CN117705964A - Dapoxetine hydrochloride and analysis method of preparation thereof - Google Patents
Dapoxetine hydrochloride and analysis method of preparation thereof Download PDFInfo
- Publication number
- CN117705964A CN117705964A CN202311594430.6A CN202311594430A CN117705964A CN 117705964 A CN117705964 A CN 117705964A CN 202311594430 A CN202311594430 A CN 202311594430A CN 117705964 A CN117705964 A CN 117705964A
- Authority
- CN
- China
- Prior art keywords
- solution
- high performance
- performance liquid
- liquid chromatography
- mobile phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 title claims abstract description 55
- 229960005217 dapoxetine Drugs 0.000 title claims abstract description 55
- 238000004458 analytical method Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000012535 impurity Substances 0.000 claims abstract description 71
- 238000000034 method Methods 0.000 claims abstract description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 26
- 239000012488 sample solution Substances 0.000 claims abstract description 21
- 239000000126 substance Substances 0.000 claims abstract description 14
- 239000007853 buffer solution Substances 0.000 claims abstract description 9
- 238000010828 elution Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000945 filler Substances 0.000 claims abstract description 3
- 239000002245 particle Substances 0.000 claims abstract description 3
- 239000003085 diluting agent Substances 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000001514 detection method Methods 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 13
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 10
- 239000000523 sample Substances 0.000 claims description 10
- 238000010790 dilution Methods 0.000 claims description 9
- 239000012895 dilution Substances 0.000 claims description 9
- 238000012360 testing method Methods 0.000 claims description 8
- 238000007865 diluting Methods 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 5
- 239000010931 gold Substances 0.000 claims description 5
- 229910052737 gold Inorganic materials 0.000 claims description 5
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000002825 nitriles Chemical group 0.000 claims description 2
- 238000003556 assay Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 239000012085 test solution Substances 0.000 abstract description 8
- 230000035945 sensitivity Effects 0.000 abstract description 5
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 125000002560 nitrile group Chemical group 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- -1 polytetrafluoroethylene Polymers 0.000 description 5
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 5
- 239000004810 polytetrafluoroethylene Substances 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000012937 correction Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 206010036596 premature ejaculation Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 239000012069 chiral reagent Substances 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- OIHULGYJXLUIFC-UHFFFAOYSA-N 3-naphthalen-1-yloxy-1-phenylpropan-1-one Chemical compound C=1C=CC2=CC=CC=C2C=1OCCC(=O)C1=CC=CC=C1 OIHULGYJXLUIFC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QTQUJRIHTSIVOF-UHFFFAOYSA-N amino(phenyl)methanol Chemical compound NC(O)C1=CC=CC=C1 QTQUJRIHTSIVOF-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000012495 forced degradation study Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- G01N30/14—Preparation by elimination of some components
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
- G01N30/86—Signal analysis
-
- 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
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
Landscapes
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pathology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- General Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Library & Information Science (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a dapoxetine hydrochloride and an analysis method of a preparation thereof. Specifically, the invention provides an analysis method of dapoxetine hydrochloride related substances, which comprises the following steps: detecting the sample solution by adopting a high performance liquid chromatography; the test solution contains dapoxetine hydrochloride and one or more of impurities F, I, C, O, G, E, J, 20, K and 9; the chromatographic column adopted by the high performance liquid chromatography is 4.6x250mm, and the filler particle size is 3.5 mu m or 5 mu m C18 column; the mobile phase A is buffer solution with pH value of 7-9 and containing 0.1% -0.3% of triethylamine or diethylamine; the mobile phase B is a nitrile solvent; the high performance liquid chromatography adopts gradient elution. The method can effectively separate the dapoxetine hydrochloride process and the degradation impurities, and has the advantages of high sensitivity, strong specificity and good accuracy.
Description
Technical Field
The invention relates to the field of medicine analysis and detection, in particular to a method for analyzing dapoxetine hydrochloride related substances by utilizing a high performance liquid chromatography.
