CN109668976A - A method of with the related substance of high effective liquid chromatography for measuring dapoxetine hydrochloride - Google Patents
A method of with the related substance of high effective liquid chromatography for measuring dapoxetine hydrochloride Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a method of with the related substance of high performance liquid chromatography measurement dapoxetine hydrochloride, the method is using ammonium hydrogen carbonate-diethylamine aqueous solution as mobile phase A, using acetonitrile as Mobile phase B, carries out gradient elution.The present invention is suitable for the Dapoxetine hydrochloride of various dosage forms and the related preparations containing Dapoxetine hydrochloride, such as Dapoxetine hydrochloride piece and the various compound preparations containing Dapoxetine hydrochloride.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of related with high performance liquid chromatography measurement dapoxetine hydrochloride
The method of substance.
Background technique
Dapoxetine hydrochloride, chemical structural formula are as follows: (S)-N, N- dimethyl -3- (naphthalene -1- oxygroup)-phenylpropyl alcohol ammonia hydrochloric acid
Salt is white powder, slightly molten in water, readily soluble in methanol, ethyl alcohol, almost insoluble in ethyl acetate.
Dapoxetine hydrochloride is a kind of selective serotonin reuptake inhibithors, half-life short, for treating male's morning
It lets out, is developed by companies such as Johnson & Johnson's pharmacy, listed in European a few countries.The medicine absorbs fastly, can quickly reach effective blood concentration,
The blood Cmax of 1.4~2.0h of peak time, single dose dapoxetine hydrochloride 30 and 60mg are respectively 297 and 498ng/mL, are in
Dosage correlation, distribution volume 21L/kg, Tissue distribution is wide, and the drug concentration and blood concentration of nerve fiber are close, absolutely
Bioavilability is 42%, protein binding rate 9%；It is metabolized through number of ways, and up to 40 kinds or so of metabolite, main generation
Thanking to product is demethyl Dapoxetine hydrochloride and Dapoxetine hydrochloride-N oxide.The characteristics of pharmacokinetics of dapoxetine hydrochloride is shown as dosage phase
Closing property and time invariance, while not influenced by multi-dose, main metabolites are not influenced similarly by multi-dose.It grinds
Study carefully the C for showing young and old peoplemaxSimilar with AUC, food can reduce the absorption rate of dapoxetine hydrochloride, but AUC is not
It is impacted.
Since Dapoxetine hydrochloride is possible to introduce retained material and other related substances in the synthesis process, in storage
It is also possible to generating catabolite, this law effectively carries out purity analysis to Dapoxetine hydrochloride, this test uses common chromatographic column
(C18 chromatographic column) fast and accurately realizes measurement of the Dapoxetine hydrochloride in relation to substance, ensure that the quality controllable of Dapoxetine hydrochloride,
The quality controlling party face of synthesis and production process has important practical significance.Dapoxetine hydrochloride of the present invention and phase containing Dapoxetine hydrochloride
The related substance detecting method for closing preparation, can fast and accurately detect the impurity and catabolite situation of Dapoxetine hydrochloride.Operation
Simple and direct, high sensitivity can preferably control product quality.
Summary of the invention
The purpose of the present invention is to provide a kind of using high performance liquid chromatography to Dapoxetine hydrochloride and containing the phase of Dapoxetine hydrochloride
Close the measuring method that preparation carries out Related substances separation.
Specifically, the present invention provides:
A method of with the related substance of high performance liquid chromatography measurement dapoxetine hydrochloride, comprising the following steps:
Chromatographic condition are as follows: room temperature, using octadecylsilane chemically bonded silica as filler；It is water-soluble with ammonium hydrogen carbonate-diethylamine
Liquid is mobile phase A, using acetonitrile as Mobile phase B, gradient elution, and flow velocity: 0.4~0.8ml/min, column temperature: 25~45 DEG C, detection
Wavelength is 293nm；It is dissolved with solvent, is configured to the sample solution of the hydrochloric 6 μ g of Dapoxetine hydrochloride of every 1ml；Liquid chromatograph is injected,
Record chromatogram；The gradient elution process are as follows: the 0.01st minute: mobile phase A 55%, Mobile phase B 45%；20th point
Clock: mobile phase A 5%, Mobile phase B 95%；22nd minute: mobile phase A 55%, Mobile phase B 45%；30th minute:
Mobile phase A is 55%, Mobile phase B 45%.
The molar ratio of ammonium hydrogen carbonate and diethylamine in mobile phase A is 5: 3.
The solvent is the mixture of phosphoric acid and methanol, and preferably the volume ratio of phosphoric acid and methanol is 35:65.
The phosphoric acid is the phosphate aqueous solution that mass fraction is 0.1%.
