CN103664659A - Dapoxetine hydrochloride crystal form and preparation method thereof - Google Patents
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Abstract
The invention relates to a dapoxetine hydrochloride crystal form and a preparation method thereof and belongs to the technical field of pharmaceutical synthesis. The dapoxetine hydrochloride crystal form uses Cu-Ka radiation and employs 2 theta angle to express characteristic peaks of X-ray powder diffraction at 6.82+/-0.2, 8.90+/-0.2, 13.69+/-0.2, 15.03+/-0.2, 16.04+/-0.2, 17.78+/-0.2, 18.82+/-0.2, 20.61+/-0.2, 21.65+/-0.2, 22.26+/-0.2, 22.66+/-0.2, 25.23+/-0.2, 27.61+/-0.2, 28.89+/-0.2; the DSC scan shows a first endothermic peak between 55-85 DEG C and a second endothermic peak between 150-200 DEG C. The invention provides a method for preparing the crystal form. The dapoxetine hydrochloride crystal form has good appearance, good temperature and humidity stability, high melting point and high purity, and is convenient for long-term storage.
Description
Technical field
The present invention relates to a kind of dapoxetine hydrochloride crystal formation and preparation method thereof, belong to technical field of medicine synthesis.
Background technology
Dapoxetine hydrochloride (dapoxetine hydrochloride), it is a kind of selectivity serotonin reuptake inhibitor (SSRI), by Lilly drugmaker (Eli Lilly), developed, in 2009, in Europe, go on the market, commodity are called Priligy, are used for the treatment of prospermia of males (PE).This medicine transformation period is short, untoward reaction is little, effect is remarkable, it is the peroral administration prescription drugs that the first goes through to treat PE in the world, that the first, for the oral therapeutic drug of this indication, is classified as and gone on the market or one of the medicine of examining five tool prospects by Thomson Reuters2009 first quarter whole world medicament research and development major progress quarterly report in the world.
Dapoxetine hydrochloride, chemical name: (S)-(+)-(N, N dimethylamine base)-3-(naphthyl-1-oxygen base)-1-phenyl-propane hydrochloride, CAS:119356-77-3, chemical structural formula is as follows:
At present, in prior art, the document of relevant dapoxetine hydrochloride crystal formation and preparation method thereof has a lot, as Chinese patent application file (publication number: the crystal formation and a kind of amorphous state dapoxetine hydrochloride and their preparation method that CN103130661A) disclose a kind of dapoxetine hydrochloride.And for example publication number is respectively the Chinese patent application file of CN103130658A and CN103130660A, and they disclose respectively dapoxetine hydrochloride crystal form A and dapoxetine hydrochloride crystal form B and preparation method.And for example publication number is respectively the Chinese patent application file of CN103130659A and CN103130660A, they disclose respectively crystal and the preparation method of the acid salt that comprises phosphoric acid, phenylformic acid, succsinic acid, fumaric acid, Whitfield's ointment one class dapoxetine, and the acid Salt And Preparation Method of gentisinic acid, vitamin B13, Cyclamic Acid or acetysalicylic dapoxetine.
Although above-mentioned several preparation method has finally synthesized dapoxetine hydrochloride crystal formation, the synthetic dapoxetine hydrochloride crystal formation purity obtaining is not high, and stable crystal form is general, and these may affect the drug effect of the finished product.
Summary of the invention
The present invention is directed to the above-mentioned problems in the prior art, at the crystal formation that the crystal formation of dapoxetine hydrochloride is carried out to a large amount of a kind of dapoxetine hydrochlorides of the system experimentation favorite outer discovery of research, and in prior art, there is no the research report about this crystal formation.The invention provides a kind of good stability, purity is high for this reason, and preparation method is simple, is applicable to the dapoxetine hydrochloride crystal formation that large-scale industrialization is produced.
Dapoxetine hydrochloride crystal formation provided by the invention, use Cu-Ka radiation, with 2 θ angles, represent that X-ray powder diffraction is 6.82 ± 0.2,8.90 ± 0.2,13.69 ± 0.2,15.03 ± 0.2,16.04 ± 0.2,17.78 ± 0.2,18.82 ± 0.2,20.61 ± 0.2,21.65 ± 0.2,22.26 ± 0.2,22.66 ± 0.2,25.23 ± 0.2,27.61 ± 0.2,28.89 ± 0.2 have characteristic peak.