Background
Dapoxetine hydrochloride (Dapoxetine hydrochloride) is the hydrochloride salt of dapoxetine, chemical name: (+) - (S) -N, N-dimethyl-alpha- [2- (1-naphtoxy) ethyl ] -benzamide hydrochloride, chemical structure:
dapoxetine is a fast acting and metabolically selective 5-hydroxytryptamine reuptake inhibitor (SSRI) which is effective in modulating 5-hydroxytryptamine levels in the central nervous system, thereby achieving an extended ejaculation latency. Dapoxetine hydrochloride tablet (Priligy) 2 months in 2009 was first marketed in europe as a medicament for treating 18-64 year old male premature ejaculation, and then entered the chinese market in 12 months 2013. Dapoxetine hydrochloride is an oral therapeutic drug for premature ejaculation for the first time in the world, is the only clinically approved premature ejaculation therapeutic drug at present, and has wide market prospect.
Because the dapoxetine hydrochloride possibly remains starting materials, intermediates, reaction byproducts and the like in the synthesis process, degradation products can be generated in the storage process, an effective analysis method of the dapoxetine hydrochloride related substances is established, and the determination of the dapoxetine hydrochloride related substances is rapidly and accurately realized, so that the controllable quality of the dapoxetine hydrochloride is ensured, and the method has important practical significance in the aspects of synthesis and quality control of preparation processes.
Five related substances of dapoxetine hydrochloride are disclosed in the imported drug registration standard JX20150184 of the food and drug administration (NMPA), as shown in table 1 below:
table 1: related substances have been disclosed
However, in the studies of dapoxetine hydrochloride, the above-mentioned impurities were found to be insufficiently studied, there were also novel impurities not disclosed, and the above-mentioned method was inferior in the form of the F-peak of the impurity and low in detection sensitivity (see FIG. 6). It is therefore necessary to further study and modify the methods of other related substances that may be present to further effectively control the drug quality of dapoxetine hydrochloride.
The preparation method of dapoxetine hydrochloride is disclosed in patents such as WO 2008035358, US5292962, CN101 012147, CN1821212, CN101875666, US5068432 and US6025517, and mainly comprises two methods: one is a method that chiral reagent is used for reduction to form a dapoxetine chiral center, then nucleophilic reaction is carried out on the dapoxetine chiral center and naphthol or fluoronaphthalene, and then amine is formed and salified; the other is a method for forming the chiral center of dapoxetine by a resolution method. As chiral reagents used in the first method, 3- (1-naphthoxy) propiophenone, aminobenzyl alcohol and the like are commonly used. To this end we supplement the possible process impurities of the first method, see in Table 2 below for impurities E, J, 9 and 20.
After forced degradation study on dapoxetine hydrochloride, we found that the stability of dapoxetine hydrochloride is slightly poor under illumination environment, the main degradation product contains impurity C and two larger unknown impurities (more than 0.1%), and after structure confirmation study on the unknown impurities, we determine that the two unknown impurities are impurity K and impurity 9 in the following table 2 respectively.
Table 2: undisclosed impurities possibly contained in dapoxetine hydrochloride
Disclosure of Invention
Aiming at the problems of poor peak type, low detection sensitivity and insufficient impurity research of the existing analysis method, the invention provides the analysis method of the dapoxetine hydrochloride and the preparation thereof, which can effectively separate the dapoxetine hydrochloride process from degraded impurities, and has the advantages of high sensitivity, strong specificity and good accuracy.
The invention provides an analysis method of dapoxetine hydrochloride related substances, which comprises the following steps:
detecting the sample solution by adopting a high performance liquid chromatography; the sample solution contains dapoxetine hydrochloride and impurities; the impurities comprise one or more of impurities F, I, C, O, G, E, J, 20, K and 9;
the chromatographic column adopted by the high performance liquid chromatography is 4.6x250mm, and the filler particle size is 3.5 mu m or 5 mu m C18 column;
the high performance liquid chromatography adopts a mobile phase A and a mobile phase B; the mobile phase A is a buffer solution with the pH value of 7-9 and containing 0.1-0.3% of triethylamine or diethylamine (wherein the% refers to mass fraction);
the mobile phase B is a nitrile solvent;
the high performance liquid chromatography adopts gradient elution; the elution gradient conditions are that
In some embodiments, mobile phase a is a buffer solution having a pH of 7 containing 0.3% triethylamine.
In some embodiments, the mobile phase a is a buffer solution of an aqueous triethylamine solution having a pH of 7,0.3% and phosphoric acid.
