CN105388237B - Detection method for 3-acetamido phthalic acid in Apremilast - Google Patents
Detection method for 3-acetamido phthalic acid in Apremilast Download PDFInfo
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- CN105388237B CN105388237B CN201510999860.5A CN201510999860A CN105388237B CN 105388237 B CN105388237 B CN 105388237B CN 201510999860 A CN201510999860 A CN 201510999860A CN 105388237 B CN105388237 B CN 105388237B
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- phthalic acid
- dihydrogen phosphate
- acetonitrile
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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
- G01N30/60—Construction of the column
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
The invention discloses a detection method for 3-acetamido phthalic acid in Apremilast. According to the method, amide-type hydrophilic interaction chromatography is adopted to effectively separate and detect the 3-acetamido phthalic acid in Apremilast. The detection result is accurate and reliable, the detection method has the advantages that the linear relation is excellent, the degree of precision is high, stability is good, repeatability is good, the recovery rate is high and operation is easy and convenient. The detection method is suitable for application and popularization.
Description
Technical field
The present invention relates to the detection method of impurity is and in particular to the detection of 3- acetylamino phthalic acid in Apremilast
Method.
Background technology
Apremilast (apremilast, (s) -2- [1- (3- ethoxy-4-methoxyphenyl) -2- methylsulfonylethyl] -
4- acetylaminoisoindoline -1,3- diketone, molecular formula: c22h24n2o7S, molecular weight: be 460.5) to be given birth to by U.S. celgene
Thing technology company develops, and March 21 in 2014, food and medicine Surveillance Authority of the Nikkei U.S. (fda) ratified for active type silver of being grown up
The treatment of bits disease arthritis (psa), trade name otezla.
In Apremilast product, often there are plurality of impurities, such as its r configuration enantiomers, 3- amino are adjacent
Phthalic acid, 3- acetylamino phthalic acid and other various intermediate and catabolite.
Because the presence of impurity can have a strong impact on the quality control of medicine and drug safety it is therefore desirable to various in medicine
The content of impurity is detected and is monitored.
Therefore, for solving the above problems, existing many document reports (such as Chinese patent cn104458961a,
Cn104792913a, cn105136933a, cn104820028a) the detection side of r configuration enantiomers impurity in Apremilast
Method.However, for the 3- acetylamino phthalic acid in Apremilast, still there is no the report of related detecting method at present.
Content of the invention
For solving the above problems, the invention provides in a kind of Apremilast 3- acetylamino phthalic acid detection side
Method it is characterised in that: it comprises the following steps:
A, prepare need testing solution:
Take Apremilast sample to be measured, flow phased soln, filters or does not filter, prepares need testing solution；
B, prepare the reference substance solution of 3- acetylamino phthalic acid:
Take 3- acetylamino phthalic acid reference substance, flow phased soln, prepares 3- acetylamino phthalic acid
Reference substance solution；
C, respectively by need testing solution and reference substance solution injection high performance liquid chromatograph detection, chromatographic condition is as follows:
Chromatographic column: chromatographic column with hydrophilic function；
Mobile phase: acetonitrile -0.02mol/l phosphate dihydrogen salt solution or methanol -0.02mol/l phosphate dihydrogen salt solution；Institute
State phosphate dihydrogen salt solution and be selected from sodium dihydrogen phosphate or potassium dihydrogen phosphate；
Detection wavelength: 230 ± 10nm, preferred Detection wavelength is 230 ± 2nm；
D, it is calculated the content of 3- acetylamino phthalic acid in Apremilast sample according to testing result.
Further, in step c, described chromatographic column with hydrophilic function is the chromatograph with the silica gel of amide linkage as filler
Post.Further, the silica gel of described amide linkage is the silica gel of acrylamide bonding.Further, in step c, described
The specification of chromatographic column is: internal diameter 4.6mm, length 250mm, 5 μm of packing material size.Further, in step c, described chromatographic column
100a ° of model venusil hilic.
Further, in step c, the volume ratio of described methanol or acetonitrile and phosphate dihydrogen salt solution be 80%:20%～
90%:10%.
