CN111665314A - Method for detecting impurity 1 and impurity 2 in Apremilast tablet - Google Patents
Method for detecting impurity 1 and impurity 2 in Apremilast tablet Download PDFInfo
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- CN111665314A CN111665314A CN202010660846.3A CN202010660846A CN111665314A CN 111665314 A CN111665314 A CN 111665314A CN 202010660846 A CN202010660846 A CN 202010660846A CN 111665314 A CN111665314 A CN 111665314A
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- 239000012535 impurity Substances 0.000 title claims abstract description 70
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 title claims abstract description 36
- 229960001164 apremilast Drugs 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000001514 detection method Methods 0.000 claims abstract description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 5
- 238000010828 elution Methods 0.000 claims abstract description 5
- 239000000945 filler Substances 0.000 claims abstract description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 26
- 238000007865 diluting Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 9
- 239000012085 test solution Substances 0.000 claims description 9
- 238000012937 correction Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 9
- 239000013558 reference substance Substances 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000011003 system suitability test Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000008822 Ankylosis Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010023198 Joint ankylosis Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000000095 emetic effect Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000002203 sacroiliac arthritis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention provides a method for detecting impurities 1 and 2 in an Apremilast tablet. The method adopts octadecylsilane chemically bonded silica as a filler and phosphoric acid solution-acetonitrile as a mobile phase for gradient elution, and quickly and accurately realizes the detection of the impurity 1 and the impurity 2 in the Apremilast tablet.
Description
Technical Field
The invention relates to a method for detecting impurities 1 and 2 in an Apremilast tablet.
Background
Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis, with psoriatic rashes and resulting in pain, swelling, tenderness, stiffness and dyskinesia in the joints and surrounding soft tissues, with some patients having sacroiliac arthritis and/or spondylitis, with prolonged course, relapse, late stage ankylosis, resulting in disability. Apremilast is a novel small molecule oral phosphodiesterase-4 (PDE-4) inhibitor, can regulate the action network of intracellular proinflammatory and anti-inflammatory factors, reduce joint swelling and improve the physiological function of joint parts. Phase III clinical trials demonstrated the safety and efficacy of apremilast. Compared with the conventional PDE4 inhibitor, the apremilast has fewer adverse reactions and lower emetic activity.
The researches show that the apremilast tablet can generate hydrolysis reaction in the presence of acid or alkali to generate an impurity 1 and an impurity 2, and the chemical structural formulas are respectively as follows:
impurity 1:
impurity 2:
at present, the Apremilast tablets are only sold in the market abroad and are not imported to the domestic; the apremilast tablet is not recorded by pharmacopoeias at home and abroad, has no legal quality standard, and has no detection method for impurities 1 and 2.
Disclosure of Invention
In order to strictly control the quality of the medicine and ensure the safety and the effectiveness of the medicine, the invention provides a method for detecting impurities 1 and 2 in an Apremilast tablet.
(1) Preparing a solution: taking a proper amount of apremilast tablet fine powder, adding acetonitrile for ultrasonic dissolution, quantitatively diluting to prepare a solution with the concentration of 0.5mg/ml, shaking up, filtering, and taking a subsequent filtrate as a test solution; precisely measuring a proper amount of the test solution, and quantitatively diluting with acetonitrile to obtain a solution with a concentration of 1 μ g/ml as a control solution.
(2) Precisely measuring 10 mul of each of the test solution and the control solution, respectively injecting into a high performance liquid chromatograph, recording the chromatogram, and the conditions of the high performance liquid chromatograph:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler, 250 × 4.6mm, 5 μm;
column temperature: 30 ℃;
detection wavelength: 230 nm;
flow rate: 1.0 ml/min;
gradient elution conditions:
the mobile phase A is prepared by taking 1000ml of water and adjusting the pH value to 3.0 by using phosphoric acid; the mobile phase B is acetonitrile.
(3) Appropriate amounts of impurity 1, impurity 2 and apremilast and other reference substances are taken, dissolved and diluted by acetonitrile to prepare a mixed solution containing 10.01 mg of impurity, 20.01 mg of impurity and 0.01mg of apremilast per 1ml, and the mixed solution is shaken up to be used as a system applicability solution. Precisely measuring 10 μ l, injecting into liquid chromatograph, and recording chromatogram, wherein the separation degree between adjacent chromatographic peaks should be not less than 1.5.
The invention screens chromatographic columns and flow equality conditions in high performance liquid chromatography, selects a proper buffer solution system, ensures that diluents and auxiliary materials do not interfere the detection of impurities 1 and 2 in a sample and ensures that the separation degree among chromatographic peaks of apremilast, the impurities 1 and the impurities 2 meets the requirement on the adjustment of the ratio of fluidity, finally establishes an HPLC analysis method of gradient elution, and realizes the detection and control of the impurities 1 and the impurities 2 in an apremilast tablet.
