CN103130661B - 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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- CN103130661B CN103130661B CN201110385109.8A CN201110385109A CN103130661B CN 103130661 B CN103130661 B CN 103130661B CN 201110385109 A CN201110385109 A CN 201110385109A CN 103130661 B CN103130661 B CN 103130661B
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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
Dapoxetine chemical name is (+) N, N-dimethyl-1-phenyl-3-(1-naphthyloxy) propylamine, be a kind of selectivity serotonin reuptake inhibithors (SSRI), the transformation period is short, can be used for treatment depression 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, for the oral therapeutic drug of this indication, 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 in the world.
Dapoxetine Yuan Yan producer is Eli Lilly Company of the U.S., 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 to explanation.Repeat in this way the dapoxetine hydrochloride crystal formation called after crystal form A that experiment obtains, 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; DSC collection of illustrative plates has endotherm(ic)peak at 177 ± 5 DEG C.In patent CN1709859, also describe the preparation of the hydrochloride of dapoxetine, but it has not been done to any sign explanation, and repeated in this way experiment, do not obtained product dapoxetine hydrochloride.
Same medicine, crystal formation difference, also may there is 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 to methylene dichloride, chloroform or 1, in 2-ethylene dichloride, drip dichloromethane solution, chloroformic solution or 1, the 2-dichloroethane solution of hydrogenchloride, or directly pass into hydrogen chloride gas, to there being Precipitation, filter, obtain precipitation, be the crystal of above-mentioned dapoxetine hydrochloride; Wherein drip solvent species in solution identical with the solvent species that dissolves before dapoxetine.
Wherein, dapoxetine is being dissolved in to methylene dichloride, chloroform or 1, in 2-ethylene dichloride time, methylene dichloride, chloroform or 1, the consumption of 2-ethylene dichloride can be dapoxetine is dissolved completely, preferably, methylene dichloride, chloroform or 1,2-ethylene dichloride are 5～20ml/g (preferably 15ml/g) with the volume mass ratio of dapoxetine.The temperature of dissolving can be conventional temperature, as 20～35 DEG C.
At the dichloromethane solution, the chloroformic solution or 1 that drip hydrogenchloride, 2-dichloroethane solution, or before directly passing into hydrogen chloride gas, preferably dapoxetine is dissolved in to methylene dichloride, chloroform or 1, solution after 2-ethylene dichloride filters, with the insoluble impurity of elimination.
Preferably, after described Precipitation, also can lower the temperature, then filter, obtain precipitation, be the crystal of above-mentioned dapoxetine hydrochloride.Wherein, the cooling extent needing when described cooling can be conventional crystallization, as be down to 0～10 DEG C.
Preferably, by after sedimentation and filtration, also can further be dried (as vacuum-drying), thereby make the sterling of above-mentioned crystal.
Hydrogenchloride in dichloromethane solution, chloroformic solution or 1, the 2-dichloroethane solution of described hydrogenchloride, or the amount of described hydrogen chloride gas can be to precipitation no longer produce till,, be in general excessive interpolation.Concentration in dichloromethane solution, chloroformic solution or 1, the 2-dichloroethane solution of described hydrogenchloride is preferably saturation concentration.
The present invention also provides a kind of amorphous state dapoxetine hydrochloride, and it does not have obvious diffraction peak in XRPD collection of illustrative plates, there is no obvious endotherm(ic)peak in 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 in methyl alcohol, ethanol, n-propyl alcohol, Virahol and propyl carbinol or two or more mixed solvent, remove insolubles, rapidly except desolventizing, it is dry.
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 solvents can be dapoxetine hydrochloride is dissolved completely,, preferably, methyl alcohol is 5～15ml/g (preferably 10ml/g) with the volume mass ratio of dapoxetine hydrochloride.Described steams and desolventizes rapidly except the mode of desolventizing can be by Rotary Evaporators rapidly.The described dry vacuum-drying that can be.Described insolubles is undissolvable impurity.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Except specified otherwise, agents useful for same of the present invention and raw material be commercially available obtaining 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 is obviously better than crystal formation of the prior art.And the present invention has also found amorphous state dapoxetine hydrochloride, its solubleness in water is obviously better than dapoxetine hydrochloride crystal of the prior art.
Brief description of the 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 selects according to catalogue.
In following each embodiment, " room temperature " refers to 20～35 DEG C.
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 916mg dapoxetine in container, under room temperature, add 15ml ethyl acetate, being stirred to solid dissolves completely, the impurity that elimination is insoluble, pass into wherein drier hydrogen chloride gas, under room temperature, stir 2h, have Precipitation, filter to obtain white powder 620mg, be A crystal formation dapoxetine hydrochloride.Its XRPD collection of illustrative plates and DSC collection of illustrative plates are shown in 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; DSC collection of illustrative plates has endotherm(ic)peak at 177 ± 5 DEG C.