Further, in step c, described mobile phase is the mixed solution of following volume ratios:
Acetonitrile -0.02mol/l potassium dihydrogen phosphate=80:20, acetonitrile -0.02mol/l potassium dihydrogen phosphate=85:
15th, acetonitrile -0.02mol/l potassium dihydrogen phosphate=90:10, methanol -0.02mol/l potassium dihydrogen phosphate=80:20, first
Alcohol -0.02mol/l potassium dihydrogen phosphate=85:15, methanol -0.02mol/l potassium dihydrogen phosphate=90:10, acetonitrile -
0.02mol/l sodium dihydrogen phosphate=80:20, acetonitrile -0.02mol/l sodium dihydrogen phosphate=85:15 or acetonitrile -
0.02mol/l sodium dihydrogen phosphate=90:10.
Further, in step c, the column temperature of described chromatographic condition is 30 DEG C～40 DEG C, flow velocity be 0.8ml/min～
1.2ml/min.
Further, in step c, the column temperature of described chromatographic condition is 30 DEG C～35 DEG C, flow velocity be .8ml/min～
1.0ml/min.
Further it is characterised in that: in step c, the sample size of described chromatographic condition is 20 μ l.
Chromatographic column with hydrophilic function refers to be applied to hydrophilic Interaction Chromatography (hydrophilic interaction liquid
Chromatography, hilic) chromatographic column.Hilic is a kind of new using polar stationary phase and water-water-miscible organic solvent d
Type chromatographic isolation means, hilic can overcome the shortcomings of normal-phase chromatography and reversed phase chromatography in polar compound separation process, past
Toward the distinct separation selectivity with reversed phase chromatography can be provided.Inventor also in the screening of chromatographic column it was also found that anti-phase
Chromatograph can not accurately detect the 3- acetylamino phthalic acid in Apremilast.
In the hydrophilic Interaction Chromatography fixing phase of silica matrix, according to its material, it is broadly divided into underivatized silica gel type, ammonia
Fundamental mode, cyano group type, glycol fundamental mode, acid amide type, poly- (butanimide) type, sugar-type and amphoteric ion type bonding facies pattern.At this
In bright specific embodiment, use the chromatographic column of acid amide type.Under normal circumstances, compare nh 2 column, amide post has more preferably
Stability.
Tests prove that, in Apremilast of the present invention, the detection method of 3- acetylamino phthalic acid, uses acyl
The chromatographic column with hydrophilic function of amine type, effectively by 3- acetylamino phthalic acid separation detection in Apremilast out, detection knot
Fruit accurately, reliable, and have that linear relationship is excellent, precision is high, good stability, the reproducible, response rate good, easy and simple to handle
Many advantages, such as, it is suitable for popularization and application.
Obviously, the above according to the present invention, according to ordinary technical knowledge and the customary means of this area, without departing from
Under the premise of the present invention above-mentioned basic fundamental thought, modification, replacement or the change of other various ways can also be made.
The specific embodiment of form by the following examples, remakes further specifically to the above of the present invention
Bright.But this scope being interpreted as the above-mentioned theme of the present invention should not be only limitted to Examples below.All based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Brief description
Fig. 1 is the testing result to system suitability for embodiment 1 the inventive method；
Fig. 2 is the testing result to mixed solution for the embodiment 1 contrast test method；
Fig. 3 is the canonical plotting of embodiment 13；
Fig. 4-6 is the testing result of embodiment 13 specificity test: Fig. 4 is (a) need testing solution；Fig. 5 is (b) reference substance
Solution；Fig. 6 is (c) solvent blank solution.
Specific embodiment
Used in the specific embodiment of the invention, raw material, equipment are known product, are obtained by buying commercially available prod.
High performance liquid chromatograph (model: lc-20at binary pump, manufacturer: Japanese Shimadzu Corporation).
Electronic balance (model: auw220d, manufacturer: Japanese Shimadzu Corporation).
Apremilast (lot number: y150102, source: Chengdu hundred Yu Jinge Lay pharmaceutcal corporation, Ltd).
Apremilast reference substance (lot number: y150101, source: Chengdu hundred Yu Jinge Lay pharmaceutcal corporation, Ltd).
3- acetylamino phthalic acid reference substance (lot number: ap-i, source: the limited public affairs of Chengdu hundred abundant gold pavilion Lay Pharmaceutical
Department).
Embodiment 1
1st, the determination of Detection wavelength
Precision weighs Apremilast in right amount, is configured to mobile phase (acetonitrile -0.02mol/l potassium dihydrogen phosphate=85:15)
Concentration is the solution of 20 μ g/ml, as need testing solution.
