CN112666267B - Method for detecting related substances of aripiprazole drug substance - Google Patents
Method for detecting related substances of aripiprazole drug substance Download PDFInfo
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- CN112666267B CN112666267B CN201910977964.4A CN201910977964A CN112666267B CN 112666267 B CN112666267 B CN 112666267B CN 201910977964 A CN201910977964 A CN 201910977964A CN 112666267 B CN112666267 B CN 112666267B
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- aripiprazole
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- performance liquid
- liquid chromatography
- ammonium acetate
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 101
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 100
- 239000000126 substance Substances 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims description 24
- 229940088679 drug related substance Drugs 0.000 title claims description 15
- 239000008186 active pharmaceutical agent Substances 0.000 title claims description 14
- 238000001514 detection method Methods 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 32
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 24
- 239000007788 liquid Substances 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 40
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 38
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 36
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 34
- 239000005695 Ammonium acetate Substances 0.000 claims description 34
- 235000019257 ammonium acetate Nutrition 0.000 claims description 34
- 229940043376 ammonium acetate Drugs 0.000 claims description 34
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 33
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 29
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 29
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 29
- 229960002216 methylparaben Drugs 0.000 claims description 28
- 238000010828 elution Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 19
- 229960000583 acetic acid Drugs 0.000 claims description 18
- 239000012362 glacial acetic acid Substances 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- CDONPRYEWWPREK-UHFFFAOYSA-N 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-1h-quinolin-2-one Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)C=CC4=CC=3)CC2)=C1Cl CDONPRYEWWPREK-UHFFFAOYSA-N 0.000 claims description 7
- -1 2, 3-dichlorophenyl Chemical group 0.000 claims description 6
- BUWPZNOVIHAWHW-UHFFFAOYSA-N 2,3-dihydro-1h-quinolin-4-one Chemical compound C1=CC=C2C(=O)CCNC2=C1 BUWPZNOVIHAWHW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000003186 pharmaceutical solution Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 230000000873 masking effect Effects 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 18
- 239000012535 impurity Substances 0.000 description 57
- 230000014759 maintenance of location Effects 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 12
- 239000013558 reference substance Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 230000005526 G1 to G0 transition Effects 0.000 description 6
- RMZZTJOADJVCIO-UHFFFAOYSA-N acetic acid;acetonitrile;hydrate Chemical compound O.CC#N.CC(O)=O RMZZTJOADJVCIO-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000007865 diluting Methods 0.000 description 5
- 229960003415 propylparaben Drugs 0.000 description 5
- 201000000980 schizophrenia Diseases 0.000 description 5
- 239000000945 filler Substances 0.000 description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- URHLNHVYMNBPEO-UHFFFAOYSA-N 7-(4-bromobutoxy)-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CC(=O)NC2=CC(OCCCCBr)=CC=C21 URHLNHVYMNBPEO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- 101150104779 HTR2A gene Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000012512 bulk drug substance Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- YXVFQADLFFNVDS-UHFFFAOYSA-N diammonium citrate Chemical compound [NH4+].[NH4+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O YXVFQADLFFNVDS-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention provides a detection method of related substances of aripiprazole medicine. The detection method of the invention comprises the following steps: separating each component of aripiprazole medicine by high performance liquid chromatography, and detecting. By adopting the detection method, the effective separation among the chromatographic peaks can be realized, and the conditions of related substances in the aripiprazole can be accurately, qualitatively and quantitatively determined, so that the quality of the aripiprazole medicine can be controlled.
Description
Technical Field
The invention relates to a detection method of related substances of aripiprazole medicine.
Background
Aripiprazole (Aripiprazole) is a dopamine autoreceptor agonist [1'2] of the chemical name 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] -3, 4-dihydroquinolin-2-one, which has the following structural formula, and was developed in combination by the Japanese 0tsuka pharmaceutical company and the American BMS company for the treatment of schizophrenia. The medicine is marketed in the beauty of 11 months in 2002, and has the advantages of good curative effect, light side effect and good tolerance. As a novel atypical anti-schizophrenia drug, aripiprazole has a bi-directional modulation of the DA energy nervous system by partial agonism of D2 and 5HTlA receptors and antagonism of 5HT2A receptors to produce an anti-schizophrenia effect. The peak time of the blood concentration after oral administration is 3-5 hours, the half-life period is 48-68 hours, and the active metabolite is dehydroaripiprazole. The foreign clinical test shows that the aripiprazole has obvious curative effect on positive and negative symptoms of the schizophrenia, has low incidence rate of external side effects of vertebral bodies, can improve the accompanying emotional symptoms and reduce the recurrence rate of the schizophrenia.
