CN103130660A - Acidic salt and crystal of dapoxetine and preparation method of crystal - Google Patents
Acidic salt and crystal of dapoxetine and preparation method of crystal Download PDFInfo
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Abstract
The invention discloses acidic salt and a crystal of dapoxetine and a preparation method of the crystal. The acidic salt of dapoxetine is gentisic acid salt, orotic acid salt, cyclamic acid slat or acetylsalicylate of the dapoxetine. The solubility of the several types of the salt and the crystal of the dapoxetine is obvious better than that of dapoxetine free alkali, and the several types of the salt and the crystal of the dapoxetine are good in stability and hygroscopicity.
Description
Technical field
The present invention is specifically related to acid salt and the crystal thereof of a class dapoxetine, and the preparation method of crystal.
Background technology
The dapoxetine chemical name is (+) N, and N-dimethyl-1-phenyl-3-(1-naphthyloxy) propylamine, be a kind of selectivity serotonin reuptake inhibithors (SSRI), and 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.
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.
The same medicine, the crystal formation difference, 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.Equally, the different salt types of same medicine also exist same difference.The present invention proposes several salt types of dapoxetine, and its physico-chemical property exists certain difference each other.
The inventor is through great many of experiments, salt and the crystal of finding a lot of acid of dapoxetine can't prepare, as the acetic acid of dapoxetine, propionic acid, isopropylformic acid, n-caprylic acid, oxyacetic acid, Pfansteihl, L-Aspartic acid, gluconic acid, urobenzoic acid, L MALIC ACID, Pidolidone, propanedioic acid, pentanedioic acid, hexanodioic acid, Phenylsulfonic acid, nicotinic acid, Lalgine, oleic acid etc. multiple acid salt and crystal all can't prepare.
Summary of the invention
Technical problem to be solved by this invention has been to provide acid salt and the crystal thereof of a class dapoxetine unlike the prior art, and the preparation method of crystal.Several salt and the crystal of dapoxetine of the present invention, its solubleness in water all obviously is better than the solubleness of dapoxetine free alkali, and preferably stability and water absorbability are arranged.
The invention provides the acid salt of a class dapoxetine, its gentisate that is dapoxetine, Orotate, cyclamate or acetylsalicylate.
The present invention also provides a kind of crystal of gentisate of dapoxetine, and in its XRPD collection of illustrative plates, source of radiation is CuK α
1, in 2 θ values, be 5.71, 7.50, 10.51, 10.84, 11.17, 11.53, 12.24, 13.34, 13.81, 14.03, 15.06, 15.95, 16.07, 16.22, 16.38, 17.31, 17.45, 17.60, 18.53, 18.67, 18.95, 19.80, 20.07, 20.96, 21.85, 22.50, 23.23, 23.34, 24.23, 24.94, 26.95, 27.86, 28.44, 28.65, 28.95, 29.15, 31.61, 31.69, 31.89, 32.37, 32.70, 34.26, 36.39, 37.66, 40.95 located diffraction peak, wherein 2 θ value limit of error are ± 0.2, its DSC collection of illustrative plates has endotherm(ic)peak at 175 ± 5 ℃.
The present invention also provides a kind of crystal of Orotate of dapoxetine, and in its XRPD collection of illustrative plates, source of radiation is CuK α
1in 2 θ values, be that 4.91,5.62,6.94,7.38,8.54,8.84,9.65,10.10,10.92,12.14,13.22,13.81,15.06,15.67,16.34,17.05,17.76,18.45,19.58,20.35,20.88,21.61,22.18,22.58,24.47,25.26,28.71,31.91,32.69,38.90,40.43 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates has endotherm(ic)peak at 119 ± 5 ℃.
The present invention also provides a kind of crystal of cyclamate of dapoxetine, and in its XRPD collection of illustrative plates, source of radiation is CuK α
1in 2 θ values, be that 6.42,7.11,11.67,12.87,14.25,15.08,17.43,18.43,18.63,19.40,19.52,20.03,21.51,21.91,23.58,24.80,25.93,27.48,27.79,27.98,30.23,30.92,31.40,31.95,32.62,33.96,36.14,37.14,37.41,41.08,43.28 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates has endotherm(ic)peak at 194 ± 5 ℃.
