WO2013075671A1 - Crystals of acid salts and acid salts of dapoxetine and preparation methods therefor - Google Patents

Crystals of acid salts and acid salts of dapoxetine and preparation methods therefor Download PDF

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Publication number
WO2013075671A1
WO2013075671A1 PCT/CN2012/085295 CN2012085295W WO2013075671A1 WO 2013075671 A1 WO2013075671 A1 WO 2013075671A1 CN 2012085295 W CN2012085295 W CN 2012085295W WO 2013075671 A1 WO2013075671 A1 WO 2013075671A1
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dapoxetine
acid
crystals
crystal
preparation
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PCT/CN2012/085295
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French (fr)
Chinese (zh)
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任国宾
任秉钧
齐明辉
乐云峰
洪鸣凰
曹国斌
陈金瑶
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厦门福满药业有限公司
上海医药工业研究院
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Publication of WO2013075671A1 publication Critical patent/WO2013075671A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to crystals, acid salts, and methods for their preparation of a class of acid salts of dapoxetine. Background technique
  • Dapoxetine chemical name is (+) ⁇ , ⁇ -dimethyl-1-phenyl-3-(1-naphthyloxy:) propylamine, a selective serotonin reuptake inhibitor (SSRI) With a short half-life, it can be used to treat depression and related affective disorders.
  • SSRI serotonin reuptake inhibitor
  • the same drug, different crystal forms, may have different bioavailability, and its stability, fluidity, and compressibility may also be different. These physical and chemical properties have certain effects on the application of drugs. Similarly, the same differences exist for different salt types of the same drug.
  • the present invention proposes several salt forms of dapoxetine, and the physical and chemical properties thereof are different from each other.
  • the technical problem to be solved by the present invention is to provide a class of dapoxetine different from the prior art.
  • the acid salt and its crystal, and the preparation method of the crystal are significantly better solubility in water than that of dapoxetine free base, and have better stability and hygroscopicity.
  • the present invention provides a crystal of mesylate salt of dapoxetine.
  • the radiation source is CuKa at diffraction angles 2 ⁇ values of 6.00, 9.63, 12.03, 14.19, 14.90, 16.25, 16.72, 18.06, 19.19.
  • the invention also provides a preparation method of the crystal of the methanesulfonate salt of the above dapoxetine, which comprises the following steps: mixing a solution formed by dissolving dapoxetine in an organic solvent with formazanic acid, Precipitating and filtering, wherein the organic solvent is an acetate and/or tetrahydrofuran of C ⁇ C-mercapto alcohol.
  • the method for preparing the crystal of the mesylate salt of dapoxetine comprises the following steps: dissolving dapoxetine in an organic solvent, filtering, adding formazansulfonic acid to the obtained filtrate, and stirring. Precipitate and precipitate, and filter.
  • the acetate of the ⁇ 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate; the volume of the organic solvent and dapoxetine is better. 7 ml / g ⁇ 12 ml / g (further preferably 10 ml / g ⁇ l lml / g).
  • the ambient temperature at which the precipitate is precipitated is preferably 0 to 35 ° C (more preferably 20 to 35 ° C).
  • the molar ratio of the formazansulfonic acid to dapoxetine is preferably 1: 1 to 1.03:1.
  • the obtained precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
  • the present invention also provides a crystal of nitrate of dapoxetine.
  • the radiation source is CuKai
  • the diffraction angles 2 are 10.26, 13.03, 13.78, 15.28, 15.95, 16.60, 17.21, 18.46, 19.60. 20.66, 21.16, 22.60, 23.07, 24.89, 25.40, 26.59, 26.78, 27.46, 27.97, 29.33, 30.30, 31.15, 32.22, 32.88, 33.56, 34.47,
  • the invention also provides a preparation method of the crystal of nitrate of the above dapoxetine, which comprises the following steps: mixing a solution formed by dissolving dapoxetine in an organic solvent with nitric acid, precipitating and filtering, and then filtering Wherein the organic solvent is an acetate of mercapto alcohol.
  • the method for preparing the nitrate crystal of dapoxetine comprises the steps of: dissolving dapoxetine in an organic solvent, filtering, dropping the nitric acid into the obtained filtrate, stirring, and precipitating the precipitate. , filter, you can.
  • the acetate of the d-C 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate.
  • the volume ratio of the organic solvent to dapoxetine is preferably from 7 ml/g to 12 ml/g (more preferably from 10 ml/g to l ml/g).
  • the ambient temperature at which the precipitate is precipitated is preferably 0 to 35 ° C (more preferably 20 to 35 ° C).
  • the molar ratio of the nitric acid to dapoxetine is preferably from 1:1 to 1.03:1.
  • the resulting precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
  • the present invention also provides a crystal of hydrobromide salt of dapoxetine.
  • the radiation source is CuKa at diffraction angles 2 ⁇ values of 6.41, 8.82, 12.84, 13.83, 15.26, 15.77, 16.08, 16.56, 16.76, 17.00, 17.67, 18.06, 18.51, 19.30, 20.39, 21.00, 21.54, 22.27, 22.58, 23.08, 23.43, 24.04, 24.95, 25.46, 25.84, 26.79, 27.16, 27.64, 28.05, 28.33, 29.04, 29.98, 30.38, 31.23, 31.59, 32.21, 32.73, 33.38, 33.73, 34.50, 35.27, 35.75, 36.28, 37.15, 38.39, 38.72, 39.34, 39.65, 40.17, 40.60, 41.11, There are diffraction peaks at 42.06, 42.50, and
  • the invention also provides a preparation method of the above-mentioned crystal of hydrobromide salt of dapoxetine, which comprises the following steps: mixing a solution formed by dissolving dapoxetine in an organic solvent with hydrobromic acid, leaving a precipitate Precipitating and filtering, wherein the organic solvent is an acetate of C ⁇ C ⁇ mercapto alcohol.
  • the method for preparing the crystal of the hydrobromide salt of dapoxetine comprises the steps of: dissolving dapoxetine in an organic solvent, filtering, dropping hydrobromic acid into the obtained filtrate, and stirring. Precipitate and precipitate, and filter.
  • the acetate of the C?Cs mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate.
  • the volume ratio of the organic solvent to dapoxetine is preferably from 7 ml/g to 12 ml/g (more preferably from 10 ml/g to l ml/g).
  • the ambient temperature at which the precipitate is precipitated is preferably 0 to 35 ° C (more preferably 20 to 35 ° C).
  • the molar ratio of the hydrobromic acid to dapoxetine is preferably from 1:1 to 1.03:1.
  • the resulting precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystal.
  • the same drug, different crystal forms, may have different bioavailability, and its stability, fluidity, and compressibility may also be different. These physical and chemical properties have certain effects on the application of drugs. Similarly, the same differences exist for different salt types of the same drug.
  • the new crystalline form of several salts of dapoxetine of the present invention has a certain difference in physical and chemical properties from each other.
  • the new crystalline form of several salts of the above-mentioned dapoxetine of the present invention has a solubility of about 267 mg/ml (dapoxetine mesylate), 2.61 mg/ml (dapoxetine nitrate), 3.52 mg, respectively. /ml (dapoxetine hydrobromide), both better than the solubility of dapoxetine free base (0.00254 mg / ml).
  • the present invention also provides a class of acid salts of dapoxetine, which is dadocetine gentisate, orotate, cyclamate, acetylsalicylate, hippurate, or 1,5-naphthalene disulfonate.
  • the present invention also provides a crystal of gentisate of dapoxetine.
  • the radiation source is CuKa at a value of 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, There are diffraction peaks at 28.95, 29.15, 31.61, 31.69, 31.89, 32.37, 32.70, 34.26, 36.39, 37.66, and 40.95, where the 2 ⁇ value error range is ⁇ 0.2; and the DSC spectrum has an endothermic peak at 175 ⁇ 5°C.
  • the present invention also provides a crystal of the orotate salt of dapoxetine.
  • the radiation source is CuKon
  • the values of 2 ⁇ are 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, 16.45, 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 with diffraction peaks
  • 2 ⁇ value error range is ⁇ 0.2; its DSC spectrum has an endothermic peak at 119 ⁇ 5 °C.
  • the present invention also provides a crystal of cyclamate of dapoxetine.
  • the radiation source is CuKon, and the values of 2 ⁇ are 6.42, 7.11, 11.67, 12.87, 14.25, 15.08, 17.43, 18.43, 18.63.
  • the present invention also provides a crystal of acetylsalicylate of dapoxetine.
  • the radiation source is CuKon
  • the values of 2 ⁇ are 5.68, 10.56, 11.31, 11.57, 12.24, 12.73, 13.05, 13.70, 14.09, 15.53, 16.18, 16.97, 19.96, 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, Diffraction at 42.27, 44.28 Peak, where 2 ⁇ value error range is ⁇ 0.2; its DSC spectrum has an endothermic peak at 114 ⁇ 5 °C.
  • salts of dapoxetine obtained by the present invention have a solubility in water (calculated as dapoxetine) of about 0.18 mg/ml (dapoxetine gentisate) and 5.72 mg/ml (whey Dapoxetine), 1.18 mg/ml (dapoxetine cyclamate), 0.24 mg/ml (dapoxetine acetylsalicylate), all superior to the solubility of dapoxetine free base (0.006 mg) /ml).
  • the preparation method of the gentisate, orotate, cyclamate or acetylsalicylate of dapoxetine of the present invention can be based on the conventional knowledge in the art, and the dapoxetine and the corresponding acid
  • the salt formation reaction can be carried out.
  • the present invention further provides a method for preparing crystals of the gentisate salt of the above dapoxetine, which comprises the steps of: dissolving dapoxetine and gentisic acid in ethyl acetate, methanol, ethanol, n-propanol, and different In propanol, chloroform, acetone or tetrahydrofuran, precipitate is precipitated, filtered, and dried.
  • the solution is dissolved in ethyl acetate, methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetone or tetrahydrofuran, and the temperature of dissolution may be the temperature required for conventional dissolution, such as 20 to 50 ° C. .
  • the temperature may be lowered, and then filtered to obtain a precipitate.
  • the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
  • the precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
  • the molar ratio of dapoxetine to gentisic acid may be a molar ratio of a conventional salt-forming reaction, preferably 1 : 1 to 1: 1.1.
  • the ethyl acetate, methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetone or tetrahydrofuran may be used to dissolve dapoxetine and gentisic acid; ethyl acetate, methanol
  • the volumetric mass of ethanol, n-propanol, isopropanol, chloroform, acetone or tetrahydrofuran with dapoxetine and gentisic acid is preferably 5-20 ml/g (preferably 10 ml/g).
  • the present invention further provides a method for preparing crystals of the oprexate of the above dapoxetine, which comprises The method comprises the steps of: dissolving dapoxetine and orotic acid in dichloromethane or ethyl acetate, performing salt formation reaction, filtering and drying, wherein the amount of dapoxetine is relative to orotic acid Equal or excess.
  • the temperature of the salt formation reaction may be a temperature required for a conventional salt formation reaction, such as
  • the temperature may be lowered, and then filtered to obtain a precipitate.
  • the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
  • the resulting filtrate may be further dried (e.g., vacuum dried) to produce a pure product of the above crystals.
  • the molar ratio of dapoxetine and orotic acid is preferably 1:1 to 1.1:1.
  • the chloroform or ethyl acetate is preferably 5 to 20 ml/g (preferably 10 ml/g) in volume volume of dapoxetine and orotic acid (both mass sum).
  • the present invention further provides a process for preparing the crystal of the above-mentioned bromotinate of dapoxetine, which comprises the steps of: dissolving dapoxetine and cyclamate in ethyl acetate, precipitating, filtering, drying , you can.
  • the dapoxetine and the cyclolacetic acid are dissolved in ethyl acetate, and the temperature of dissolution may be a temperature required for conventional dissolution, such as 20 to 50 °C.
  • the temperature may be lowered, and then filtered to obtain a precipitate.
  • the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
  • the precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
  • the molar ratio of the dapoxetine to the cyclolacetic acid may be a molar ratio of the conventional salt-forming reaction, preferably from 1:1 to 1:1.1.
  • the ethyl acetate can be used in such a manner that dapoxetine and cyclamate are just dissolved; the volumetric mass of ethyl acetate with dapoxetine and cyclamate is preferably 5-20 ml/g. (preferably 10 ml/g).
  • the present invention further provides a method for preparing crystals of acetyl salicylate of dapoxetine, which comprises the steps of: mixing dapoxetine, acetylsalicylic acid and acetone, clarifying the solution, adding hexane, positive Pentamidine or petroleum ether, precipitated and filtered.
  • dapoxetine acetylsalicylic acid and acetone
  • it is preferably stirred to add a solution to the precipitate before the precipitate is precipitated.
  • the dapoxetine, acetylsalicylic acid and acetone are mixed, and the mixing temperature may be a temperature required for conventional dissolution, such as 20 to 50 °C.
  • the temperature may be lowered, and then filtered to obtain a precipitate.
  • the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
  • the precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
  • the dapoxetine and acetylsalicylic acid may be in a molar ratio of a conventional salt-forming reaction, preferably 1 : 1 to 1: 1.1.
  • the acetone preferably having a volumetric mass of dapoxetine and acetylsalicylic acid (both mass sum), is 5 to 20 ml/g (preferably 10 ml/g).
  • the amount of the n-hexanyl, n-pentamidine or petroleum ether may be a conventional amount of a low-polarity solvent when the mixed solvent is crystallized, and the volume of n-hexyl, n-pentamidine or petroleum ether and acetone is preferably 1:0.5 ⁇ 1 : 2.
  • the present invention also provides a crystal of horseradish of dapoxetine.
  • the radiation source 3 ⁇ 4 CuKa has a diffraction angle of 2 ⁇ values of 12.99, 13.86, 16.21, 16.70, 19.38, 19.94, 21.69, 21.85, 22.23, 23.43, 23.75, 25.72, 26.19, 27.16, 27.99, 28.90, 29.27, 30.54, 31.05, 31.76, 32.20, 32.83, 33.63, 33.89, 34.70, 35.35, 36.12, 36.72, 37.18, 38.04, 39.72, 40.43, 40.86, 41.73, There are diffraction peaks at 42.78 and 43.92, where the 2 ⁇ value error range is ⁇ 0.2; the DSC spectrum has an endothermic peak at 190 ⁇ 5 °C.
  • the present invention also provides a method for preparing a crystal of a horse salt of dapoxetine, which comprises the steps of: forming a salt reaction of dapoxetine and hippuric acid in an acetate of ⁇ 3 mercapto alcohol, Filter, you can. Wherein, the ⁇ .
  • the acetate of 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate.
  • the volume of the acetate and dapoxetine of the ⁇ 3 mercapto alcohol is preferably from 9 ml/g to 12 ml/g (e.g., 10.6 ml/g).
