CN103926335B - The high-efficient liquid phase chromatogram process measuring method of related substance in a kind of Dapoxetine hydrochloride - Google Patents
The high-efficient liquid phase chromatogram process measuring method of related substance in a kind of Dapoxetine hydrochloride Download PDFInfo
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- CN103926335B CN103926335B CN201310619658.6A CN201310619658A CN103926335B CN 103926335 B CN103926335 B CN 103926335B CN 201310619658 A CN201310619658 A CN 201310619658A CN 103926335 B CN103926335 B CN 103926335B
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Abstract
The invention discloses a kind of detection method of Dapoxetine hydrochloride, specifically adopt diode array detector, with phosphate buffer (by phosphoric acid adjust ph for 3.2)-acetonitrile-methanol solution for mobile phase.Get Dapoxetine hydrochloride and the related preparations containing Dapoxetine hydrochloride is appropriate, add mobile phase and be mixed with solution containing Dapoxetine hydrochloride 0.2mg in every 1ml, as need testing solution.And be diluted to the solution about containing 2 μ g in every 1ml with mobile phase, solution in contrast.Respectively sample introduction, in need testing solution chromatogram each impurity peak area and the main peak area that must not be greater than contrast solution.The related substance detection method of Dapoxetine hydrochloride of the present invention and the related preparations containing Dapoxetine hydrochloride, can detect impurity and the catabolite situation of Dapoxetine hydrochloride fast and accurately.Simple to operation, highly sensitive, product quality can be controlled preferably.
Description
Technical field
The present invention relates to the related substance detection method of a kind of Dapoxetine hydrochloride and the related preparations containing Dapoxetine hydrochloride, belong to Pharmaceutical Analysis detection field.
Background technology
Dapoxetine hydrochloride (INN, trade name Priligy) is the medicine of first prevention premature ejaculation in the world.Chemistry (S)-N, N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine by name, structural formula is as follows:
.
Molecular formula is: C
21h
23nO, molecular weight: 305.413, because Dapoxetine hydrochloride likely introduces retained material and other related substance in building-up process, also likely produces catabolite in storage, this law effectively carries out purity analysis to Dapoxetine hydrochloride, and this test adopts common chromatographic column (C
18chromatographic column) achieve the mensuration of Dapoxetine hydrochloride related substance fast and accurately, ensure that the quality controllable of Dapoxetine hydrochloride, at synthesis and preparation
The quality control aspect of process has important practical significance.The related substance detection method of Dapoxetine hydrochloride of the present invention and the related preparations containing Dapoxetine hydrochloride, can detect impurity and the catabolite situation of Dapoxetine hydrochloride fast and accurately.Simple to operation, highly sensitive, product quality can be controlled preferably.Not yet retrieve the assay method of the high performance liquid chromatography of Dapoxetine hydrochloride and related substance thereof at present.
Summary of the invention
The object of the present invention is to provide a kind of diode array detector that adopts to Dapoxetine hydrochloride and the assay method carrying out Related substances separation containing the related preparations of Dapoxetine hydrochloride.
The realization of Related substances separation method of the present invention comprises the following steps:
(1) chromatographic condition: detecting device adopts diode array detector, column temperature 25 DEG C ~ 35 DEG C, flow velocity 1.0ml/min.The mobile phase of chromatographic condition is made up of phosphate buffer (be 3.2 by phosphoric acid adjust ph)-acetonitrile-methanol, and its proportioning is 40:30:30.Theoretical cam curve calculates by Dapoxetine hydrochloride peak and is not less than 3000.
(2) preparation of need testing solution:
Get Dapoxetine hydrochloride or the related preparations containing Dapoxetine hydrochloride is appropriate, add the solution that mobile phase is mixed with 0.2mg/ml, as need testing solution.
(3) preparation of contrast solution:
Measure above-mentioned (2) need testing solution appropriate, add mobile phase and be diluted to the solution about containing 2 μ g in every 1ml, solution in contrast.
(4) assay method:
Get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, major component chromatogram peak height is made to be about 10% of full scale, get need testing solution 10 μ l injection liquid chromatography again, record chromatogram is to 2 times of Dapoxetine hydrochloride main peak retention time, if any impurity peaks in need testing solution chromatogram, measure each impurity peak area and, the peak area (see accompanying drawing 1, accompanying drawing 2) of main peak in contrast solution must not be greater than.