It is appropriate, with mobile phase (acetonitrile -0.02mol/l phosphoric acid that precision weighs reference substance (3- acetylamino phthalic acid)
Potassium dihydrogen=85:15) it is configured to the solution that concentration is 20 μ g/ml, as reference substance solution.
Take above-mentioned need testing solution, reference substance solution, be scanned in 200nm～400nm wave-length coverage, test knot
Fruit is shown in Table 1.
Table 1, the UV scanning result of the present invention
| Project | Spike length (nm) | Peak value | Paddy wavelength (nm) | Valley |
| Need testing solution | 230 | 0.617 | 215 | 0.226 |
| Reference substance solution | 229 | 0.834 | 276 | 0.006 |
Result of the test shows, Detection wavelength, in the range of 220nm～230nm, is suitable for the high performance liquid chromatography of the present invention
Detection method；Preferably, Detection wavelength is 230 ± 2nm.
2nd, system suitability
Prepare need testing solution: weigh Apremilast 25mg, be placed in 50ml measuring bottle, plus mobile phase (acetonitrile -0.02mol/
L potassium dihydrogen phosphate=85:15) appropriate, shake 10 minutes, plus mobile phase is diluted to scale, shakes up, as need testing solution.
Preparation reference substance solution: weigh 3- acetylamino phthalic acid reference substance 5mg, be placed in 100ml measuring bottle, accurate
Measure 1ml, be placed in 100ml measuring bottle, plus mobile phase (acetonitrile -0.02mol/l potassium dihydrogen phosphate=85:15) is diluted to scale,
Shake up, as reference substance solution.
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
System suitability: take Apremilast 0.5mg, 3- acetylamino phthalic acid reference substance 0.5 μ g, add
1ml mobile phase (acetonitrile -0.02mol/l potassium dihydrogen phosphate=85:15), as system suitability solution；The 20 μ l systems that measure are fitted
Inject chromatograph of liquid with property solution, record chromatogram, the separating degree between Apremilast and 3- acetylamino phthalic acid
2.0 should be not less than, theoretical cam curve is pressed Apremilast peak and calculated and should be not less than 2000.
The testing result of system suitability is shown in Fig. 1, Apremilast (retention time is 3.038min) and 3- acetyl ammonia
Separating degree between base phthalic acid reference substance (retention time is 6.469min) is 10.782, and theoretical cam curve is (by 3- second
Acylamino- phthalic acid chromatographic peak calculates) it is 8891, hydrophilic Interaction Chromatography of the present invention can be used for detecting 3- in Apremilast
The content of acetylamino phthalic acid
3rd, high-efficiency liquid chromatography method for detecting
Prepare need testing solution: weigh Apremilast 25mg, be placed in 50ml measuring bottle, plus mobile phase (acetonitrile -0.02mol/
L potassium dihydrogen phosphate=85:15) appropriate, shake 10 minutes, plus mobile phase is diluted to scale, shakes up, as need testing solution.
Preparation reference substance solution: weigh 3- acetylamino phthalic acid reference substance 5mg, be placed in 100ml measuring bottle, accurate
Measure 1ml, be placed in 100ml measuring bottle, plus mobile phase (acetonitrile -0.02mol/l potassium dihydrogen phosphate=85:15) is diluted to scale,
Shake up, as reference substance solution.
Respectively by need testing solution and reference substance solution injection high performance liquid chromatograph detection, entered using hydrophilic Interaction Chromatography
Row detection, chromatographic condition is as follows:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
High performance liquid chromatography detection need testing solution of the present invention, result is: does not detect 3- acetylamino neighbour's benzene in test sample
Dioctyl phthalate.
Comparative experimental example is detected using reversed-phase liquid chromatography
According to Apremilast from the plan relevant substance detecting method of quality standard:
The filler of chromatographic column: with octadecylsilane chemically bonded silica be filler (inertsil ods3,250 ×
4.6mm, 5 μm)
Mobile phase: with acetonitrile -0.02mol/l potassium dihydrogen phosphate (50:50) as mobile phase；
Flow velocity: 1.0ml/min；
Detection wavelength: 216nm；
Preparation reference substance solution: weigh 3- acetylamino phthalic acid reference substance 25mg, be placed in 50ml measuring bottle, plus stream
Dynamic mutually appropriate, shake 0 minute, plus mobile phase is diluted to scale, shakes up, as need testing solution.