  • the molar ratio of dapoxetine and hippuric acid is preferably 1.03: 1 ⁇ 1:1.
  • the temperature of the salt formation reaction is preferably 40 to 60 ° C (preferably 50 ° C).
  • the salt formation reaction time is preferably from 3 to 6 hours (for example, the salt formation reaction can be carried out by stirring for 3 to 6 hours).
  • the precipitate obtained by filtration can be further dried (e.g., vacuum dried) to obtain a pure product of the above crystal.
  • the present invention also provides a crystal of 1,5-naphthalene disulfonate of dapoxetine.
  • the radiation source is CuKa at diffraction angles 2 ⁇ values of 8.23, 9.69, 10.15, 11.08, 11.47, 12.29,
  • the invention also provides a preparation method of the crystal of the 1,5-naphthalenedisulfonate of dapoxetine described above, which comprises the following steps: in the acetate and/or tetrahydrofuran of C ⁇ C-mercapto alcohol, Pocytin and 1,5-naphthalenedisulfonic acid are subjected to salt formation reaction and filtered.
  • the acetate of 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate.
  • the volume of the acetate and/or tetrahydrofuran of C ⁇ C ⁇ mercapto alcohol and dapoxetine is preferably from 9 ml/g to 12 ml/g (e.g., 10.6 ml/g).
  • the molar ratio of dapoxetine and 1,5-naphthalenedisulfonic acid is preferably 1.03:1 ⁇ 1:1.
  • the temperature of the salt formation reaction is preferably from 10 to 50 ° C (preferably from 20 to 35 ° C).
  • the salt formation reaction time is preferably from 3 to 6 hours (for example, the salt formation reaction can be carried out by stirring for 3 to 6 hours).
  • the precipitate obtained by filtration can be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
  • the same drug, different crystal forms may have different bioavailability, and its stability, fluidity, and compressibility may also be different. These physical and chemical properties have certain effects on the application of drugs. Similarly, the same differences exist for different salt types of the same drug.
  • the present invention proposes several salt forms of dapoxetine, and the physical and chemical properties thereof are different from each other.
  • salts of dapoxetine obtained by the present invention have a solubility of about 0.0158 mg/ml (dapoxetine hippurate) and 0.0122 mg/ml (dapoxetine 1,5-naphthalene disulfate), respectively. Both are superior to the solubility of dapoxetine free base (0.00254 mg/ml). o
  • the above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, and the preferred examples of the present invention are obtained.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the present invention is as follows:
  • the present invention provides four salts and crystals of dapoxetine which are different from the prior art, and their solubility in water is significantly better than that of dapoxetine free base, and there are Good stability and hygroscopicity.
  • Figure 1 is an XRPD pattern of dapoxetine gentisate of the present invention.
  • Figure 2 is a DSC map of dapoxetine gentisate of the present invention.
  • Figure 3 is an XRPD pattern of dapoxetine orotate of the present invention.
  • Figure 4 is a DSC chart of dapoxetine orotate of the present invention.
  • Figure 5 is an XRPD pattern of dapoxetine cyclamate of the present invention.
  • Figure 6 is a DSC chart of dapoxetine cyclamate of the present invention.
  • Figure 7 is an XRPD pattern of dapoxetine acetylsalicylate of the present invention.
  • Figure 8 is a DSC chart of dapoxetine acetylsalicylate of the present invention.
  • Figure 9 is an XRPD pattern of crystals of the mesylate salt of dapoxetine of the present invention.
  • Figure 10 is a DSC chart of the crystal of the mesylate salt of dapoxetine of the present invention.
  • Figure 11 is an XRPD pattern of the crystal of nitrate of dapoxetine of the present invention.
  • Figure 12 is a DSC chart of crystals of nitrate of dapoxetine of the present invention.
  • Figure 13 is an XRPD pattern of crystals of the hydrobromide salt of dapoxetine of the present invention.
  • Figure 14 is a DSC chart of the crystal of the hydrobromide salt of dapoxetine of the present invention.
  • Figure 15 is an XRPD pattern of crystals of the hippurate of dapoxetine of the present invention.
  • Figure 16 is a DSC chart of crystals of the hippurate salt of dapoxetine of the present invention.
  • Figure 17 is an XRPD pattern of 1,5-naphthalene disulfonate of dapoxetine of the present invention.
  • Figure 18 is a DSC chart of 1,5-naphthalene disulfonate of dapoxetine of the present invention. detailed description
  • XRPD test method Instrument model: Bruker D8 advance XRD, diffraction line: CuKa (40 kV, 40 mA), scan rate: 8 ⁇ (2 ⁇ value), scanning range: 3° ⁇ 45° (2 ⁇ value); DSC test method : Instrument model: TA Q2000, heating rate 10 °C / min.
  • room temperature means 20 to 35 °C.
  • the XRPD spectrum is shown in Figure 1.
  • the radiation source is CuKon, and the value of 2 is 5.71, 7.50, 10.51.
  • the XRPD spectrum is shown in Fig. 3.
  • the radiation source is CuKon, and the values of 2 ⁇ are 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.
  • the XRPD spectrum is shown in Fig. 5.
  • the radiation source is CuKon, and the values are 2.42, 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.
  • the XRPD spectrum is shown in Fig. 7.
  • the radiation source is CuKa at 2 ⁇ values of 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.
  • Diffraction peaks at 18.53, 19.26, 19.54, 20.66, 21.49, 24.67, 25.75, 23.90, 24.17, 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, of which 2 ⁇
  • the value error range is ⁇ 0.2.
  • the radiation source is CuKon
  • the diffraction angles 2 are 6.00, 9.63, 12.03, 14.19, 14.90, 16.25, 16.72, 18.06, 19.19, 19.60, 20.92, 21.30, 22.26, 23.04, 23.51, 24.52, 25.07, 25.35, 25.76, 26.63, 27.28, 27.75, 28.07, 28.62, 28.90, 29.96, 30.36, 30.74, 31.05, 31.31, 32.08, 32.45, 32.86, 33.54, 33.81, 34.05, 34.70, 35.37, 35.63, 36.24, 36.64, 37.13
  • the radiation source is CuKon
  • the diffraction angles 2 are 10.26, 13.03, 13.78, 15.28, 15.95, 16.60, 17.21, 18.46, 19.60, 20.66, 21.16, 22.60, 23.07, 24.89, 25.40, 26.59, 26.78, 27.46, 27.97, 29.33, 30.30, 31.15, 32.22, 34.86, 36.18, 36.44, 37.17, 38.04, 39.02, 39.75, 39.99, 41.20, 41.73, 42.87, 43.17, 44.22, 44.55 with diffraction peaks,
  • the 2 ⁇ value error range is ⁇ 0.2; its DSC spectrum has an endothermic peak at 142 ⁇ 5 °C.
  • the radiation source is CuKon
  • the diffraction angles 2 are 12.99, 13.86, 16.21, 16.70, 19.38, 19.94, 21.69, 21.85, 22.23, 23.43, 23.75, 25.72, 26.19, 27.16, 27.99, 28.90, 29.27
  • Diffraction peaks at 30.54, 31.05, 31.76, 32.20, 32.83, 33.63, 33.89, 34.70, 35.35, 36.12, 36.72, 37.18, 38.04, 39.72, 40.43, 40.86, 41.73, 42.78, 43.92, where the range of 2 ⁇ error is ⁇ 0.2
  • Its DSC spectrum has an endothermic peak at 190 ⁇ 5 °C.
  • the dapoxetine standards were prepared at concentrations of 5 g/ml, 25 g/ml, 50 g/ml, 100 g/mK 150 g/ml, and 200 g/ml, respectively, by HPLC, and the peak area of dapoxetine was plotted against the concentration.
  • the sample to be tested is made into a supersaturated aqueous solution or suspension, shaken at 25 °C for 12 hours, placed in a sonicator for 30 s, filtered, diluted by appropriate multiples, HPLC analysis, and the obtained dapoxetine chromatography
  • the peak area is substituted into the standard curve equation, and the concentration of the corresponding sample is calculated, and then converted to the solubility of the sample based on dapoxetine according to the molecular weight of the sample.
  • the solubility in water was about 0.18 mg/ml (the dapoxetine crystal of gentisate obtained in Example 1), 5.72 mg/ml (the whey acid obtained in Example 2) Xiting crystal), 1.18 mg/ml (the crystal of dapoxetine cyclamate obtained in Example 3), 0.24 mg/ml (the crystal of dapoxetine acetylsalicylate obtained in Example 4), all superior to The solubility of posidine free base (0.006 mg/ml) o
  • the sample was placed in an oven at 80 ° C. After one week, the sample was taken out for DSC and XRPD tests to examine the crystal stability of the sample to temperature.
  • the experimental results show that the gentisate crystal of dapoxetine obtained in Example 1, the orotate crystal of dapoxetine obtained in Example 2, and the Dapoxi obtained in Example 4 under the conditions examined.
  • the spectrum of the acetyl salicylate crystal of Ting has not changed, indicating that its crystal form has good thermal stability.
  • the sample was placed in a 40V, 75% RH constant temperature and humidity chamber. After one week, the sample was taken out for DSC and XRPD tests to examine the crystal stability of the sample against humidity.
  • the experimental results show the spectrum of the gentisate crystal of dapoxetine obtained in Example 1, the ruthenium salt crystal of dapoxetine obtained in Example 3, and the crystal of the acetyl salicylate crystal obtained in Example 4. No change occurred, indicating that the crystal form has good humidity stability.
  • the sample was placed in a 45% RH constant temperature and humidity chamber at 40 ° C. After one week, the sample was taken out for TGA testing to examine the hygroscopicity of the sample.
  • the experimental results show that: the gentisate crystal of dapoxetine obtained in Example 1, the ruthenium salt crystal of dapoxetine obtained in Example 3, and the hygroscopic increase of the acetyl salicylate crystal obtained in Example 4.
  • the weight average is less than 0.2%, indicating that it does not absorb moisture under the conditions.
  • Dapexidine standards were prepared at concentrations of 5 g/ml, 25 g/ml, 50 g/ml, 100 g/ml, 150 g/ml, 200 g/ml, respectively, by HPLC, with dapoxetine chromatography Peak area to thick
  • the sample to be tested is made into a supersaturated aqueous solution or suspension, stirred for 12 hours, filtered, diluted by appropriate multiples, and subjected to HPLC analysis.
  • the obtained dapoxetine peak area is substituted into the standard curve equation, and the concentration of the corresponding sample is calculated.
  • the solubility of the sample in terms of dapoxetine was then converted to the molecular weight of the sample.
  • the solubility in water was about 267 mg/ml (dapoxetine mesylate prepared in Example 12), 2.61 mg/ml (dapoxetine nitrate prepared in Example 14). ), 3.52 mg/ml (dapoxetine hydrobromide prepared in Example 15), both superior to the solubility of dapoxetine free base (0.00254 mg/ml).
  • Dapexidine standards were prepared at concentrations of 5 g/ml, 25 g/ml, 50 g/ml, 100 g/ml, 150 g/ml, 200 g/ml, respectively, by HPLC, with dapoxetine chromatography The peak area is plotted against the concentration.
  • the sample to be tested is made into a supersaturated aqueous solution or suspension, stirred for 12 hours, filtered, diluted by appropriate multiples, and subjected to HPLC analysis.
  • the obtained dapoxetine peak area is substituted into the standard curve equation, and the concentration of the corresponding sample is calculated.
  • the solubility of the sample in terms of dapoxetine was then converted to the molecular weight of the sample.
  • the solubility in water was about 0.0158 mg/ml (dapoxetine fumarate prepared in Example 16), 0.0122 mg/ml (1,5-naphthalene prepared in Example 17). Dapoxetine disulfate) is superior to the solubility of dapoxetine free base (0.00254 mg/ml).

Abstract

Disclosed are crystals of acid salts and the acid salts of dapoxetine and preparation methods therefor. The crystals are crystals of methanesulfonate, nitrate, and hydrobromide of dapoxetine, and crystals of gentisate, orotate, cyclamate, acetyl salicylate, hippurate, or 1,5-naphthalene sulfonate. The acid salts of dapoxetine are gentisate, orotate, acetyl salicylate, hippurate, or 1,5-naphthalene sulfonate of dapoxetine. The aqueous solubility of the several salts and crystals of dapoxetine of the present invention are all significantly greater than the solubility of dapoxitine free base, and have improved stability and hygroscopicity.

Description

一类达泊西汀的酸式盐的晶体， 酸式盐以及其制备方法 技术领域  Crystal of acid salt of dapoxetine, acid salt and preparation method thereof
本发明具体的涉及一类达泊西汀的酸式盐的晶体， 酸式盐以及其制备方 法。 背景技术  More particularly, the present invention relates to crystals, acid salts, and methods for their preparation of a class of acid salts of dapoxetine. Background technique
达泊西汀化学名称为 (+) Ν,Ν-二甲基 -1-苯基 -3-(1-萘氧基:)丙胺， 是一种 选择性 5-羟色胺再吸收抑制剂 (SSRI), 半衰期短， 可用于治疗抑郁和相关的 情感障碍。 2009年 2月作为治疗男性早泄的药物 (Prilig™)在欧洲批准上市， 这是世界上第一种用于此适应症的口服治疗药物， 被 Thomson Reuters 2009 年第一季度全球药物研发重大进展季度报告列为五个已经上市或正在审批 的最具前景药物之一。  Dapoxetine chemical name is (+) Ν, Ν-dimethyl-1-phenyl-3-(1-naphthyloxy:) propylamine, a selective serotonin reuptake inhibitor (SSRI) With a short half-life, it can be used to treat depression and related affective disorders. In February 2009, PriligTM was approved for marketing in Europe as the first oral therapy for this indication in the world. The report is listed as one of the five most promising drugs that have been listed or are being approved.
达泊西汀原研厂家为美国伊莱利利公司， 其原始专利 EP 0288188描述 了达泊西汀的制备方法。  The original manufacturer of Dapoxetine is Ehrlily, USA, and its original patent EP 0288188 describes the preparation method of dapoxetine.
同一种药物， 晶型不同， 其生物利用度也可能会存在差别， 另外其稳定 性、 流动性、 可压缩性也可能会不同， 这些理化性质对药物的应用产生一定 的影响。 同样， 同一种药物的不同盐型也存在着同样差别。 本发明提出达泊 西汀的几种盐型， 其理化性质彼此之间存在着一定的差别。  The same drug, different crystal forms, may have different bioavailability, and its stability, fluidity, and compressibility may also be different. These physical and chemical properties have certain effects on the application of drugs. Similarly, the same differences exist for different salt types of the same drug. The present invention proposes several salt forms of dapoxetine, and the physical and chemical properties thereof are different from each other.
