CN103130661A - Crystal and amorphous substance of dapoxetine hydrochloride and preparation method thereof - Google Patents
Crystal and amorphous substance of dapoxetine hydrochloride and preparation method thereof Download PDFInfo
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- CN103130661A CN103130661A CN2011103851098A CN201110385109A CN103130661A CN 103130661 A CN103130661 A CN 103130661A CN 2011103851098 A CN2011103851098 A CN 2011103851098A CN 201110385109 A CN201110385109 A CN 201110385109A CN 103130661 A CN103130661 A CN 103130661A
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Abstract
The invention discloses a crystal of dapoxetine hydrochloride, amorphous substance of the dapoxetine hydrochloride and a preparation method of the crystal and the amorphous substance of the dapoxetine hydrochloride. The stability of the crystal is better than that of crystal forms in the prior art, and the solubility of the amorphous substance is obvious higher than that of existing dapoxetine hydrochloride.
Description
Technical field
The present invention is specifically related to crystal, amorphous substance of a kind of dapoxetine hydrochloride and preparation method thereof.
Background technology
The dapoxetine chemical name is (+) N, and N-dimethyl-1-phenyl-3-(1-naphthyloxy) propylamine is a kind of selectivity serotonin reuptake inhibithors (SSRI), and the transformation period is short, can be used for treating depressed and relevant affective disorder.In February, 2009 is as the medicine (Prilig for the treatment of prospermia of males
TM) in Europe approval listing, this is that the first is used for the oral therapeutic drug of this indication in the world, is classified as one of five tool prospect medicines that gone on the market or examined by the Thomson Reuters first quarter in 2009 whole world medicament research and development major progress quarterly report.
The former producer of grinding of dapoxetine is U.S. Eli Lilly Company, and its original patent EP 0288188 has described the preparation method of dapoxetine.
Patent US 5292962 and WO 2008035358 have provided respectively the preparation method of dapoxetine hydrochloride, and preparation process is basic identical, but its crystal formation problem are not characterized explanation.The dapoxetine hydrochloride crystal formation called after crystal form A that obtains of repeated experiments in this way, its XRPD collection of illustrative plates is that 6.33,8.92,14.42,15.11,16.34,16.65,16.95,17.84,18.93,19.18,20.70,20.93,21.16,22.73,23.82,25.34,26.66,27.80,29.03,29.52,31.28,31.58,33.03,33.67,34.24,36.05,37.32,38.88,41.68,43.45,44.58 places have diffraction peak in 2 θ values, and wherein 2 θ value limit of error are ± 0.2; The DSC collection of illustrative plates has endotherm(ic)peak at 177 ± 5 ℃.Also describe the preparation of the hydrochloride of dapoxetine in patent CN1709859, but it has not been done the explanation of any sign, and repeated experiments in this way, the product dapoxetine hydrochloride do not obtained.
The same medicine, crystal formation is different, and also may there be difference in its bioavailability, and its stability, mobility, compressibility also may be different in addition, and these physico-chemical properties produce certain impact to the application of medicine.
Summary of the invention
Technical problem to be solved by this invention has been to provide crystal, amorphous substance of a kind of dapoxetine hydrochloride unlike the prior art and preparation method thereof.The stability of crystal of the present invention is better than crystal formation of the prior art, and the solubleness of amorphous substance in water is apparently higher than existing dapoxetine hydrochloride.
The invention provides a kind of crystal of dapoxetine hydrochloride, in its XRPD collection of illustrative plates, source of radiation is CuK α
1Be that 6.29,8.84,14.33,15.06,16.28,16.38,16.61,16.89,17.78,18.87,20.62,20.76,21.10,21.82,22.69,23.78,25.30,26.66,27.75,28.46,28.97,29.48,30.19,31.22,31.54,32.11,32.96,33.57,34.91,35.25,35.92,38.88,41.64,44.54 places have diffraction peak in angle of diffraction 2 θ values, wherein 2 θ value limit of error are ± 0.2; It belongs to rhombic system, and unit cell parameters is
α=β=γ=90.00 °, unit cell volume
In structure cell, asymmetry unit is counted Z=4.
Crystal of the present invention, called after dapoxetine hydrochloride crystal form B, its stability is better than crystal form A of the prior art.Experiment shows that crystal form A can be converted into crystal form B under certain conditions.
