 11,13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent, the high-efficient liquid phase chromatogram (embodiment 8) that Acitretin mixes
Embodiment:
Following examples are measured with high performance liquid chromatograph, and in embodiment, except special instruction, condition determination is all performed as follows:
High performance liquid chromatograph (U.S. Agilent), binary pump, VWD detecting device, Agilent chem workstation.
Reagent:
Methyl alcohol, chromatographically pure; Pure water; Acetic acid, analyzes pure
11,13-di-cis Acitretin standard items (lot number: 070101, content: 99.0%);
11-cis Acitretin standard items (lot number: 070208, content: 98.2%);
13-cis Acitretin standard items (lot number: 070401, content: 99.4%);
13 ethyl Acitretin standard items (lot number: 090601, content: 93.8%);
Acitretin sample (lot number: 0601001); Manufacturer is Huabang Pharmaceutical Co., Ltd., Chongqing.
Chromatographic condition: methyl alcohol-0.5% acetic acid aqueous solution (83: 17) is (V/V) mobile phase, chromatographic column is ZORBAX ODS post (250mm * 4.6mm, 5 μ m), column temperature is 25 ℃, flow velocity is 1.0ml/min, sample size: 20 μ l, detect wavelength: 360nm number of theoretical plate calculates and should be not less than 5000 by Acitretin peak.
The separating effect of embodiment 1 European Pharmacopoeia chromatographic process to cis-isomer and ethyl substituent
1, experimental apparatus and chromatographic condition
Instrument: high performance liquid chromatograph (SHIMADZU LC-2010A
hT), quaternary pump, UV detecting device, LCsolution chem workstation
Chromatographic column: HPLC-cartridge PAH, stainless steel column, 4 * 250mm, 5 μ m
Mobile phase: alcohol-water-acetic acid (90: 10: 0.3) (V/V)
Flow velocity: 0.55ml/min, sample size: 10 μ l
2, solution preparation
Get respectively and passed through 11 of structural identification, each is appropriate for 13-di-cis Acitretin, 11-cis Acitretin, 13-cis Acitretin, 13-ethyl substituent standard items, adding a small amount of tetrahydrofuran dissolves and makes certain density solution with ethanol, by above-mentioned chromatographic condition, respectively get successively 10 μ l sample introductions, record chromatogram (Fig. 1～4).
Get Acitretin sample appropriate, add the solution that a small amount of tetrahydrofuran dissolves and be diluted to ethanol the about 0.25mg of every 1ml, by above-mentioned chromatographic condition sample introduction 10 μ l, record chromatogram (Fig. 5).
After separately getting above-mentioned each standard solution and mixing with Acitretin sample solution in right amount, obtain mixed solution, by above-mentioned chromatographic condition sample introduction 10 μ l, record chromatogram (Fig. 6).
3, result
From above-mentioned chromatogram, in this chromatographic system, ethyl substituent can not be separated with Acitretin main peak, although three cis-isomers can be separated with Acitretin main peak, but completely overlapping between three cis-isomers, can not be separated from each other, therefore cannot carry out quantitatively ethyl substituent, also cannot carry out respectively quantitatively three cis-isomers.
The chromatogram of embodiment 2 cis-isomers and ethyl substituent and detectability, quantitative limit fundamental research
1, LC is qualitative
Get and pass through 11 of structural identification, 13-di-cis Acitretin standard items are appropriate, add the solution that a small amount of tetrahydrofuran dissolves and be diluted to methyl alcohol the about 0.1mg of every 1ml, by above-mentioned chromatographic condition sample introduction 20 μ l, record chromatogram (Fig. 7).
Get that to pass through the 11-cis Acitretin standard items of structural identification appropriate, add the solution that a small amount of tetrahydrofuran dissolves and be diluted to methyl alcohol the about 0.1mg of every 1ml, by above-mentioned chromatographic condition sample introduction 20 μ l, record chromatogram (Fig. 8).
Get that to pass through the 13-cis Acitretin standard items of structural identification appropriate, add the solution that a small amount of tetrahydrofuran dissolves and be diluted to methyl alcohol the about 0.1mg of every 1ml, by above-mentioned chromatographic condition sample introduction 20 μ l, record chromatogram (Fig. 9).
Get that to pass through the 13-ethyl substituent standard items of structural identification appropriate, add the solution that a small amount of tetrahydrofuran dissolves and be diluted to methyl alcohol the about 0.2mg of every 1ml, by above-mentioned chromatographic condition sample introduction 20 μ l, record chromatogram (Figure 10).
Get Acitretin sample appropriate, add the solution that a small amount of tetrahydrofuran dissolves and be diluted to methyl alcohol the about 0.5mg of every 1ml, by above-mentioned chromatographic condition sample introduction 20 μ l, record chromatogram (Figure 11).