本发明人经过大量实验， 发现达泊西汀的很多酸的盐或盐的晶体是无法 制备得到的， 如达泊西汀的乙酸、 丙酸、 异丁酸、 正辛酸、 乙醇酸、 L-乳酸、 L-天冬氨酸、 葡萄糖酸、 L-苹果酸、 L-谷氨酸、 丙二酸、 戊二酸、 己二酸、 苯磺酸、 烟酸、 海藻酸、 油酸等等多种酸式盐及晶体都无法制备得到。 发明内容  The inventors have found through extensive experiments that crystals of many acid salts or salts of dapoxetine cannot be prepared, such as dapoxetine acetate, propionic acid, isobutyric acid, n-octanoic acid, glycolic acid, L- Lactic acid, L-aspartic acid, gluconic acid, L-malic acid, L-glutamic acid, malonic acid, glutaric acid, adipic acid, benzenesulfonic acid, nicotinic acid, alginic acid, oleic acid, etc. Both acid salts and crystals cannot be prepared. Summary of the invention
本发明所要解决的技术问题是提供了与现有技术不同的一类达泊西汀 的酸式盐及其晶体， 以及晶体的制备方法。 本发明的达泊西汀的几种盐及晶 体， 其在水中的溶解度均明显优于达泊西汀游离碱的溶解度， 并且有较佳的 稳定性和吸湿性。 The technical problem to be solved by the present invention is to provide a class of dapoxetine different from the prior art. The acid salt and its crystal, and the preparation method of the crystal. Several salts and crystals of dapoxetine of the present invention have significantly better solubility in water than that of dapoxetine free base, and have better stability and hygroscopicity.
本发明提供了一种达泊西汀的甲磺酸盐的晶体， 其 XRPD图谱中， 辐射 源为 CuKa 在衍射角度 2Θ值为 6.00、 9.63、 12.03、 14.19、 14.90、 16.25、 16.72、 18.06、 19.19、 19.60、 20.92、 21.30 、 22.26、 23.04、 23.51、 24.52、 25.07、 25.35、 25.76、 26.63、 27.28、 27.75、 28.07、 28.62、 28.90、 29.96、 30.36、 30.74、 31.05、 31.31、 32.08、 32.45、 32.86、 33.54、 33.81、 34.05、 34.70、 35.37、 35.63、 36.24、 36.64、 37.13、 37.44、 37.76、 38.59、 39.24、 40.31、 41.22、 42.66、 43.76处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC 图谱在 174± 5 °C有吸热峰。  The present invention provides a crystal of mesylate salt of dapoxetine. In the XRPD pattern, the radiation source is CuKa at diffraction angles 2 Θ values of 6.00, 9.63, 12.03, 14.19, 14.90, 16.25, 16.72, 18.06, 19.19. 19.60, 20.92, 21.30, 22.26, 23.04, 23.51, 24.52, 25.07, 25.35, 25.76, 26.63, 27.28, 27.75, 28.07, 28.62, 28.90, 29.96, 30.36, 30.74, 31.05, 31.31, 32.08, 32.45, 32.86, 33.54 , 33.81, 34.05, 34.70, 35.37, 35.63, 36.24, 36.64, 37.13, 37.44, 37.76, 38.59, 39.24, 40.31, 41.22, 42.66, 43.76 with diffraction peaks, where 2 误差 value error range is ±0.2; its DSC spectrum is There is an endothermic peak at 174 ± 5 °C.
本发明还提供了一种上述达泊西汀的甲磺酸盐的晶体的制备方法，其包 含下列步骤： 将达泊西汀溶于有机溶剂中形成的溶液与甲垸磺酸混合， 待有 沉淀析出， 过滤， 即可； 其中， 所述的有机溶剂为 C^C^垸基醇的醋酸酯和 /或四氢呋喃。  The invention also provides a preparation method of the crystal of the methanesulfonate salt of the above dapoxetine, which comprises the following steps: mixing a solution formed by dissolving dapoxetine in an organic solvent with formazanic acid, Precipitating and filtering, wherein the organic solvent is an acetate and/or tetrahydrofuran of C^C-mercapto alcohol.
较佳的， 所述的达泊西汀的甲磺酸盐的晶体的制备方法包含下列步骤： 将达泊西汀溶于有机溶剂中， 过滤， 将甲垸磺酸加入所得滤液中， 搅拌， 待 有沉淀析出， 过滤， 即可。  Preferably, the method for preparing the crystal of the mesylate salt of dapoxetine comprises the following steps: dissolving dapoxetine in an organic solvent, filtering, adding formazansulfonic acid to the obtained filtrate, and stirring. Precipitate and precipitate, and filter.
所述的制备方法中，所述的 ~ 3垸基醇的醋酸酯较佳的为乙酸乙酯和 /或乙酸异丙酯； 所述的有机溶剂与达泊西汀的体积质量比较佳的为 7ml/g~12ml/g (进一步优选 10ml/g~l lml/g) 。 所述的制备方法中， 使所述沉 淀析出的环境温度较佳的为 0~35°C (进一步优选 20~35 °C ) 。 In the preparation method, the acetate of the ~ 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate; the volume of the organic solvent and dapoxetine is better. 7 ml / g ~ 12 ml / g (further preferably 10 ml / g ~ l lml / g). In the above production method, the ambient temperature at which the precipitate is precipitated is preferably 0 to 35 ° C (more preferably 20 to 35 ° C).
所述的制备方法中， 所述的甲垸磺酸与达泊西汀的摩尔比较佳的为 1 : 1~1·03: 1。  In the preparation method, the molar ratio of the formazansulfonic acid to dapoxetine is preferably 1: 1 to 1.03:1.
所述的制备方法中， 所得沉淀也可进一步干燥 （如真空干燥）， 从而制 得上述晶体的纯品。 本发明还提供了一种达泊西汀的硝酸盐的晶体， 其 XRPD 图谱中， 辐 射源为 CuKai ,在衍射角度 2Θ值为 10.26、 13.03、 13.78、 15.28、 15.95、 16.60、 17.21、 18.46、 19.60、 20.66、 21.16、 22.60、 23.07、 24.89、 25.40、 26.59、 26.78、 27.46、 27.97、 29.33、 30.30、 31.15、 32.22、 32.88、 33.56、 34.47、In the preparation method, the obtained precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals. The present invention also provides a crystal of nitrate of dapoxetine. In the XRPD spectrum, the radiation source is CuKai, and the diffraction angles 2 are 10.26, 13.03, 13.78, 15.28, 15.95, 16.60, 17.21, 18.46, 19.60. 20.66, 21.16, 22.60, 23.07, 24.89, 25.40, 26.59, 26.78, 27.46, 27.97, 29.33, 30.30, 31.15, 32.22, 32.88, 33.56, 34.47,
34.86、 36.18、 36.44、 37.17、 38.04、 39.02、 39.75、 39.99、 41.20、 41.73、34.86, 36.18, 36.44, 37.17, 38.04, 39.02, 39.75, 39.99, 41.20, 41.73,
42.87、 43.17、 44.22、 44.55处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC 图谱在 142 ± 5 °C有吸热峰。 There are diffraction peaks at 42.87, 43.17, 44.22, and 44.55, where the 2 Θ value error range is ±0.2; and the DSC spectrum has an endothermic peak at 142 ± 5 °C.
本发明还提供了上述达泊西汀的硝酸盐的晶体的制备方法，其包含下列 步骤： 将达泊西汀溶于有机溶剂中形成的溶液与硝酸混合， 待有沉淀析出， 过滤， 即可； 其中， 所述的有机溶剂为 垸基醇的醋酸酯。  The invention also provides a preparation method of the crystal of nitrate of the above dapoxetine, which comprises the following steps: mixing a solution formed by dissolving dapoxetine in an organic solvent with nitric acid, precipitating and filtering, and then filtering Wherein the organic solvent is an acetate of mercapto alcohol.
较佳的，所述的达泊西汀的硝酸盐的晶体的制备方法包含下列步骤：将 达泊西汀溶于有机溶剂中， 过滤， 将硝酸滴入所得滤液中， 搅拌， 待有沉淀 析出， 过滤， 即可。  Preferably, the method for preparing the nitrate crystal of dapoxetine comprises the steps of: dissolving dapoxetine in an organic solvent, filtering, dropping the nitric acid into the obtained filtrate, stirring, and precipitating the precipitate. , filter, you can.
所述达泊西汀的硝酸盐的晶体的制备方法中，所述的 d~C3垸基醇的醋 酸酯较佳的为乙酸乙酯和 /或乙酸异丙酯。所述的有机溶剂与达泊西汀的体积 质量比较佳的为 7ml/g~12ml/g (进一步优选 10ml/g~l lml/g) 。 所述的制备 方法中， 使所述沉淀析出的环境温度较佳的为 0~35 °C (进一步优选 20-35 °C ) 。 In the method for preparing crystals of the nitrate of dapoxetine, the acetate of the d-C 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate. The volume ratio of the organic solvent to dapoxetine is preferably from 7 ml/g to 12 ml/g (more preferably from 10 ml/g to l ml/g). In the above production method, the ambient temperature at which the precipitate is precipitated is preferably 0 to 35 ° C (more preferably 20 to 35 ° C).
所述达泊西汀的硝酸盐的晶体的制备方法中，所述的硝酸与达泊西汀的 摩尔比较佳的为 1 : 1~1.03: 1。  In the method for preparing crystals of the nitrate of dapoxetine, the molar ratio of the nitric acid to dapoxetine is preferably from 1:1 to 1.03:1.
所述达泊西汀的硝酸盐的晶体的制备方法中，所得沉淀也可进一步干燥 (如真空干燥）， 从而制得上述晶体的纯品。  In the method for preparing crystals of nitrate of dapoxetine, the resulting precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
本发明还提供了一种达泊西汀的氢溴酸盐的晶体， 其 XRPD 图谱中， 辐射源为 CuKa 在衍射角度 2Θ值为 6.41、 8.82、 12.84、 13.83、 15.26、 15.77、 16.08、 16.56、 16.76、 17.00、 17.67、 18.06、 18.51、 19.30、 20.39、 21.00、 21.54、 22.27、 22.58、 23.08、 23.43、 24.04、 24.95、 25.46、 25.84、 26.79、 27.16、 27.64、 28.05、 28.33、 29.04、 29.98、 30.38、 31.23、 31.59、 32.21、 32.73、 33.38、 33.73、 34.50、 35.27、 35.75、 36.28、 37.15、 38.39、 38.72、 39.34、 39.65、 40.17、 40.60、 41.11、 42.06、 42.50、 43.58处有衍射峰， 其中 2Θ值误差范围为 ± 0.2; 其 DSC图谱在 175 ± 5 °C有吸热峰。 The present invention also provides a crystal of hydrobromide salt of dapoxetine. In the XRPD spectrum, the radiation source is CuKa at diffraction angles 2 Θ values of 6.41, 8.82, 12.84, 13.83, 15.26, 15.77, 16.08, 16.56, 16.76, 17.00, 17.67, 18.06, 18.51, 19.30, 20.39, 21.00, 21.54, 22.27, 22.58, 23.08, 23.43, 24.04, 24.95, 25.46, 25.84, 26.79, 27.16, 27.64, 28.05, 28.33, 29.04, 29.98, 30.38, 31.23, 31.59, 32.21, 32.73, 33.38, 33.73, 34.50, 35.27, 35.75, 36.28, 37.15, 38.39, 38.72, 39.34, 39.65, 40.17, 40.60, 41.11, There are diffraction peaks at 42.06, 42.50, and 43.58, where the 2 Θ value error range is ± 0.2; and the DSC spectrum has an endothermic peak at 175 ± 5 °C.
本发明还提供了一种上述达泊西汀的氢溴酸盐的晶体的制备方法，其包 含下列步骤： 将达泊西汀溶于有机溶剂中形成的溶液与氢溴酸混合， 待有沉 淀析出， 过滤， 即可； 其中， 所述的有机溶剂为 C^C^垸基醇的醋酸酯。  The invention also provides a preparation method of the above-mentioned crystal of hydrobromide salt of dapoxetine, which comprises the following steps: mixing a solution formed by dissolving dapoxetine in an organic solvent with hydrobromic acid, leaving a precipitate Precipitating and filtering, wherein the organic solvent is an acetate of C^C^ mercapto alcohol.
较佳的， 所述的达泊西汀的氢溴酸盐的晶体的制备方法包含下列步骤： 将达泊西汀溶于有机溶剂中， 过滤， 将氢溴酸滴入所得滤液中， 搅拌， 待有 沉淀析出， 过滤， 即可。  Preferably, the method for preparing the crystal of the hydrobromide salt of dapoxetine comprises the steps of: dissolving dapoxetine in an organic solvent, filtering, dropping hydrobromic acid into the obtained filtrate, and stirring. Precipitate and precipitate, and filter.
所述达泊西汀的硝酸盐的氢溴酸盐的晶体的制备方法中， 所述的 C^Cs 垸基醇的醋酸酯较佳的为乙酸乙酯和 /或乙酸异丙酯。所述的有机溶剂与达泊 西汀的体积质量比较佳的为 7ml/g~12ml/g (进一步优选 10ml/g~l lml/g) 。 所述的制备方法中，使所述沉淀析出的环境温度较佳的为 0~35°C (进一步优 选 20~35°C ) 。  In the method for preparing the crystal of the hydrobromide salt of the nitrate of dapoxetine, the acetate of the C?Cs mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate. The volume ratio of the organic solvent to dapoxetine is preferably from 7 ml/g to 12 ml/g (more preferably from 10 ml/g to l ml/g). In the above preparation method, the ambient temperature at which the precipitate is precipitated is preferably 0 to 35 ° C (more preferably 20 to 35 ° C).
所述达泊西汀的氢溴酸盐的晶体的制备方法中，所述的氢溴酸与达泊西 汀的摩尔比较佳的为 1 : 1~1.03: 1。  In the method for preparing the crystal of the hydrobromide salt of dapoxetine, the molar ratio of the hydrobromic acid to dapoxetine is preferably from 1:1 to 1.03:1.
所述达泊西汀的氢溴酸盐的晶体的制备方法中，所得沉淀也可进一步干 燥 （如真空干燥）， 从而制得上述晶体的纯品。  In the method for preparing the crystal of the hydrobromide salt of dapoxetine, the resulting precipitate may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystal.
同一种药物， 晶型不同， 其生物利用度也可能会存在差别， 另外其稳定 性、 流动性、 可压缩性也可能会不同， 这些理化性质对药物的应用产生一定 的影响。 同样， 同一种药物的不同盐型也存在着同样差别。 本发明上述的达 泊西汀几种盐的新晶型， 其理化性质彼此之间存在着一定的差别。  The same drug, different crystal forms, may have different bioavailability, and its stability, fluidity, and compressibility may also be different. These physical and chemical properties have certain effects on the application of drugs. Similarly, the same differences exist for different salt types of the same drug. The new crystalline form of several salts of dapoxetine of the present invention has a certain difference in physical and chemical properties from each other.