The X-ray powder diffraction test of dapoxetine hydrochloride crystal formation of the present invention has been measured under envrionment temperature and ambient moisture." envrionment temperature " is generally 0-40 ℃; " ambient moisture " is generally the relative humidity of 30-80%.
The representational X-ray powder diffraction of dapoxetine hydrochloride crystal formation of the present invention is shown in accompanying drawing 1." representational X-ray powder diffraction " refers to the whole pattern that compound collection of illustrative plates of X-ray powder diffraction feature of this crystal formation shows.Be understandable that in test process, owing to being subject to the impact of many factors, as test sample granularity, when test sample treatment process, instrument, test parameter, test operation etc., the X-ray powder diffraction that same crystal formation is measured go out peak position or peak intensity has certain difference.Therefore, the X-ray powder diffraction of dapoxetine hydrochloride crystal formation of the present invention is shown in Fig. 1, the experimental error of its diffraction peak 2 θ values is generally ± and 0.2.
Dapoxetine hydrochloride crystal formation of the present invention, its DSC scanning has first endotherm(ic)peak between 55-85 ℃, particularly 81.36 ℃ of left and right, has larger endotherm(ic)peak; The second endotherm(ic)peak, between 150-200 ℃, particularly has maximum endotherm(ic)peak 183.37 ℃ of left and right.The DSC spectrogram of dapoxetine hydrochloride crystal formation of the present invention is shown in Fig. 2.
Dapoxetine hydrochloride crystal formation of the present invention, the infrared absorption pattern recording with KBr compressing tablet, at 3434.22cm
-1, 3045.20cm
-1, 2929.86cm
-1, 2889.41cm
-1, 2543.88cm
-1, 2451.96cm
-1, 1625.31cm
-1, 1579.55cm
-1, 1486.56cm
-1, 1451.51cm
-1, 1434.28cm
-1, 1393.63cm
-1, 1269.94cm
-1, 1238.07cm
-1, 1160.65cm
-1, 1100.66cm
-1, 1068.83cm
-1, 1016.14cm
-1, 915.68cm
-1, 795.98cm
-1, 764.96cm
-1, 698.40cm
-1there is absorption peak at place.The infrared absorpting light spectra of dapoxetine hydrochloride crystal formation of the present invention is shown in Fig. 3.
The characteristic displacement of the solid-state nuclear magnetic resonance hydrogen spectrum of dapoxetine hydrochloride crystal formation of the present invention, its H
1nMR (400MHz, DMSO-d
6) δ=11.47 (s, 1H), 8.06-8.08 (m, 1H), 7.83-7.85 (m, 1H), 7.66-7.68 (m, 2H), 7.42-7.55 (m, 6H), 7.31 (t, J=8.8Hz, 1H), 6.74 (d, J=6.8Hz, 1H), 4.72 (d, J=11.2Hz, 1H), 4.10-4.15 (m, 1H), 3.68-3.74 (m, 1H), 2.58-2.98 (m, 6H), 2.50-2.52 (m, 2H).The proton nmr spectra spectrogram of dapoxetine hydrochloride crystal formation of the present invention is shown in Fig. 4.
The outward appearance of dapoxetine hydrochloride crystal formation of the present invention is white powder, and fusing point is 182.5-182.9 ℃
Liquid phase-mass spectrum LC/MS of dapoxetine hydrochloride crystal formation of the present invention is 306.3(M
+-HCl), its liquid phase-mass spectrogram is shown in Fig. 5, Fig. 6.
The chiral purity of dapoxetine hydrochloride crystal formation of the present invention is high, reaches 99.51%, and its chiral chromatography spectrogram is shown in Fig. 7.
Another object of the present invention is to provide the preparation method of above-mentioned dapoxetine hydrochloride crystal formation, and described preparation method comprises following three kinds of methods, but is not limited to following method:
Method one: dapoxetine is dissolved in good solvent, adds concentrated hydrochloric acid, standing after stirring, separate the one deck being suspended between good solvent layer and water layer, concentrated, with suction filtration after the solvent making beating of pulling an oar, collect crystal, dry, obtain dapoxetine hydrochloride crystal formation.
Method two: dapoxetine is dissolved in good solvent and forms reaction solution, pass into dry hydrogen chloride gas to separating out without solid while stirring in reaction solution in cryosel is bathed, suction filtration is collected crystal, and drying obtains dapoxetine hydrochloride crystal formation.