In some embodiments, the chromatographic column is a Thermo Hypersil GOLD 4.6.6x250 mm,5 μm C18 column.
In some embodiments, the mobile phase B is acetonitrile.
In some embodiments, the high performance liquid chromatography employs a detection wavelength of 293nm.
In some embodiments, the high performance liquid chromatography employs a flow rate of 0.5 to 1.0ml/min; preferably 0.6ml/min.
In some embodiments, the high performance liquid chromatography employs a column temperature of 35-45 ℃; preferably 40 ℃.
In some embodiments, the high performance liquid chromatography employs a sample volume of 20-40 μl; preferably 20. Mu.L.
In some embodiments, the solvent in the sample solution is a mixed solution of 0.1% phosphoric acid aqueous solution and methanol, preferably a mixed solution of 0.1% phosphoric acid aqueous solution and methanol in a volume ratio of 35:65.
In some embodiments, the amount of dapoxetine hydrochloride and impurities in the test solution is determined using a self-dilution control method.
Preferably, in the self-dilution control method, the self-dilution control solution is obtained by diluting the sample solution with a diluent by a certain dilution factor, wherein the dilution factor can be 100 times; the diluent is the solvent.
In some embodiments, the high performance liquid chromatography uses a Thermo Hypersil GOLD 4.6.6x250 mm,5 μm C18 column as the chromatographic column, uses a buffer solution formed from acetonitrile, a 7,0.3% aqueous triethylamine solution and phosphoric acid as the mobile phase, and performs gradient elution, the detection wavelength is 293nm, the flow rate is 0.6ml/min, the column temperature is 40 ℃, and the sample injection volume is 20 μl.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: compared with the prior art, the method can realize the detection of more dapoxetine hydrochloride related substances (including 10 process impurities and degradation impurities), has strong specificity, higher sensitivity and good accuracy, and tablet auxiliary materials do not interfere with the detection, can better control the quality of the dapoxetine hydrochloride raw material or preparation, and has remarkable progress.
Drawings
FIG. 1 is a high performance liquid chromatogram of the mixed solution 1 of example 1.
FIG. 2 is a high performance liquid chromatogram of the self-control solution of example 2.
FIG. 3 is a high performance liquid chromatogram of the sample solution of example 2.
FIG. 4 is a high performance liquid chromatogram of the self-control solution of example 3.
FIG. 5 is a high performance liquid chromatogram of the sample solution illuminated in example 3.
Fig. 6 is a high performance liquid chromatogram of the mixed solution 2 of comparative example 1.
Fig. 7 is a high performance liquid chromatogram of the mixed solution 2 of comparative example 2.
FIG. 8 is a high performance liquid chromatogram of the mixed solution 2 of comparative example 3.
FIG. 9 is a high performance liquid chromatogram of the mixed solution 2 of comparative example 4.
Detailed Description
The sample and control sources involved in the examples are as follows:
table 3: information table of sample and reference substance
The HPLC apparatus used in the following examples and comparative examples are both SHIMADZU brand (LC 20AT or LC2030 type, UV or DAD detector).
In examples 1-3 below, the chromatographic conditions are as follows:
the chromatographic column is as follows: thermo Hypersil GOLD 4.6.6x250mm, 5 μm C column;
mobile phase a was a 0.3% aqueous triethylamine solution (pH adjusted to 7.00±0.05 with phosphoric acid);
mobile phase B is acetonitrile;
the gradient elution procedure was:
column temperature is 40 ℃; the sample injection amount is 20 mu L; the detection wavelength was 293nm and the flow rate was 0.6ml/min.
In the following examples and comparative examples, (1) the diluent was 0.1% phosphoric acid solution-methanol (35:65 by volume); (2) In the impurity content calculation process, each impurity correction factor is respectively: f (F) F impurity / C/G/9/20/J/K/unknown hetero ＝1.0，F I impurity ＝0.63，F O impurity ＝1.43。
EXAMPLE 1 determination-specificity of dapoxetine hydrochloride related substances
The apparatus and chromatographic conditions are as described above, test steps:
impurity localization solution: taking 20mg of each impurity, respectively placing into different 25ml measuring flasks, adding a diluent, dissolving and uniformly mixing to obtain the product.