The preparation of embodiment 1B crystal formation dapoxetine hydrochloride
Take 916mg dapoxetine in container, add 15ml methylene dichloride, stirring at room temperature to solid dissolves completely, elimination insolubles, more slowly splash into the methylene dichloride saturated solution of 1.5ml hydrogenchloride, under room temperature, stir 2h, there is Precipitation, be cooled to 5 DEG C, after filtration, vacuum-drying, obtain white powder 800mg, be B crystal formation dapoxetine hydrochloride of the present invention.Its XRPD collection of illustrative plates and single crystal structure figure are shown in 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 to 20mL methyl alcohol, and elimination insolubles after dissolving completely, revolves to steam and removes fast desolventizing, obtains 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 shown in respectively Fig. 5 and Fig. 6.
The preparation of embodiment 3B crystal formation dapoxetine hydrochloride
Take 916mg dapoxetine in container, add 15ml1,2-ethylene dichloride, stirring at room temperature to solid dissolves completely, elimination insolubles, slowly splash into 1 of 1.5ml hydrogenchloride, 2-ethylene dichloride saturated solution, stirs 2h under room temperature again, there is Precipitation, be cooled to 5 DEG C, after filtration, vacuum-drying, obtain white powder 665mg, be B crystal formation dapoxetine hydrochloride of the present invention.Its XRPD collection of illustrative plates and single crystal structure figure are shown in 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 to 20mL Virahol, and elimination insolubles after dissolving completely, revolves to steam and removes fast desolventizing, obtains 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 shown in 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 to 20mL propyl carbinol, and elimination insolubles after dissolving completely, revolves to steam and removes fast desolventizing, obtains 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 shown in respectively Fig. 5 and Fig. 6.)
Comparative example 1A, the comparison of B crystal formation dapoxetine hydrochloride stability
Respectively A, B crystal formation dapoxetine hydrochloride sample are placed in 80 DEG C of baking ovens, after one week, sample are taken out and carries out DSC, XRPD test, to investigate the stable crystal form of sample to temperature.Result shows, under this condition, A crystal form samples is converted into B crystal formation, and 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, with dapoxetine chromatographic peak area, to concentration mapping drawing standard curve, gained typical curve equation is: A=8.43 × 10
4c+5.97 × 10
4(A is chromatographic peak area, and C is concentration.
Testing sample is made to supersaturated aqueous solution or suspension, put 25 DEG C of shaking table concussions after 12 hours, put ultrasonic 30s in ultrasonic apparatus, filter, dilute suitable multiple, carry out HPLC analysis, the dapoxetine chromatographic peak area substitution typical curve equation of gained, calculate the concentration of counter sample, molecular weight is more per sample 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), is obviously better than the solubleness (being about 85mg/ml) (in dapoxetine) of the crystal form A that reference example makes.
Claims (8)
1. a crystal for dapoxetine hydrochloride, 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 to methylene dichloride, chloroform or 1, in 2-ethylene dichloride, drip dichloromethane solution, chloroformic solution or 1, the 2-dichloroethane solution of hydrogenchloride, or directly pass into hydrogen chloride gas, to there being Precipitation, filter, obtain precipitation, be the crystal of described dapoxetine hydrochloride; Wherein drip solvent species in solution 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 to methylene dichloride, chloroform or 1, in 2-ethylene dichloride time, described methylene dichloride, chloroform or 1,2-ethylene dichloride is 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: described methylene dichloride, chloroform or 1,2-ethylene dichloride is 15ml/g with the volume mass of dapoxetine ratio.
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, 2-dichloroethane solution, or before directly passing into hydrogen chloride gas, dapoxetine is dissolved in to methylene dichloride, chloroform or 1, solution after 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, obtain precipitation, be the crystal of described dapoxetine hydrochloride.
7. the preparation method of crystal as claimed in claim 6, is characterized in that: described cooling is for being down to 0～10 DEG C.
8. the preparation method of the crystal as described in claim 2 or 6, is characterized in that: by after sedimentation and filtration, dry, thus make the sterling of crystal.
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| Application Number | Priority Date | Filing Date | Title |
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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 |
| 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 CN103130661A (en) | 2013-06-05 |
| CN103130661B true CN103130661B (en) | 2014-09-17 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN108264465B (en) * | 2016-12-30 | 2020-08-11 | 苏州科伦药物研究有限公司 | Dapoxetine hydrochloride monohydrate, 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 |
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 |
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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 |
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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》.2011,第21卷(第1期), |
| 戴蓉等.盐酸达泊西汀的合成.《中国新药杂志》.2008,第17卷(第24期),第2119-2121页. |
| 盐酸达泊西汀的合成;戴蓉等;《中国新药杂志》;20081231;第17卷(第24期);第2119-2121页 * |
| 盐酸达泊西汀的合成;薛大泉等;《合成化学》;20101231;第18卷(第5期);第648页右栏(3) * |
| 盐酸达泊西汀的合成工艺研究;尹玲丽等;《中国药物化学杂志》;20110228;第21卷(第1期);第38页右栏第2.5节 * |
| 薛大泉等.盐酸达泊西汀的合成.《合成化学》.2010,第18卷(第5期),647～649页. |
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| CN103130661A (en) | 2013-06-05 |
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