Testing result is shown in Fig. 2, and the retention time of 3- acetylamino phthalic acid is 3.104min, and appearance time leans on very much
Before, interference is big, is not suitable for the needs of this product 3- acetylamino phthalic acid detection.
Embodiment 2
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；As: model venusil of chromatographic column
100a ° of hilic, specification is: internal diameter is 4.6mm, and length is 250mm, and filler particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
3.038min) separating degree and 3- acetylamino phthalic acid reference substance (being 6.469min for its retention time) between is
10.782, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 8891,3- acetylamino O-phthalic
The tailing factor of acid color spectral peak is 1.036.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 3
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；As: model venusil of chromatographic column
100a ° of hilic, specification is: internal diameter is 4.6mm, and length is 250mm, and filler particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 80:20)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
2.713min) separating degree and 3- acetylamino phthalic acid reference substance (being 5.217min for its retention time) between is
6.871, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 9811,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 1.005.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 4
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；As: model venusil of chromatographic column
100a ° of hilic, specification is: internal diameter is 4.6mm, and length is 250mm, and filler particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 90:10)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
4.389min) separating degree and 3- acetylamino phthalic acid reference substance (being 9.961min for its retention time) between is
12.128, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 5617,3- acetylamino O-phthalic
The tailing factor of acid color spectral peak is 1.172.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 5
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；As: model venusil of chromatographic column
100a ° of hilic, specification is: internal diameter is 4.6mm, and length is 250mm, and filler particle diameter is 5 μm；
Mobile phase: methanol -0.02mol/l potassium dihydrogen phosphate (volume ratio is 80:20)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
3.751min) separating degree and 3- acetylamino phthalic acid reference substance (being 7.581min for its retention time) between is
7.113, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 6113,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 1.272.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 6
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: methanol -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
4.017min) separating degree and 3- acetylamino phthalic acid reference substance (being 8.552min for its retention time) between is
8.123, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 5896,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 1.189.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 7
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: methanol -0.02mol/l potassium dihydrogen phosphate (volume ratio is 90:10)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
4.585min) separating degree and 3- acetylamino phthalic acid reference substance (being 10.237min for its retention time) between is
7.926, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 7712,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 1.387.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 8
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l sodium dihydrogen phosphate (volume ratio is 80:20)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
4.222min) separating degree and 3- acetylamino phthalic acid reference substance (being 8.825min for its retention time) between is
11.727, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 6565,3- acetylamino O-phthalic
The tailing factor of acid color spectral peak is 0.988,.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 9
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l sodium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
3.973min) separating degree and 3- acetylamino phthalic acid reference substance (being 7.028min for its retention time) between is
7.751, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 7201,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 0.991.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 10
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l sodium dihydrogen phosphate (volume ratio is 90:10)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
4.339min) separating degree and 3- acetylamino phthalic acid reference substance (being 7.656min for its retention time) between is
8.889, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 7001,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 1.022.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 11
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 30 DEG C；
Flow velocity: 0.8ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
3.572min) separating degree and 3- acetylamino phthalic acid reference substance (being 8.229min for its retention time) between is
9.511, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 6887,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 1.04.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
Embodiment 12
Detected using hydrophilic Interaction Chromatography:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 40 DEG C；
Flow velocity: 1.2ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and result shows: (retention time is Apremilast
2.887min) separating degree and 3- acetylamino phthalic acid reference substance (being 5.955min for its retention time) between is
6.262, theoretical cam curve (calculating by 3- acetylamino phthalic acid chromatographic peak) is 8981,3- acetylamino phthalic acid
The tailing factor of chromatographic peak is 0.997.
It can be seen that, hydrophilic Interaction Chromatography of the present invention can accurately detect containing of 3- acetylamino phthalic acid in Apremilast
Amount.
The chromatographic condition screening of embodiment 13 present invention
1st, mobile phase screening test
Different mobile phases are selected to carry out screening test, other chromatographic conditions are as follows:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: table 2；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and testing result is shown in Table 2.