The related substance detection method of Dapoxetine hydrochloride of the present invention and the related preparations containing Dapoxetine hydrochloride, the preparation of need testing solution in above-mentioned (2): for meeting the needs of need testing solution detectable concentration, get Dapoxetine hydrochloride appropriate, being mixed with concentration with mobile phase is the solution of every 1ml containing 0.2mg, as need testing solution.Be diluted to the solution of a series of variable concentrations more respectively with mobile phase, respectively sample introduction 10 μ l, make it to produce the signal that main peak is baseline noise three times.Through test, detectability is 0.2ng(S/N >=3), if calculate with concentration 0.2mg/ml during Related substances separation, its limit of detection is 0.1%.
The related substance detection method of Dapoxetine hydrochloride of the present invention and the related preparations containing Dapoxetine hydrochloride, the preparation of contrast solution in above-mentioned (3): precision measures above-mentioned need testing solution 1ml, put in 100ml measuring bottle, add mobile phase and dissolve and be diluted to scale, solution in contrast.When this contrast solution concentration range is in 1 ~ 10 μ g/ml, peak area and concentration are good linear relationship, and its linearly dependent coefficient is that 0.9998(is shown in accompanying drawing 3).
Dapoxetine hydrochloride of the present invention and the related substance detection method of related preparations containing Dapoxetine hydrochloride, its related substance detects in high-efficient liquid phase chromatogram, occurs if any impurity peaks, measure each impurity peak area and, the main peak area (1%) of contrast solution should be greater than.
The related substance detection method of Dapoxetine hydrochloride of the present invention and the related preparations containing Dapoxetine hydrochloride, be applicable to various need to carry out related substance detection Dapoxetine hydrochloride and related preparations containing Dapoxetine hydrochloride, as Dapoxetine hydrochloride sheet and the various compound preparation containing Dapoxetine hydrochloride.
Good effect of the present invention is:
1, the present invention uses diode array detector to carry out related substance detection to this product, establish a kind of effective ways of evaluation chromatographic peak purity of quicklook: the purity that can judge chromatographic peak intuitively, and judge the position that there is Interference Peaks, whole spectral informations of " at stream " can be obtained, obtain the absorption spectrum of chromatographic component fast, the UV-visible detector that diode array detector is more general, it is qualitative that advantage is to rely on the retention time of chromatogram to carry out, and the spectral information that can provide according to it carries out qualitative, substantially increases confidence level qualitatively.
2, the present invention is applicable to the Dapoxetine hydrochloride of various formulation and the related preparations containing Dapoxetine hydrochloride, as Dapoxetine hydrochloride sheet and the various compound preparation containing Dapoxetine hydrochloride.
3, detection method is accurate, simple to operation, and favorable reproducibility is highly sensitive, fully can meet the requirement that Related substances separation measures with decomposition product, the special impurities preferably in Quality control, guarantee product quality, practical at work.
Embodiment
embodiment one:
1, chromatographic condition and system suitability:
1.1, the selection of chromatographic condition:
Instrument: Shimadzu: LC-20AT, SPD-M20A, SIL-20A, DGU-20A5, its optimum column temperature 30 DEG C, flow velocity 1.0ml/min.Liquid-phase chromatographic column octadecylsilane chemically bonded silica is filling agent (250mm × 4.6mm, 5 μm), with reference to pertinent literature binding tests concrete condition, successively select the multiple condition such as methanol-water, acetonitrile-water, methanol-water-glacial acetic acid, methanol-acetonitrile-phosphate buffer, finally determine that mobile phase is made up of phosphate buffer (be 3.2 by phosphoric acid adjust ph)-acetonitrile-methanol, its optimum proportioning is (40: 30: 30).Sample size 10 μ l.
Under this chromatographic condition, Dapoxetine hydrochloride main peak retention time is moderate, and peak shape is better.
1.2, to get Dapoxetine hydrochloride reference substance appropriate for sensitivity determination, being mixed with concentration with mobile phase is the solution of every 1ml containing 0.2mg, be diluted to the solution of a series of variable concentrations more respectively with mobile phase, respectively sample introduction 10 μ l, make it to produce the signal that main peak is baseline noise three times.Through test, detectability is 0.2ng(S/N >=3), if calculate with concentration 0.2mg/ml during Related substances separation, its limit of detection is 0.1%.Result proves, the method is highly sensitive, fully can meet the requirement that Related substances separation measures.
1.3, stability of solution is got with a need testing solution, respectively at 0,2,4,8,10 hour respectively sample introduction measure, its main peak peak area and determination of related substances result basicly stable in 10 hours.
Above test findings shows, the method is easy to be sensitive, favorable reproducibility, can detect preferably the quality of Dapoxetine hydrochloride in sample preferably.