The aripiprazole formulation currently marketed is an oral common tablet, capsule, orally disintegrating tablet, oral liquid, injection and long-acting intramuscular injection. Intravenous administration is extremely inconvenient for patients and has poor compliance: the tablet is taken with water, and is not suitable for the elderly, children, mental patients, etc.: the orally disintegrating tablet disintegrates rapidly, has high requirement on mouth feel, has very high development difficulty of long-acting injection, severe preservation condition and high price, and is difficult to accept long-term treatment for most mental patients. The aripiprazole oral liquid disclosed by the invention has good taste, covers up bad smell and bitter taste of the medicine, improves the long-term medicine taking compliance of patients, and is especially suitable for children patients.
The aripiprazole bulk drug substance contains an impurity I and an impurity II, wherein the chemical name of the impurity I is 7- [4- [4- (2, 3-dichlorophenyl) 1-oxo-piperazinyl ] butoxy ] -3, 4-dihydro-quinolone; impurity II is chemically named 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] quinolone.
In the preparation of the aripiprazole oral liquid, the auxiliary materials are methyl parahydroxybenzoate and propyl parahydroxybenzoate.
In order to control the quality of the aripiprazole oral liquid, a detection method capable of simultaneously detecting the contents of related substances of the aripiprazole oral liquid is required.
Closest to the present invention, the prior art: at present, the related literature and patent do not show specific reports on the method of the substances related to the aripiprazole oral liquid. The quality standards of the aripiprazole bulk drugs and preparations are obtained in the current Chinese pharmacopoeia, united states pharmacopoeia and European pharmacopoeia. The content determination method of the aripiprazole preparation carried in the current Chinese pharmacopoeia adopts an isocratic elution chromatographic condition, and the retention of methyl parahydroxybenzoate and propyl parahydroxybenzoate in the system applicability under the chromatographic condition is weaker; and buffer salt concentration in the mobile phase [ citrate buffer solution (9.6 g of diammonium citrate, 1.6g of citric acid and 2.0g of sodium dodecyl sulfate are taken, dissolved and diluted to 1000mL by adding water, and pH is regulated to 4.7 by ammonia water) -acetonitrile (55:45) ] is higher, and the reagent containing ions has larger damage to the chromatographic column. The existing method for measuring the content of the bulk drug of the aripiprazole, which is carried in United states pharmacopoeia, adopts gradient elution chromatographic conditions, and can increase the separation degree of chromatographic peaks of the aripiprazole and the propyl p-hydroxybenzoate by adjusting the flow rate, the column temperature and the gradient, but the chromatographic peaks of the propyl p-hydroxybenzoate can interfere the measurement of impurity I or impurity II.
Therefore, there is a lack of a detection method capable of simultaneously detecting related substances in an aripiprazole drug substance.
Disclosure of Invention
The invention aims to overcome the defect that the prior art cannot detect the related substances of the aripiprazole drug substance at the same time, and provides a detection method of the related substances of the aripiprazole drug substance. By adopting the detection method, the content of each component of the aripiprazole medicine can be measured at the same time, so that the quality of the aripiprazole medicine can be controlled.
The invention provides a detection method of aripiprazole drug related substances, which comprises the following steps: separating and detecting each component of the aripiprazole medicine by adopting a high performance liquid chromatography;
the chromatographic column of the high performance liquid chromatography is a reversed phase column;
the mobile phase of the high performance liquid chromatography consists of a mobile phase A and a mobile phase B; the mobile phase A is ammonium acetate aqueous solution-acetonitrile with the volume ratio of 90:10, and the mobile phase B is ammonium acetate aqueous solution-acetonitrile with the volume ratio of 10:90; wherein the pH of the ammonium acetate aqueous solution is 4.5-6.8;
the high performance liquid chromatography adopts gradient elution; the gradient elution adopts the following gradient: the initial gradient is that the mobile phase B accounts for 8-17% of the volume of the mobile phase and is changed to 38%, and the final gradient is that the mobile phase B accounts for 12% of the volume of the mobile phase.