Table 2 mobile phase screening test result
In table 2, mobile phase " for example: acetonitrile -0.02mol/l potassium dihydrogen phosphate (85:15) " has Chinese Pharmacopoeia 2015 years
The implication that version generally has, wherein 85:15 represents the volume ratio of acetonitrile and 0.02mol/l potassium dihydrogen phosphate (85:15)；During reservation
Between refer to the retention time of 3- acetylamino phthalic acid；Separating degree refers to Apremilast and 3- acetylamino phthalic acid
Between separating degree；Tailing factor refers to the tailing factor of 3- acetylamino phthalic acid chromatographic peak；Theoretical cam curve refers to
Theoretical cam curve (is calculated by Apremilast peak).
Result of the test shows, acetonitrile -0.02mol/l potassium dihydrogen phosphate (80:20), acetonitrile -0.02mol/l potassium dihydrogen phosphate
(85:15), acetonitrile -0.02mol/l potassium dihydrogen phosphate (90:10), methanol -0.02mol/l potassium dihydrogen phosphate (80:20), methanol -
0.02mol/l potassium dihydrogen phosphate (85:15), methanol -0.02mol/l potassium dihydrogen phosphate (90:10), acetonitrile -0.02mol/l phosphoric acid
Sodium dihydrogen (80:20), acetonitrile -0.02mol/l sodium dihydrogen phosphate (85:15), acetonitrile -0.02mol/l sodium dihydrogen phosphate (90:10)
When, it is suitable for the content for detecting 3- acetylamino phthalic acid in Apremilast.
2nd, column temperature and flow velocity screening test
Different column temperatures and flow velocity is selected to carry out screening test, other chromatographic conditions are as follows:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: table 3；
Flow velocity: table 3；
Detection wavelength: 230nm；
Sample size: 20 μ l.
Method according to embodiment 1 carries out system suitability, and testing result is shown in Table 3:
Table 3 column temperature and flow velocity screening test result
In table 3, retention time refers to the retention time of 3- acetylamino phthalic acid；Separating degree refer to Apremilast with
Separating degree between 3- acetylamino phthalic acid；Tailing factor refers to the tailing factor at Apremilast peak；Theoretical cam curve
Refer to theoretical cam curve (calculating by Apremilast peak).
Result of the test shows, under different column temperatures and flow velocity, the inventive method all can effectively accurately detect in Apremilast
Octylated diphenylamine content, preferred column temperature be 30 DEG C～35 DEG C；Preferably flow velocity is 0.8ml/min～1.0ml/min.
The Method validation of embodiment 14 the inventive method
In Method validation, chromatographic condition is all as follows:
The filler of chromatographic column: the silica gel with acrylamide bonding is filler；
100a ° of the model venusil hilic of chromatographic column, specification is: internal diameter is 4.6mm, and length is 250mm, filling
Agent particle diameter is 5 μm；
Mobile phase: acetonitrile -0.02mol/l potassium dihydrogen phosphate (volume ratio is 85:15)；
Column temperature: 35 DEG C；
Flow velocity: 1.0ml/min；
Detection wavelength: 230nm；
Sample size: 20 μ l.
1st, linear relationship
Take reference substance (3- acetylamino phthalic acid), make a series of comparison of concentration in table 4 with flowing phase dilution
Product solution.According to above-mentioned chromatographic condition, detected respectively, testing result is shown in Table 4.
The testing result of table 4 linear relationship test
With 3- acetylamino O-phthalic acid concentration x as abscissa, peak area y is vertical coordinate, carries out linear regression, must return
The equation is returned to be: y=59964x-13865, r2=0.999.
Result of the test shows, the concentration of 3- acetylamino phthalic acid in the range of 0.171 μ g/ml～21.4 μ g/ml,
Its peak area is in good linear relationship with measuring concentration.
2nd, specificity
Prepare need testing solution, reference substance solution according to the inventive method and prepare the mobile phase as solvent.
Precision measures above-mentioned each solution 20 μ l injection chromatograph of liquid, records chromatogram, sees Fig. 4-6:(a) test sample is molten
Liquid；(b) reference substance solution；(c) solvent blank solution.
Result of the test shows, blank solution will not be to 3- acetylamino in hydrophilic Interaction Chromatography of the present invention detection Apremilast
The method of phthalate content interferes.