Method three: dapoxetine is dissolved in and forms reaction solution in good solvent, in bathing, cryosel passes into while stirring dry hydrogen chloride gas, lead to and within 30 minutes, in backward reaction solution, drip cold poor solvent crystallization, suction filtration is collected crystal, and drying obtains dapoxetine hydrochloride crystal formation.
The crystallization condition of same compound is different, and especially recrystallisation solvent is different, and the crystal habit obtaining also may be different.The present invention screens by the recrystallisation solvent to dapoxetine hydrochloride, optimizes the crystallization method and the recrystallisation solvent that are applicable to forming dapoxetine hydrochloride crystal formation.
And can be various for the solvent species of crystallization in prior art, and the mixed solvent of the solvent composition of different sorts and ratio cannot be counted especially, and crystallization practice also stays in experience substantially, generally cannot dope the crystal formation that crystallization goes out according to crystallization condition.The present invention can be for the mixed solvent formula of crystallization dapoxetine hydrochloride crystal formation favorite outer discovery of long-term a large amount of experimental study.The dimethylin of dapoxetine hydrochloride, on ether oxygen base, contain lone-pair electron, energy and polar solvent, as water, methyl alcohol etc. forms hydrogen bond under certain conditions, and the volume of this molecule is larger, intermolecular tap density is low, and water, methyl alcohol equal-volume are little, thereby the large molecule of polarity also easily enters the formation that has promoted crystal formation in molecular lattice under given conditions.
In the preparation method of above-mentioned dapoxetine hydrochloride crystal formation, as preferably, described good solvent comprises one or more in toluene, ethyl acetate, Iso Butyl Acetate, methyl acetate, ethyl formate.Further preferably, described good solvent is ethyl acetate.
In the preparation method of above-mentioned dapoxetine hydrochloride crystal formation, as preferably, described poor solvent comprises one or more in sherwood oil, ether, methyl tertiary butyl ether, isopropyl ether, normal hexane, normal heptane, hexanaphthene, suberane.Further preferably, described poor solvent is sherwood oil.
Wherein, in above-mentioned dapoxetine hydrochloride crystal formation preparation method's method one, described making beating solvent is the alkyl alcohol containing 3-6 carbon atom, specifically comprises one or more in n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol.
In the preparation method of above-mentioned dapoxetine hydrochloride crystal formation, described dapoxetine can be purchased, and also can prepare by known references.
The present invention has the following advantages:
1, the outward appearance of dapoxetine hydrochloride crystal formation of the present invention is good, not containing recrystallisation solvent and crystal water, and temperature and humidity good stability, fusing point is high, and purity is high, facilitates the adaptability of preparation technical process, is convenient to standing storage.
2, the preparation method of dapoxetine hydrochloride crystal formation of the present invention is simple to operate, and the used time is shorter, and suitability for industrialized production is easy to operate, quality controllable, is conducive to save energy.
Accompanying drawing explanation
Fig. 1 is that dapoxetine hydrochloride crystal formation does not add the powder x-ray diffraction figure that monochromator obtains, and length axis represents diffracted intensity, and axis of abscissa represents diffraction angle (2 θ).
Fig. 2 is the DSC spectrogram of dapoxetine hydrochloride crystal formation.
Fig. 3 is the infrared absorpting light spectra of dapoxetine hydrochloride crystal formation.
Fig. 4 is the proton nmr spectra spectrogram of dapoxetine hydrochloride crystal formation.
Fig. 5,6 is the liquid phase-mass spectrogram of dapoxetine hydrochloride crystal formation.
Fig. 7 is the chiral chromatography spectrogram of dapoxetine hydrochloride crystal formation.
Fig. 8 is the liquid chromatography spectrogram of dapoxetine hydrochloride crystal formation.
Embodiment
In order to make technical problem solved by the invention, technical scheme and beneficial effect clearer, below in conjunction with specific embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
Dapoxetine required in the following example of the present invention can be purchased, and also can make by known references:
Get 10g dapoxetine and be dissolved in the ethyl acetate of 30mL, add while stirring 10mL concentrated hydrochloric acid, standing after stirring, separate the one deck being suspended between ethyl acetate layer and water layer, concentrated, with suction filtration after the making beating of 20mL Virahol, collect crystal, dry, obtain 10.2g dapoxetine hydrochloride crystal formation.Its purity is 99.79%, and chiral purity is 99.51%, and yield is 92%.