In the invention, the aripiprazole medicine can be used for preventing diseases of people, purposefully regulating physiological functions of people and prescribing indication or functional indications, usage and dosage of the aripiprazole medicine, and is preferably one or more of aripiprazole bulk drugs, aripiprazole oral liquid and aripiprazole preparations.
The aripiprazole bulk drug can be bulk drugs sold in the market or produced according to a conventional process and used for producing various aripiprazole preparations, and the aripiprazole bulk drug produced according to the conventional process is preferred.
The aripiprazole oral liquid is preferably a pharmaceutical solution comprising aripiprazole, a suitable pharmaceutically acceptable solvent system, one or more taste-enhancing/masking agents and one or more selected from lactic acid, acetic acid, tartaric acid and poncirc acid, or a pharmaceutical solution comprising aripiprazole, 7- [4- [4- (2, 3-dichlorophenyl) 1-oxopiperazinyl ] butoxy ] -3, 4-dihydroquinolone, 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] quinolone and an adjuvant.
The auxiliary materials are preferably propyl parahydroxybenzoate and/or methyl parahydroxybenzoate. In the auxiliary material, the mass ratio of the propyl parahydroxybenzoate to the methyl parahydroxybenzoate is preferably 0.05-0.5, for example, 0.15.
The aripiprazole preparation can be prepared according to certain dosage form requirements, and can be finally provided for a subject to be used, and is preferably one or more of aripiprazole tablets, aripiprazole capsules and aripiprazole disintegrating tablets.
In the present invention, the aripiprazole drug substance is preferably present as an aripiprazole drug substance solution prior to injection.
The solvent of the aripiprazole drug substance solution can be selected from a nitrile solvent, a mixed solution of water and an organic acid; in the mixed solution, the volume ratio of the nitrile solvent, the water and the organic acid is preferably (30-50): (50-70): 1, for example, 40:60:1. the nitrile solvent is preferably acetonitrile. The organic acid is preferably acetic acid.
The amount of the solvent of the aripiprazole drug substance solution may be conventional in the art, preferably its volume to mass ratio to aripiprazole is 1 to 10L/g, for example, 5L/g.
In the present invention, the related substances are preferably 7- [4- [4- (2, 3-dichlorophenyl) 1-oxopiperazinyl ] butoxy ] -3, 4-dihydroquinolone and/or 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] quinolone.
In the present invention, the chromatographic column of the high performance liquid chromatography is preferably a reversed phase column using octadecylsilane chemically bonded silica as a filler, for example Agilent Eclipse Plus C, 4.6x100mm,3.5um.
In the present invention, the pore diameter of the column may be 3 μm to 5 μm, for example, 3.5 μm; the chromatographic column may have a length of 75mm to 150mm. The diameter of the chromatographic column can be 2 mm-5 mm.
In the present invention, the hplc may be a conventional hplc in the art, such as Agilent 1260 lc.
In the present invention, the pH of the aqueous ammonium acetate solution is preferably 5.2 to 6.8, more preferably 5.2 to 5.4, and most preferably 5.3.
In the present invention, the pH of the aqueous ammonium acetate solution is preferably adjusted by an organic acid, more preferably by glacial acetic acid.
In the present invention, the concentration of the aqueous ammonium acetate solution may be a chromatographic detection concentration conventional in the art, preferably 0.008 to 0.012mol/L, for example, 0.01mol/L.
In the invention, the gradient elution can be gradient elution for detection or separation in the field, and the volume ratio of the mobile phase is generally continuously adjusted so as to separate all components in the sample.
In the present invention, the initial gradient is that the volume percentage of the mobile phase B in the mobile phase is preferably 10% -15% to 38%, more preferably 12% -38%.
In the present invention, the gradient elution preferably employs the following gradient: the initial gradient is that the volume percentage of the mobile phase B in the mobile phase is changed from 12% to 38%; the second gradient is that the mobile phase B accounts for 38 percent of the volume of the mobile phase; the third gradient is that the volume fraction of the mobile phase B in the mobile phase is changed from 38% to 88%; the fourth gradient is that the mobile phase B accounts for 88 percent of the volume of the mobile phase; a fifth gradient is that the mobile phase B accounts for 88% to 12% of the volume fraction of the mobile phase; the final gradient was 12% by volume of mobile phase B.