The present invention further provides the preparation method of above-mentioned crystal, it comprises the following step: dapoxetine is dissolved in methylene dichloride, chloroform or 1, in the 2-ethylene dichloride, drip dichloromethane solution, chloroformic solution or 1, the 2-dichloroethane solution of hydrogenchloride, perhaps directly pass into hydrogen chloride gas, to Precipitation is arranged, filter, get precipitation, be the crystal of above-mentioned dapoxetine hydrochloride; The solvent species that wherein drips in solution is identical with the solvent species that dissolves before dapoxetine.
Wherein, dapoxetine is being dissolved in methylene dichloride, chloroform or 1, in the time of in the 2-ethylene dichloride, methylene dichloride, chloroform or 1, the consumption of 2-ethylene dichloride can be dapoxetine is dissolved fully and gets final product, better, methylene dichloride, chloroform or 1,2-ethylene dichloride are 5～20ml/g (preferred 15ml/g) with the volume mass ratio of dapoxetine.The temperature of dissolving can be conventional temperature, as 20～35 ℃.
At the dichloromethane solution, the chloroformic solution or 1 that drip hydrogenchloride, the 2-dichloroethane solution, before perhaps directly passing into hydrogen chloride gas, better methylene dichloride, chloroform or 1 that dapoxetine is dissolved in, solution after the 2-ethylene dichloride filters, with the insoluble impurity of elimination.
Better, after described Precipitation, also can lower the temperature, then filter, get precipitation, be the crystal of above-mentioned dapoxetine hydrochloride.Wherein, the cooling extent that needs when described cooling can be conventional crystallization, as be down to 0～10 ℃.
Better, after with sedimentation and filtration, also further dry (as vacuum-drying), thus make the sterling of above-mentioned crystal.
Hydrogenchloride in the dichloromethane solution of described hydrogenchloride, chloroformic solution or 1,2-dichloroethane solution till perhaps the amount of described hydrogen chloride gas can be and no longer produces to precipitation, gets final product, and is in general excessive interpolation.What the concentration in the dichloromethane solution of described hydrogenchloride, chloroformic solution or 1,2-dichloroethane solution was better is saturation concentration.
The present invention also provides a kind of amorphous state dapoxetine hydrochloride, and it does not have obvious diffraction peak in the XRPD collection of illustrative plates, there is no obvious endotherm(ic)peak in the DSC collection of illustrative plates.
Amorphous state dapoxetine hydrochloride in the present invention, its solubleness (being about 95mg/ml) in water is better than crystal form A (being about 85mg/ml).
The present invention also provides the preparation method of above-mentioned amorphous state dapoxetine hydrochloride, it comprises the following step: dapoxetine hydrochloride is dissolved in a kind of solvent or two or more mixed solvent in methyl alcohol, ethanol, n-propyl alcohol, Virahol and propyl carbinol, remove insolubles, desolventizing rapidly, drying gets final product.
Wherein, described dapoxetine hydrochloride can be the B crystal formation in this area existing A crystal formation dapoxetine hydrochloride or the present invention.
The consumption of described a kind of solvent or two or more mixed solvent can be dapoxetine hydrochloride is dissolved fully, gets final product, and is better, and methyl alcohol is 5～15ml/g (preferred 10ml/g) with the volume mass ratio of dapoxetine hydrochloride.The mode of described rapid desolventizing can be to steam rapidly by Rotary Evaporators and desolventizes.Described drying can be vacuum-drying.Described insolubles is undissolvable impurity.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Except specified otherwise, agents useful for same of the present invention and raw material be commercially available getting all.
Positive progressive effect of the present invention is: the present invention has found the brand-new crystal of a kind of dapoxetine hydrochloride, and the stability of this crystal obviously is better than crystal formation of the prior art.And the present invention has also found the amorphous state dapoxetine hydrochloride, and its solubleness in water obviously is better than dapoxetine hydrochloride crystal of the prior art.
Description of drawings
Fig. 1 is the XRPD collection of illustrative plates of B crystal formation dapoxetine hydrochloride of the present invention.
Fig. 2 is the single crystal structure figure of B crystal formation dapoxetine hydrochloride of the present invention.
Fig. 3 is the XRPD collection of illustrative plates of A crystal formation dapoxetine hydrochloride of the prior art.
Fig. 4 is the DSC collection of illustrative plates of A crystal formation dapoxetine hydrochloride of the prior art.
Fig. 5 is the XRPD collection of illustrative plates of amorphous state dapoxetine hydrochloride of the present invention.