Get in the methyl acetate that 10g dapoxetine is dissolved in 30mL, add while stirring 10mL concentrated hydrochloric acid, standing after stirring, separate the one deck being suspended between ethyl acetate layer and water layer, concentrated, with suction filtration after the making beating of 20mL propyl carbinol, collect crystal, dry, obtain 10.5g dapoxetine hydrochloride crystal formation.Its purity is 99.31%, and chiral purity is 99.10%, and yield is 94.7%.
Get in the Iso Butyl Acetate that 10g dapoxetine is dissolved in 30mL and form reaction solution, in cryosel is bathed, pass into dry hydrogen chloride gas to separating out without solid while stirring in reaction solution, suction filtration is collected crystal, and drying obtains 9.9g dapoxetine hydrochloride crystal formation.Its yield is 89.2%, and purity is 99.12%, and chiral purity is 99.01%.
Embodiment 4
Get 10g dapoxetine and be dissolved in the ethyl acetate of 30mL and form reaction solution, in cryosel is bathed, pass into dry hydrogen chloride gas to separating out without solid while stirring in reaction solution, suction filtration is collected crystal, and drying obtains 10.54g dapoxetine hydrochloride crystal formation.Its yield is 95%, and purity is 99.32%, and chiral purity is 99.12%.
Embodiment 5
Get in the anhydrous acetic acid methyl esters that 10g dapoxetine is dissolved in 25mL and form reaction solution, in bathing, cryosel passes into while stirring dry hydrogen chloride gas, lead to and within 30 minutes, in backward reaction solution, drip the sherwood oil help crystallization that 20mL is cold, suction filtration is collected crystal, and drying obtains 10.3g dapoxetine hydrochloride crystal formation.Its yield is 93%, and purity is 99.42%, and chiral purity is 99.30%.
Get in the Glacial acetic acid isopropyl ester that 10g dapoxetine is dissolved in 25mL and form reaction solution, in bathing, cryosel passes into while stirring dry hydrogen chloride gas, lead to and within 30 minutes, in backward reaction solution, drip the methyl tertiary butyl ether help crystallization that 20mL is cold, suction filtration is collected crystal, and drying obtains 10.8g dapoxetine hydrochloride crystal formation.Its yield is 96%, and purity is 99.12%, and chiral purity is 99.33%.
The dapoxetine hydrochloride crystal formation of randomly drawing in the embodiment of the present invention detects by liquid chromatography.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatographs;
Chromatographic column: Luna C18,4.6mm * 250mm, 5 μ m;
Column temperature: 25 ℃;
Flow velocity: 1.0mL/min;
Detect wavelength: 210nm;
Sampling volume: 5.0 μ L;
Moving phase: acetonitrile: 0.1% phosphate aqueous solution=60:40 (v/v);
Working time: 30min.
Detect the liquid chromatography spectrogram of dapoxetine hydrochloride crystal form samples in the rear embodiment of the present invention as shown in Figure 8; Analytical results is as shown in table 1.
Table 1: the stratographic analysis result of dapoxetine hydrochloride crystal form samples of the present invention
From Fig. 8 and table 1, can find out, the very high purity of dapoxetine hydrochloride crystal formation of the present invention, reaches 99.79%.
The dapoxetine hydrochloride crystal form samples of randomly drawing in the embodiment of the present invention detects by chiral chromatography.As shown in Figure 7, analytical results is as shown in table 2 for chiral chromatography spectrogram after detection.
Table 2: the chiral chromatographic analysis result of dapoxetine hydrochloride crystal form samples of the present invention
From Fig. 7 and table 2, can find out, dapoxetine hydrochloride crystal formation chiral purity of the present invention is high, reaches 99.51%.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any modifications of doing within the spirit and principles in the present invention, be equal to and replace and improvement etc., within all should being included in protection scope of the present invention.
Claims (9)
1. a dapoxetine hydrochloride crystal formation, it is characterized in that, described dapoxetine hydrochloride crystal formation: use Cu-Ka radiation, with 2 θ angles, represent that X-ray powder diffraction is 6.82 ± 0.2,8.90 ± 0.2,13.69 ± 0.2,15.03 ± 0.2,16.04 ± 0.2,17.78 ± 0.2,18.82 ± 0.2,20.61 ± 0.2,21.65 ± 0.2,22.26 ± 0.2,22.66 ± 0.2,25.23 ± 0.2,27.61 ± 0.2,28.89 ± 0.2 have characteristic peak.