3rd, precision
Take 3- acetylamino phthalic acid reference substance appropriate, accurately weighed, plus flowing phased soln quantitative dilution make
Solution containing 0.5 μ g in every 1ml, as reference substance solution；
According to the chromatographic condition of test example 3, precision measures 20 μ l reference substance solution, injects chromatograph of liquid, continuous sample introduction 6
Secondary, record chromatogram.
Testing result is shown in Table 5.
The testing result of table 5 precision test
Result of the test shows, the inventive method precision is good.
4th, stability
Take Apremilast, be configured to need testing solution and 3- acetylamino phthalic acid pair according to the inventive method
According to product solution, take need testing solution respectively at 0h, 2h, 4h, 6h, 8h, sample detection；According to the chromatographic condition of test example 3, accurate
Measure 20 μ l reference substance solution, inject chromatograph of liquid, by external standard method with 3- acetylamino neighbour benzene in calculated by peak area test sample
The content of dioctyl phthalate, the results are shown in Table 6.
The testing result of table 6 stability test
| Sample injection time | 0h | 2h | 4h | 6h | 8h |
| Specification: 80mg | 0 | 0 | 0 | 0 | 0 |
| Specification: 125mg | 0 | 0 | 0 | 0 | 0 |
Result of the test shows, the inventive method has good stability.
5th, repeatability
Take Apremilast, be configured to need testing solution according to the inventive method, 6 parts of test samples of parallel preparation are molten respectively
Liquid, and prepare 3- acetylamino phthalic acid reference substance solution；According to aforementioned chromatographic condition, it is molten that precision measures 20 μ l reference substances
Liquid and need testing solution, are injected separately into chromatograph of liquid, by external standard method with 3- acetylamino neighbour benzene in calculated by peak area test sample
The content of dioctyl phthalate, the results are shown in Table 7.
The testing result of table 7 replica test
Result of the test shows, the inventive method is reproducible.
6th, system suitability
Take Apremilast 0.5mg and 3- acetylamino phthalic acid reference substance 0.5 μ g, plus mobile phase 1ml makes dissolving, make
For system suitability solution；Measure 20 μ l system suitability solution injection chromatograph of liquid, record chromatogram, Apremilast and 3-
Separating degree between acetylamino phthalic acid should be not less than 2.0, and theoretical cam curve presses 3- acetylamino phthalic acid peak
Calculating should be not less than 2000.
Prepare need testing solution: claim Apremilast 25mg, be placed in 50ml measuring bottle, plus mobile phase (acetonitrile -0.02mol/l
Potassium dihydrogen phosphate=85:15) appropriate, shake 10 minutes, plus mobile phase is diluted to scale, shakes up, filtration, take subsequent filtrate as confession
Test sample solution.
Preparation reference substance solution: weigh reference substance (3- acetylamino phthalic acid) 5mg, be placed in 100ml measuring bottle, essence
Close measure 1ml, be placed in 100ml measuring bottle, plus mobile phase (acetonitrile -0.02mol/l potassium dihydrogen phosphate=85:15) be diluted to quarter
Degree, shakes up, as reference substance solution.
Take reference substance solution 20 μ l, inject chromatograph of liquid, adjust detection sensitivity, make 3- acetylamino phthalic acid
The peak height of chromatographic peak is about the 20% of monitor full scale, then precision measures need testing solution and each 20 μ l of reference substance solution, point
Not Zhu Ru chromatograph of liquid, record chromatogram.If display 3- acetylamino phthalic acid in the chromatogram of need testing solution
Chromatographic peak, 0.1% must not be crossed by external standard method with the content of calculated by peak area 3- acetylamino phthalic acid.According to above-mentioned
Method, carries out detecting 3 times to Apremilast.
Result of the test shows, does not detect 3- acetylamino phthalic acid, Apremilast and 3- acetylamino in test sample
Phthalic acid reaches good baseline separation.
7th, quantitative limit and test limit
Weigh 3- acetylamino phthalic acid reference substance 5.46mg, be placed in 25ml measuring bottle, plus flowing phased soln calmly
Hold to scale, shake up, as reference substance stock solution.
Preparation reference substance solution: measure each 1.0ml of above-mentioned reference substance solution, be placed in 50ml measuring bottle, plus flowing phased soln
And it is settled to scale, shake up, then measure 2.5ml, be placed in 25ml measuring bottle, plus mobile phase is settled to scale, as contrast solution.