Fig. 6 is the DSC collection of illustrative plates of amorphous state dapoxetine hydrochloride of the present invention.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
In following each embodiment, " room temperature " refers to 20～35 ℃.
The various testing method experiment condition used of the crystal that following examples obtain:
Monocrystalline testing method: instrument model: Bruker SMART APEX-II, diffracted ray: CuK α (40kV, 30mA), scan mode: Φ/ω scanning; XRPD testing method: instrument model: Bruker D8advance XRD, diffracted ray: CuK α (40kV, 40mA), scanning speed: 8 °/min (2 θ value), sweep limit: 3 °～45 ° (2 θ value).)
The preparation of reference example A crystal formation dapoxetine hydrochloride
Take the 916mg dapoxetine in container, add the 15ml ethyl acetate under room temperature, being stirred to solid dissolves fully, the impurity that elimination is insoluble, pass into wherein drier hydrogen chloride gas, stir 2h under room temperature, Precipitation is arranged, filter to get white powder 620mg, be A crystal formation dapoxetine hydrochloride.Its XRPD collection of illustrative plates and DSC collection of illustrative plates are seen Fig. 3 and Fig. 4.Its XRPD collection of illustrative plates is that 6.33,8.92,14.42,15.11,16.34,16.65,16.95,17.84,18.93,19.18,20.70,20.93,21.16,22.73,23.82,25.34,26.66,27.80,29.03,29.52,31.28,31.58,33.03,33.67,34.24,36.05,37.32,38.88,41.68,43.45,44.58 places have diffraction peak in 2 θ values, and wherein 2 θ value limit of error are ± 0.2; The DSC collection of illustrative plates has endotherm(ic)peak at 177 ± 5 ℃.
The preparation of embodiment 1B crystal formation dapoxetine hydrochloride
Take the 916mg dapoxetine in container, add the 15ml methylene dichloride, stirring at room to solid dissolves fully, the elimination insolubles, more slowly splash into the methylene dichloride saturated solution of 1.5ml hydrogenchloride, stir 2h under room temperature, Precipitation is arranged, be cooled to 5 ℃, get white powder 800mg after filtration, vacuum-drying, be B crystal formation dapoxetine hydrochloride of the present invention.Its XRPD collection of illustrative plates and single crystal structure figure see respectively Fig. 1 and Fig. 2.In its XRPD collection of illustrative plates, source of radiation is CuK α
1Be that 6.29,8.84,14.33,15.06,16.28,16.38,16.61,16.89,17.78,18.87,20.62,20.76,21.10,21.82,22.69,23.78,25.30,26.66,27.75,28.46,28.97,29.48,30.19,31.22,31.54,32.11,32.96,33.57,34.91,35.25,35.92,38.88,41.64,44.54 places have diffraction peak in angle of diffraction 2 θ values, wherein 2 θ value limit of error are ± 0.2; It belongs to rhombic system, and unit cell parameters is
α=β=γ=90.00 °, unit cell volume
In structure cell, asymmetry unit is counted Z=4.
The preparation of embodiment 2 amorphous state dapoxetine hydrochlorides
500mg dapoxetine hydrochloride (the B crystal formation that embodiment 1 obtains) is dissolved in 20mL methyl alcohol, and elimination insolubles after the dissolving, revolve and steam quick desolventizing fully, gets white solid after vacuum-drying, is amorphous state dapoxetine hydrochloride of the present invention.Its XRPD collection of illustrative plates and DSC collection of illustrative plates are seen respectively Fig. 5 and Fig. 6.
The preparation of embodiment 3B crystal formation dapoxetine hydrochloride
Take the 916mg dapoxetine in container, add 15ml1, the 2-ethylene dichloride, stirring at room to solid dissolves fully, the elimination insolubles, slowly splash into 1 of 1.5ml hydrogenchloride, 2-ethylene dichloride saturated solution stirs 2h under room temperature again, Precipitation is arranged, be cooled to 5 ℃, get white powder 665mg after filtration, vacuum-drying, be B crystal formation dapoxetine hydrochloride of the present invention.Its XRPD collection of illustrative plates and single crystal structure figure see respectively Fig. 1 and Fig. 2.In its XRPD collection of illustrative plates, source of radiation is CuK α
1Be that 6.29,8.84,14.33,15.06,16.28,16.38,16.61,16.89,17.78,18.87,20.62,20.76,21.10,21.82,22.69,23.78,25.30,26.66,27.75,28.46,28.97,29.48,30.19,31.22,31.54,32.11,32.96,33.57,34.91,35.25,35.92,38.88,41.64,44.54 places have diffraction peak in angle of diffraction 2 θ values, wherein 2 θ value limit of error are ± 0.2; It belongs to rhombic system, and unit cell parameters is
α=β=γ=90.00 °, unit cell volume
In structure cell, asymmetry unit is counted Z=4.