The elution time of the initial gradient is preferably 7 to 13min, more preferably 10min.
The elution time of the second gradient is preferably 3 to 8min, more preferably 5min.
The elution time of the third gradient is preferably 7 to 13min, more preferably 10min.
The elution time of the fourth gradient is preferably 3 to 8min, more preferably 5min.
The elution time of the fifth gradient is preferably 0.5 to 5min, more preferably 1min.
The elution time of the final gradient is preferably 6 to 12min, more preferably 9min.
The preferred detection conditions of the invention are: the chromatographic column is a reversed phase column taking octadecylsilane chemically bonded silica as a filler; taking ammonium acetate aqueous solution-acetonitrile with the volume ratio of 90:10 as a mobile phase A, and taking ammonium acetate solution-acetonitrile with the volume ratio of 10:90 as a mobile phase B; wherein the pH value of the ammonium acetate aqueous solution is=5.2-6.8; gradient elution was performed as in table 1;
TABLE 1
The better detection conditions of the invention are: the chromatographic column is a reversed phase column taking octadecylsilane chemically bonded silica as a filler; taking ammonium acetate aqueous solution-acetonitrile with the volume ratio of 90:10 as a mobile phase A, and taking ammonium acetate solution-acetonitrile with the volume ratio of 10:90 as a mobile phase B; wherein the pH value of the ammonium acetate aqueous solution is=5.2-5.4; gradient elution was performed as in table 1.
The optimal detection conditions of the invention are as follows: the chromatographic column is a reversed phase column taking octadecylsilane chemically bonded silica as a filler; taking ammonium acetate aqueous solution-acetonitrile with the volume ratio of 90:10 as a mobile phase A, and taking ammonium acetate solution-acetonitrile with the volume ratio of 10:90 as a mobile phase B; wherein the pH of the aqueous ammonium acetate solution=5.3; gradient elution was performed as in table 1.
In the present invention, the column temperature of the high performance liquid chromatography is preferably 20 to 35 ℃, more preferably 25 ℃.
In the present invention, the flow rate of the HPLC is preferably 0.8 to 1.2mL/min, for example, 1.0mL/min.
In the present invention, the sample injection amount of the high performance liquid chromatography can be referred to the conventional sample injection amount of HPLC detection analysis in the art, preferably 1uL to 15uL, for example, 10uL.
In the present invention, the detector for high performance liquid chromatography is preferably an ultraviolet absorption detector.
In the present invention, the detection wavelength of the high performance liquid chromatography is preferably 200 to 300nm, more preferably 254nm.
In the present invention, the detection method preferably includes the steps of: and (3) separating each component of the aripiprazole medicine by using the high performance liquid chromatograph, and detecting.
The invention also provides a separation method of the related substances of the aripiprazole medicine, which comprises the following steps: separating the components of the aripiprazole medicine by high performance liquid chromatography; the separation method and conditions are as described above.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
In the present invention, unless otherwise noted, the ratio of any solvent means the volume ratio.
The reagents and materials of the invention are commercially available.
The invention has the positive progress effects that:
the detection method can realize effective separation among chromatographic peaks, accurately and qualitatively and quantitatively determine the conditions of related substances in the aripiprazole, thereby controlling the quality of the aripiprazole medicine.
Compared with the prior art, the detection method can enhance the chromatographic retention of the aripiprazole and the impurity II, and after the peak time is delayed, the peak types of the methyl parahydroxybenzoate, the 7- [4- [4- (2, 3-dichlorophenyl) 1-oxo-piperazinyl ] butoxy ] -3, the propyl parahydroxybenzoate, the 4-dihydro-quinolone and/or the 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] quinolone and the aripiprazole are good, and the theoretical plate number and the separation degree are good, so that the effective separation and quantitative detection of various impurities and auxiliary materials are realized, and the safety of the medicine is improved.
Drawings
FIG. 1 is a liquid chromatogram of a methylparaben control.
FIG. 2 is a liquid chromatogram of a propyl parahydroxybenzoate control.
FIG. 3 is a liquid chromatogram of an impurity I control.
Fig. 4 is a liquid chromatogram of the impurity II control.
Fig. 5 is a liquid chromatogram of the aripiprazole control.