2, the preparation of need testing solution:
Get Dapoxetine hydrochloride or the related preparations containing Dapoxetine hydrochloride is appropriate, add the solution that mobile phase is mixed with 0.2mg/ml, as need testing solution.
3, the preparation of contrast solution:
Measure above-mentioned (2) need testing solution appropriate, add mobile phase and be diluted to the solution about containing 2 μ g in every 1ml, solution in contrast.
4, the detection of Dapoxetine hydrochloride and the related preparations related substance containing Dapoxetine hydrochloride:
Get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, major component chromatogram peak height is made to be about 10% of full scale, get need testing solution 10 μ l injection liquid chromatography again, record chromatogram is to 2 times of Dapoxetine hydrochloride main peak retention time, if any impurity peaks in need testing solution chromatogram, measure each impurity peak area and, the peak area of main peak in contrast solution must not be greater than.
the mensuration of embodiment two, Dapoxetine hydrochloride sheet related substance
Get this product 20, accurately weighed, porphyrize, precision takes in right amount (being about equivalent to Dapoxetine hydrochloride 2mg),
Add mobile phase and be mixed with the solution containing 0.2mg in every 1ml, filter, get filtrate as need testing solution.Precision measures in right amount, adds mobile phase and is diluted to the solution about containing 2 μ g in every 1ml, solution in contrast.Under following selected chromatographic condition: diode array detector (Shimadzu: LC-20AT, SPD-M20A, SIL-20A, DGU-20A5), be filling agent with octadecylsilane chemically bonded silica, with phosphate buffer (by phosphoric acid adjust ph for 3.2)-acetonitrile-methanol (40: 30: 30) for mobile phase, chromatogram column temperature is 30 DEG C, flow velocity 1.0ml/min.Theoretical cam curve should be not less than 3000. by the calculating of Dapoxetine hydrochloride peak and get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make that contrast solution main peak is high is about 10% of full scale, get each 10 μ l of need testing solution again, injection liquid chromatography respectively, record chromatogram is to 2 times of major component peak retention time.If any impurity peaks in need testing solution chromatogram, measure each impurity peak area and, the main peak area of contrast solution must not be greater than.
Table 1. Dapoxetine hydrochloride sheet determination of related substances result
| First second batch of lot number the 3rd batch |
| Related substance (%) 0.15 0.11 0.18 |
embodiment three: the mensuration of Dapoxetine hydrochloride capsule related substance
Get this product content appropriate, porphyrize, precision takes fine powder (being about equivalent to Dapoxetine hydrochloride 2mg), adds mobile phase and is mixed with the solution containing 0.2mg in every 1ml, filter, get filtrate as need testing solution.Precision measures in right amount, adds mobile phase and is diluted to the solution about containing 2 μ g in every 1ml, solution in contrast.Under following selected chromatographic condition: diode array detector (Shimadzu: LC-20AT, SPD-M20A, SIL-20A, DGU-20A5), be filling agent with octadecylsilane chemically bonded silica, with phosphate buffer (by phosphoric acid adjust ph for 3.2)-acetonitrile-methanol (40: 30: 30) for mobile phase, chromatogram column temperature is 30 DEG C, flow velocity 1.0ml/min.Theoretical cam curve should be not less than 3000. by the calculating of Dapoxetine hydrochloride peak and get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make that contrast solution main peak is high is about 10% of full scale, get each 10 μ l of need testing solution again, injection liquid chromatography respectively, record chromatogram is to 2 times of major component peak retention time.If any impurity peaks in need testing solution chromatogram, measure each impurity peak area and, the main peak area of contrast solution must not be greater than.
Table 2. Dapoxetine hydrochloride capsule determination of related substances result
| First second batch of lot number the 3rd batch |
| Related substance (%) 0.22 0.21 0.24 |
embodiment three: the mensuration of Dapoxetine hydrochloride sustained release tablets related substance
Get this product appropriate, porphyrize, precision takes fine powder (being about equivalent to Dapoxetine hydrochloride 2mg), adds mobile phase and is mixed with the solution containing 0.2mg in every 1ml, filter, get filtrate as need testing solution.Precision measures in right amount, adds mobile phase and is diluted to the solution about containing 2 μ g in every 1ml, solution in contrast.Under following selected chromatographic condition: diode array detector (Shimadzu: LC-20AT, SPD-M20A, SIL-20A, DGU-20A5), be filling agent with octadecylsilane chemically bonded silica, with phosphate buffer (by phosphoric acid adjust ph for 3.2)-acetonitrile-methanol (40: 30: 30) for mobile phase, chromatogram column temperature is 30 DEG C, flow velocity 1.0ml/min.Theoretical cam curve calculates should be not less than 3000 by Dapoxetine hydrochloride peak.Get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make that contrast solution main peak is high is about 10% of full scale, then get each 10 μ l of need testing solution, respectively injection liquid chromatography, record chromatogram is to 2 times of major component peak retention time.If any impurity peaks in need testing solution chromatogram, measure each impurity peak area and, the main peak area of contrast solution must not be greater than.