After separately getting above-mentioned each standard solution and mixing with Acitretin sample solution in right amount, obtain mixed solution, by above-mentioned chromatographic condition sample introduction 20 μ l, record chromatogram (Figure 12).
From above-mentioned chromatogram, in this chromatographic system, three cis-isomers of Acitretin and its and ethyl substituent are all separated good.Go out peak position respectively: peak 1 is that 11,13-di-cis Acitretin peak, peak 2 are that 13-cis Acitretin peak, peak 3 are that 11-cis Acitretin peak, peak 4 are that Acitretin peak, peak 5 are 13-ethyl substituent peak.
2, detectability
Get in " 1 " each standard solution appropriate, add methyl alcohol stepwise dilution, when signal to noise ratio (S/N ratio) reaches 3: 1, be detectability solution, by above-mentioned chromatographic condition, respectively get 20 μ l sample introductions, continuous 2 times, refer to table 1.
The detectability of table 2 chromatographic system to cis-isomer and ethyl substituent
In this chromatographic system 11, the detectability of 13-di-cis Acitretin is 2.4 * 10
-8g/ml, the detectability of 11-cis Acitretin is 3.0 * 10
-8g/ml, the detectability of 13-cis Acitretin is 1.4 * 10
-8g/ml, the detectability of 13-ethyl Acitretin is 1.5 * 10
-7g/ml, 0.01% isomer impurities all can be examined and arrive, and 0.03% ethyl substituent can be examined and arrive.
3, quantitative limit
Get in " 1 " each standard solution appropriate, add methyl alcohol stepwise dilution, when signal to noise ratio (S/N ratio) reaches 10: 1, be quantitative limit solution, by above-mentioned chromatographic condition, respectively get 20 μ l sample introductions, continuous 3 times, refer to table 2.
The quantitative limit of table 3 chromatographic system to cis-isomer and ethyl substituent
In this chromatographic system, the quantitative limit of 11-cis Acitretin is 1 * 10
-7g/ml, the quantitative limit of 13-cis Acitretin is 5 * 10
-8g/ml, the quantitative limit of 13-ethyl Acitretin is 5 * 10
-7g/ml.
Cis-isomer and ethyl substituent assay in embodiment 3 Acitretin bulk drugs
1, assay method
With octadecylsilane chemically bonded silica, it is filling agent; 0.5% acetic acid aqueous solution-the methyl alcohol (17: 83) of take is mobile phase; Detection wavelength is 360nm.Get 11,13-di-cis Acitretin, 11-cis Acitretin, each is appropriate for 13-cis Acitretin standard items, after adding a small amount of tetrahydrofuran and dissolving with methyl alcohol be diluted to every 1ml each approximately containing 11, the solution of 13-di-cis Acitretin 0.5 μ g, 11-cis Acitretin 0.5 μ g, 13-cis Acitretin 1.5 μ g, 13-ethyl Acitretin 2.5 μ g, by above-mentioned chromatographic condition sample introduction 20 μ l, records chromatogram.Number of theoretical plate calculates and is not less than 5000 by Acitretin, and the degree of separation of Acitretin peak and adjacent isomeride and ethyl substituent should be not less than 1.5.
Get Acitretin appropriate, after adding a small amount of tetrahydrofuran and dissolving, with methyl alcohol dilution, make every 1ml approximately containing the solution of 0.5mg, shake up, precision is got 20 μ l injection liquid chromatographies, record chromatogram, measure each cis-isomer peak area and ethyl substituent peak area, by impurity reference substance counter point, calculate the content of cis-isomer and ethyl substituent in Acitretin.
2, the range of linearity
Precision takes each cis-isomer standard items respectively, is verifying that separately in scope, preparing respectively several concentration tests.With the corresponding corresponding average peak area of sample average concentration, do regression curve, calculate regression equation and corresponding linear regression coeffficient.Obtain:
11-cis Acitretin regression equation is: Y=90.22189*X-0.139022r=0.99998 (n=6),
13-cis Acitretin regression equation is: y=156.08203*X+1.55239r=0.99997 (n=6),
13-ethyl Acitretin regression equation is: Y=135.50404X+6.44316r=0.99968 (n=5).
Result shows:
11-cis Acitretin is 1 * 10
-7g/ml～2.5 * 10
-6within the scope of g/ml,
13-cis Acitretin is 5 * 10
-8g/ml～2.5 * 10
-6within the scope of g/ml,
13-ethyl Acitretin is 5 * 10
-7g/ml～7.5 * 10
-6within the scope of g/ml, peak area and concentration linear relationship are good.