Fig. 6 is a liquid chromatogram corresponding to example 2.
Fig. 7 is a liquid chromatogram after enlarging the liquid chromatogram corresponding to example 2.
Fig. 8 is a liquid chromatogram corresponding to example 3.
Fig. 9 is an enlarged liquid chromatogram of the liquid chromatogram corresponding to example 3.
Fig. 10 is a liquid chromatogram corresponding to example 4.
Fig. 11 is a liquid chromatogram after enlarging the liquid chromatogram corresponding to example 4.
Fig. 12 is a liquid chromatogram corresponding to example 5.
Fig. 13 is a liquid chromatogram after enlarging the liquid chromatogram corresponding to example 5.
Fig. 14 is a liquid chromatogram corresponding to example 6.
Fig. 15 is a liquid chromatogram after enlarging the liquid chromatogram corresponding to example 6.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
In the following examples, the following examples were used:
the aripiprazole lot number is 100776-201302, the manufacturer is China food and drug inspection institute, and the content is 99.9%;
the batch number of the methylparaben is 100278-201705, and the manufacturer is China food and drug inspection institute with the content of 100.0%;
propyl p-hydroxybenzoate batch number is 100444-201604, and the manufacturer is China food and drug inspection institute with content of 99.6%;
aripiprazole impurity I is 7- [4- [4- (2, 3-dichlorophenyl) 1-oxopiperazinyl ] butoxy ] -3, 4-dihydroquinolone, batch A771015, manufacturer TRC;
aripiprazole impurity II is 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] quinolone lot D229155, manufacturer TRC.
The column used was Agilent Eclipse Plus C, 4.6X100mm,3.5um.
The high performance liquid chromatograph used was an Agilent 1260 liquid chromatograph.
The detector used was an ultraviolet detector.
Example 1
Preparation of a control solution: respectively taking a proper amount of aripiprazole, methyl parahydroxybenzoate, propyl parahydroxybenzoate, impurity I and impurity II reference substances, precisely weighing, respectively adding a solvent [ acetonitrile-water-acetic acid (40:60:1) ] to dissolve and dilute, and preparing into a solution containing 0.2mg of aripiprazole, 0.2mg of methyl parahydroxybenzoate, 0.03mg of propyl parahydroxybenzoate, 0.005mg of impurity I and 0.005mg of impurity II in each 1 mL.
Chromatographic conditions: the stationary phase is a reverse phase column of carbon octadecyl bonded silica gel, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.3 by glacial acetic acid) -acetonitrile (90:10) is taken as a mobile phase A, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.3 by glacial acetic acid) -acetonitrile (10:90) is taken as a mobile phase B, gradient elution is carried out according to the table 1, the column temperature is 25 ℃, and the flow rate is 1.0mL/min; the detection wavelength was 254nm.
The measuring method comprises the following steps: precisely sucking 10 μl of reference solution, and injecting into liquid chromatograph for measurement.
The liquid chromatograms of the obtained control are shown in fig. 1 to 5.
Example 2
System applicability solution preparation: the method comprises the steps of taking a proper amount of each of the reference substances of aripiprazole, methyl parahydroxybenzoate, propyl parahydroxybenzoate, impurity I and impurity II, dissolving and diluting the reference substances by adding a solvent [ acetonitrile-water-acetic acid (40:60:1) ] to prepare mixed solutions which respectively contain 0.2mg of aripiprazole, 0.2mg of methyl parahydroxybenzoate, 0.03mg of propyl parahydroxybenzoate, 0.005mg of impurity I and 0.005mg of impurity II in each 1mL, and taking the mixed solutions as a system applicability solution.
Chromatographic conditions: the stationary phase is a reverse phase column of carbon octadecyl bonded silica gel, 0.01mol/L ammonium acetate solution (pH is regulated to 4.5 by glacial acetic acid) -acetonitrile (90:10) is taken as a mobile phase A, 0.01mol/L ammonium acetate solution (pH is regulated to 4.5 by glacial acetic acid) -acetonitrile (10:90) is taken as a mobile phase B, gradient elution is carried out according to the table 1, the column temperature is 25 ℃, and the flow rate is 1.0mL/min; the detection wavelength was 254nm.
The measuring method comprises the following steps: and (5) precisely sucking 10 mu L of system applicability solution, injecting into a high performance liquid chromatograph, and measuring to obtain the product.