The present invention also provides a kind of crystal of acetylsalicylate of dapoxetine, and in its XRPD collection of illustrative plates, source of radiation is CuK α
1in 2 θ values, be that 5.68,10.56,11.31,11.57,12.24,12.73,13.05,13.70,14.09,15.53,16.18,16.97,17.96,18.53,19.26,19.54,20.66,21.49,22.01,22.79,23.82,24.67,25.75,27.90,29.17,30.23,31.38,32.76,34.00,36.04,37.46,38.22,41.42,42.27,44.28 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates has endotherm(ic)peak at 114 ± 5 ℃.
Several salt of the dapoxetine that the present invention obtains, its solubleness (in dapoxetine) in water is respectively about 0.18mg/ml (gentisinic acid dapoxetine), 5.72mg/ml (vitamin B13 dapoxetine), 1.18mg/ml (Cyclamic Acid dapoxetine), 0.24mg/ml (acetylsalicylic acid dapoxetine), all is better than the solubleness (0.006mg/ml) of dapoxetine free alkali.
The preparation method of the gentisate of dapoxetine of the present invention, Orotate, cyclamate or acetylsalicylate, can carry out salt-forming reaction by dapoxetine and corresponding acid according to the conventional knowledge in this area, can make.
The present invention further provides the preparation method of crystal of the gentisate of above-mentioned dapoxetine, it comprises the following step: dapoxetine and gentisinic acid are dissolved in ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride, acetone or tetrahydrofuran (THF), Precipitation to be had, filter, drying, get final product.
Wherein, described being dissolved in ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride, acetone or tetrahydrofuran (THF), it is temperature required that the temperature of dissolving can be conventional dissolving, as 20～50 ℃.
After dapoxetine and gentisinic acid are dissolved in to ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride, acetone or tetrahydrofuran (THF), before Precipitation, preferably also carry out filtration step, to remove insoluble impurity, remove the laggard step of impurity and can also pass through stirred solution, make Precipitation.
Preferably, after described Precipitation, also can lower the temperature, then be filtered, obtain precipitation, get final product.Wherein, the cooling extent needed when described cooling can be conventional crystallization, as be down to 0～10 ℃.
Preferably, by after described sedimentation and filtration, also further dry (as vacuum-drying), thus make the sterling of above-mentioned crystal.
Wherein, the mol ratio of described dapoxetine and gentisinic acid can be the molar ratio of conventional salt-forming reaction, is preferably 1: 1～1: 1.1.The consumption of described ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride, acetone or tetrahydrofuran (THF) can be dapoxetine and gentisinic acid are just dissolved and get final product; Ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride, acetone or tetrahydrofuran (THF) are preferably 5～20ml/g (preferably 10ml/g) with the volume mass ratio of dapoxetine and gentisinic acid.
The present invention further provides the preparation method of crystal of the Orotate of above-mentioned dapoxetine, it comprises the following step: dapoxetine and vitamin B13 are placed in to methylene dichloride or ethyl acetate, after carrying out salt-forming reaction, filter, drying, get final product; The relative vitamin B13 equivalent of the molar weight of dapoxetine or excessive wherein.
Wherein, it is temperature required that the temperature of described salt-forming reaction can be conventional salt-forming reaction, as 20～50 ℃.
Preferably, after described salt-forming reaction, also can lower the temperature, then be filtered, obtain precipitation, get final product.Wherein, the cooling extent needed when described cooling can be conventional crystallization, as be down to 0～10 ℃.
Preferably, after filtration, also can be further by gained permeate dry (as vacuum-drying), thereby make the sterling of above-mentioned crystal.
Wherein, the mol ratio of described dapoxetine and vitamin B13 is preferably 1: 1～1.1: 1.Described methylene dichloride or ethyl acetate, with the volume mass of dapoxetine and vitamin B13 (both quality and) than being preferably 5～20ml/g (preferably 10ml/g).
The present invention further provides the preparation method of crystal of the cyclamate of above-mentioned dapoxetine, it comprises the following step: dapoxetine and Cyclamic Acid are dissolved in ethyl acetate, and Precipitation to be had, filter, and drying, get final product.
Wherein, described dapoxetine and Cyclamic Acid are dissolved in ethyl acetate, the temperature of dissolving can be conventional dissolve temperature required, as 20～50 ℃.