Compared with the prior art, the present invention has the following advantages and good effect:
1, the Dapoxetine hydrochloride and related preparations containing Dapoxetine hydrochloride that the present invention is suitable for various dosage forms, as Dapoxetine hydrochloride piece with
And the various compound preparations containing Dapoxetine hydrochloride.
2, detection method is accurate, simple to operation, favorable reproducibility, high sensitivity, can sufficiently meet related substance
It checks the requirement with decomposition product measurement, the preferably special impurities in control sample, guarantees product quality, it is practical at work
Property is strong.
Detailed description of the invention
The liquid chromatogram of Fig. 1 dapoxetine hydrochloride and its impurity.
The high-efficient liquid phase chromatogram of Fig. 2 dapoxetine hydrochloride raw material.
The high-efficient liquid phase chromatogram (auxiliary material blank) of Fig. 3 dapoxetine hydrochloride piece.
The high-efficient liquid phase chromatogram of Fig. 4 dapoxetine hydrochloride piece.
Specific embodiment
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
Dapoxetine hydrochloride is prepared according to 200610024697.1 the method for Chinese patent ZL.
1, chromatographic condition and system suitability:
The selection of 1.1 chromatographic conditions:
Instrument: Shimadzu: LC-20AT, SPD-M20A, SIL-20A, DGU-20A5,35 DEG C of optimum column temperature, flow velocity 1.0ml/
min.Liquid-phase chromatographic column is filler (250mm × 4.6mm, 5 μm) with octadecylsilane chemically bonded silica, is selected described in table 1
Mobile phase eluted, 10 μ l of sample volume.
Standard Stock solutions: 1000mg/L, weigh hydrochloric acid silaenafil, impurity A, impurity B, impurity C, impurity D, impurity E,
8 kinds of each 0.1000g of reference substance (purity is all larger than 99%) such as impurity F, impurity G, with solvent [phosphoric acid (1 → 1000): methanol=
35:65] dissolution after, be transferred in 100ml volumetric flask.Silaenafil uses solvent constant volume after first being dissolved with a small amount of water again.When use
The mixed standard solution of required mass concentration is diluted to solvent.
Sample 0.5000g is weighed in 100ml volumetric flask, be added water 10ml dissolution, then plus methanol 80ml, ultrasonic extraction
30min is crossed 0.45 μm of filter membrane, is measured by chromatographic condition with methanol dilution to scale.
Table 1 flows phase composition
Conclusion: use acetonitrile-water-glacial acetic acid-triethylamine mixed solution as mobile phase, point of Dapoxetine hydrochloride and impurity A
From ineffective, use phosphoric acid triethylamine-methanol-acetonitrile mixed solution as mobile phase, the separation of Dapoxetine hydrochloride and impurity B is imitated
Fruit is bad, and separation is preferable when using acetonitrile-phosphate buffer solution as mobile phase, but impurity D and impurity G are produced seriously
Trailing phenomenon.Therefore, it is separated while test realizes said components using acetonitrile-ammonium hydrogen carbonate-diethylamine and quantitative
Analysis.Flowing phase composition after optimization is that the diethylamine aqueous solution of 10mmol/L ammonium hydrogen carbonate and 6mmol/L are mobile phase A, with
Acetonitrile is Mobile phase B；According to the form below carries out linear gradient elution, and Dapoxetine hydrochloride main peak retention time is moderate, and peak shape is preferable.
1.2, sensitivity determination takes Dapoxetine hydrochloride reference substance appropriate, and being configured to concentration with mobile phase is every 1ml containing 0.2mg
Solution, then a series of solution of various concentrations is diluted to mobile phase respectively, respectively 10 μ l of sample introduction, is allowed to generate main peak to be base
The signal of line noise three times.Through testing, detectability is 0.2ng (S/N >=3), if concentration when with Related substances separation
0.2mg/ml is calculated, limit of detection 0.1%.The results show that this method high sensitivity, can sufficiently meet related substance inspection
Look into the requirement of measurement.
1.3, stability of solution takes with a test solution, measures respectively at 0,2,4,8,10 hour difference sample introduction,
Main peak peak area and related substance-measuring result are basicly stable in 10 hours.
The above test results show that the method simplicity is sensitive, favorable reproducibility, matter that can preferably to Dapoxetine hydrochloride in sample
Amount is preferably detected.
2, the preparation of test solution:
It takes Dapoxetine hydrochloride or related preparations containing Dapoxetine hydrochloride appropriate, mobile phase is added to be configured to the solution of 0.6mg/ml, make
For test solution.
3, the preparation of contrast solution:
Above-mentioned (2) appropriate test solution is measured, mobile phase is added to be diluted to containing about the solution of 6 μ g in every 1ml, as right
According to solution.