The specific results are shown in FIGS. 6 to 7.
In FIGS. 6 to 7, the compound having a retention time of 6.844min is methylparaben, the compound having a retention time of 11.624min is impurity I, the compound having a retention time of 12.304min is propylparaben, the compound having a retention time of 12.444min is impurity II, and the compound having a retention time of 13.110min is aripiprazole.
Specifically as shown in table 2:
TABLE 2
Conclusion: the peak types of the impurity I and the impurity II are trailing, the symmetry factors are 1.32 and 2.04 respectively, the separation degree of the propyl p-hydroxybenzoate and the impurity II is poor, the separation degree is 0.51, and the theoretical plate number is good.
Example 3
System applicability solution preparation: the method comprises the steps of taking a proper amount of each of the reference substances of aripiprazole, methyl parahydroxybenzoate, propyl parahydroxybenzoate, impurity I and impurity II, dissolving and diluting the reference substances by adding a solvent [ acetonitrile-water-acetic acid (40:60:1) ] to prepare mixed solutions which respectively contain 0.2mg of aripiprazole, 0.2mg of methyl parahydroxybenzoate, 0.03mg of propyl parahydroxybenzoate, 0.005mg of impurity I and 0.005mg of impurity II in each 1mL, and taking the mixed solutions as a system applicability solution.
Chromatographic conditions: the stationary phase is a reverse phase column of carbon octadecyl bonded silica gel, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.2 by glacial acetic acid) -acetonitrile (90:10) is taken as a mobile phase A, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.2 by glacial acetic acid) -acetonitrile (10:90) is taken as a mobile phase B, gradient elution is carried out according to the table 1, the column temperature is 25 ℃, and the flow rate is 1.0mL/min; the detection wavelength was 254nm.
The measuring method comprises the following steps: and (5) precisely sucking 10 mu L of system applicability solution, injecting into a high performance liquid chromatograph, and measuring to obtain the product.
The specific results are shown in FIGS. 8 to 9
In fig. 8 to 9, the compound having a retention time of 6.831min is methylparaben, the compound having a retention time of 12.284min is impurity I, the compound having a retention time of 13.091min is propylparaben, the compound having a retention time of 13.451min is impurity II, and the compound having a retention time of 15.171min is aripiprazole.
As shown in table 3:
TABLE 3 Table 3
Conclusion: the peak-type trailing of the impurity I and the impurity II is improved, the symmetry factors are respectively 1.08 and 1.04, the separation degree of propyl parahydroxybenzoate and the impurity II is improved, the separation degree is 1.77, the peak-type trailing of the aripiprazole is 1.47, and the theoretical plate number and the separation degree are good.
Example 4
System applicability solution preparation: the method comprises the steps of taking a proper amount of each of the reference substances of aripiprazole, methyl parahydroxybenzoate, propyl parahydroxybenzoate, impurity I and impurity II, dissolving and diluting the reference substances by adding a solvent [ acetonitrile-water-acetic acid (40:60:1) ] to prepare mixed solutions which respectively contain 0.2mg of aripiprazole, 0.2mg of methyl parahydroxybenzoate, 0.03mg of propyl parahydroxybenzoate, 0.005mg of impurity I and 0.005mg of impurity II in each 1mL, and taking the mixed solutions as a system applicability solution.
Chromatographic conditions: the stationary phase is a reverse phase column of carbon octadecyl bonded silica gel, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.3 by glacial acetic acid) -acetonitrile (90:10) is taken as a mobile phase A, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.3 by glacial acetic acid) -acetonitrile (10:90) is taken as a mobile phase B, gradient elution is carried out according to the table 1, the column temperature is 25 ℃, and the flow rate is 1.0mL/min; the detection wavelength was 254nm.
The measuring method comprises the following steps: and (5) precisely sucking 10 mu L of system applicability solution, injecting into a high performance liquid chromatograph, and measuring to obtain the product.
The specific results are shown in FIGS. 10 to 11.
In FIGS. 10 to 11, the compound having a retention time of 3.995min was methyl parahydroxybenzoate, the compound having a retention time of 7.915min was impurity I, the compound having a retention time of 9.055min was propyl parahydroxybenzoate, the compound having a retention time of 10.088min was impurity II, and the compound having a retention time of 11.615min was aripiprazole.