After dapoxetine and Cyclamic Acid are dissolved in to ethyl acetate, before Precipitation, preferably also carry out filtration step, to remove insoluble impurity, remove the laggard step of impurity and can also pass through stirred solution, make Precipitation.
Preferably, after described Precipitation, also can lower the temperature, then be filtered, obtain precipitation, get final product.Wherein, the cooling extent needed when described cooling can be conventional crystallization, as be down to 0～10 ℃.
Preferably, by after described sedimentation and filtration, also further dry (as vacuum-drying), thus make the sterling of above-mentioned crystal.
Wherein, the mol ratio of described dapoxetine and Cyclamic Acid can be the molar ratio of conventional salt-forming reaction, is preferably 1: 1～1: 1.1.The consumption of described ethyl acetate can be dapoxetine and Cyclamic Acid are just dissolved and get final product; Ethyl acetate is preferably 5～20ml/g (preferably 10ml/g) with the volume mass ratio of dapoxetine and Cyclamic Acid.
The present invention further provides the preparation method of crystal of the acetylsalicylate of above-mentioned dapoxetine, it comprises the following step: dapoxetine, acetylsalicylic acid are mixed with acetone, after the solution clarification, add normal hexane, Skellysolve A or sherwood oil, Precipitation to be had, filter, and gets final product.
Wherein, after dapoxetine, acetylsalicylic acid and acetone are mixed, add normal hexane by before Precipitation, preferably also stirred, make the solution clarification.
Wherein, described dapoxetine, acetylsalicylic acid are mixed with acetone, the temperature of mixing can be conventional dissolve temperature required, as 20～50 ℃.
Preferably, after described Precipitation, also can lower the temperature, then be filtered, obtain precipitation, get final product.Wherein, the cooling extent needed when described cooling can be conventional crystallization, as be down to 0～10 ℃.
Preferably, by after described sedimentation and filtration, also further dry (as vacuum-drying), thus make the sterling of above-mentioned crystal.
Wherein, described dapoxetine and acetylsalicylic acid can be the molar ratio of conventional salt-forming reaction, are preferably 1: 1～1: 1.1.Described acetone, with the volume mass of dapoxetine and acetylsalicylic acid (both quality and) than being preferably 5～20ml/g (preferably 10ml/g).The conventional amount used of low polar solvent when the consumption of described normal hexane, Skellysolve A or sherwood oil can be mixed solvent crystallization, normal hexane, Skellysolve A or sherwood oil and with the volume ratio of acetone be preferably 1: 0.5～1: 2.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination obtains the preferred embodiments of the invention.
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 invention provides four kinds of salt and the crystal of dapoxetine unlike the prior art, its solubleness in water all obviously is better than the solubleness of dapoxetine free alkali, and preferably stability and water absorbability are arranged.
The accompanying drawing explanation
The XRPD collection of illustrative plates that Fig. 1 is gentisinic acid dapoxetine of the present invention.
The DSC collection of illustrative plates that Fig. 2 is gentisinic acid dapoxetine of the present invention.
The XRPD collection of illustrative plates that Fig. 3 is vitamin B13 dapoxetine of the present invention.
The DSC collection of illustrative plates that Fig. 4 is vitamin B13 dapoxetine of the present invention.
The XRPD collection of illustrative plates that Fig. 5 is Cyclamic Acid dapoxetine of the present invention.
The DSC collection of illustrative plates that Fig. 6 is Cyclamic Acid dapoxetine of the present invention.
The XRPD collection of illustrative plates that Fig. 7 is acetylsalicylic acid dapoxetine of the present invention.
The DSC collection of illustrative plates that Fig. 8 is acetylsalicylic acid dapoxetine 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 select according to catalogue.
The various testing method experiment condition used of the crystal that following examples obtain:
XRPD testing method: instrument model: Bruker D8 advance XRD, diffracted ray: CuK (40kV, 40mA), scanning speed: 8 °/min (2 θ value), sweep limit: 3 °～45 ° (2 θ value); DSC testing method: instrument model: TA Q2000,10 ℃/min of temperature rise rate.
The preparation of embodiment 1 gentisinic acid dapoxetine crystal
Take 916mg dapoxetine and 475mg gentisinic acid in container, add the 15ml ethyl acetate, be stirred to solid and dissolve fully, the elimination insolubles, stir 2h under room temperature, and Precipitation is arranged, be cooled to 5 ℃, obtain pale yellow powder 1.306g (95%) after filtration, vacuum-drying.