本发明上述的达泊西汀的几种盐的新晶型， 其溶解度分别为约 267 mg/ml (甲磺酸达泊西汀）、 2.61 mg/ml (硝酸达泊西汀）、 3.52 mg/ml (氢溴 酸达泊西汀）， 均优于达泊西汀游离碱的溶解度 （0.00254 mg/ml )。 本发明还提供了一类达泊西汀的酸式盐， 其为达泊西汀的龙胆酸盐、 乳 清酸盐、 环拉酸盐、 乙酰水杨酸盐、 马尿酸盐、 或者 1,5-萘二磺酸盐。 The new crystalline form of several salts of the above-mentioned dapoxetine of the present invention has a solubility of about 267 mg/ml (dapoxetine mesylate), 2.61 mg/ml (dapoxetine nitrate), 3.52 mg, respectively. /ml (dapoxetine hydrobromide), both better than the solubility of dapoxetine free base (0.00254 mg / ml). The present invention also provides a class of acid salts of dapoxetine, which is dadocetine gentisate, orotate, cyclamate, acetylsalicylate, hippurate, or 1,5-naphthalene disulfonate.
本发明还提供了一种达泊西汀的龙胆酸盐的晶体， 其 XRPD图谱中，辐 射源为 CuKa 在 2Θ值为 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处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC图谱在 175±5°C有吸热峰。  The present invention also provides a crystal of gentisate of dapoxetine. In the XRPD spectrum, the radiation source is CuKa at a value of 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, There are diffraction peaks at 28.95, 29.15, 31.61, 31.69, 31.89, 32.37, 32.70, 34.26, 36.39, 37.66, and 40.95, where the 2 Θ value error range is ±0.2; and the DSC spectrum has an endothermic peak at 175±5°C.
本发明还提供了一种达泊西汀的乳清酸盐的晶体， 其 XRPD图谱中，辐 射源为 CuKon , 在 2Θ值为 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处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC图谱 在 119±5°C有吸热峰。  The present invention also provides a crystal of the orotate salt of dapoxetine. In the XRPD pattern, the radiation source is CuKon, and the values of 2Θ are 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, 16.45, 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 with diffraction peaks, 2 Θ value error range is ± 0.2; its DSC spectrum has an endothermic peak at 119 ± 5 °C.
本发明还提供了一种达泊西汀的环拉酸盐的晶体， 其 XRPD图谱中，辐 射源为 CuKon , 在 2Θ值为 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处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC 图谱在 194±5°C有吸热峰。  The present invention also provides a crystal of cyclamate of dapoxetine. In the XRPD spectrum, the radiation source is CuKon, and the values of 2Θ are 6.42, 7.11, 11.67, 12.87, 14.25, 15.08, 17.43, 18.43, 18.63. , diffraction peaks at 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, 2 Θ value error range is ± 0.2; its DSC spectrum has an endothermic peak at 194 ± 5 ° C.
本发明还提供了一种达泊西汀的乙酰水杨酸盐的晶体， 其 XRPD 图谱 中， 辐射源为 CuKon , 在 2Θ值为 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 处有衍射 峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC图谱在 114±5°C有吸热峰。 The present invention also provides a crystal of acetylsalicylate of dapoxetine. In the XRPD spectrum, the radiation source is CuKon, and the values of 2Θ are 5.68, 10.56, 11.31, 11.57, 12.24, 12.73, 13.05, 13.70, 14.09, 15.53, 16.18, 16.97, 19.96, 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, Diffraction at 42.27, 44.28 Peak, where 2 误差 value error range is ±0.2; its DSC spectrum has an endothermic peak at 114±5 °C.
本发明得到的达泊西汀的几种盐， 其在水中的溶解度 （以达泊西汀计） 分别为约 0.18 mg/ml (龙胆酸达泊西汀）、 5.72 mg/ml (乳清酸达泊西汀）、 1.18 mg/ml (环拉酸达泊西汀）、 0.24 mg/ml (乙酰水杨酸达泊西汀）， 均优于 达泊西汀游离碱的溶解度 （0.006 mg/ml)。  Several salts of dapoxetine obtained by the present invention have a solubility in water (calculated as dapoxetine) of about 0.18 mg/ml (dapoxetine gentisate) and 5.72 mg/ml (whey Dapoxetine), 1.18 mg/ml (dapoxetine cyclamate), 0.24 mg/ml (dapoxetine acetylsalicylate), all superior to the solubility of dapoxetine free base (0.006 mg) /ml).
本发明的达泊西汀的龙胆酸盐、 乳清酸盐、 环拉酸盐、 或者乙酰水杨酸 盐的制备方法， 都可以根据本领域常规知识， 将达泊西汀和相应的酸进行成 盐反应， 即可制得。  The preparation method of the gentisate, orotate, cyclamate or acetylsalicylate of dapoxetine of the present invention can be based on the conventional knowledge in the art, and the dapoxetine and the corresponding acid The salt formation reaction can be carried out.
本发明进一步提供了上述达泊西汀的龙胆酸盐的晶体的制备方法，其包 含下列步骤： 将达泊西汀和龙胆酸溶于乙酸乙酯、 甲醇、 乙醇、 正丙醇、 异 丙醇、 二氯甲垸、 丙酮或四氢呋喃中， 待有沉淀析出， 过滤， 干燥， 即可。  The present invention further provides a method for preparing crystals of the gentisate salt of the above dapoxetine, which comprises the steps of: dissolving dapoxetine and gentisic acid in ethyl acetate, methanol, ethanol, n-propanol, and different In propanol, chloroform, acetone or tetrahydrofuran, precipitate is precipitated, filtered, and dried.
其中， 所述的溶于乙酸乙酯、 甲醇、 乙醇、 正丙醇、 异丙醇、 二氯甲垸、 丙酮或四氢呋喃中， 溶解的温度可为常规溶解所需温度， 如 20~50°C。  Wherein, the solution is dissolved in ethyl acetate, methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetone or tetrahydrofuran, and the temperature of dissolution may be the temperature required for conventional dissolution, such as 20 to 50 ° C. .
将达泊西汀和龙胆酸溶于乙酸乙酯、 甲醇、 乙醇、 正丙醇、 异丙醇、 二 氯甲垸、 丙酮或四氢呋喃后， 沉淀析出之前， 较佳的还进行过滤步骤， 以除 去不溶的杂质， 除去杂质后进一步还可以通过搅拌溶液， 使沉淀析出。  After dissolving dapoxetine and gentisic acid in ethyl acetate, methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetone or tetrahydrofuran, it is preferred to carry out a filtration step before precipitation. The insoluble impurities are removed, and after the impurities are removed, the precipitate can be further precipitated by stirring the solution.
较佳的， 在所述的沉淀析出后， 还可降温， 再进行过滤， 得沉淀， 即可。 其中， 所述的降温可为常规结晶时需要的降温幅度， 如降至 0~10°C。  Preferably, after the precipitation is precipitated, the temperature may be lowered, and then filtered to obtain a precipitate. Wherein, the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
较佳的， 在将所述沉淀过滤后， 也可进一步干燥 （如真空干燥）， 从而 制得上述晶体的纯品。  Preferably, after filtering the precipitate, it may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
其中，所述的达泊西汀和龙胆酸的摩尔比可为常规的成盐反应的摩尔比 例， 较佳的为 1 : 1~1 : 1.1。 所述的乙酸乙酯、 甲醇、 乙醇、 正丙醇、 异丙醇、 二氯甲垸、 丙酮或四氢呋喃的用量可为将达泊西汀和龙胆酸刚刚溶解即可； 乙酸乙酯、 甲醇、 乙醇、 正丙醇、 异丙醇、 二氯甲垸、 丙酮或四氢呋喃与达 泊西汀和龙胆酸的体积质量比较佳的为 5~20ml/g (优选 10ml/g)。  Wherein, the molar ratio of dapoxetine to gentisic acid may be a molar ratio of a conventional salt-forming reaction, preferably 1 : 1 to 1: 1.1. The ethyl acetate, methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetone or tetrahydrofuran may be used to dissolve dapoxetine and gentisic acid; ethyl acetate, methanol The volumetric mass of ethanol, n-propanol, isopropanol, chloroform, acetone or tetrahydrofuran with dapoxetine and gentisic acid is preferably 5-20 ml/g (preferably 10 ml/g).
本发明进一步提供了上述达泊西汀的乳清酸盐的晶体的制备方法，其包 含下列步骤： 将达泊西汀和乳清酸置于二氯甲垸或乙酸乙酯中， 进行成盐反 应后， 过滤， 干燥， 即可； 其中达泊西汀的摩尔量相对乳清酸等量或过量。 The present invention further provides a method for preparing crystals of the oprexate of the above dapoxetine, which comprises The method comprises the steps of: dissolving dapoxetine and orotic acid in dichloromethane or ethyl acetate, performing salt formation reaction, filtering and drying, wherein the amount of dapoxetine is relative to orotic acid Equal or excess.
其中， 所述的成盐反应的温度可为常规的成盐反应所需温度， 如 Wherein, the temperature of the salt formation reaction may be a temperature required for a conventional salt formation reaction, such as
20~50°C。 20~50 °C.
较佳的， 在所述的成盐反应后， 还可降温， 再进行过滤， 得沉淀， 即可。 其中， 所述的降温可为常规结晶时需要的降温幅度， 如降至 0~10°C。  Preferably, after the salt formation reaction, the temperature may be lowered, and then filtered to obtain a precipitate. Wherein, the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
较佳的， 在过滤后， 也可进一步将所得滤过物干燥 （如真空干燥）， 从 而制得上述晶体的纯品。  Preferably, after filtration, the resulting filtrate may be further dried (e.g., vacuum dried) to produce a pure product of the above crystals.
其中， 所述的达泊西汀和乳清酸的摩尔比较佳的为 1:1~1.1:1。所述的二 氯甲垸或乙酸乙酯， 与达泊西汀和乳清酸（两者质量和） 的体积质量比较佳 的为 5~20ml/g (优选 10ml/g)。  Wherein, the molar ratio of dapoxetine and orotic acid is preferably 1:1 to 1.1:1. The chloroform or ethyl acetate is preferably 5 to 20 ml/g (preferably 10 ml/g) in volume volume of dapoxetine and orotic acid (both mass sum).
本发明进一步提供了上述达泊西汀的环拉酸盐的晶体的制备方法，其包 含下列步骤： 将达泊西汀和环拉酸溶于乙酸乙酯中， 待有沉淀析出， 过滤， 干燥， 即可。  The present invention further provides a process for preparing the crystal of the above-mentioned bromotinate of dapoxetine, which comprises the steps of: dissolving dapoxetine and cyclamate in ethyl acetate, precipitating, filtering, drying , you can.
其中， 所述的将达泊西汀和环拉酸溶于乙酸乙酯中， 溶解的温度可为常 规溶解所需温度， 如 20~50°C。  Wherein, the dapoxetine and the cyclolacetic acid are dissolved in ethyl acetate, and the temperature of dissolution may be a temperature required for conventional dissolution, such as 20 to 50 °C.
将达泊西汀和环拉酸溶于乙酸乙酯后， 沉淀析出之前， 较佳的还进行过 滤步骤， 以除去不溶的杂质， 除去杂质后进一步还可以通过搅拌溶液， 使沉 淀析出。  After dissolving dapoxetine and cyclamate in ethyl acetate, it is preferred to carry out a filtration step to remove insoluble impurities, and to remove the impurities, and further to precipitate the precipitate by stirring the solution.
较佳的， 在所述的沉淀析出后， 还可降温， 再进行过滤， 得沉淀， 即可。 其中， 所述的降温可为常规结晶时需要的降温幅度， 如降至 0~10°C。  Preferably, after the precipitation is precipitated, the temperature may be lowered, and then filtered to obtain a precipitate. Wherein, the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
较佳的， 在将所述沉淀过滤后， 也可进一步干燥 （如真空干燥）， 从而 制得上述晶体的纯品。  Preferably, after filtering the precipitate, it may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
其中，所述的达泊西汀和环拉酸的摩尔比可为常规的成盐反应的摩尔比 例， 较佳的为 1:1~1:1.1。所述的乙酸乙酯的用量可为将达泊西汀和环拉酸刚 刚溶解即可；乙酸乙酯与达泊西汀和环拉酸的体积质量比较佳的为 5~20ml/g (优选 10ml/g)。 Wherein, the molar ratio of the dapoxetine to the cyclolacetic acid may be a molar ratio of the conventional salt-forming reaction, preferably from 1:1 to 1:1.1. The ethyl acetate can be used in such a manner that dapoxetine and cyclamate are just dissolved; the volumetric mass of ethyl acetate with dapoxetine and cyclamate is preferably 5-20 ml/g. (preferably 10 ml/g).
本发明进一步提供了上述达泊西汀的乙酰水杨酸盐的晶体的制备方法， 其包含下列步骤： 将达泊西汀、 乙酰水杨酸与丙酮混合， 溶液澄清后， 加入 正己垸、 正戊垸或石油醚， 待有沉淀析出， 过滤， 即可。  The present invention further provides a method for preparing crystals of acetyl salicylate of dapoxetine, which comprises the steps of: mixing dapoxetine, acetylsalicylic acid and acetone, clarifying the solution, adding hexane, positive Pentamidine or petroleum ether, precipitated and filtered.
其中， 将达泊西汀、 乙酰水杨酸和丙酮混合后， 加入正己垸将沉淀析出 之前， 较佳的还进行搅拌， 使溶液澄清。  Among them, after mixing dapoxetine, acetylsalicylic acid and acetone, it is preferably stirred to add a solution to the precipitate before the precipitate is precipitated.
其中， 所述的将达泊西汀、 乙酰水杨酸与丙酮混合， 混合的温度可为常 规溶解所需温度， 如 20~50°C。  Wherein, the dapoxetine, acetylsalicylic acid and acetone are mixed, and the mixing temperature may be a temperature required for conventional dissolution, such as 20 to 50 °C.
较佳的， 在所述的沉淀析出后， 还可降温， 再进行过滤， 得沉淀， 即可。 其中， 所述的降温可为常规结晶时需要的降温幅度， 如降至 0~10°C。  Preferably, after the precipitation is precipitated, the temperature may be lowered, and then filtered to obtain a precipitate. Wherein, the cooling may be a cooling range required for conventional crystallization, such as falling to 0 to 10 °C.
较佳的， 在将所述沉淀过滤后， 也可进一步干燥 （如真空干燥）， 从而 制得上述晶体的纯品。  Preferably, after filtering the precipitate, it may be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals.