Measure above-mentioned reference substance solution 1.0ml, be placed in 25ml measuring bottle, plus the phased soln be settled to scale of flowing, shake up,
Detection solution (s/n ≈ 10) as quantitative limit test.
Measure above-mentioned reference substance solution 3ml, be placed in 10ml measuring bottle, plus the phased soln be settled to scale of flowing, shake up, make
Detection solution (s/n ≈ 3) for test limit test.
The quantitation recording 3- acetylamino phthalic acid is limited to 17.47ng/ml.
The detection recording 3- acetylamino phthalic acid is limited to 5.24ng/ml.
8th, the response rate
Concentration 1: weigh Apremilast reference substance 12.5mg, be placed in 25ml measuring bottle, add 3- acetylamino O-phthalic
Sour reference substance stock solution (4.28 μ g/ml) 2ml, solubilizer is diluted to scale, shakes up, and prepares three parts with method, standby；Concentration 2: claim
Take Apremilast reference substance 12.5mg, be placed in 25ml measuring bottle, add 3- acetylamino phthalic acid reference substance stock solution
(4.28 μ g/ml) 2.5ml, solubilizer is diluted to scale, shakes up, and prepares three parts with method, standby；Concentration 3: weigh Apremilast pair
According to product 12.5mg, it is placed in 25ml measuring bottle, add 3- acetylamino phthalic acid reference substance stock solution (4.28 μ g/ml) 3ml,
Solubilizer is diluted to scale, shakes up, and prepares three parts with method, standby；In addition, preparing 3- acetylamino according to the above-mentioned method drafted
Phthalic acid reference substance solution, accurate absorption test sample and 3- acetylamino phthalic acid reference substance solution 20 μ l sample introduction are surveyed
Fixed, record chromatogram, and calculate measured amount and the response rate of mentioned component, it the results are shown in Table 8.
Table 8 3- acetylamino phthalic acid recovery test result table
Above result of the test shows, the method measures the content of 3- acetylamino phthalic acid, and the response rate preferably, measures
Response rate relative standard deviation less, accuracy is higher.
9th, destructive testing
Detect the specificity of chromatographic system in order to investigate 3- acetylamino phthalic acid further, intend with acid, alkali, oxygen
Sample feeding after change, high temperature, high light destroy is analyzed, and investigates the degraded situation of sample.
Acid destroys: weighs lab scale y150102 batch sample 11.51mg, puts in 25ml measuring bottle, add 0.1mol/l hydrochloric acid 2ml,
Shake up, add 0.1mol/l sodium hydroxide 2ml neutralization, plus acetonitrile-water (50:50) is diluted to scale, shakes up, obtains final product.
Alkali destroys: weighs lab scale y150102 batch sample 11.23mg, puts in 25ml measuring bottle, plus 0.1mol/l sodium hydroxide
2ml, shakes up, and adds 0.1mol/l hydrochloric acid 2ml neutralization, plus acetonitrile-water (50:50) is diluted to scale, shakes up, obtains final product.
Oxidative demage: weigh lab scale y150102 batch sample 13.91mg, put in 25ml measuring bottle, plus 30% hydrogenperoxide steam generator
2ml, places 30 minutes, plus acetonitrile-water (50:50) is diluted to scale, shakes up, obtains final product.
High temperature: in 130 DEG C of baking ovens of learning from else's experience, the heating y150102 of 3 hours criticizes lab scale sample, and precision weighs 10.98mg,
Put in 25ml measuring bottle, plus after acetonitrile-water (50:50) dissolving and be diluted to scale, shake up, obtain final product.
High light destroys: weighs lab scale y150102 batch sample 12.01mg, puts in 25ml measuring bottle, plus acetonitrile-water (50:50) is molten
After solution and be diluted to scale, shake up, place 24h under ultra-violet lamp, obtain final product.
Do not destroy sample: weigh lab scale y150102 batch sample 12.20mg, be placed in 25ml measuring bottle, plus acetonitrile-water (50:
50) dissolve and be diluted to scale, shake up, obtain final product.
The preparation of soda acid blank solution: take 0.1mol/l hydrochloric acid 2ml, put in 25ml measuring bottle, add 0.1mol/l hydroxide
Sodium solution 2ml neutralizes, plus acetonitrile-water (50:50) is diluted to scale, shakes up, obtains final product.