2. dapoxetine hydrochloride crystal formation according to claim 1, is characterized in that, the DSC scanning of described dapoxetine hydrochloride crystal formation has first endotherm(ic)peak between 55-85 ℃, and the second endotherm(ic)peak is between 150-200 ℃.
3. dapoxetine hydrochloride crystal formation according to claim 1, is characterized in that, the infrared absorption spectrum that described dapoxetine hydrochloride crystal formation records with KBr compressing tablet, at 3434.22cm
-1, 3045.20cm
-1, 2929.86cm
-1, 2889.41cm
-1, 2543.88cm
-1, 2451.96cm
-1, 1625.31cm
-1, 1579.55cm
-1, 1486.56cm
-1, 1451.51cm
-1, 1434.28cm
-1, 1393.63cm
-1, 1269.94cm
-1, 1238.07cm
-1, 1160.65cm
-1, 1100.66cm
-1, 1068.83cm
-1, 1016.14cm
-1, 915.68cm
-1, 795.98cm
-1, 764.96cm
-1, 698.40cm
-1there is absorption peak at place.
4. dapoxetine hydrochloride crystal formation according to claim 1, is characterized in that, the chemical shift of the proton nmr spectra of described dapoxetine hydrochloride crystal formation is H
1nMR (400MHz, DMSO-d
6) δ=11.47 (s, 1H), 8.06-8.08 (m, 1H), 7.83-7.85 (m, 1H), 7.66-7.68 (m, 2H), 7.42-7.55 (m, 6H), 7.31 (t, J=8.8Hz, 1H), 6.74 (d, J=6.8Hz, 1H), 4.72 (d, J=11.2Hz, 1H), 4.10-4.15 (m, 1H), 3.68-3.74 (m, 1H), 2.58-2.98 (m, 6H), 2.50-2.52 (m, 2H).
5. dapoxetine hydrochloride crystal formation according to claim 1, is characterized in that, liquid phase-mass spectrum LC/MS of described dapoxetine hydrochloride crystal formation is 306.3(M
+-HCl), fusing point is 182.5-182.9 ℃.
6. the synthetic method of the dapoxetine hydrochloride crystal formation described in arbitrary claim in claim 1-5, it is characterized in that, this synthetic method comprises the steps: dapoxetine to be dissolved in good solvent, add concentrated hydrochloric acid, standing after stirring, separate the one deck being suspended between good solvent layer and water layer, concentrated, with suction filtration after the making beating of making beating solvent, collect crystal, dry, obtain dapoxetine hydrochloride crystal formation.
7. the synthetic method of dapoxetine hydrochloride crystal formation according to claim 6, is characterized in that, described making beating solvent is the alkyl alcohol containing 3-6 carbon atom.
8. the synthetic method of the dapoxetine hydrochloride crystal formation described in arbitrary claim in claim 1-5, it is characterized in that, this synthetic method comprises the steps: dapoxetine to be dissolved in and in good solvent, to form reaction solution, in bathing, cryosel in reaction solution, passes into dry hydrogen chloride gas to separating out without solid while stirring, suction filtration is collected crystal, and drying obtains dapoxetine hydrochloride crystal formation.
9. the synthetic method of the dapoxetine hydrochloride crystal formation described in arbitrary claim in claim 1-5, it is characterized in that, this synthetic method comprises the steps: dapoxetine to be dissolved in and in good solvent, to form reaction solution, in bathing, cryosel passes into while stirring dry hydrogen chloride gas, lead to and within 30 minutes, in backward reaction solution, drip cold poor solvent crystallization, suction filtration is collected crystal, and drying obtains dapoxetine hydrochloride crystal formation.
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| CN104496829A (en) * | 2014-11-28 | 2015-04-08 | 重庆华邦制药有限公司 | New crystal form of dapoxetine hydrochloride as well as preparation method and application thereof |
| 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 |
| CN108264465A (en) * | 2016-12-30 | 2018-07-10 | 苏州科伦药物研究有限公司 | Dapoxetine hydrochloride monohydrate and its preparation method and application |
| CN108663460A (en) * | 2018-08-03 | 2018-10-16 | 安徽省金楠医疗科技有限公司 | A kind of dapoxetine hydrochloride isomery body detecting method |
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
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| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN110903203B (en) * | 2018-09-14 | 2022-11-18 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
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