3, sample detection
Getting Acitretin consecutive numbers, to criticize finished product appropriate, adds after a small amount of tetrahydrofuran dissolves, to add methyl alcohol and be diluted to every 1ml approximately containing the solution of 0.5mg, and sample introduction 20 μ l, record chromatogram as stated above.Its cis-isomer and ethyl substituent content detection data are in Table 3.
Cis-isomer and ethyl substituent content (%) in table 4 Acitretin
Mobile phase: methyl alcohol-0.2% acetic acid aqueous solution (83: 17) (V/V)
Mixed solution compound method is with embodiment 2.
Assay method
Get mixed solution 20 μ l sample introductions, record chromatogram.Result Acitretin and its three kinds of cis-isomers and ethyl substituent under this chromatographic condition all can reach baseline separation, can be for the content of each cis-isomer of quantitative measurement and 13-ethyl substituent.Separating effect is shown in Figure 13.Peak sequence is with embodiment 2.
1, experimental apparatus and chromatographic condition
Mobile phase: methyl alcohol-1.5% acetic acid aqueous solution (83: 17) (V/V)
2, mixed solution preparation
Compound method is with embodiment 2.
3, assay method
Get mixed solution 20 μ l sample introductions, record chromatogram.Result Acitretin and its three kinds of cis-isomers and ethyl substituent under this chromatographic condition all can reach baseline separation, can be for the content of each cis-isomer of quantitative measurement and 13-ethyl substituent.Separating effect is shown in Figure 14.Peak sequence is with embodiment 2.
1, experimental apparatus and chromatographic condition
Mobile phase: methyl alcohol-0.5% acetic acid aqueous solution (90: 10) (V/V)
2, mixed solution preparation
Compound method is with embodiment 2.
3, assay method
Get mixed solution 20 μ l sample introductions, record chromatogram.Result Acitretin and its three kinds of cis-isomers and ethyl substituent under this chromatographic condition all can reach baseline separation, can be for the content of each cis-isomer of quantitative measurement and 13-ethyl substituent.Separating effect is shown in Figure 15.Peak sequence is with embodiment 2.
Embodiment 7
1, experimental apparatus and chromatographic condition
Mobile phase: methyl alcohol-acetonitrile-0.5% acetic acid aqueous solution (50: 25: 25) (V/V)
2, mixed solution preparation
Compound method is with embodiment 2.
3, assay method
Get mixed solution 20 μ l sample introductions, record chromatogram.Result Acitretin and its three kinds of cis-isomers and ethyl substituent under this chromatographic condition all can reach baseline separation, can be for the content of each cis-isomer of quantitative measurement and 13-ethyl substituent.Separating effect is shown in Figure 16.Peak sequence is with embodiment 2.
1, experimental apparatus and chromatographic condition
Mobile phase: methyl alcohol-ethanol-0.5% acetic acid aqueous solution (70: 10: 20) (V/V)
2, mixed solution preparation
Compound method is with embodiment 2.
3, assay method
Get mixed solution 20 μ l sample introductions, record chromatogram.Result Acitretin and its three kinds of cis-isomers and ethyl substituent under this chromatographic condition all can reach baseline separation, can be for the content of each cis-isomer of quantitative measurement and 13-ethyl substituent.Separating effect is shown in Figure 17.Peak sequence is with embodiment 2.
Claims (3)
- One kind separated and measure the method for related substance in Acitretin synthetic product by high performance liquid chromatography, use octadecylsilane chemically bonded silica to make the fixedly phase of chromatographic column, it is characterized by: acetic acid aqueous solution and organic solvent that mobile phase is 0.2%～0.5% by volume ratio form, the ratio of described acetic acid aqueous solution and organic solvent is: 10%～25%:75%～90%, and described organic solvent is lower alcohol or rudimentary nitrile;Described related substance is 11 of the 13-ethyl substituent of Acitretin and Acitretin, 13-di-cis, 13-cis, tri-kinds of cis-isomers of 11-cis;The quilitative method of described related substance is: according to peak sequence: peak 1 be 11,13-di-cis, peak 2 be 13-cis, peak 3 for 11-cis, peak 4 for Acitretin, peak 5 be 13-ethyl substituent.
- 2. method claimed in claim 1, to Acitretin and cis-isomer thereof and the quantitative method of 13-ethyl substituent, be, measure respectively the area at described peak 1, peak 2, peak 3, peak 4 and peak 5, by external standard method, calculate the content of cis-isomer and ethyl substituent in Acitretin.
- 3. the method described in claim 1 or 2, described organic solvent is selected from one or more in methyl alcohol, acetonitrile or ethanol.
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| Title |
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| N.R.Al-Mallah，et al.Rapid determination of acitretin or isotretinoin and their major metabolites by high-performance liquid chromatography.《Analytical letters》.1988,第21卷(第9期), * |
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