[ description of the drawings ]
FIG. 1 is a diagram of a system suitability solution for detecting impurity 1 and impurity 2 in Apremilast tablets in example 1.
[ detailed description ] embodiments
The present invention is further described below by way of examples, which, however, do not limit the scope of the invention.
Example 1: detection of impurities 1 and 2 in Apremilast tablets
Measured by high performance liquid chromatography (the general regulation 0512 of the 2015 pharmacopoeia of China).
Chromatographic conditions and system suitability test using octadecylsilane bonded silica gel as filler (250 × 4.6mm, 5 μm); taking a phosphoric acid solution (1000 ml of water is taken, and the pH value is adjusted to 3.0 by using phosphoric acid) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out gradient elution according to the following table; the column temperature is 30 ℃; the detection wavelength is 230 nm; the flow rate was 1.0 ml/min. Taking appropriate amount of impurity 1, impurity 2 and apremilast and other reference substances, dissolving with acetonitrile, diluting to obtain mixed solution containing 0.01mg of impurity 1, impurity 2 and apremilast per 1ml, shaking up, and using as system applicability solution. Precisely measuring 10 μ l, injecting into a liquid chromatograph, and recording chromatogram, wherein the impurity 1, the impurity 2 and apremilast are sequentially separated, and the separation degree between adjacent chromatogram peaks is not less than 1.5.
The determination method comprises taking appropriate amount of Apremilast tablet fine powder, adding acetonitrile, ultrasonic dissolving, quantitatively diluting to obtain 0.5mg/ml solution, shaking, filtering, and collecting the filtrate as sample solution. Precisely measuring a proper amount of the test solution, and quantitatively diluting with acetonitrile to obtain a solution with a concentration of 1 μ g/ml as a control solution. Precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a high performance liquid chromatograph, and recording chromatogram. If a chromatographic peak consistent with the retention time of the impurity 1 and the impurity 2 exists in a chromatogram of the test solution, the area of the peak of the impurity 1 multiplied by a correction factor 3.2 is not larger than the area of the main peak of the control solution, and the area of the peak of the impurity 2 multiplied by a correction factor 2.4 is not larger than the area of the main peak of the control solution.
1. System suitability test
Taking appropriate amount of impurity 1, impurity 2 and apremilast and other reference substances, dissolving with acetonitrile, diluting to obtain mixed solution containing 0.01mg of impurity 1, impurity 2 and apremilast per 1ml, shaking up, and using as system applicability solution. Precisely measuring 10 mu l, injecting into a liquid chromatograph, and recording a chromatogram map, wherein the impurity 1, the impurity 2 and the apremilast generate peaks in sequence, and the separation degree between adjacent chromatographic peaks is not less than 1.5.
2. Limit of detection and limit of quantitation tests for impurity 1, impurity 2 and apremilast
Taking appropriate amount of impurity 1, impurity 2 and Apremilast reference substance, dissolving and diluting with acetonitrile respectively to obtain stock solution with certain concentration, gradually diluting with acetonitrile, taking signal-to-noise ratio of 3:1 as detection limit and signal-to-noise ratio of 10:1 as quantification limit, and testing results are as follows
| Components | Detection limit (mu g/ml) | Quantitative limit (mu g/ml) |
| Impurity 1 | 0.0701 | 0.2336 |
| Impurity 2 | 0.0453 | 0.1509 |
| Apremilast | 0.0448 | 0.1495 |
3. Linear regression of impurity 1, impurity 2 and Apremilast
Taking appropriate amount of impurities 1, 2 and Apremilast and other reference substances, dissolving and diluting with acetonitrile to prepare a series of mixed solutions with gradient concentration, precisely measuring 10 mu l, injecting into a liquid chromatograph, drawing a standard curve of each component by taking each peak area A as a vertical coordinate and the corresponding concentration C as a horizontal coordinate, calculating a linear regression equation, and simultaneously calculating correction factors of the impurities 1 and 2, wherein the test results are as follows.
The test result shows that the concentration and the peak area of the solution are in good linearity when the impurity 1 is in the range of 0.2336-1.9469 mug/ml: the linear equation is y =0.3098x-0.0282, R = 0.998; the concentration and the peak area of the solution are in good linearity when the impurity 2 is in the range of 0.1509-2.0127 mug/ml: the linear equation is y =0.4149x-0.0035, R = 0.999; in the range of 0.1495-1.9930 mug/ml, the solution concentration and the peak area are in good linearity: the linear equation is y =0.9927x +0.0185, R = 0.999.