其中， 所述的达泊西汀和乙酰水杨酸可为常规的成盐反应的摩尔比例， 较佳的为 1 : 1~1 : 1.1。 所述的丙酮， 与达泊西汀和乙酰水杨酸 （两者质量和） 的体积质量比较佳的为 5~20ml/g (优选 10 ml/g)。 所述的正己垸、 正戊垸或 石油醚的用量可为混合溶剂结晶时低极性溶剂的常规用量， 正己垸、 正戊垸 或石油醚与与丙酮的体积比较佳的为 1 :0.5~1 :2。  Wherein, the dapoxetine and acetylsalicylic acid may be in a molar ratio of a conventional salt-forming reaction, preferably 1 : 1 to 1: 1.1. The acetone, preferably having a volumetric mass of dapoxetine and acetylsalicylic acid (both mass sum), is 5 to 20 ml/g (preferably 10 ml/g). The amount of the n-hexanyl, n-pentamidine or petroleum ether may be a conventional amount of a low-polarity solvent when the mixed solvent is crystallized, and the volume of n-hexyl, n-pentamidine or petroleum ether and acetone is preferably 1:0.5~ 1 : 2.
本发明还提供了达泊西汀的马尿酸盐的晶体， 其 XRPD图谱中， 辐射源 ¾ CuKa 在衍射角度 2Θ值为 12.99、 13.86、 16.21、 16.70、 19.38、 19.94、 21.69、 21.85、 22.23、 23.43、 23.75、 25.72、 26.19、 27.16、 27.99、 28.90、 29.27、 30.54、 31.05、 31.76、 32.20、 32.83、 33.63、 33.89、 34.70、 35.35、 36.12、 36.72、 37.18、 38.04、 39.72、 40.43、 40.86、 41.73、 42.78、 43.92处 有衍射峰，其中 2Θ值误差范围为 ± 0.2;其 DSC图谱在 190 ± 5 °C有吸热峰。  The present invention also provides a crystal of horseradish of dapoxetine. In the XRPD pattern, the radiation source 3⁄4 CuKa has a diffraction angle of 2 Θ values of 12.99, 13.86, 16.21, 16.70, 19.38, 19.94, 21.69, 21.85, 22.23, 23.43, 23.75, 25.72, 26.19, 27.16, 27.99, 28.90, 29.27, 30.54, 31.05, 31.76, 32.20, 32.83, 33.63, 33.89, 34.70, 35.35, 36.12, 36.72, 37.18, 38.04, 39.72, 40.43, 40.86, 41.73, There are diffraction peaks at 42.78 and 43.92, where the 2 Θ value error range is ± 0.2; the DSC spectrum has an endothermic peak at 190 ± 5 °C.
本发明还提供了上述达泊西汀的马尿酸盐的晶体的制备方法， 其包含下 列步骤： 在 ~ 3垸基醇的醋酸酯中， 将达泊西汀和马尿酸进行成盐反应， 过滤， 即可。 其中， 所述的 ~。3垸基醇的醋酸酯较佳的为乙酸乙酯和 /或乙酸异丙 酯。 所述的 ^~ 3垸基醇的醋酸酯和达泊西汀的体积质量比较佳的为 9ml/g ~12ml/g (如 10.6ml/g )。 所述的达泊西汀和马尿酸的摩尔比较佳的为 1.03: 1~1 : 1。 所述的成盐反应的温度较佳的为 40~60°C (优选 50°C )。 成盐反 应的时间较佳的为 3~6小时 （例如可以搅拌 3~6小时进行成盐反应）。 The present invention also provides a method for preparing a crystal of a horse salt of dapoxetine, which comprises the steps of: forming a salt reaction of dapoxetine and hippuric acid in an acetate of ~ 3 mercapto alcohol, Filter, you can. Wherein, the ~. The acetate of 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate. The volume of the acetate and dapoxetine of the ^~ 3 mercapto alcohol is preferably from 9 ml/g to 12 ml/g (e.g., 10.6 ml/g). The molar ratio of dapoxetine and hippuric acid is preferably 1.03: 1~1:1. The temperature of the salt formation reaction is preferably 40 to 60 ° C (preferably 50 ° C). The salt formation reaction time is preferably from 3 to 6 hours (for example, the salt formation reaction can be carried out by stirring for 3 to 6 hours).
其中， 过滤所得沉淀也可进一步干燥 （如真空干燥）， 从而制得上述晶 体的纯品。  Among them, the precipitate obtained by filtration can be further dried (e.g., vacuum dried) to obtain a pure product of the above crystal.
本发明还提供了达泊西汀的 1,5-萘二磺酸盐的晶体， 其 XRPD图谱中， 辐射源为 CuKa 在衍射角度 2Θ值为 8.23、 9.69、 10.15、 11.08、 11.47、 12.29、 The present invention also provides a crystal of 1,5-naphthalene disulfonate of dapoxetine. In the XRPD pattern, the radiation source is CuKa at diffraction angles 2 Θ values of 8.23, 9.69, 10.15, 11.08, 11.47, 12.29,
12.55、 13.09、 13.84、 14.61、 15.59、 15.81、 16.15、 16.54、 16.70、 18.34、12.55, 13.09, 13.84, 14.61, 15.59, 15.81, 16.15, 16.54, 16.70, 18.34,
18.73、 19.42、 20.37、 21.04、 21.24、 21.60、 22.05、 22.96、 23.23、 23.57、18.73, 19.42, 20.37, 21.04, 21.24, 21.60, 22.05, 22.96, 23.23, 23.57,
23.75、 24.45、 24.91、 25.23、 25.72、 26.92、 27.24、 27.73、 28.40、 28.94、23.75, 24.45, 24.91, 25.23, 25.72, 26.92, 27.24, 27.73, 28.40, 28.94,
29.47、 29.97、 30.54、 30.81、 31.80、 32.33、 33.00、 33.40、 33.71、 34.45、29.47, 29.97, 30.54, 30.81, 31.80, 32.33, 33.00, 33.40, 33.71, 34.45,
34.84、 35.18、 35.91、 36.20、 36.75、 37.86、 39.44、 39.83、 40.05、 42.79处 有衍射峰，其中 2Θ值误差范围为 ±0.2;其 DSC图谱在 106± 5 °C有吸热峰。 34.84, 35.18, 35.91, 36.20, 36.75, 37.86, 39.44, 39.83, 40.05, 42.79 have diffraction peaks, of which 2 误差 value error range is ±0.2; and its DSC spectrum has an endothermic peak at 106±5 °C.
本发明还提供了上述达泊西汀的 1,5-萘二磺酸盐的晶体的制备方法， 其 包含下列步骤： 在 C^C^垸基醇的醋酸酯和 /或四氢呋喃中， 将达泊西汀和 1,5-萘二磺酸进行成盐反应， 过滤， 即可。  The invention also provides a preparation method of the crystal of the 1,5-naphthalenedisulfonate of dapoxetine described above, which comprises the following steps: in the acetate and/or tetrahydrofuran of C^C-mercapto alcohol, Pocytin and 1,5-naphthalenedisulfonic acid are subjected to salt formation reaction and filtered.
其中， 所述的 ~。3垸基醇的醋酸酯较佳的为乙酸乙酯和 /或乙酸异丙 酯。所述的 C^C^垸基醇的醋酸酯和 /或四氢呋喃， 与达泊西汀的体积质量比 较佳的为 9ml/g ~12ml/g (如 10.6ml/g)。 所述的达泊西汀和 1,5-萘二磺酸的 摩尔比较佳的为 1.03: 1~1 : 1。 所述的成盐反应的温度较佳的为 10~50°C (优 选 20~35°C )。 成盐反应的时间较佳的为 3~6小时 （例如可以搅拌 3~6小时 进行成盐反应）。 Wherein, the ~. The acetate of 3 mercapto alcohol is preferably ethyl acetate and/or isopropyl acetate. The volume of the acetate and/or tetrahydrofuran of C^C^ mercapto alcohol and dapoxetine is preferably from 9 ml/g to 12 ml/g (e.g., 10.6 ml/g). The molar ratio of dapoxetine and 1,5-naphthalenedisulfonic acid is preferably 1.03:1~1:1. The temperature of the salt formation reaction is preferably from 10 to 50 ° C (preferably from 20 to 35 ° C). The salt formation reaction time is preferably from 3 to 6 hours (for example, the salt formation reaction can be carried out by stirring for 3 to 6 hours).
其中， 过滤所得沉淀也可进一步干燥 （如真空干燥）， 从而制得上述晶 体的纯品。 同一种药物， 晶型不同， 其生物利用度也可能会存在差别， 另外其稳定 性、 流动性、 可压缩性也可能会不同， 这些理化性质对药物的应用产生一定 的影响。 同样， 同一种药物的不同盐型也存在着同样差别。 本发明提出达泊 西汀的几种盐型， 其理化性质彼此之间存在着一定的差别。 Among them, the precipitate obtained by filtration can be further dried (e.g., vacuum dried) to obtain a pure product of the above crystals. The same drug, different crystal forms, may have different bioavailability, and its stability, fluidity, and compressibility may also be different. These physical and chemical properties have certain effects on the application of drugs. Similarly, the same differences exist for different salt types of the same drug. The present invention proposes several salt forms of dapoxetine, and the physical and chemical properties thereof are different from each other.
本发明得到的达泊西汀的几种盐， 其溶解度分别为约 0.0158 mg/ml (马 尿酸达泊西汀）、 0.0122 mg/ml ( 1,5-萘二磺酸达泊西汀）， 均优于达泊西汀游 离碱的溶解度 （0.00254 mg/ml ) o 在不违背本领域常识的基础上， 上述各优 选条件， 可任意组合， 即得本发明各较佳实例。  Several salts of dapoxetine obtained by the present invention have a solubility of about 0.0158 mg/ml (dapoxetine hippurate) and 0.0122 mg/ml (dapoxetine 1,5-naphthalene disulfate), respectively. Both are superior to the solubility of dapoxetine free base (0.00254 mg/ml). o The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, and the preferred examples of the present invention are obtained.
本发明所用试剂和原料均市售可得。  The reagents and starting materials used in the present invention are commercially available.
本发明的积极进步效果在于： 本发明提供了与现有技术不同的达泊西汀 的四种盐及晶体， 其在水中的溶解度均明显优于达泊西汀游离碱的溶解度， 并且有较佳的稳定性和吸湿性。 附图说明  The positive progress of the present invention is as follows: The present invention provides four salts and crystals of dapoxetine which are different from the prior art, and their solubility in water is significantly better than that of dapoxetine free base, and there are Good stability and hygroscopicity. DRAWINGS
图 1为本发明的龙胆酸达泊西汀的 XRPD图谱。  Figure 1 is an XRPD pattern of dapoxetine gentisate of the present invention.
图 2为本发明的龙胆酸达泊西汀的 DSC图谱。  Figure 2 is a DSC map of dapoxetine gentisate of the present invention.
图 3为本发明的乳清酸达泊西汀的 XRPD图谱。  Figure 3 is an XRPD pattern of dapoxetine orotate of the present invention.
图 4为本发明的乳清酸达泊西汀的 DSC图谱。  Figure 4 is a DSC chart of dapoxetine orotate of the present invention.
图 5为本发明的环拉酸达泊西汀的 XRPD图谱。  Figure 5 is an XRPD pattern of dapoxetine cyclamate of the present invention.
图 6为本发明的环拉酸达泊西汀的 DSC图谱。  Figure 6 is a DSC chart of dapoxetine cyclamate of the present invention.
图 7为本发明的乙酰水杨酸达泊西汀的 XRPD图谱。  Figure 7 is an XRPD pattern of dapoxetine acetylsalicylate of the present invention.
图 8为本发明的乙酰水杨酸达泊西汀的 DSC图谱。  Figure 8 is a DSC chart of dapoxetine acetylsalicylate of the present invention.
图 9为本发明的达泊西汀的甲磺酸盐的晶体的 XRPD图谱。  Figure 9 is an XRPD pattern of crystals of the mesylate salt of dapoxetine of the present invention.
图 10为本发明的达泊西汀的甲磺酸盐的晶体的 DSC图谱。  Figure 10 is a DSC chart of the crystal of the mesylate salt of dapoxetine of the present invention.
图 11为本发明的达泊西汀的硝酸盐的晶体的 XRPD图谱。  Figure 11 is an XRPD pattern of the crystal of nitrate of dapoxetine of the present invention.
图 12为本发明的达泊西汀的硝酸盐的晶体的 DSC图谱。 图 13为本发明的达泊西汀的氢溴酸盐的晶体的 XRPD图谱。 Figure 12 is a DSC chart of crystals of nitrate of dapoxetine of the present invention. Figure 13 is an XRPD pattern of crystals of the hydrobromide salt of dapoxetine of the present invention.
图 14为本发明的达泊西汀的氢溴酸盐的晶体的 DSC图谱。  Figure 14 is a DSC chart of the crystal of the hydrobromide salt of dapoxetine of the present invention.
图 15为本发明的达泊西汀的马尿酸盐的晶体的 XRPD图谱。  Figure 15 is an XRPD pattern of crystals of the hippurate of dapoxetine of the present invention.
图 16为本发明的达泊西汀的马尿酸盐的晶体的 DSC图谱。  Figure 16 is a DSC chart of crystals of the hippurate salt of dapoxetine of the present invention.
图 17为本发明的达泊西汀的 1,5-萘二磺酸盐的 XRPD图谱。  Figure 17 is an XRPD pattern of 1,5-naphthalene disulfonate of dapoxetine of the present invention.
图 18为本发明的达泊西汀的 1,5-萘二磺酸盐的 DSC图谱。 具体实施方式  Figure 18 is a DSC chart of 1,5-naphthalene disulfonate of dapoxetine of the present invention. detailed description
下列实施例中未注明具体条件的实验方法， 按照常规方法和条件， 或 按照商品说明书选择。  The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.
以下实施例得到的晶体的各种测试方法所用的实验条件：  The experimental conditions used in the various test methods for the crystals obtained in the following examples:
XRPD测试方法： 仪器型号： Bruker D8 advance XRD, 衍射线： CuKa (40 kV, 40 mA)， 扫描速率： 8 ηώι (2θ值）， 扫描范围： 3°~45° (2Θ值)； DSC 测试方法： 仪器型号： TA Q2000, 升温速率 10°C/min。  XRPD test method: Instrument model: Bruker D8 advance XRD, diffraction line: CuKa (40 kV, 40 mA), scan rate: 8 ηώι (2θ value), scanning range: 3°~45° (2Θ value); DSC test method : Instrument model: TA Q2000, heating rate 10 °C / min.
下述各实施例中， "室温"是指 20~35 °C。  In the following examples, "room temperature" means 20 to 35 °C.