Fig. 1 is shown in by its XRPD collection of illustrative plates, and source of radiation is CuK α
1, in 2 θ values, be 5.71, 7.50, 10.51, 10.84, 11.17, 11.53, 12.24, 13.34, 13.81, 14.03, 15.06, 15.95, 16.07, 16.22, 16.38, 17.31, 17.45, 17.60, 18.53, 18.67, 18.95, 19.80, 20.07, 20.96, 21.85, 22.50, 23.23, 23.34, 24.23, 24.94, 26.95, 27.86, 28.44, 28.65, 28.95, 29.15, 31.61, 31.69, 31.89, 32.37, 32.70, 34.26, 36.39, 37.66, 40.95 located diffraction peak, wherein 2 θ value limit of error are ± 0.2.
Fig. 2 is shown in by its DSC collection of illustrative plates, at 175 ± 5 ℃, endotherm(ic)peak arranged.
The preparation of embodiment 2 vitamin B13 dapoxetine crystal
Take 916mg dapoxetine and 480mg vitamin B13 in container, add the 15ml methylene dichloride, solid does not dissolve, and under room temperature, stirs 2h, is cooled to 5 ℃, obtains white powder 692mg (50%) after filtration, vacuum-drying.
Fig. 3 is shown in by its XRPD collection of illustrative plates, and source of radiation is CuK α
1in 2 θ values, be that 4.91,5.62,6.94,7.38,8.54,8.84,9.65,10.10,10.92,12.14,13.22,13.81,15.06,15.67,16.34,17.05,17.76,18.45,19.58,20.35,20.88,21.61,22.18,22.58,24.47,25.26,28.71,31.91,32.69,38.90,40.43 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2.
Fig. 4 is shown in by its DSC collection of illustrative plates, at 119 ± 5 ℃, endotherm(ic)peak arranged.
The preparation of embodiment 3 Cyclamic Acid dapoxetine crystal
Take 916mg dapoxetine and 550mg Cyclamic Acid in container, add the 15ml ethyl acetate, be stirred to solid and dissolve fully, the elimination insolubles, stir 2h under room temperature, is cooled to 5 ℃, standing over night has Precipitation, obtains white powder 455mg (31%) after filtration, vacuum-drying.
Fig. 5 is shown in by its XRPD collection of illustrative plates, and source of radiation is CuK α
1in 2 θ values, be that 6.42,7.11,11.67,12.87,14.25,15.08,17.43,18.43,18.63,19.40,19.52,20.03,21.51,21.91,23.58,24.80,25.93,27.48,27.79,27.98,30.23,30.92,31.40,31.95,32.62,33.96,36.14,37.14,37.41,41.08,43.28 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2.
Fig. 6 is shown in by its DSC collection of illustrative plates, at 194 ± 5 ℃, endotherm(ic)peak arranged.
The preparation of embodiment 4 acetylsalicylic acid dapoxetine crystal
Take 916mg dapoxetine and 560mg acetylsalicylic acid in container, add 15ml acetone, solid does not dissolve, after stirring 2h under room temperature, solution is clarified, slowly add the 25ml normal hexane to Precipitation is arranged, be cooled to 5 ℃, obtain white powder 433mg (30%) after filtration, vacuum-drying.
Fig. 7 is shown in by its XRPD collection of illustrative plates, and source of radiation is CuK α
1in 2 θ values, be that 5.68,10.56,11.31,11.57,12.24,12.73,13.05,13.70,14.09,15.53,16.18,16.97,17.96,18.53,19.26,19.54,20.66,21.49,22.01,22.79,23.82,24.67,25.75,27.90,29.17,30.23,31.38,32.76,34.00,36.04,37.46,38.22,41.42,42.27,44.28 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2.
Fig. 8 is shown in by its DSC collection of illustrative plates, and it has endotherm(ic)peak at 114 ± 5 ℃.
The preparation of embodiment 5 gentisinic acid dapoxetine crystal
Take 916mg dapoxetine and 475mg gentisinic acid in container, add 15ml methyl alcohol, be stirred to solid and dissolve fully, the elimination insolubles, stir 2h under room temperature, and Precipitation is arranged, and is cooled to 5 ℃, obtains pale yellow powder 1.21g after filtration, vacuum-drying.Fig. 1 is shown in by its XRPD collection of illustrative plates, and Fig. 2 is shown in by its DSC collection of illustrative plates.