As shown in table 4:
TABLE 4 Table 4
Conclusion: the chromatographic retention of methyl parahydroxybenzoate, impurity I, propyl parahydroxybenzoate and aripiprazole is weaker and the peak is faster; the aripiprazole has good peak form, the symmetry factor is 1.11, the tail of the impurity I and impurity II peak forms is improved, the symmetry factors are 1.26 and 1.18 respectively, and the theoretical plate number and the separation degree of each peak are good.
Example 5
System applicability solution preparation: the method comprises the steps of taking a proper amount of each of the reference substances of aripiprazole, methyl parahydroxybenzoate, propyl parahydroxybenzoate, impurity I and impurity II, dissolving and diluting the reference substances by adding a solvent [ acetonitrile-water-acetic acid (40:60:1) ] to prepare mixed solutions which respectively contain 0.2mg of aripiprazole, 0.2mg of methyl parahydroxybenzoate, 0.03mg of propyl parahydroxybenzoate, 0.005mg of impurity I and 0.005mg of impurity II in each 1mL, and taking the mixed solutions as a system applicability solution.
Chromatographic conditions: the stationary phase is a reverse phase column of carbon octadecyl bonded silica gel, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.4 by glacial acetic acid) -acetonitrile (90:10) is taken as a mobile phase A, 0.01mol/L ammonium acetate solution (pH is adjusted to 5.4 by glacial acetic acid) -acetonitrile (10:90) is taken as a mobile phase B, gradient elution is carried out according to the table 1, the column temperature is 25 ℃, and the flow rate is 1.0mL/min; the detection wavelength was 254nm.
The measuring method comprises the following steps: and (5) precisely sucking 10 mu L of system applicability solution, injecting into a high performance liquid chromatograph, and measuring to obtain the product.
The specific results are shown in FIGS. 12 to 13.
In FIGS. 12 to 13, the compound having a retention time of 6.829min is methylparaben, the compound having a retention time of 12.289min is impurity I, the compound having a retention time of 13.102min is propylparaben, the compound having a retention time of 14.496min is impurity II, and the compound having a retention time of 16.836min is aripiprazole.
As shown in table 5:
TABLE 5
Conclusion: enhanced chromatographic retention of methylparaben, impurity I, propylparaben, and aripiprazole, delayed peak formation; the peak type, theoretical plate number and separation degree of each peak are all good.
Example 6
System applicability solution preparation: the method comprises the steps of taking a proper amount of each of the reference substances of aripiprazole, methyl parahydroxybenzoate, propyl parahydroxybenzoate, impurity I and impurity II, dissolving and diluting the reference substances by adding a solvent [ acetonitrile-water-acetic acid (40:60:1) ] to prepare mixed solutions which respectively contain 0.2mg of aripiprazole, 0.2mg of methyl parahydroxybenzoate, 0.03mg of propyl parahydroxybenzoate, 0.005mg of impurity I and 0.005mg of impurity II in each 1mL, and taking the mixed solutions as a system applicability solution.
Chromatographic conditions: the stationary phase is a reverse phase column of carbon octadecyl bonded silica gel, 0.01mol/L ammonium acetate solution (pH is regulated to 6.8 by glacial acetic acid) -acetonitrile (90:10) is taken as a mobile phase A, 0.01mol/L ammonium acetate solution (pH is regulated to 6.8 by glacial acetic acid) -acetonitrile (10:90) is taken as a mobile phase B, gradient elution is carried out according to the table 1, the column temperature is 25 ℃, and the flow rate is 1.0mL/min; the detection wavelength was 254nm.
The measuring method comprises the following steps: and (5) precisely sucking 10 mu L of system applicability solution, injecting into a high performance liquid chromatograph, and measuring to obtain the product.
The specific results are shown in FIGS. 14 to 15.
In fig. 14 to 15, the compound having a retention time of 6.822min is methylparaben, the compound having a retention time of 12.275min is impurity I, the compound having a retention time of 13.102min is propylparaben, the compound having a retention time of 21.408min is impurity II, and the compound having a retention time of 22.828min is aripiprazole.