实施例 1 龙胆酸达泊西汀晶体的制备  Example 1 Preparation of crystals of dapoxetine gentisate
称取 916 mg达泊西汀和 475 mg龙胆酸于容器中，加入 15 ml乙酸乙酯， 搅拌至固体完全溶解， 滤去不溶物， 室温下搅拌 2 h， 有沉淀析出， 降温至 5 °C， 过滤、 真空干燥后得淡黄色粉末 1.306 g (95%)。  Weigh 916 mg of dapoxetine and 475 mg of gentisic acid in a container, add 15 ml of ethyl acetate, stir until the solid is completely dissolved, filter off the insoluble matter, stir at room temperature for 2 h, precipitate out, and cool down to 5 ° C, filtered, vacuum dried to give a pale yellow powder 1.306 g (95%).
其 XRPD图谱见图 1， 辐射源为 CuKon , 在 2Θ值为 5.71、 7.50、 10.51、 The XRPD spectrum is shown in Figure 1. The radiation source is CuKon, and the value of 2 is 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、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、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、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、28.65, 28.95, 29.15, 31.61, 31.69, 31.89, 32.37, 32.70, 34.26, 36.39,
37.66、 40.95处有衍射峰， 其中 2Θ值误差范围为 ±0.2。 There are diffraction peaks at 37.66 and 40.95, where the range of 2 误差 error is ±0.2.
其 DSC图谱见图 2， 在 175±5 °C有吸热峰。 实施例 2 乳清酸达泊西汀晶体的制备 Its DSC spectrum is shown in Figure 2, with an endothermic peak at 175 ± 5 °C. Example 2 Preparation of Dapoxetine Crystals of Orotate
称取 916 mg达泊西汀和 480 mg乳清酸于容器中，加入 15 ml二氯甲垸， 固体不溶解， 室温下搅拌 2 h， 降温至 5 °C， 过滤、 真空干燥后得白色粉末 692 mg ( 50%)。  Weigh 916 mg of dapoxetine and 480 mg of orotic acid in a container, add 15 ml of dichloromethane, the solid is not dissolved, stir at room temperature for 2 h, cool to 5 ° C, filter, vacuum dry to obtain white powder 692 mg (50%).
其 XRPD图谱见图 3， 辐射源为 CuKon , 在 2Θ值为 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处有衍射峰， 其中 2Θ值 误差范围为 ±0.2。  The XRPD spectrum is shown in Fig. 3. The radiation source is CuKon, and the values of 2Θ are 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. There are diffraction peaks at 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, where the range of 2 误差 error is ±0.2.
其 DSC图谱见图 4， 在 119±5 °C有吸热峰。  Its DSC spectrum is shown in Figure 4, with an endothermic peak at 119 ± 5 °C.
实施例 3 环拉酸达泊西汀晶体的制备  Example 3 Preparation of crystals of dapoxetine cyclamate
称取 916 mg达泊西汀和 550 mg环拉酸于容器中，加入 15 ml乙酸乙酯， 搅拌至固体完全溶解， 滤去不溶物， 室温下搅拌 2 h， 降温至 5 °C， 静置过 夜有沉淀析出， 过滤、 真空干燥后得白色粉末 455 mg (31%)。  Weigh 916 mg of dapoxetine and 550 mg of cyclamate in a container, add 15 ml of ethyl acetate, stir until the solid is completely dissolved, filter off the insoluble matter, stir at room temperature for 2 h, cool to 5 ° C, and let stand. Precipitation was precipitated overnight, filtered and dried in vacuo to give 455 mg (31%) of white powder.
其 XRPD图谱见图 5， 辐射源为 CuKon , 在 2Θ值为 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处有衍射峰， 其中 2Θ值误差范围为 ±0.2。  The XRPD spectrum is shown in Fig. 5. The radiation source is CuKon, and the values are 2.42, 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. There are diffraction peaks at 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, where the range of 2 误差 error is ±0.2.
其 DSC图谱见图 6， 在 194±5°C有吸热峰。  Its DSC spectrum is shown in Fig. 6, with an endothermic peak at 194 ± 5 °C.
实施例 4 乙酰水杨酸达泊西汀晶体的制备  Example 4 Preparation of crystals of dapoxetine acetylsalicylate
称取 916 mg达泊西汀和 560 mg乙酰水杨酸于容器中，加入 15 ml丙酮， 固体不溶解， 室温下搅拌 2 h后溶液澄清， 缓慢加入 25 ml正己垸至有沉淀 析出， 降温至 5 °C， 过滤、 真空干燥后得白色粉末 433 mg (30%)。  Weigh 916 mg of dapoxetine and 560 mg of acetylsalicylic acid in a container, add 15 ml of acetone, the solid is not dissolved, stir the solution at room temperature for 2 h, then clarify the solution, slowly add 25 ml of hexane to precipitate, and cool down to After filtration at 5 ° C, vacuum drying gave 433 mg (30%) of white powder.
其 XRPD图谱见图 7， 辐射源为 CuKa 在 2Θ值为 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处有衍射峰， 其中 2Θ值误差范围为 ±0.2. The XRPD spectrum is shown in Fig. 7. The radiation source is CuKa at 2Θ values of 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. Diffraction peaks at 18.53, 19.26, 19.54, 20.66, 21.49, 24.67, 25.75, 23.90, 24.17, 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, of which 2Θ The value error range is ±0.2.
其 DSC图谱见图 8， 其在 114±5°C有吸热峰。  Its DSC spectrum is shown in Figure 8, which has an endothermic peak at 114 ± 5 °C.
实施例 5龙胆酸达泊西汀晶体的制备  Example 5 Preparation of crystals of dapoxetine gentisate
称取 916 mg达泊西汀和 475 mg龙胆酸于容器中， 加入 15 ml甲醇， 搅 拌至固体完全溶解，滤去不溶物，室温下搅拌 2 h，有沉淀析出，降温至 5 °C， 过滤、 真空干燥后得淡黄色粉末 1.21 其 XRPD图谱见图 1， 其 DSC图谱 见图 2。  Weigh 916 mg of dapoxetine and 475 mg of gentisic acid in a container, add 15 ml of methanol, stir until the solid is completely dissolved, filter off the insoluble matter, stir at room temperature for 2 h, precipitate out, and cool down to 5 °C. Filtration and vacuum drying gave a pale yellow powder 1.21. The XRPD pattern is shown in Figure 1. The DSC spectrum is shown in Figure 2.
实施例 6龙胆酸达泊西汀晶体的制备  Example 6 Preparation of crystals of dapoxetine gentisate
称取 916 mg达泊西汀和 475 mg龙胆酸于容器中， 加入 15 ml异丙醇， 搅拌至固体完全溶解， 滤去不溶物， 室温下搅拌 2 h， 有沉淀析出， 降温至 5 °C， 过滤、 真空干燥后得淡黄色粉末 1.12 g。 其 XRPD图谱见图 1， 其 DSC 图谱见图 2。  Weigh 916 mg of dapoxetine and 475 mg of gentisic acid in a container, add 15 ml of isopropanol, stir until the solid is completely dissolved, filter out insoluble matter, stir at room temperature for 2 h, precipitate out, and cool down to 5 ° C, filtered, vacuum dried to give a pale yellow powder 1.12 g. The XRPD spectrum is shown in Figure 1. The DSC spectrum is shown in Figure 2.
实施例 7龙胆酸达泊西汀晶体的制备  Example 7 Preparation of crystals of dapoxetine gentisate
称取 916 mg达泊西汀和 475 mg龙胆酸于容器中，加入 15 ml二氯甲垸， 搅拌至固体完全溶解， 滤去不溶物， 室温下搅拌 2 h， 有沉淀析出， 降温至 5 °C， 过滤、 真空干燥后得淡黄色粉末 1.28 g。 其 XRPD图谱见图 1， 其 DSC 图谱见图 2。  Weigh 916 mg of dapoxetine and 475 mg of gentisic acid in a container, add 15 ml of dichloromethane, stir until the solid is completely dissolved, filter off the insoluble matter, stir at room temperature for 2 h, precipitate out, and cool down to 5 After filtration at °C, vacuum drying gave 1.28 g of pale yellow powder. The XRPD spectrum is shown in Figure 1. The DSC spectrum is shown in Figure 2.
实施例 8龙胆酸达泊西汀晶体的制备  Example 8 Preparation of Dapoxetine Crystal
称取 916 mg达泊西汀和 475 mg龙胆酸于容器中， 加入 15 ml丙酮， 搅 拌至固体完全溶解，滤去不溶物，室温下搅拌 2 h，有沉淀析出，降温至 5 °C， 过滤、 真空干燥后得淡黄色粉末 1.23 其 XRPD图谱见图 1， 其 DSC图谱 见图 2。  Weigh 916 mg of dapoxetine and 475 mg of gentisic acid in a container, add 15 ml of acetone, stir until the solid is completely dissolved, filter off the insoluble matter, stir at room temperature for 2 h, precipitate out, and cool down to 5 °C. Filtration and vacuum drying gave a pale yellow powder 1.23. The XRPD spectrum is shown in Figure 1. The DSC spectrum is shown in Figure 2.
实施例 9龙胆酸达泊西汀晶体的制备  Example 9 Preparation of crystals of dapoxetine gentisate
称取 916 mg达泊西汀和 475 mg龙胆酸于容器中，加入 15 ml四氢呋喃， 搅拌至固体完全溶解， 滤去不溶物， 室温下搅拌 2 h， 有沉淀析出， 降温至 5 °C， 过滤、 真空干燥后得淡黄色粉末 1.09 g。 其 XRPD图谱见图 1， 其 DSC 图谱见图 2。 Weigh 916 mg of dapoxetine and 475 mg of gentisic acid in a container and add 15 ml of tetrahydrofuran. Stir until the solid is completely dissolved. The insoluble material is filtered off, stirred at room temperature for 2 h, precipitated and precipitated, cooled to 5 ° C, filtered and dried in vacuo to give a pale yellow powder of 1.09 g. Its XRPD spectrum is shown in Figure 1, and its DSC spectrum is shown in Figure 2.
实施例 10 乳清酸达泊西汀晶体的制备  Example 10 Preparation of Dapoxetine Crystals of Orotate
称取 916 mg达泊西汀和 480 mg乳清酸于容器中，加入 15 ml乙酸乙酯， 固体不溶解， 室温下搅拌 2 h， 降温至 5 °C， 过滤、 真空干燥后得白色粉末 513 mg。 其 XRPD图谱见图 3， 其 DSC图谱见图 4。  Weigh 916 mg of dapoxetine and 480 mg of orotic acid in a container, add 15 ml of ethyl acetate, the solid is not dissolved, stir at room temperature for 2 h, cool to 5 ° C, filter, and vacuum dry to obtain white powder 513 Mg. Its XRPD spectrum is shown in Figure 3, and its DSC spectrum is shown in Figure 4.
实施例 11 乙酰水杨酸达泊西汀晶体的制备  Example 11 Preparation of crystals of dapoxetine acetylsalicylate
称取 916 mg达泊西汀和 560 mg乙酰水杨酸于容器中，加入 15 ml丙酮， 固体不溶解， 室温下搅拌 2 h后溶液澄清， 缓慢加入 25 ml石油醚至有沉淀 析出， 降温至 5 °C， 过滤、 真空干燥后得白色粉末 405 mg。 其 XRPD图谱 见图 7， 其 DSC图谱见图 8。  Weigh 916 mg of dapoxetine and 560 mg of acetylsalicylic acid in a container, add 15 ml of acetone, the solid is not dissolved, stir the solution at room temperature for 2 h, then clarify the solution, slowly add 25 ml of petroleum ether to precipitate, and cool down to After filtration at 5 ° C, vacuum drying gave 405 mg of white powder. Its XRPD spectrum is shown in Figure 7, and its DSC spectrum is shown in Figure 8.
实施例 12 达泊西汀的甲磺酸盐的晶体的制备  Example 12 Preparation of Crystals of Mesylate Salt of Dapoxetine
称取 916 mg达泊西汀于容器中， 加入 10 ml乙酸乙酯， 搅拌至固体完 全溶解， 滤去不溶物， 再加入 204 μΐ甲垸磺酸 （98% ) , 室温下搅拌 2 h， 有 沉淀析出， 过滤、 真空干燥后得白色粉末 1.09 g (产率 91%)。 其 XRPD图 谱见图 9， DSC图谱见图 10。 其 XRPD图谱中， 辐射源为 CuKon , 在衍射 角度 2Θ值为 6.00、 9.63、 12.03、 14.19、 14.90、 16.25、 16.72、 18.06、 19.19、 19.60、 20.92、 21.30 、 22.26、 23.04、 23.51、 24.52、 25.07、 25.35、 25.76、 26.63、 27.28、 27.75、 28.07、 28.62、 28.90、 29.96、 30.36、 30.74、 31.05、 31.31、 32.08、 32.45、 32.86、 33.54、 33.81、 34.05、 34.70、 35.37、 35.63、 36.24、 36.64、 37.13、 37.44、 37.76、 38.59、 39.24、 40.31、 41.22、 42.66、 43.76处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC图谱在 174± 5 °C有 吸热峰。  Weigh 916 mg of dapoxetine in a container, add 10 ml of ethyl acetate, stir until the solid is completely dissolved, filter out insoluble matter, add 204 μM of formazansulfonic acid (98%), stir at room temperature for 2 h, The precipitate was precipitated, filtered and dried in vacuo to give white powder (yield: 91%). The XRPD spectrum is shown in Figure 9. The DSC spectrum is shown in Figure 10. In its XRPD spectrum, the radiation source is CuKon, and the diffraction angles 2 are 6.00, 9.63, 12.03, 14.19, 14.90, 16.25, 16.72, 18.06, 19.19, 19.60, 20.92, 21.30, 22.26, 23.04, 23.51, 24.52, 25.07, 25.35, 25.76, 26.63, 27.28, 27.75, 28.07, 28.62, 28.90, 29.96, 30.36, 30.74, 31.05, 31.31, 32.08, 32.45, 32.86, 33.54, 33.81, 34.05, 34.70, 35.37, 35.63, 36.24, 36.64, 37.13, There are diffraction peaks at 37.44, 37.76, 38.59, 39.24, 40.31, 41.22, 42.66, and 43.76, where the 2 Θ value error range is ±0.2; and the DSC spectrum has an endothermic peak at 174 ± 5 °C.