The preparation of embodiment 6 gentisinic acid dapoxetine crystal
Take 916mg dapoxetine and 475mg gentisinic acid in container, add the 15ml Virahol, be stirred to solid and dissolve fully, the elimination insolubles, stir 2h under room temperature, and Precipitation is arranged, and is cooled to 5 ℃, obtains pale yellow powder 1.12g after filtration, vacuum-drying.Fig. 1 is shown in by its XRPD collection of illustrative plates, and Fig. 2 is shown in by its DSC collection of illustrative plates.
The preparation of embodiment 7 gentisinic acid dapoxetine crystal
Take 916mg dapoxetine and 475mg gentisinic acid in container, add the 15ml methylene dichloride, be stirred to solid and dissolve fully, the elimination insolubles, stir 2h under room temperature, and Precipitation is arranged, and is cooled to 5 ℃, obtains pale yellow powder 1.28g after filtration, vacuum-drying.Fig. 1 is shown in by its XRPD collection of illustrative plates, and Fig. 2 is shown in by its DSC collection of illustrative plates.
The preparation of embodiment 8 gentisinic acid dapoxetine crystal
Take 916mg dapoxetine and 475mg gentisinic acid in container, add 15ml acetone, be stirred to solid and dissolve fully, the elimination insolubles, stir 2h under room temperature, and Precipitation is arranged, and is cooled to 5 ℃, obtains pale yellow powder 1.23g after filtration, vacuum-drying.Fig. 1 is shown in by its XRPD collection of illustrative plates, and Fig. 2 is shown in by its DSC collection of illustrative plates.
The preparation of embodiment 9 gentisinic acid dapoxetine crystal
Take 916mg dapoxetine and 475mg gentisinic acid in container, add the 15ml tetrahydrofuran (THF), be stirred to solid and dissolve fully, the elimination insolubles, stir 2h under room temperature, and Precipitation is arranged, and is cooled to 5 ℃, obtains pale yellow powder 1.09g after filtration, vacuum-drying.Fig. 1 is shown in by its XRPD collection of illustrative plates, and Fig. 2 is shown in by its DSC collection of illustrative plates.
The preparation of embodiment 10 vitamin B13 dapoxetine crystal
Take 916mg dapoxetine and 480mg vitamin B13 in container, add the 15ml ethyl acetate, solid does not dissolve, and under room temperature, stirs 2h, is cooled to 5 ℃, obtains white powder 513mg after filtration, vacuum-drying.Fig. 3 is shown in by its XRPD collection of illustrative plates, and Fig. 4 is shown in by its DSC collection of illustrative plates.
The preparation of embodiment 11 acetylsalicylic acid dapoxetine crystal
Take 916mg dapoxetine and 560mg acetylsalicylic acid in container, add 15ml acetone, solid does not dissolve, after stirring 2h under room temperature, solution is clarified, slowly add the 25ml sherwood oil to Precipitation is arranged, be cooled to 5 ℃, obtain white powder 405mg after filtration, vacuum-drying.Fig. 7 is shown in by its XRPD collection of illustrative plates, and Fig. 8 is shown in by its DSC collection of illustrative plates.
Effect embodiment 1 crystal of the present invention and dapoxetine free alkali solubleness test, the contrast experiment in water
The dapoxetine standard substance that compound concentration is respectively 5g/ml, 25g/ml, 50g/ml, 100g/ml, 150g/ml, 200g/ml detect by HPLC, with the 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 ℃ of shaking table concussions after 12 hours, put ultrasonic 30s in ultrasonic apparatus, filter, dilute suitable multiple, carry out the HPLC analysis, 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.
Result is as follows:
Solubleness in water (in dapoxetine) is respectively about 0.18mg/ml (the gentisinic acid dapoxetine crystal that embodiment 1 obtains), 5.72mg/ml (the vitamin B13 dapoxetine crystal that embodiment 2 obtains), 1.18mg/ml (the Cyclamic Acid dapoxetine crystal that embodiment 3 obtains), 0.24mg/ml (the acetylsalicylic acid dapoxetine crystal that embodiment 4 obtains), all is better than the solubleness (0.006mg/ml) of dapoxetine free alkali.