Impurity mixed stock solution: precisely measuring the impurity positioning solutions of 0.8ml each, placing into a 10ml measuring flask, fixing the volume with diluent, and mixing uniformly.
Mixed solution 1: taking 1 dapoxetine hydrochloride tablet, placing into a 200ml measuring flask, adding 2ml of impurity mixed stock solution, adding a proper amount of diluent, shaking for 60 minutes to dissolve, diluting to scale with the diluent, shaking uniformly, filtering (0.45 mu m polytetrafluoroethylene filter membrane, phi 25 mm), and taking the subsequent filtrate.
Dapoxetine hydrochloride blank solution: taking 1 dapoxetine hydrochloride blank tablet (without API), placing into a 200ml measuring flask, adding a proper amount of diluent, shaking for 60 minutes to dissolve, diluting to scale with the diluent, shaking uniformly, filtering (0.45 μm polytetrafluoroethylene filter membrane, phi 25 mm), and taking the subsequent filtrate.
The diluent and the solutions are taken and analyzed according to the chromatographic conditions, the spectrum of the mixed solution 1 is shown in the attached figure 1, the specific results are shown in the following tables 4-5, the results show that the impurities are well separated, no interference is caused by air assist, and the method specificity is good.
Table 4:
table 5: raw data of mixed solution map
EXAMPLE 2 determination of dapoxetine hydrochloride drug substance 1
Test solution: taking about 30mg of dapoxetine hydrochloride bulk drug and adding a diluent to dissolve the dapoxetine hydrochloride bulk drug to prepare a test sample solution with the concentration of 0.3 mg/mL.
Self-control solution: precisely transferring 1ml of the sample solution, placing in a 100ml volumetric flask, adding diluent to scale, and preparing into one percent self-control solution.
Taking the diluent and the solution, analyzing according to the chromatographic conditions, recording the chromatogram, and calculating the content of dapoxetine hydrochloride and related impurities in the sample solution.
The impurity content calculation formula is as follows:
total impurity = Σ single impurity content
Wherein: f (F) Impurity(s) -various impurity correction factors
A Feed device -peak areas of the respective impurities in the test solution;
A for a pair of The area of the principal component peak in the self-control solution.
The detection patterns are shown in fig. 2-3, and the detection results are shown in tables 6-7 below.
TABLE 6 example 2 test solutions and self-control solutions test results
TABLE 7 example 2 results of content test in sample solution
| Component name | Content (%) |
| Dapoxetine hydrochloride | 99.95 |
| Impurity C | 0.03 |
| Sum of unknown impurities | 0.02 |
| Total impurities | 0.05 |
。
EXAMPLE 3 determination of dapoxetine hydrochloride tablet related substances 2
Illuminating the test solution: taking 1 dapoxetine hydrochloride tablet, placing into a 200ml measuring flask, adding a proper amount of diluent, shaking for 60 minutes to dissolve, diluting with the diluent to scale, shaking uniformly, filtering (0.45 mu m polytetrafluoroethylene filter membrane, phi 25 mm), placing the continuous filtrate into an illumination box (4500 lx+/-500 lx), and placing for 10 days to obtain the dapoxetine hydrochloride tablet.
Self-control solution: precisely transferring 1ml of the illumination sample solution, placing into a 100ml volumetric flask, adding diluent to scale, and preparing into one percent self-control solution.
Taking the diluent and the solution, analyzing the diluent and the solution by sample injection according to the chromatographic conditions, recording a chromatogram, and calculating the content of the dapoxetine hydrochloride and related impurities in the sample to be detected in the sample solution.
The impurity content calculation formula is as follows:
total impurity = Σ single impurity content
Wherein: f (F) Impurity(s) -various impurity correction factors
A Feed device -peak areas of the respective impurities in the test solution;
A for a pair of The area of the principal component peak in the self-control solution.
The detection patterns are shown in fig. 4-5, and the detection results are shown in tables 8-9 below.