实施例 13 达泊西汀的甲磺酸盐的晶体的制备  Example 13 Preparation of Crystals of Mesylate Salt of Dapoxetine
称取 916 mg达泊西汀于容器中， 加入 10 ml四氢呋喃， 搅拌至固体完 全溶解， 滤去不溶物， 再加入 204 μΐ甲垸磺酸 （98% ) , 室温下搅拌 2 h， 有 沉淀析出， 过滤、 真空干燥后得白色粉末 1.03 g (产率 86%)。 其 XRPD图 谱见图 9， DSC图谱见图 10。 其 XRPD图谱中， 辐射源为 CuKon , 在衍射 角度 2Θ值为 6.00、 9.63、 12.03、 14.19、 14.90、 16.25、 16.72、 18.06、 19.19、Weigh 916 mg of dapoxetine in a container, add 10 ml of tetrahydrofuran, stir until solid The solution was completely dissolved, and the insoluble matter was filtered off. Then, 204 μM of formazansulfonic acid (98%) was added thereto, and the mixture was stirred at room temperature for 2 hours to precipitate, which was filtered and dried in vacuo to give white powder (yield: 86%). The XRPD pattern is shown in Figure 9, and the DSC spectrum is shown in Figure 10. In the XRPD spectrum, the radiation source is CuKon, and the diffraction angles 2 are 6.00, 9.63, 12.03, 14.19, 14.90, 16.25, 16.72, 18.06, 19.19,
19.60、 20.92、 21.30 、 22.26、 23.04、 23.51、 24.52、 25.07、 25.35、 25.76、19.60, 20.92, 21.30, 22.26, 23.04, 23.51, 24.52, 25.07, 25.35, 25.76,
26.63、 27.28、 27.75、 28.07、 28.62、 28.90、 29.96、 30.36、 30.74、 31.05、26.63, 27.28, 27.75, 28.07, 28.62, 28.90, 29.96, 30.36, 30.74, 31.05,
31.31、 32.08、 32.45、 32.86、 33.54、 33.81、 34.05、 34.70、 35.37、 35.63、31.31, 32.08, 32.45, 32.86, 33.54, 33.81, 34.05, 34.70, 35.37, 35.63,
36.24、 36.64、 37.13、 37.44、 37.76、 38.59、 39.24、 40.31、 41.22、 42.66、36.24, 36.64, 37.13, 37.44, 37.76, 38.59, 39.24, 40.31, 41.22, 42.66,
43.76处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC图谱在 174± 5 °C有 吸热峰。 There are diffraction peaks at 43.76, where the 2 Θ value error range is ±0.2; and its DSC spectrum has an endothermic peak at 174 ± 5 °C.
实施例 14 达泊西汀的硝酸盐晶体的制备  Example 14 Preparation of nitrate crystals of dapoxetine
称取 916 mg达泊西汀于容器中， 加入 10 ml乙酸乙酯， 搅拌至固体完 全溶解， 滤去不溶物， 再缓慢滴入 138 μΐ硝酸， 室温下搅拌 2 h， 有沉淀析 出， 过滤、 真空干燥后得淡黄色粉末 610 mg (产率 55% ) 。 其 XRPD图谱 见图 11， 其 DSC图谱见图 12。 其 XRPD图谱中， 辐射源为 CuKon , 在衍射 角度 2Θ值为 10.26、 13.03、 13.78、 15.28、 15.95、 16.60、 17.21、 18.46、 19.60、 20.66、 21.16、 22.60、 23.07、 24.89、 25.40、 26.59、 26.78、 27.46、 27.97、 29.33、 30.30、 31.15、 32.22、 32.88、 33.56、 34.47、 34.86、 36.18、 36.44、 37.17、 38.04、 39.02、 39.75、 39.99、 41.20、 41.73、 42.87、 43.17、 44.22、 44.55处有衍射峰， 其中 2Θ值误差范围为 ±0.2; 其 DSC图谱在 142 ± 5 °C有 吸热峰。  Weigh 916 mg of dapoxetine in a container, add 10 ml of ethyl acetate, stir until the solid is completely dissolved, filter out insoluble matter, slowly add 138 μl of nitric acid, stir at room temperature for 2 h, precipitate out, filter, After drying in vacuo, a pale yellow powder (yield: 55%) was obtained. Its XRPD spectrum is shown in Figure 11, and its DSC spectrum is shown in Figure 12. In the XRPD spectrum, the radiation source is CuKon, and the diffraction angles 2 are 10.26, 13.03, 13.78, 15.28, 15.95, 16.60, 17.21, 18.46, 19.60, 20.66, 21.16, 22.60, 23.07, 24.89, 25.40, 26.59, 26.78, 27.46, 27.97, 29.33, 30.30, 31.15, 32.22, 34.86, 36.18, 36.44, 37.17, 38.04, 39.02, 39.75, 39.99, 41.20, 41.73, 42.87, 43.17, 44.22, 44.55 with diffraction peaks, The 2 Θ value error range is ±0.2; its DSC spectrum has an endothermic peak at 142 ± 5 °C.
实施例 15 达泊西汀的氢溴酸盐的晶体的制备  Example 15 Preparation of crystals of hydrobromide salt of dapoxetine
称取 916 mg达泊西汀于容器中， 加入 10 ml乙酸乙酯， 搅拌至固体完 全溶解， 滤去不溶物， 再缓慢滴入 420 μΐ氢溴酸溶液 （40% ) ， 室温下搅拌 2 h， 有沉淀析出， 过滤、 真空干燥后得白色粉末 660 mg (产率 57% ) 。 其 XRPD图谱见图 13，其 DSC图谱见图 14。其 XRPD图谱中，辐射源为 CuKon , 在衍射角度 2Θ值为 6.41、 8.82、 12.84、 13.83、 15.26、 15.77、 16.08、 16.56、Weigh 916 mg of dapoxetine in a container, add 10 ml of ethyl acetate, stir until the solid is completely dissolved, filter out insoluble matter, and slowly drip 420 μΐ hydrobromic acid solution (40%), stir at room temperature for 2 h. , precipitated, filtered, and dried under vacuum to give 660 mg of white powder (yield: 57%). Its XRPD pattern is shown in Figure 13, and its DSC spectrum is shown in Figure 14. In its XRPD spectrum, the radiation source is CuKon. The diffraction angles 2 Θ are 6.41, 8.82, 12.84, 13.83, 15.26, 15.77, 16.08, 16.56,
16.76、 17.00、 17.67、 18.06、 18.51、 19.30、 20.39、 21.00、 21.54、 22.27、16.76, 17.00, 17.67, 18.06, 18.51, 19.30, 20.39, 21.00, 21.54, 22.27,
22.58、 23.08、 23.43、 24.04、 24.95、 25.46、 25.84、 26.79、 27.16、 27.64、22.58, 23.08, 23.43, 24.04, 24.95, 25.46, 25.84, 26.79, 27.16, 27.64,
28.05、 28.33、 29.04、 29.98、 30.38、 31.23、 31.59、 32.21、 32.73、 33.38、28.05, 28.33, 29.04, 29.98, 30.38, 31.23, 31.59, 32.21, 32.73, 33.38,
33.73、 34.50、 35.27、 35.75、 36.28、 37.15、 38.39、 38.72、 39.34、 39.65、33.73, 34.50, 35.27, 35.75, 36.28, 37.15, 38.39, 38.72, 39.34, 39.65,
40.17、 40.60、 41.11、 42.06、 42.50、 43.58处有衍射峰， 其中 2Θ值误差范围 为 ±0.2; 其 DSC图谱在 175 ± 5 °C有吸热峰。 There are diffraction peaks at 40.17, 40.60, 41.11, 42.06, 42.50, and 43.58, where the 2 Θ value error range is ±0.2; and the DSC spectrum has an endothermic peak at 175 ± 5 °C.
实施例 16达泊西汀的马尿酸盐的晶体的制备方法  Example 16 Method for preparing crystals of horse urate of dapoxetine
称取 943 mg达泊西汀和 536 mg马尿酸于容器中，加入 10 ml乙酸乙酯， 固体不溶解， 于 50 °C下搅拌 5 h， 过滤、真空干燥后得白色粉末 520 mg (产 率 36%)。 其 XRPD图谱见图 15， 其 DSC图谱见图 16。 其 XRPD图谱中， 辐射源为 CuKon , 在衍射角度 2Θ值为 12.99、 13.86、 16.21、 16.70、 19.38、 19.94、 21.69、 21.85、 22.23、 23.43、 23.75、 25.72、 26.19、 27.16、 27.99、 28.90、 29.27、 30.54、 31.05、 31.76、 32.20、 32.83、 33.63、 33.89、 34.70、 35.35、 36.12、 36.72、 37.18、 38.04、 39.72、 40.43、 40.86、 41.73、 42.78、 43.92处有衍射峰， 其中 2Θ值误差范围为 ± 0.2; 其 DSC图谱在 190 ± 5 °C 有吸热峰。  Weigh 943 mg of dapoxetine and 536 mg of hippuric acid in a container, add 10 ml of ethyl acetate, dissolve in solids, stir at 50 °C for 5 h, filter and vacuum dry to obtain 520 mg of white powder. 36%). Its XRPD spectrum is shown in Figure 15, and its DSC spectrum is shown in Figure 16. In its XRPD pattern, the radiation source is CuKon, and the diffraction angles 2 are 12.99, 13.86, 16.21, 16.70, 19.38, 19.94, 21.69, 21.85, 22.23, 23.43, 23.75, 25.72, 26.19, 27.16, 27.99, 28.90, 29.27, Diffraction peaks at 30.54, 31.05, 31.76, 32.20, 32.83, 33.63, 33.89, 34.70, 35.35, 36.12, 36.72, 37.18, 38.04, 39.72, 40.43, 40.86, 41.73, 42.78, 43.92, where the range of 2 误差 error is ± 0.2 Its DSC spectrum has an endothermic peak at 190 ± 5 °C.
实施例 17达泊西汀的 1,5-萘二磺酸盐的晶体的制备方法  Example 17 Method for preparing crystals of 1,5-naphthalenedisulfonate of dapoxetine
称取 943 mg达泊西汀和 1.103 gl,5-萘二磺酸于容器中，加入 10 ml乙酸 乙酯， 固体不溶解， 室温下搅拌 5 h， 过滤、 真空干燥后得白色粉末 1.492 g (产率 75%)。 其 XRPD图谱见图 17， 其 DSC图谱见图 18。， 其 XRPD图 谱中，辐射源为 CuKai ,在衍射角度 2Θ值为 8.23、 9.69、 10.15、 11.08、 11.47、 Weigh 943 mg of dapoxetine and 1.103 gl, 5-naphthalenedisulfonic acid in a container, add 10 ml of ethyl acetate, the solid is insoluble, stir at room temperature for 5 h, filter and vacuum dry to obtain white powder 1.92 g ( Yield 75%). Its XRPD spectrum is shown in Figure 17, and its DSC spectrum is shown in Figure 18. In the XRPD spectrum, the radiation source is CuKai, and the diffraction angles 2 are 8.23, 9.69, 10.15, 11.08, 11.47.
12.29、 12.55、 13.09、 13.84、 14.61、 15.59、 15.81、 16.15、 16.54、 16.70、12.29, 12.55, 13.09, 13.84, 14.61, 15.59, 15.81, 16.15, 16.54, 16.70,
18.34、 18.73、 19.42、 20.37、 21.04、 21.24、 21.60、 22.05、 22.96、 23.23、18.34, 18.73, 19.42, 20.37, 21.04, 21.24, 21.60, 22.05, 22.96, 23.23,
23.57、 23.75、 24.45、 24.91、 25.23、 25.72、 26.92、 27.24、 27.73、 28.40、23.57, 23.75, 24.45, 24.91, 25.23, 25.72, 26.92, 27.24, 27.73, 28.40,
28.94、 29.47、 29.97、 30.54、 30.81、 31.80、 32.33、 33.00、 33.40、 33.71、 34.45、 34.84、 35.18、 35.91、 36.20、 36.75、 37.86、 39.44、 39.83、 40.05、 42.79处有衍射峰， 其中 2Θ值误差范围为 ± 0.2; 其 DSC图谱在 106± 5 °C 有吸热峰。 28.94, 29.47, 29.97, 30.54, 30.81, 31.80, 32.33, 33.00, 33.40, 33.71 34.45, 34.84, 35.18, 35.91, 36.20, 36.75, 37.86, 39.44, 39.83, 40.05, 42.79 have diffraction peaks, of which the range of 2 误差 error is ± 0.2; the DSC spectrum has an endothermic peak at 106 ± 5 °C.
实施例 18达泊西汀的 1,5-萘二磺酸盐的晶体的制备方法  Example 18 Method for preparing crystals of 1,5-naphthalene disulfonate of dapoxetine
称取 943 mg达泊西汀和 1.103 gl,5-萘二磺酸于容器中，加入 10 ml四氢 呋喃， 固体不溶解， 室温下搅拌 5 h， 过滤、 真空干燥后得白色粉末 1.52 g (产率 75%)。 其 XRPD图谱见图 17， 其 DSC图谱见图 18。， 其 XRPD图 谱中，辐射源为 CuKon ,在衍射角度 2Θ值为 8.23、 9.69、 10.15、 11.08、 11.47、 Weigh 943 mg of dapoxetine and 1.103 gl, 5-naphthalenedisulfonic acid in a container, add 10 ml of tetrahydrofuran, the solid is not dissolved, stir at room temperature for 5 h, filter and vacuum dry to obtain 1.52 g of white powder. 75%). Its XRPD spectrum is shown in Figure 17, and its DSC spectrum is shown in Figure 18. In the XRPD spectrum, the radiation source is CuKon, and the diffraction angles 2 are 8.23, 9.69, 10.15, 11.08, 11.47.
12.29、 12.55、 13.09、 13.84、 14.61、 15.59、 15.81、 16.15、 16.54、 16.70、12.29, 12.55, 13.09, 13.84, 14.61, 15.59, 15.81, 16.15, 16.54, 16.70,
18.34、 18.73、 19.42、 20.37、 21.04、 21.24、 21.60、 22.05、 22.96、 23.23、18.34, 18.73, 19.42, 20.37, 21.04, 21.24, 21.60, 22.05, 22.96, 23.23,
23.57、 23.75、 24.45、 24.91、 25.23、 25.72、 26.92、 27.24、 27.73、 28.40、23.57, 23.75, 24.45, 24.91, 25.23, 25.72, 26.92, 27.24, 27.73, 28.40,
28.94、 29.47、 29.97、 30.54、 30.81、 31.80、 32.33、 33.00、 33.40、 33.71、28.94, 29.47, 29.97, 30.54, 30.81, 31.80, 32.33, 33.00, 33.40, 33.71
34.45、 34.84、 35.18、 35.91、 36.20、 36.75、 37.86、 39.44、 39.83、 40.05、34.45, 34.84, 35.18, 35.91, 36.20, 36.75, 37.86, 39.44, 39.83, 40.05,
42.79处有衍射峰， 其中 2Θ值误差范围为 ± 0.2; 其 DSC图谱在 106 ± 5 °C 有吸热峰。 There are diffraction peaks at 42.79, where the 2 Θ value error range is ± 0.2; the DSC spectrum has an endothermic peak at 106 ± 5 °C.