According to the impurities 1, 2 and the slope of the Apremilast linear equation, the correction factor of the impurities 1 is 3.2, and the correction factor of the impurities 2 is 2.4.
4. Recovery of impurities 1 and 2
Removing appropriate amount of impurity 1 and impurity 2 reference substances, adding the reference substances into the Apremilast tablet blank auxiliary material according to the limit of 80-120%, and calculating the recovery rate of each impurity according to the ratio of the measured amount to the added amount. The test results are as follows:
recovery test results for impurity 1:
recovery test results for impurity 2:
the test result shows that: the recovery rate test results of the impurities 1 and 2 accord with the pharmacopoeia regulations.
Claims (2)
1. A method for detecting impurities 1 and 2 in an Apremilast tablet is characterized in that:
(1) preparing a solution: taking a proper amount of apremilast tablet fine powder, adding acetonitrile for ultrasonic dissolution, quantitatively diluting to prepare a solution with the concentration of 0.5mg/ml, shaking up, filtering, and taking a subsequent filtrate as a test solution; precisely measuring a proper amount of a test solution, and quantitatively diluting with acetonitrile to prepare a solution with the concentration of 1 mu g/ml as a control solution;
(2) precisely measuring 10 mul of each of the test solution and the control solution, respectively injecting into a high performance liquid chromatograph, recording the chromatogram, and the conditions of the high performance liquid chromatograph:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler, 250 × 4.6mm, 5 μm;
column temperature: 30 ℃;
detection wavelength: 230 nm;
flow rate: 1.0 ml/min;
gradient elution conditions:
The mobile phase A is prepared by taking 1000ml of water and adjusting the pH value to 3.0 by using phosphoric acid; the mobile phase B is acetonitrile.
2. The method for detecting impurity 1 and impurity 2 in an Apremilast tablet according to claim 1, wherein: the detection limit of impurities is: the area of the peak of impurity 1 multiplied by the correction factor 3.2 must not be larger than the area of the main peak of the control solution, and the area of the peak of impurity 2 multiplied by the correction factor 2.4 must not be larger than the area of the main peak of the control solution.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113173878A (en) * | 2021-04-20 | 2021-07-27 | 梯尔希（南京）药物研发有限公司 | Preparation method of apremilast impurity |
| CN113960208A (en) * | 2021-10-28 | 2022-01-21 | 济南良福精合医药科技有限公司 | Method for measuring content of active ingredients in preparation containing apremilast |
| CN115541778A (en) * | 2022-11-28 | 2022-12-30 | 山东省食品药品检验研究院 | Detection method for determining apremilast concentration in human plasma |
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| CN105588886A (en) * | 2014-11-18 | 2016-05-18 | 重庆医药工业研究院有限责任公司 | Method for assaying impurities in apremilast and preparations thereof through liquid chromatography |
| CN107305198A (en) * | 2016-04-19 | 2017-10-31 | 重庆华邦胜凯制药有限公司 | A kind of high performance liquid chromatography separation is with determining Apremilast and the method about material |
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2020
- 2020-07-10 CN CN202010660846.3A patent/CN111665314A/en active Pending
Patent Citations (3)
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| Title |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113173878A (en) * | 2021-04-20 | 2021-07-27 | 梯尔希（南京）药物研发有限公司 | Preparation method of apremilast impurity |
| CN113173878B (en) * | 2021-04-20 | 2022-03-15 | 梯尔希（南京）药物研发有限公司 | Preparation method of apremilast impurity |
| CN113960208A (en) * | 2021-10-28 | 2022-01-21 | 济南良福精合医药科技有限公司 | Method for measuring content of active ingredients in preparation containing apremilast |
| CN115541778A (en) * | 2022-11-28 | 2022-12-30 | 山东省食品药品检验研究院 | Detection method for determining apremilast concentration in human plasma |
| CN115541778B (en) * | 2022-11-28 | 2023-08-15 | 山东省食品药品检验研究院 | Detection method for measuring apremilast concentration in human plasma |
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Address after: No. 35, Jingxin Road, industrial park, Xibei Town, Xishan District, Wuxi City, Jiangsu Province, 214000 Applicant after: Jiangsu Zhiyuan Pharmaceutical Co.,Ltd. Address before: No. 35, Jingxin Road, industrial park, Xibei Town, Xishan District, Wuxi City, Jiangsu Province, 214000 Applicant before: JIANGSU ZHIYUAN PHARMACEUTICAL Co.,Ltd. |
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