The temperature stability test of effect embodiment 2 crystal of the present invention
Sample is placed in 80 ℃ of baking ovens, after one week, sample is taken out and carry out DSC, XRPD test, to investigate the stable crystal form of sample to temperature.Experimental result shows: under the condition of investigating, the spectrogram of the acetylsalicylate crystal of the dapoxetine that the Orotate crystal of the dapoxetine that the gentisate crystal of the dapoxetine that embodiment 1 obtains, embodiment 2 obtain, embodiment 4 obtain does not all change, and shows its crystal formation better heat stability.
The Isothermal experiments at constant humidity of effect embodiment 3 crystal of the present invention
Sample is placed in to 40 ℃, in the 75%RH climatic chamber, after one week, sample is taken out and carry out DSC, XRPD test, to investigate the stable crystal form of sample to humidity.Experimental result shows: the spectrogram of the acetylsalicylate crystal that the cyclamate crystal of the dapoxetine that the gentisate crystal of the dapoxetine that embodiment 1 obtains, embodiment 3 obtain, embodiment 4 obtain does not all change, and shows that its crystal formation humidity stability is better.
The water absorbability of effect embodiment 4 crystal of the present invention is investigated test
Sample is placed in to 40 ℃, in the 75%RH climatic chamber, after one week, sample is taken out and carries out the TGA test, to investigate the water absorbability of sample.Experimental result shows: the moisture absorption weightening finish of the acetylsalicylate crystal that the cyclamate crystal of the dapoxetine that the gentisate crystal of the dapoxetine that embodiment 1 obtains, embodiment 3 obtain, embodiment 4 obtain all is less than 0.2%, shows that it is all non-hygroscopic under this condition.
Claims (10)
1. the acid salt of a class dapoxetine, its gentisate that is dapoxetine, Orotate, cyclamate or acetylsalicylate.
2. the crystal of the gentisate of a dapoxetine, in its XRPD collection of illustrative plates, source of radiation is CuK α
1, in 2 θ values, be 5.71, 7.50, 10.51, 10.84, 11.17, 11.53, 12.24, 13.34, 13.81, 14.03, 15.06, 15.95, 16.07, 16.22, 16.38, 17.31, 17.45, 17.60, 18.53, 18.67, 18.95, 19.80, 20.07, 20.96, 21.85, 22.50, 23.23, 23.34, 24.23, 24.94, 26.95, 27.86, 28.44, 28.65, 28.95, 29.15, 31.61, 31.69, 31.89, 32.37, 32.70, 34.26, 36.39, 37.66, 40.95 located diffraction peak, wherein 2 θ value limit of error are ± 0.2, its DSC collection of illustrative plates has endotherm(ic)peak at 175 ± 5 ℃.
3. the crystal of the Orotate of a dapoxetine, in its XRPD collection of illustrative plates, source of radiation is CuK α
1in 2 θ values, be that 4.91,5.62,6.94,7.38,8.54,8.84,9.65,10.10,10.92,12.14,13.22,13.81,15.06,15.67,16.34,17.05,17.76,18.45,19.58,20.35,20.88,21.61,22.18,22.58,24.47,25.26,28.71,31.91,32.69,38.90,40.43 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates has endotherm(ic)peak at 119 ± 5 ℃.
4. the crystal of the cyclamate of a dapoxetine, in its XRPD collection of illustrative plates, source of radiation is CuK α
1in 2 θ values, be that 6.42,7.11,11.67,12.87,14.25,15.08,17.43,18.43,18.63,19.40,19.52,20.03,21.51,21.91,23.58,24.80,25.93,27.48,27.79,27.98,30.23,30.92,31.40,31.95,32.62,33.96,36.14,37.14,37.41,41.08,43.28 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates has endotherm(ic)peak at 194 ± 5 ℃.
5. the crystal of the acetylsalicylate of a dapoxetine, in its XRPD collection of illustrative plates, source of radiation is CuK α
1in 2 θ values, be that 5.68,10.56,11.31,11.57,12.24,12.73,13.05,13.70,14.09,15.53,16.18,16.97,17.96,18.53,19.26,19.54,20.66,21.49,22.01,22.79,23.82,24.67,25.75,27.90,29.17,30.23,31.38,32.76,34.00,36.04,37.46,38.22,41.42,42.27,44.28 places have diffraction peak, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates has endotherm(ic)peak at 114 ± 5 ℃.