效果实施例 1 本发明的晶体及达泊西汀游离碱在水中的溶解度测试、 对比实验  Effect Example 1 Solubility test and comparative experiment of crystal of the present invention and dapoxetine free base in water
配制浓度分别为 5 g/ml、 25g/ml、 50g/ml、 lOOg/mK 150g/ml、 200g/ml 的达泊西汀标准品通过 HPLC检测， 以达泊西汀色谱峰面积对浓度作图绘制 标准曲线， 所得标准曲线方程为： A = 8.43xl04 C + 5.97xl04 (A为色谱峰面 积， C为浓度）。 The dapoxetine standards were prepared at concentrations of 5 g/ml, 25 g/ml, 50 g/ml, 100 g/mK 150 g/ml, and 200 g/ml, respectively, by HPLC, and the peak area of dapoxetine was plotted against the concentration. Draw a standard curve and the resulting standard curve equation is: A = 8.43xl0 4 C + 5.97xl0 4 (A is the peak area of the chromatogram and C is the concentration).
将待测样品制成过饱和水溶液或悬浮液， 置 25 °C摇床震荡 12小时后， 置超声仪中超声 30 s， 过滤， 稀释适当的倍数， 进行 HPLC分析， 所得的达 泊西汀色谱峰面积代入标准曲线方程， 计算得到对应样品的浓度， 再根据样 品的分子量换算为以达泊西汀计的该样品的溶解度。  The sample to be tested is made into a supersaturated aqueous solution or suspension, shaken at 25 °C for 12 hours, placed in a sonicator for 30 s, filtered, diluted by appropriate multiples, HPLC analysis, and the obtained dapoxetine chromatography The peak area is substituted into the standard curve equation, and the concentration of the corresponding sample is calculated, and then converted to the solubility of the sample based on dapoxetine according to the molecular weight of the sample.
结果如下： 在水中的溶解度 （以达泊西汀计） 分别为约 0.18 mg/ml (实施例 1得到 的龙胆酸达泊西汀晶体）、 5.72 mg/ml (实施例 2得到的乳清酸达泊西汀晶 体）、 1.18 mg/ml (实施例 3得到的环拉酸达泊西汀晶体）、 0.24 mg/ml (实施 例 4 得到的乙酰水杨酸达泊西汀晶体）， 均优于达泊西汀游离碱的溶解度 (0.006 mg/ml ) o The results are as follows: The solubility in water (calculated as dapoxetine) was about 0.18 mg/ml (the dapoxetine crystal of gentisate obtained in Example 1), 5.72 mg/ml (the whey acid obtained in Example 2) Xiting crystal), 1.18 mg/ml (the crystal of dapoxetine cyclamate obtained in Example 3), 0.24 mg/ml (the crystal of dapoxetine acetylsalicylate obtained in Example 4), all superior to The solubility of posidine free base (0.006 mg/ml) o
效果实施例 2 本发明的晶体的温度稳定性试验  Effect Example 2 Temperature stability test of the crystal of the present invention
将样品置于 80°C烘箱内， 一周后将样品取出进行 DSC、 XRPD测试， 以考察样品对温度的晶型稳定性。 实验结果表明： 在考察的条件下， 实施例 1得到的达泊西汀的龙胆酸盐晶体、 实施例 2得到的达泊西汀的乳清酸盐晶 体、 实施例 4得到的达泊西汀的乙酰水杨酸盐晶体的谱图均未发生变化， 表 明其晶型热稳定性较好。  The sample was placed in an oven at 80 ° C. After one week, the sample was taken out for DSC and XRPD tests to examine the crystal stability of the sample to temperature. The experimental results show that the gentisate crystal of dapoxetine obtained in Example 1, the orotate crystal of dapoxetine obtained in Example 2, and the Dapoxi obtained in Example 4 under the conditions examined. The spectrum of the acetyl salicylate crystal of Ting has not changed, indicating that its crystal form has good thermal stability.
效果实施例 3本发明的晶体的恒温恒湿稳定性试验  Effect Example 3 Constant temperature and humidity stability test of the crystal of the present invention
将样品置于 40V， 75% RH恒温恒湿箱内，一周后将样品取出进行 DSC、 XRPD测试， 以考察样品对湿度的晶型稳定性。 实验结果表明： 实施例 1得 到的达泊西汀的龙胆酸盐晶体、 实施例 3得到的达泊西汀的环拉酸盐晶体、 实施例 4得到的乙酰水杨酸盐晶体的谱图均未发生变化，表明其晶型湿度稳 定性较好。  The sample was placed in a 40V, 75% RH constant temperature and humidity chamber. After one week, the sample was taken out for DSC and XRPD tests to examine the crystal stability of the sample against humidity. The experimental results show the spectrum of the gentisate crystal of dapoxetine obtained in Example 1, the ruthenium salt crystal of dapoxetine obtained in Example 3, and the crystal of the acetyl salicylate crystal obtained in Example 4. No change occurred, indicating that the crystal form has good humidity stability.
效果实施例 4本发明的晶体的吸湿性考察试验  Effect Example 4 The hygroscopicity test of the crystal of the present invention
将样品置于 40°C， 75% RH恒温恒湿箱内，一周后将样品取出进行 TGA 测试， 以考察样品的吸湿性。 实验结果表明： 实施例 1得到的达泊西汀的龙 胆酸盐晶体、 实施例 3得到的达泊西汀的环拉酸盐晶体、 实施例 4得到的乙 酰水杨酸盐晶体的吸湿增重均小于 0.2% , 表明其在该条件下均不吸湿。  The sample was placed in a 45% RH constant temperature and humidity chamber at 40 ° C. After one week, the sample was taken out for TGA testing to examine the hygroscopicity of the sample. The experimental results show that: the gentisate crystal of dapoxetine obtained in Example 1, the ruthenium salt crystal of dapoxetine obtained in Example 3, and the hygroscopic increase of the acetyl salicylate crystal obtained in Example 4. The weight average is less than 0.2%, indicating that it does not absorb moisture under the conditions.
效果实施例 5本发明的晶体及达泊西汀游离碱在水中的溶解度测试、对 比实验  Effect Example 5 Solubility test and contrast test of crystal of the present invention and dapoxetine free base in water
配制浓度分别为 5 g/ml、 25 g/ml、 50 g/ml、 100 g/ml、 150 g/ml、 200 g/ml的达泊西汀标准品通过 HPLC检测， 以达泊西汀色谱峰面积对浓 度作图绘制标准曲线， 所得标准曲线方程为： A= 6.33X 104C- 6.99X104 (A 为色谱峰面积， C为浓度。 Dapexidine standards were prepared at concentrations of 5 g/ml, 25 g/ml, 50 g/ml, 100 g/ml, 150 g/ml, 200 g/ml, respectively, by HPLC, with dapoxetine chromatography Peak area to thick The standard curve is plotted and the resulting standard curve equation is: A = 6.33X 10 4 C- 6.99X10 4 (A is the chromatographic peak area and C is the concentration.
将待测样品制成过饱和水溶液或悬浮液， 搅拌 12小时后， 过滤， 稀释 适当的倍数， 进行 HPLC分析， 所得的达泊西汀色谱峰面积代入标准曲线方 程， 计算得到对应样品的浓度， 再根据样品的分子量换算为以达泊西汀计的 该样品的溶解度。  The sample to be tested is made into a supersaturated aqueous solution or suspension, stirred for 12 hours, filtered, diluted by appropriate multiples, and subjected to HPLC analysis. The obtained dapoxetine peak area is substituted into the standard curve equation, and the concentration of the corresponding sample is calculated. The solubility of the sample in terms of dapoxetine was then converted to the molecular weight of the sample.
结果如下：  The results are as follows:
在水中的溶解度（以达泊西汀计）分别为约 267mg/ml (实施例 12制得 的甲磺酸达泊西汀）、 2.61 mg/ml (实施例 14制得的硝酸达泊西汀）、 3.52 mg/ml (实施例 15制得的氢溴酸达泊西汀）， 均优于达泊西汀游离碱的溶解 度 （0.00254 mg/ml )。  The solubility in water (in dapoxetine) was about 267 mg/ml (dapoxetine mesylate prepared in Example 12), 2.61 mg/ml (dapoxetine nitrate prepared in Example 14). ), 3.52 mg/ml (dapoxetine hydrobromide prepared in Example 15), both superior to the solubility of dapoxetine free base (0.00254 mg/ml).
效果实施例 6本发明的晶体及达泊西汀游离碱在水中的溶解度测试、 对比实验  Effect Example 6 Solubility Test and Comparative Experiment of Crystal of the Invention and Dapoxetine Free Base in Water
配制浓度分别为 5 g/ml、 25 g/ml、 50 g/ml、 100 g/ml、 150 g/ml、 200 g/ml的达泊西汀标准品通过 HPLC检测， 以达泊西汀色谱峰面积对浓 度作图绘制标准曲线， 所得标准曲线方程为： A = 6.33X 104C- 6.99X104 (A 为色谱峰面积， C为浓度。 Dapexidine standards were prepared at concentrations of 5 g/ml, 25 g/ml, 50 g/ml, 100 g/ml, 150 g/ml, 200 g/ml, respectively, by HPLC, with dapoxetine chromatography The peak area is plotted against the concentration. The resulting standard curve equation is: A = 6.33X 10 4 C- 6.99X10 4 (A is the chromatographic peak area and C is the concentration.
将待测样品制成过饱和水溶液或悬浮液， 搅拌 12小时后， 过滤， 稀释 适当的倍数， 进行 HPLC分析， 所得的达泊西汀色谱峰面积代入标准曲线方 程， 计算得到对应样品的浓度， 再根据样品的分子量换算为以达泊西汀计的 该样品的溶解度。  The sample to be tested is made into a supersaturated aqueous solution or suspension, stirred for 12 hours, filtered, diluted by appropriate multiples, and subjected to HPLC analysis. The obtained dapoxetine peak area is substituted into the standard curve equation, and the concentration of the corresponding sample is calculated. The solubility of the sample in terms of dapoxetine was then converted to the molecular weight of the sample.
结果如下：  The results are as follows:
在水中的溶解度 （以达泊西汀计） 分别为约 0.0158 mg/ml (实施例 16 制得的马尿酸达泊西汀）、 0.0122 mg/ml (实施例 17制得的 1,5-萘二磺酸达 泊西汀）， 均优于达泊西汀游离碱的溶解度 （0.00254 mg/ml )。  The solubility in water (as dapoxetine) was about 0.0158 mg/ml (dapoxetine fumarate prepared in Example 16), 0.0122 mg/ml (1,5-naphthalene prepared in Example 17). Dapoxetine disulfate) is superior to the solubility of dapoxetine free base (0.00254 mg/ml).
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理 解， 这些仅是举例说明， 在不背离本发明的原理和实质的前提下， 可以对这 些实施方式做出多种变更或修改。 因此， 本发明的保护范围由所附权利要求 书限定。 Although the specific embodiments of the present invention have been described above, those skilled in the art should The present invention is to be considered as illustrative only, and various changes and modifications may be made to these embodiments without departing from the spirit and scope of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims

1、一种达泊西汀的甲磺酸盐的晶体，其 XRPD图谱中，辐射源为 CuKon , 在衍射角度 2Θ值为 6.00、 9.63、 12.03、 14.19、 14.90、 16.25、 16.72、 18.06、 19.19、 19.60、 20.92、 21.30 、 22.26、 23.04、 23.51、 24.52、 25.07、 25.35、 25.76、 26.63、 27.28、 27.75、 28.07、 28.62、 28.90、 29.96、 30.36、 30.74、 31.05、 31.31、 32.08、 32.45、 32.86、 33.54、 33.81、 34.05、 34.70、 35.37、 35.63、 36.24、 36.64、 37.13、 37.44、 37.76、 38.59、 39.24、 40.31、 41.22、 42.66、 43.76处有衍射峰， 其中 2Θ值误差范围为 ±0.2 ; 其 DSC图谱在 174 ± 5 °C有吸热峰。 1. A crystal of mesylate salt of dapoxetine. In the XRPD pattern, the radiation source is CuKon, and the diffraction angles 2 are 6.00, 9.63, 12.03, 14.19, 14.90, 16.25, 16.72, 18.06, 19.19, 19.60, 20.92, 21.30, 22.26, 23.04, 23.51, 25.56, 26.63, 25.28, 27.75, 28.07, 28.62, 28.90, 29.96, 30.36, 30.74, 31.05, 31.31, 32.08, 32.45, 32.86, 33.54, 33.81, 34.05, 34.70, 35.37, 35.63, 36.24, 36.64, 37.13, 37.44, 37.76, 38.59, 39.24, 40.31, 41.22, 42.66, 43.76 have diffraction peaks, of which 2 误差 value error range is ±0.2; its DSC spectrum is at 174 There is an endothermic peak at ± 5 °C.
2、 如权利要求 1所述的达泊西汀的甲磺酸盐的晶体的制备方法， 其包 含下列步骤： 将达泊西汀溶于有机溶剂中形成的溶液与甲垸磺酸混合， 待有 沉淀析出， 过滤， 即可； 其中， 所述的有机溶剂为 C^Cg垸基醇的醋酸酯和 /或四氢呋喃。  2. A method for preparing crystals of a methanesulfonate salt of dapoxetine according to claim 1, which comprises the steps of: mixing a solution of dapoxetine in an organic solvent with formamidine sulfonic acid, to be Precipitating and filtering, wherein the organic solvent is an acetate of C^Cg mercapto alcohol and/or tetrahydrofuran.
3、 如权利要求 2所述的制备方法， 其特征在于： 所述的制备方法包含 下列步骤：将达泊西汀溶于有机溶剂中，过滤，将甲垸磺酸加入所得滤液中， 搅拌， 待有沉淀析出， 过滤， 即可。  3. The preparation method according to claim 2, wherein the preparation method comprises the steps of: dissolving dapoxetine in an organic solvent, filtering, adding formazansulfonic acid to the obtained filtrate, and stirring. Precipitate and precipitate, and filter.
4、 如权利要求 2或 3所述的制备方法， 其特征在于： 所述的 d C ^ 基醇的醋酸酯为乙酸乙酯和 /或乙酸异丙酯。  The process according to claim 2 or 3, wherein the acetate of the d C ^ -based alcohol is ethyl acetate and/or isopropyl acetate.
5、 如权利要求 2或 3所述的制备方法， 其特征在于： 所述的有机溶剂 与达泊西汀的体积质量比为 7ml/g~12ml/g。  The method according to claim 2 or 3, wherein the volume ratio of the organic solvent to dapoxetine is from 7 ml/g to 12 ml/g.
6、 如权利要求 2或 3所述的制备方法， 其特征在于： 所述的制备方法 中， 使所述沉淀析出的环境温度为 0~35 °C。  The preparation method according to claim 2 or 3, wherein in the preparation method, the ambient temperature at which the precipitate is precipitated is 0 to 35 °C.
7、 如权利要求 2或 3所述的制备方法， 其特征在于： 所述的甲垸磺酸 与达泊西汀的摩尔比为 1 : 1~1.03: 1。  The preparation method according to claim 2 or 3, wherein the molar ratio of the formazansulfonic acid to dapoxetine is 1:1 to 1.03:1.
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