Table 3. Dapoxetine hydrochloride sustained release tablets determination of related substances result
| First second batch of lot number the 3rd batch |
| Related substance (%) 0.31 0.24 0.26 |
accompanying drawing illustrates:
Fig. 1 is the high performance liquid chromatography collection of illustrative plates of contrast solution;
Fig. 2 is the high performance liquid chromatography collection of illustrative plates of need testing solution;
Fig. 3 is Dapoxetine hydrochloride l.o.i linear relationship chart.
Claims (3)
1. a related substance detection method for Dapoxetine hydrochloride and the related preparations containing Dapoxetine hydrochloride, is characterized in that detection method comprises the following steps;
(1) chromatographic condition:
Employing octadecylsilane chemically bonded silica is filling agent, specification is 250mm × 4.6mm, 5 μm, mobile phase is made up of the mixture of acetonitrile-phosphate buffer-methyl alcohol by phosphoric acid adjust ph being 3.2, its proportioning is 40:30:30, and detecting device adopts diode array detector, column temperature 25 DEG C ~ 35 DEG C, flow velocity 1.0ml/min, theoretical cam curve calculates by Dapoxetine hydrochloride peak and is not less than 3000;
(2) preparation of need testing solution:
Get Dapoxetine hydrochloride or the related preparations containing Dapoxetine hydrochloride is appropriate, add the solution that mobile phase is mixed with 0.2mg/ml, as need testing solution;
(3) preparation of contrast solution:
Measure above-mentioned (2) need testing solution appropriate, add mobile phase and be diluted to the solution containing 2 μ g in every 1ml, solution in contrast;
(4) assay method:
Get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, major component chromatogram peak height is made to be 10% of full scale, get need testing solution 10 μ l injection liquid chromatography again, record chromatogram to 2 times of Dapoxetine hydrochloride main peak retention time, if any impurity peaks in need testing solution chromatogram, measure each impurity peak area and, the peak area of main peak in contrast solution must not be greater than, namely 1.0%.
2. the related substance detection method of Dapoxetine hydrochloride according to claim 1 and the related preparations containing Dapoxetine hydrochloride, it is characterized in that: the wherein preparation of (3) contrast solution: the related preparations getting Dapoxetine hydrochloride is appropriate, add the solution that mobile phase is mixed with 0.2mg/ml, as need testing solution; Precision measures need testing solution 1ml again, puts in 100ml measuring bottle, adds mobile phase and dissolves and be diluted to scale, solution in contrast.
3. according to the related substance detection method of described Dapoxetine hydrochloride arbitrary in claim 1,2 and the related preparations containing Dapoxetine hydrochloride, it is characterized in that: the method is applicable to variously need to carry out the Dapoxetine hydrochloride of related substance detection and the related preparations containing Dapoxetine hydrochloride.
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| CN105548396B (en) * | 2015-12-24 | 2017-11-07 | 重庆华邦胜凯制药有限公司 | The method of separation determination dapoxetine hydrochloride and its potential genetoxic impurity |
| CN108610264A (en) * | 2016-12-09 | 2018-10-02 | 扬子江药业集团江苏紫龙药业有限公司 | Dapoxetine hydrochloride process contaminants, preparation and purposes |
| CN109668976A (en) * | 2018-07-09 | 2019-04-23 | 华控创新（北京）药物研究院有限公司 | A method of with the related substance of high effective liquid chromatography for measuring dapoxetine hydrochloride |
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Non-Patent Citations (3)
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| DEVELOPMENT AND VALIDATION OF RP-HPLC METHOD FOR THE ESTIMATION OF DAPOXETINE HYDROCHLORIDE IN TABLET FORMS;M. Sandhya Madhuri 等;《International Journal of Pharmaceutical Sciences Review and Research》;20121231;第14卷(第1期);摘要、第33页左栏表2-3，右栏第4-8段 * |
| VALIDATED HPLC METHOD FOR SIMULTANEOUS QUANTITATION OF TADALAFIL AND DAPOXETINE HYDROCHLORIDE IN BULK DRUG AND FORMULATION;ABHA D. GIRI 等;《International Journal of Pharmacy and Pharmaceutical Sciences》;20121231;第4卷(第2期);654-658 * |
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