4, Dapoxetine hydrochloride and detection of the related preparations in relation to substance containing Dapoxetine hydrochloride:
It takes 10 μ l of contrast solution to inject liquid chromatograph, adjusts detection sensitivity, make the about full amount of principal component chromatography peak height
The 10% of journey, then 10 μ l of test solution is taken to inject liquid chromatograph, record chromatogram to the 2 of Dapoxetine hydrochloride main peak retention time
Times, if any impurity peaks in test solution chromatogram, the sum of each impurity peak area is measured, is not greater than main peak in contrast solution
Peak area.
Embodiment 1
Instrument and condition: Shimadzu: LC-20AT, SPD-M20A, SIL-20A, DGU-20A5, chromatographic column: C18250 ×
4.6mm, 5 μm, Detection wavelength: 293nm, mobile phase: the diethylamine aqueous solution with 10mmol/L ammonium hydrogen carbonate and 6mmol/L is
Mobile phase A, using acetonitrile as Mobile phase B, gradient elution, flow velocity: 0.6ml/min, column temperature: 35 DEG C, Detection wavelength 293nm；With
Solvent dissolution, is configured to the sample solution of the hydrochloric 6 μ g of Dapoxetine hydrochloride of every 1ml；Liquid chromatograph is injected, chromatogram is recorded；Institute
State gradient elution process are as follows: the 0.01st minute: mobile phase A 55%, Mobile phase B 45%；20th minute: mobile phase A was
5%, Mobile phase B 95%；22nd minute: mobile phase A 55%, Mobile phase B 45%；30th minute: mobile phase A was
55%, Mobile phase B 45%.
Experimental procedure:
Dapoxetine hydrochloride and impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G respectively about 20mg are taken, is set
In 100ml measuring bottle, solubilizer [phosphoric acid (1 → 1000): methanol=35:65] dissolves and is diluted to scale, shakes up, as confession
Test sample solution.Blank reagent solution and test solution are taken respectively, are carried out high-efficient liquid phase analysis by above-mentioned condition, are recorded chromatography
Figure, the result is shown in Figure 1.
The chromatographic peak that retention time is 12.35 minutes in Fig. 1 is the chromatographic peak of dapoxetine hydrochloride, remaining chromatographic peak is
The chromatographic peak of impurity.The chromatographic peak separating degree of dapoxetine hydrochloride and its impurity is good under the above conditions, can satisfy China
The requirement of pharmacopeia.
Embodiment 2
Instrument and condition: Shimadzu: LC-20AT, SPD-M20A, SIL-20A, DGU-20A5, chromatographic column: C18250 ×
4.6mm, 5 μm, Detection wavelength: 293nm, mobile phase: the diethylamine aqueous solution with 10mmol/L ammonium hydrogen carbonate and 6mmol/L is
Mobile phase A, using acetonitrile as Mobile phase B, gradient elution, flow velocity: 0.6ml/min, column temperature: 35 DEG C, Detection wavelength 293nm；With
Solvent dissolution, is configured to the sample solution of the hydrochloric 6 μ g of Dapoxetine hydrochloride of every 1ml；Liquid chromatograph is injected, chromatogram is recorded；Institute
State gradient elution process are as follows: the 0.01st minute: mobile phase A 55%, Mobile phase B 45%；20th minute: mobile phase A was
5%, Mobile phase B 95%；22nd minute: mobile phase A 55%, Mobile phase B 45%；30th minute: mobile phase A was
55%, Mobile phase B 45%.
Experimental procedure: it is protected from light operation.Take dapoxetine hydrochloride about 5mg, solubilizer [phosphoric acid (1 → 1000): methanol=35:
65] ultrasound makes to dissolve and dilute the solution being made in every 1ml containing about 0.6mg, as test solution, takes test solution, on photograph
It states condition and carries out high-efficient liquid phase analysis, record chromatogram, as a result see Fig. 2.
The chromatographic peak that retention time is 13.100 minutes in Fig. 2 is the chromatographic peak of dapoxetine hydrochloride, in relation to substance list
One impurity is less than 0.15%, and total impurities are less than 0.5%, the results showed that the related substance of dapoxetine hydrochloride raw material reaches bulk pharmaceutical chemicals
It is required that this law can be used for the quality-monitoring of dapoxetine hydrochloride.
Embodiment 3
Instrument and condition: Japanese Shimadzu LC-10ATVP pump, Shimadzu SPD-10AVP ultraviolet-visible multiwavelength detector,
RHEODYNE7725i sample injector and TL9900 Data Processing in Chromatography Workstation, chromatographic column: C18250 × 4.6mm, 5 μm, ultraviolet detection
Wavelength: 220nm, mobile phase: (0.02mol/L potassium dihydrogen phosphate is phosphate buffer with 10% phosphoric acid,diluted tune pH
4.0)-methanol (35: 65)
Experimental procedure: it is protected from light operation.Take dapoxetine hydrochloride piece 20mg, solubilizer [phosphoric acid (1 → 1000): methanol=35:
65] ultrasound makes to dissolve and dilute the solution being made in every 1ml containing about 0.6mg, and as test solution, precision measures 10 μ l, note
Enter liquid chromatograph, records chromatogram；Test solution is taken, carries out high-efficient liquid phase analysis according to above-mentioned condition, and carry out with method
Auxiliary material blank test result is shown in Fig. 3, Fig. 4.