6. the preparation method of the crystal of the gentisate of dapoxetine as claimed in claim 2, it comprises the following step: dapoxetine and gentisinic acid are dissolved in ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride, acetone or tetrahydrofuran (THF), Precipitation to be had, filter, drying, get final product.
7. preparation method as claimed in claim 6, is characterized in that: after described Precipitation, also by cooling, then filtered, obtain precipitation, get final product; Wherein, described cooling is for being down to 0～10 ℃.
8. the preparation method of the crystal of the Orotate of dapoxetine as claimed in claim 3, it comprises the following step: dapoxetine and vitamin B13 are placed in to methylene dichloride or ethyl acetate, after carrying out salt-forming reaction, filter, drying, get final product; The relative vitamin B13 equivalent of the molar weight of dapoxetine or excessive wherein.
9. the preparation method of the crystal of the cyclamate of dapoxetine as claimed in claim 4, it comprises the following step: dapoxetine and Cyclamic Acid are dissolved in ethyl acetate, and Precipitation to be had, filter, and drying, get final product.
10. the preparation method of the crystal of the acetylsalicylate of dapoxetine as claimed in claim 5, it comprises the following step: dapoxetine, acetylsalicylic acid are mixed with acetone, after the solution clarification, add normal hexane, Skellysolve A or sherwood oil, Precipitation to be had, filter, and gets final product.
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| CN201110385064.4A CN103130660B (en) | 2011-11-25 | 2011-11-25 | Acidic salt and crystal of dapoxetine and preparation method of crystal |
| PCT/CN2012/085295 WO2013075671A1 (en) | 2011-11-25 | 2012-11-26 | Crystals of acid salts and acid salts of dapoxetine and preparation methods therefor |
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| CN109400490A (en) * | 2017-08-17 | 2019-03-01 | 扬子江药业集团江苏紫龙药业有限公司 | A kind of preparation method of dapoxetine hydrochloride free alkali |
| CN113845520A (en) * | 2021-09-09 | 2021-12-28 | 安徽皓元药业有限公司 | Palbociclib orotate and preparation method thereof |
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| ZA93694B (en) * | 1993-02-01 | 1993-06-03 | Lilly Co Eli | Pharmaceutical treatments. |
| CN1387432A (en) * | 1999-09-03 | 2002-12-25 | 伊莱利利公司 | Methods of sing rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfnction |
| US20090076163A1 (en) * | 2007-09-15 | 2009-03-19 | Protia, Llc | Deuterium-enriched dapoxetine |
| US20090227682A1 (en) * | 2008-03-04 | 2009-09-10 | Pharma Pass Ii Llc | Xetine compositions |
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| PT87163B (en) * | 1987-04-09 | 1992-07-31 | Lilly Co Eli | 1-PHENYL-3-NAFTALENYLXY-PROPANAMINES PREPARATION |
| WO2008035358A2 (en) * | 2006-06-05 | 2008-03-27 | Cadila Healthcare Limited | Process for preparing dapoxetine |
| DE602007014206D1 (en) * | 2006-06-22 | 2011-06-09 | Univ Ramot | Novel serotonin reuptake inhibitor as a drug with peripheric system-restricted activity |
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| ZA93694B (en) * | 1993-02-01 | 1993-06-03 | Lilly Co Eli | Pharmaceutical treatments. |
| CN1387432A (en) * | 1999-09-03 | 2002-12-25 | 伊莱利利公司 | Methods of sing rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfnction |
| EP1225881B1 (en) * | 1999-09-03 | 2006-02-22 | APBI Holdings, LLC | The use of dapoxetine, a rapid-onset selective serotonin reuptake inhibitor, for treating sexual dysfunction |
| US20090076163A1 (en) * | 2007-09-15 | 2009-03-19 | Protia, Llc | Deuterium-enriched dapoxetine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109400490A (en) * | 2017-08-17 | 2019-03-01 | 扬子江药业集团江苏紫龙药业有限公司 | A kind of preparation method of dapoxetine hydrochloride free alkali |
| CN113845520A (en) * | 2021-09-09 | 2021-12-28 | 安徽皓元药业有限公司 | Palbociclib orotate and preparation method thereof |
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| CN103130660B (en) | 2014-09-17 |
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