The preparation of embodiment 4 amorphous state dapoxetine hydrochlorides
500mg dapoxetine hydrochloride (the B crystal formation that embodiment 1 obtains) is dissolved in the 20mL Virahol, and elimination insolubles after the dissolving, revolve and steam quick desolventizing fully, gets white solid after vacuum-drying, is amorphous state dapoxetine hydrochloride of the present invention.Its XRPD collection of illustrative plates and DSC collection of illustrative plates are seen respectively Fig. 5 and Fig. 6.
The preparation of embodiment 5 amorphous state dapoxetine hydrochlorides
500mg dapoxetine hydrochloride (the B crystal formation that embodiment 1 obtains) is dissolved in the 20mL propyl carbinol, and elimination insolubles after the dissolving, revolve and steam quick desolventizing fully, gets white solid after vacuum-drying, is amorphous state dapoxetine hydrochloride of the present invention.Its XRPD collection of illustrative plates and DSC collection of illustrative plates are seen respectively Fig. 5 and Fig. 6.)
Comparative example 1A, B crystal formation dapoxetine hydrochloride stability are relatively
Respectively A, B crystal formation dapoxetine hydrochloride sample are placed in 80 ℃ of baking ovens, after the week, sample are taken out and carry out DSC, XRPD test, to investigate sample to the stable crystal form of temperature.Result shows, under this condition, the A crystal form samples is converted into the B crystal formation, and the B crystal form samples is unchanged.
The solubleness contrast experiment of the A crystal formation dapoxetine hydrochloride of comparative example 2 amorphous state dapoxetine hydrochloride of the present invention and prior art
The dapoxetine standard substance that compound concentration is respectively 5 μ g/ml, 25 μ g/ml, 50 μ g/ml, 100 μ g/ml, 150 μ g/ml, 200 μ g/ml detect by HPLC, to concentration mapping drawing standard curve, gained typical curve equation is: A=8.43 * 10 with the dapoxetine chromatographic peak area
4C+5.97 * 10
4(A is chromatographic peak area, and C is concentration.
Testing sample is made supersaturated aqueous solution or suspension, put 25 ℃ of shaking table concussions after 12 hours, put ultrasonic 30s in ultrasonic apparatus, filter, dilute suitable multiple, carry out HPLC and analyze, the dapoxetine chromatographic peak area substitution typical curve equation of gained, calculate the concentration of counter sample, then molecular weight per sample is scaled the solubleness in this sample of dapoxetine.
As calculated, the amorphous state dapoxetine hydrochloride that the embodiment of the present invention 2 makes, its solubleness in water is about 95mg/ml (in dapoxetine), obviously is better than the solubleness (being about 85mg/ml) (in dapoxetine) of the crystal form A that reference example makes.
Claims (10)
1. the crystal of a dapoxetine hydrochloride, it is characterized in that: in its XRPD collection of illustrative plates, source of radiation is CuK α
1Be that 6.29,8.84,14.33,15.06,16.28,16.38,16.61,16.89,17.78,18.87,20.62,20.76,21.10,21.82,22.69,23.78,25.30,26.66,27.75,28.46,28.97,29.48,30.19,31.22,31.54,32.11,32.96,33.57,34.91,35.25,35.92,38.88,41.64,44.54 places have diffraction peak in angle of diffraction 2 θ values, wherein 2 θ value limit of error are ± 0.2; It belongs to rhombic system, and unit cell parameters is
α=β=γ=90.00 °, unit cell volume
In structure cell, asymmetry unit is counted Z=4.
2. the preparation method of crystal as claimed in claim 1, it comprises the following step: dapoxetine is dissolved in methylene dichloride, chloroform or 1, in the 2-ethylene dichloride, drip dichloromethane solution, chloroformic solution or 1, the 2-dichloroethane solution of hydrogenchloride, perhaps directly pass into hydrogen chloride gas, to Precipitation is arranged, filter, get precipitation, be the crystal of described dapoxetine hydrochloride; The solvent species that wherein drips in solution is identical with the solvent species that dissolves before dapoxetine.