The preparation of oxidation blank solution: take 30% hydrogenperoxide steam generator 2ml, put in 25ml measuring bottle, plus acetonitrile-water (50:
50) it is diluted to scale, shakes up, obtain final product.
According to the aforementioned chromatographic condition drafted, take each 20 μ l of above-mentioned solution to be injected separately into chromatograph of liquid, record chromatogram.Knot
Fruit is shown in Table 9.
Table 9 failure test result table
Result of the test shows, under chromatographic condition of the present invention, this product under acid, alkali, oxidation, hot conditionss all undegraded go out
Impurity 3- acetylamino phthalic acid, under ultraviolet light, sample 3- acetylamino phthalic acid is slightly for need testing solution
There is increase, therefore 3- acetylamino phthalic acid may be photodegradative product by force.
In sum, in Apremilast of the present invention 3- acetylamino phthalic acid detection method, use amide
The chromatographic column with hydrophilic function of type, effectively by 3- acetylamino phthalic acid separation detection in Apremilast out, testing result
Accurately, reliable, and have that linear relationship is excellent, precision is high, good stability, reproducible, the response rate is good, easy and simple to handle etc.
Plurality of advantages, is suitable for popularization and application.
Claims (8)
1. in Apremilast 3- acetylamino phthalic acid detection method it is characterised in that: it comprises the following steps:
A, prepare need testing solution:
Take Apremilast sample to be measured, flow phased soln, filters or does not filter, prepares need testing solution；
B, prepare the reference substance solution of 3- acetylamino phthalic acid:
Take 3- acetylamino phthalic acid reference substance, flow phased soln, prepares the right of 3- acetylamino phthalic acid
According to product solution；
C, respectively by need testing solution and reference substance solution injection high performance liquid chromatograph detection, chromatographic condition is as follows: chromatographic column:
The silica gel being bonded with acrylamide is as the chromatographic column with hydrophilic function of filler；
Mobile phase: acetonitrile -0.02mol/l phosphate dihydrogen salt solution or methanol -0.02mol/l phosphate dihydrogen salt solution；Described phosphorus
Acid dihydride saline solution is selected from sodium dihydrogen phosphate or potassium dihydrogen phosphate；
Described methanol or acetonitrile are 80:20～90:10 with the volume ratio of phosphate dihydrogen salt solution；
Detection wavelength: 230 ± 10nm；
D, it is calculated the content of 3- acetylamino phthalic acid in Apremilast sample according to testing result.
2. detection method according to claim 1 it is characterised in that: described Detection wavelength be 230 ± 2nm.
3. detection method according to claim 1 it is characterised in that: in step c, the specification of described chromatographic column is: internal diameter
4.6mm, length 250mm, 5 μm of packing material size.
4. detection method according to claim 3 it is characterised in that: in step c, the model of described chromatographic column
venusil hilic 100a°.
5. detection method according to claim 1 it is characterised in that: in step c, described mobile phase is following volume ratio
Mixed solution:
Acetonitrile -0.02mol/l potassium dihydrogen phosphate=80:20, acetonitrile -0.02mol/l potassium dihydrogen phosphate=85:15,
Acetonitrile -0.02mol/l potassium dihydrogen phosphate=90:10, methanol -0.02mol/l potassium dihydrogen phosphate=80:20, methanol -
0.02mol/l potassium dihydrogen phosphate=85:15, methanol -0.02mol/l potassium dihydrogen phosphate=90:10, acetonitrile -
0.02mol/l sodium dihydrogen phosphate=80:20, acetonitrile -0.02mol/l sodium dihydrogen phosphate=85:15 or acetonitrile -
0.02mol/l sodium dihydrogen phosphate=90:10.
6. the detection method according to any one of claim 1-5 it is characterised in that: in step c, the post of described chromatographic condition
Temperature is 30 DEG C～40 DEG C, and flow velocity is 0.8ml/min～1.2ml/min.
7. detection method according to claim 6 it is characterised in that: in step c, the column temperature of described chromatographic condition is 30 DEG C
～35 DEG C, flow velocity is 0.8ml/min～1.0ml/min.
8. the detection method according to claim 1-5 or 7 any one it is characterised in that: in step c, described chromatographic condition
Sample size be 20 μ l.
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