TABLE 8 example 3 test results of illuminating test solutions and self-control solutions
TABLE 9 example 3 results of content test in illuminated sample solutions
| Component name | Content (%) |
| Dapoxetine hydrochloride | 95.78 |
| Impurity C | 2.81 |
| Impurity K | 0.13 |
| Impurity 9 | 0.86 |
| Sum of unknown impurities | 0.42 |
| Total impurities | 4.22 |
。
Comparative examples 1 to 4
In comparative examples 1 to 4 below, the chromatographic conditions were as follows:
the column and mobile phase are shown in table 10, the gradient procedure is as follows, and the remaining chromatographic conditions are the same as in the examples.
The gradient elution procedure was:
the test steps are as follows:
impurity localization solution: taking 20mg of each impurity, respectively placing into different 25ml measuring flasks, adding a diluent, dissolving and uniformly mixing to obtain the product.
Impurity mixed stock solution: taking 3mg of each of the impurity F, the impurity I, the impurity C, the impurity O and the impurity G, placing the impurities into a same 50ml measuring flask, adding a diluent to dissolve the impurities to a certain volume to obtain an impurity mixed stock solution;
mixed solution 2: taking 1 dapoxetine hydrochloride tablet, placing into a 200ml measuring flask, adding 2ml of the impurity mixed stock solution, adding a proper amount of diluent, shaking for 60 minutes to dissolve, diluting to a scale with the diluent, shaking uniformly, filtering (0.45 mu m polytetrafluoroethylene filter membrane, phi 25 mm), and taking the subsequent filtrate.
Dapoxetine hydrochloride blank solution: taking 1 dapoxetine hydrochloride blank tablet (without API), placing into a 200ml measuring flask, adding a proper amount of diluent, shaking for 60 minutes to dissolve, diluting to scale with the diluent, shaking uniformly, filtering (0.45 μm polytetrafluoroethylene filter membrane, phi 25 mm), and taking the subsequent filtrate.
The diluent and each solution described above were sampled and analyzed, and the results are shown in table 10 below.
Table 10
/>
TABLE 11
/>
Table 12
TABLE 13
/>
TABLE 14
/>
Claims (10)
1. A method for analyzing dapoxetine hydrochloride related substances, comprising the steps of: detecting the sample solution by adopting a high performance liquid chromatography;
the sample solution contains dapoxetine hydrochloride and impurities; the impurities comprise one or more of impurities F, I, C, O, G, E, J, 20, K and 9;
the chromatographic column adopted by the high performance liquid chromatography is 4.6x250mm, and the filler particle size is 3.5 mu m or 5 mu m C18 column;
the high performance liquid chromatography adopts a mobile phase A and a mobile phase B; the mobile phase A is buffer solution with pH value of 7-9 and containing 0.1% -0.3% of triethylamine or diethylamine; the mobile phase B is a nitrile solvent;
the high performance liquid chromatography adopts gradient elution; the elution gradient conditions are that
2. The analytical method according to claim 1, characterized in that it fulfils one or more of the following conditions:
(1) The mobile phase A is a buffer solution with the pH value of 7 and containing 0.3 percent of triethylamine;
(2) The chromatographic column is a Thermo Hypersil GOLD 4.6.6X250 mm,5 μm C18 column;
and (3) the mobile phase B is acetonitrile.
3. The method according to claim 2, wherein the mobile phase a is a buffer solution of an aqueous triethylamine solution having a pH of 7,0.3% and phosphoric acid.
4. The analytical method according to claim 1, characterized in that it fulfils one or more of the following conditions:
(1) The detection wavelength adopted by the high performance liquid chromatography is 293nm;
(2) The flow rate adopted by the high performance liquid chromatography is 0.5-1.0ml/min;
(3) The column temperature adopted by the high performance liquid chromatography is 35-45 ℃;
and (4) the sample injection volume adopted by the high performance liquid chromatography is 20-40 mu L.
5. The analytical method according to claim 4, characterized in that it satisfies one or more of the following conditions:
(1) The flow rate adopted by the high performance liquid chromatography is 0.6ml/min;
(2) The column temperature adopted by the high performance liquid chromatography is 40 ℃;
and (3) the sample injection volume adopted by the high performance liquid chromatography is 20 mu L.
6. The method according to claim 1, wherein the solvent in the sample solution is a mixed solution of 0.1% phosphoric acid aqueous solution and methanol.
7. The method according to claim 6, wherein the solvent in the sample solution is a mixed solution of a 0.1% phosphoric acid aqueous solution and methanol in a volume ratio of 35:65.