As shown in table 6:
TABLE 6
Conclusion: the chromatographic retention of methyl parahydroxybenzoate, impurity I, propyl parahydroxybenzoate, impurity II and aripiprazole is strong, and the peak is delayed; the peak front of aripiprazole has a symmetry factor of 0.84, and has good theoretical plate number and separation degree.
In summary, the scheme of example 4 is a preferred scheme, and the respective impurities and auxiliary materials of the aripiprazole achieve baseline separation, have good peak type, good separation degree and good theoretical plate number, and meet the analysis requirements of the related substances of the aripiprazole drug product. The method has the advantages of strong specificity, accurate result, good stability and simple operation, is more suitable for measuring related substances of the medicine, and can more scientifically control the quality of the aripiprazole medicine.
Claims (10)
1. A method for detecting substances related to aripiprazole drug substance, characterized in that it comprises the steps of: separating and detecting each component of the aripiprazole medicine by adopting a high performance liquid chromatography;
the chromatographic column was Agilent Eclipse Plus C, 4.6X100mm,3.5 μm; taking ammonium acetate aqueous solution-acetonitrile with the volume ratio of 90:10 as a mobile phase A, and taking ammonium acetate aqueous solution-acetonitrile with the volume ratio of 10:90 as a mobile phase B; wherein the pH value of the ammonium acetate aqueous solution is=5.4-6.8; gradient elution was performed as in table 1;
TABLE 1
The related substances are 7- [4- [4- (2, 3-dichlorophenyl) 1-oxo-piperazinyl ] butoxy ] -3, 4-dihydro-quinolone and 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] quinolone; the auxiliary materials in the medicine are propyl p-hydroxybenzoate and/or methyl p-hydroxybenzoate.
2. The detection method according to claim 1, wherein,
the aripiprazole medicine is one or more of aripiprazole oral liquid, aripiprazole tablet and aripiprazole capsule;
and/or, the aripiprazole drug substance is present as an aripiprazole drug substance solution prior to sample injection;
and/or, the high performance liquid chromatograph of the high performance liquid chromatography is an Agilent 1260 liquid chromatograph;
and/or, the pH of the ammonium acetate aqueous solution is adjusted by an organic acid;
and/or the concentration of the ammonium acetate aqueous solution is 0.008-0.012 mol/L.
3. The method for detecting aripiprazole according to claim 2, wherein said aripiprazole oral liquid is a pharmaceutical solution comprising: aripiprazole; a suitable pharmaceutically acceptable solvent system; one or more taste-enhancing/masking agents; one or more of lactic acid, acetic acid, tartaric acid and citric acid.
4. The detection method according to claim 2, wherein,
the solvent of the aripiprazole drug substance solution is selected from a nitrile solvent, a mixed solution of water and an organic acid;
and/or the volume-mass ratio of the solvent of the aripiprazole drug substance solution to the aripiprazole is 1-10L/g;
and/or, the pH of the ammonium acetate aqueous solution is adjusted by glacial acetic acid;
and/or the concentration of the ammonium acetate aqueous solution is 0.01mol/L.
5. The method of claim 2, wherein the aripiprazole tablet is an aripiprazole disintegrating tablet.
6. The method according to claim 4, wherein the volume ratio of the nitrile solvent, the water and the organic acid in the mixed solution is (30-50): (50-70): 1.
7. The detection method according to claim 1, wherein,
in the auxiliary materials, the mass ratio of the propyl parahydroxybenzoate to the methyl parahydroxybenzoate is 0.05-0.5.
8. The detection method according to claim 6, wherein,
the nitrile solvent is acetonitrile;
and/or, the organic acid is acetic acid.
9. The detection method according to claim 1, wherein,
the column temperature of the high performance liquid chromatography is 20-35 ℃;
and/or the flow rate of the high performance liquid chromatography is 0.8-1.2 mL/min;
and/or the sample injection amount of the high performance liquid chromatography is 1-15 mu L;
and/or, the detector of the high performance liquid chromatography is an ultraviolet absorption detector;
and/or the detection wavelength of the high performance liquid chromatography is 200-300 nm.
10. The method according to claim 9, wherein the high performance liquid chromatography is performed at a column temperature of 25 ℃;
and/or the flow rate of the high performance liquid chromatography is 1.0mL/min;
and/or the sample injection amount of the high performance liquid chromatography is 10 mu L;
and/or the detection wavelength of the high performance liquid chromatography is 254nm.
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