3. the preparation method of crystal as claimed in claim 2, it is characterized in that: dapoxetine is dissolved in methylene dichloride, chloroform or 1, in the time of in the 2-ethylene dichloride, described methylene dichloride, chloroform or 1,2-ethylene dichloride are 5～20ml/g with the volume mass ratio of dapoxetine.
4. the preparation method of crystal as claimed in claim 3 is characterized in that: the volume mass of described methylene dichloride, chloroform or 1,2-ethylene dichloride and dapoxetine is than being 15ml/g.
5. the preparation method of crystal as claimed in claim 2, it is characterized in that: at the dichloromethane solution, the chloroformic solution or 1 that drip hydrogenchloride, the 2-dichloroethane solution, before perhaps directly passing into hydrogen chloride gas, dapoxetine is dissolved in methylene dichloride, chloroform or 1, solution after the 2-ethylene dichloride filters, with the insoluble impurity of elimination.
6. the preparation method of crystal as claimed in claim 2, is characterized in that: after described Precipitation, also lower the temperature, refilter, get precipitation, be the crystal of described dapoxetine hydrochloride.
7. the preparation method of crystal as claimed in claim 6, it is characterized in that: described cooling is for being down to 0～10 ℃.
8. as the preparation method of claim 2 or 6 described crystal, it is characterized in that: after with sedimentation and filtration, drying, thus make the sterling of crystal.
9. amorphous state dapoxetine hydrochloride, it does not have obvious diffraction peak in the XRPD collection of illustrative plates, there is no obvious endotherm(ic)peak in the DSC collection of illustrative plates.
10. the preparation method of amorphous state dapoxetine hydrochloride as claimed in claim 9, it comprises the following step: dapoxetine hydrochloride is dissolved in a kind of solvent or two or more mixed solvent in methyl alcohol, ethanol, n-propyl alcohol, Virahol and propyl carbinol, remove insolubles, desolventizing rapidly, drying gets final product.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110385109.8A CN103130661B (en) | 2011-11-25 | 2011-11-25 | Crystal and amorphous substance of dapoxetine hydrochloride and preparation method thereof |
| PCT/CN2012/085284 WO2013075669A1 (en) | 2011-11-25 | 2012-11-26 | Crystal and amorphous substance of dapoxetine hydrochloride and preparation method therefor |
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| CN201110385109.8A CN103130661B (en) | 2011-11-25 | 2011-11-25 | Crystal and amorphous substance of dapoxetine hydrochloride and preparation method thereof |
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| CN103130661A true CN103130661A (en) | 2013-06-05 |
| CN103130661B CN103130661B (en) | 2014-09-17 |
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| WO (1) | WO2013075669A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5292962A (en) * | 1992-12-11 | 1994-03-08 | Eli Lilly And Company | Intermediates to 1-phenyl-3-naphthalenyloxy-propanamines |
| CN100402488C (en) * | 2006-03-15 | 2008-07-16 | 上海玛耀化学技术有限公司 | Synthetic method for dapoxetine |
| WO2010112203A1 (en) * | 2009-03-31 | 2010-10-07 | Ratiopharm Gmbh | Pills comprising dapoxetin and dry processing methods for the production thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035358A2 (en) * | 2006-06-05 | 2008-03-27 | Cadila Healthcare Limited | Process for preparing dapoxetine |
-
2011
- 2011-11-25 CN CN201110385109.8A patent/CN103130661B/en active Active
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2012
- 2012-11-26 WO PCT/CN2012/085284 patent/WO2013075669A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5292962A (en) * | 1992-12-11 | 1994-03-08 | Eli Lilly And Company | Intermediates to 1-phenyl-3-naphthalenyloxy-propanamines |
| CN100402488C (en) * | 2006-03-15 | 2008-07-16 | 上海玛耀化学技术有限公司 | Synthetic method for dapoxetine |
| WO2010112203A1 (en) * | 2009-03-31 | 2010-10-07 | Ratiopharm Gmbh | Pills comprising dapoxetin and dry processing methods for the production thereof |
Non-Patent Citations (3)
| Title |
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| 尹玲丽等: "盐酸达泊西汀的合成工艺研究", 《中国药物化学杂志》 * |
| 戴蓉等: "盐酸达泊西汀的合成", 《中国新药杂志》 * |
| 薛大泉等: "盐酸达泊西汀的合成", 《合成化学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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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| Publication number | Publication date |
|---|---|
| CN103130661B (en) | 2014-09-17 |
| WO2013075669A1 (en) | 2013-05-30 |
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