Fig. 3 proves, auxiliary material blank not interference measurement, and the chromatographic peak that retention time is 12.442 minutes in Fig. 4 is that hydrochloric acid reaches
The chromatographic peak in the spit of fland Bo Xi, in relation to substance single contaminant less than 0.15%, total impurities are less than 0.5%, the results showed that hydrochloric acid reaches pool
The related substance of western spit of fland preparation reaches the requirement of preparation, and this law can be used for the quality-monitoring of dapoxetine hydrochloride preparation.
Claims (5)
1. a kind of measure method of the dapoxetine hydrochloride in relation to substance with high performance liquid chromatography, which is characterized in that including following step
It is rapid:
Chromatographic condition are as follows: room temperature, using octadecylsilane chemically bonded silica as filler；It is with ammonium hydrogen carbonate-diethylamine aqueous solution
Mobile phase A, using acetonitrile as Mobile phase B, gradient elution, flow velocity: 0.4~0.8ml/min, column temperature: 25~45 DEG C, Detection wavelength is
293nm；It is dissolved with solvent, is configured to the sample solution of the hydrochloric 6 μ g of Dapoxetine hydrochloride of every 1ml；Liquid chromatograph is injected, color is recorded
Spectrogram；The gradient elution process are as follows: the 0.01st minute: mobile phase A 55%, Mobile phase B 45%；20th minute: flowing
Phase A is 5%, Mobile phase B 95%；22nd minute: mobile phase A 55%, Mobile phase B 45%；30th minute: mobile phase A
It is 55%, Mobile phase B 45%.
2. according to the method described in claim 1, it is characterized in that the molar ratio of ammonium hydrogen carbonate and diethylamine in mobile phase A is
5∶3。
3. according to the method described in claim 1, it is characterized in that the solvent used in the preparation of sample solution is phosphoric acid and first
The mixture of alcohol composition.
4. according to the method described in claim 3, it is characterized in that the solvent used in the preparation of sample solution is for volume ratio
The phosphoric acid and methanol of 35:65 forms.
5. according to the method described in claim 3, it is characterized in that, the phosphoric acid is the phosphoric acid water that mass fraction is 0.1%
Solution.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1821212A (en) * | 2006-03-15 | 2006-08-23 | 上海玛耀化学技术有限公司 | Synthetic method for dapoxetine |
| CN103926335A (en) * | 2013-11-29 | 2014-07-16 | 山东省医药工业研究所 | High performance liquid chromatography detection method for related substances in dapoxetine |
| CN105548396A (en) * | 2015-12-24 | 2016-05-04 | 重庆华邦胜凯制药有限公司 | Method for separating and determining dapoxetine hydrochloride and potential genetic toxicity impurities thereof |
| CN105987971A (en) * | 2015-02-12 | 2016-10-05 | 重庆华邦制药有限公司 | Separation and determination methods for dapoxetine hydrochloride intermediate SM1 and related impurities |
-
2018
- 2018-07-09 CN CN201810744951.8A patent/CN109668976A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1821212A (en) * | 2006-03-15 | 2006-08-23 | 上海玛耀化学技术有限公司 | Synthetic method for dapoxetine |
| CN103926335A (en) * | 2013-11-29 | 2014-07-16 | 山东省医药工业研究所 | High performance liquid chromatography detection method for related substances in dapoxetine |
| CN105987971A (en) * | 2015-02-12 | 2016-10-05 | 重庆华邦制药有限公司 | Separation and determination methods for dapoxetine hydrochloride intermediate SM1 and related impurities |
| CN105548396A (en) * | 2015-12-24 | 2016-05-04 | 重庆华邦胜凯制药有限公司 | Method for separating and determining dapoxetine hydrochloride and potential genetic toxicity impurities thereof |
Non-Patent Citations (3)
| Title |
|---|
| ANDRAS D ET AL.: "Structure elucidation of a process-related impurity of Dapoxetine", 《JOURNAL OF PHARMACETICAL AND BIOMEDICAL ANALYSIS》 * |
| 张剑 等: "反相高效液相色谱法同时测定壮阳类保健品中达泊西汀和４种PDE5抑制剂", 《理化检验-化学分册》 * |
| 罗西: "盐酸达泊西汀片剂研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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