8. The assay of claim 1 wherein the amount of dapoxetine hydrochloride and impurities in the test sample solution is determined using a self-dilution control method.
9. The analytical method according to claim 8, wherein in the self-dilution control method, the self-dilution control solution is obtained by diluting a sample solution with a diluent by a dilution factor of 100; the diluent is the solvent in the sample solution.
10. The analytical method according to claim 1, wherein the high performance liquid chromatography uses a C18 column of Thermo Hypersil GOLD 4.6.6 x 250mm and 5 μm as a chromatographic column, uses a buffer solution of acetonitrile, a water solution of triethylamine with a pH of 7,0.3% and phosphoric acid as a mobile phase, and performs gradient elution, the detection wavelength is 293nm, the flow rate is 0.6ml/min, the column temperature is 40 ℃, and the sample injection volume is 20 μl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311594430.6A CN117705964A (en) | 2023-11-27 | 2023-11-27 | Dapoxetine hydrochloride and analysis method of preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311594430.6A CN117705964A (en) | 2023-11-27 | 2023-11-27 | Dapoxetine hydrochloride and analysis method of preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117705964A true CN117705964A (en) | 2024-03-15 |
Family
ID=90156121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311594430.6A Pending CN117705964A (en) | 2023-11-27 | 2023-11-27 | Dapoxetine hydrochloride and analysis method of preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117705964A (en) |
-
2023
- 2023-11-27 CN CN202311594430.6A patent/CN117705964A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112782327B (en) | Method for separating and determining carbocisteine and impurities thereof by liquid chromatography | |
| CN107064350B (en) | Method for detecting suspected genotoxic impurity of tofacitinib citrate | |
| CN104965041A (en) | High performance liquid chromatography detection method for parecoxib sodium isomer | |
| CN110824093A (en) | Method for detecting brivaracetam and related substances thereof | |
| CN112697906B (en) | Method for detecting chiral intermediate and enantiomer of tofacitinib | |
| CN107271592B (en) | Liquid chromatographic purity detection method for completely separating tipiraxib hydrochloride from related impurities | |
| CN109307716B (en) | Detection method of brexpiprazole related substance | |
| CN110642767B (en) | Separation and purification method of acetylcysteine enantiomer | |
| CN107434794B (en) | Preparation method and application of vortioxetine hydrobromide degradation product | |
| CN112213424A (en) | Method for simultaneously determining coexisting impurities in atorvastatin calcium intermediate | |
| CN117705964A (en) | Dapoxetine hydrochloride and analysis method of preparation thereof | |
| CN116908347A (en) | Method for detecting bacteriostatic agent and flavoring agent of amisulpride oral solution | |
| CN114295748B (en) | Method for detecting pitavastatin calcium intermediate and impurities | |
| CN113820417B (en) | Method for separating and measuring piroxicam and impurities thereof | |
| CN108872405B (en) | HPLC analysis detection method for relative substances of lodoxylamine tromethamine | |
| CN114563495A (en) | Detection method of acetylcysteine and related substances thereof | |
| CN109001342B (en) | High performance liquid chromatography method for detecting N-2, 3-dimethoxybenzyl piperonylethylamine and salt content thereof | |
| CN108037221B (en) | Method for simultaneously separating and determining methionine sulfoxide and methionine sulfone impurities in compound amino acid injection 18AA by liquid chromatography | |
| CN116735746B (en) | Method for separating and measuring clopidodine hydrochloride and impurities thereof | |
| CN112816567A (en) | Determination of melatonin and vitamin B6High performance liquid chromatography analysis method | |
| CN106442793B (en) | A kind of detection method of the intermediate for preparing Afatinib and its enantiomter | |
| CN110850012B (en) | Detection method of 1- (2, 3-dichlorophenyl) piperazine hydrochloride and related substances thereof | |
| CN115656389B (en) | Method for measuring content of R-3-aminopiperidine dihydrochloride in alogliptin benzoate by using LC-MS | |
| CN115266963B (en) | Method for detecting cysteine and cystine in compound amino acid injection | |
| Hamsa et al. | Analytical profile of cinacalcet hydrochloride: A review |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |