CN103145569A - Crystal form B of dapoxetine hydrochloride, and preparation method thereof - Google Patents
Crystal form B of dapoxetine hydrochloride, and preparation method thereof Download PDFInfo
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- CN103145569A CN103145569A CN2011103727156A CN201110372715A CN103145569A CN 103145569 A CN103145569 A CN 103145569A CN 2011103727156 A CN2011103727156 A CN 2011103727156A CN 201110372715 A CN201110372715 A CN 201110372715A CN 103145569 A CN103145569 A CN 103145569A
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Abstract
The invention relates to a crystal form B of dapoxetine hydrochloride which is a drug for treating male premature ejaculation, and a preparation method thereof. The crystal form B of dapoxetine hydrochloride is characterized in that the X-ray powder diffraction pattern thereof has corresponding characteristic diffraction peaks at positions of 2[theta] angle values being 9.2 degrees, 14.7 degrees, 16.2 degrees, 16.9 degrees, 18.0 degrees, 21.8 degrees, 23.2 degrees, 24.9 degrees, and 27.1 degrees.
Description
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, be specifically related to a kind of new crystal B that treats prospermia of males medicine dapoxetine hydrochloride and preparation method thereof, the pharmaceutical composition that contains this new crystal, and this crystal formation is for the manufacture of the application in treatment prospermia of males medicine.
Technical background
Dapoxetine hydrochloride (Dapoxetine Hydrochloride), chemical name S-(+)-dapoxetine hydrochloride (S-(+)-N, N-dimethyl-3-(naphthalene-1-yloxy)-1-
Phenylpropan-1-amine Hydrochloride), shown in chemical structural formula following (I), can be prepared by disclosed method in patent EP0288188.
Dapoxetine hydrochloride is a kind of selective serotonin reuptake inhibitor (SSRI), is used for the treatment of adult's prospermia of males and erective dysfunction, is the first medicine that is used for the treatment of this indication in the whole world.Dapoxetine hydrochloride can selectivity suppresses presynaptic neuron to thrombotonin absorptive function again, increases and the thrombotonin level of postsynaptic neuron receptors bind, thereby reaches the effect for the treatment of premature ejaculation.The characteristics such as dapoxetine hydrochloride belongs to fugitive type SSRI, compares with traditional long-acting type SSRI, has drug effect fast, and the transformation period is short, and side effect is low.
The preparation method of dapoxetine hydrochloride is open in the patents such as EP0288188, WO2008035358, US5292962, CN101012147, CN1821212, CN101875666, but its crystal formation and crystal formation preparation method are without bibliographical information.
Dapoxetine hydrochloride generally uses with solid form in preparation, therefore the research tool of its crystal formation is of great significance.The inventor in the research process to the dapoxetine hydrochloride crystal formation, the pleasantly surprised new crystal of preparing another kind of dapoxetine hydrochloride, this stable crystal form is good; purity is high, and the preparation method is simple, is conducive to the operation in its preparation process; be applicable to several formulations, be fit to large-scale production.
Summary of the invention
The object of the present invention is to provide a kind of new crystal of dapoxetine hydrochloride, be suitable for use in the manufacturing of several formulations and the preparation method is simple, industrial applicibility is strong.
For realizing purpose of the present invention, the invention provides a kind of new crystal of dapoxetine hydrochloride, be defined as hydrochloric acid and reach urgent western spit of fland crystal form B.
In one embodiment, the X-ray powder diffraction of dapoxetine hydrochloride crystal form B of the present invention is about the position of 9.2 °, 14.7 °, 16.2 °, 16.9 °, 18.0 °, 21.8 °, 23.2 °, 24.9 °, 27.1 ° to characteristic diffraction peak should be arranged in 2 θ values.
In above-mentioned embodiment, described dapoxetine hydrochloride new crystal B also further is included in 2 θ values and is about the position of 12.5 °, 13.9 °, 15.9 °, 19.8 °, 20.8 °, 21.0 °, 22.4 °, 25.7 °, 27.5 °, 29.0 °, 29.5 °, 29.7 °, 30.0 °, 30.3 °, 31.3 °, 34.1 °, 36.8 ° etc. also to diffraction peak should be arranged.
Dapoxetine hydrochloride new crystal B of the present invention also can have the feature of the X-ray powder diffraction representative as shown in figure one.
Dapoxetine hydrochloride crystal form B of the present invention is a kind of hydrate crystal of dapoxetine hydrochloride.
Preferably, the X-ray powder diffraction of dapoxetine hydrochloride crystal form B of the present invention is about the position of 2.5 °, 9.2 °, 13.9 °, 14.7 °, 15.9 °, 16.2 °, 16.9 °, 18.0 °, 19.8 °, 20.8 °, 21.0 °, 21.8 °, 22.4 °, 23.2 °, 24.9 °, 25.7 °, 27.1 °, 27.5 °, 29.0 °, 29.5 °, 29.7 °, 30.0 °, 30.3 °, 31.3 °, 34.1 °, 36.8 ° to characteristic diffraction peak should be arranged in 2 θ values.
The X-ray powder diffraction test of dapoxetine hydrochloride crystal form B of the present invention is under envrionment temperature and ambient moisture, completes through the CuK α source (α=1.5406) of Japanese Shimadzu XRD-6000 type x-ray diffractometer mensuration." envrionment temperature " is generally 0～40 ℃; " ambient moisture " is generally 30%～80% relative humidity.
The representational X-ray powder diffraction of dapoxetine hydrochloride crystal form B of the present invention is listed in accompanying drawing." representational X-ray powder diffraction " refers to that the X-ray powder diffraction feature of this crystal formation meets the whole pattern that this collection of illustrative plates shows, be understandable that in test process, due to the impact that is subject to many factors, the treatment process of sample, instrument, test parameter, test operation etc. during as the granularity of specimen, test, the X-ray powder diffraction that the same crystal formation is measured go out the peak position or peak intensity has certain difference.Therefore, the X-ray powder diffraction of dapoxetine hydrochloride crystal form B of the present invention, the experimental error of its diffraction peak 2 θ values be generally ± 0.2 °.
Dapoxetine hydrochloride crystal form B of the present invention, its purity comprise more than or equal to 97.5%, 98.0%, 98.5%, 99.0%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% more than or equal to 97.0%.Here said purity is to identify with high performance liquid chromatography (HPLC) percentage area, is to measure with the HPLC area normalization method.The numerical value of purity is through the take off data gained that rounds up.Detection method can adopt: octadecylsilane chemically bonded silica is weighting agent, and the detection wavelength is 210nm, selects suitable mobile mutual-assistance test to satisfy conventional requirement, records color atlas, uses the area normalization method calculated purity.
Dapoxetine hydrochloride crystal form B of the present invention, its optical purity ee value comprises more than or equal to 98.5%, 99.0%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% more than or equal to 98.0%.Here said optical purity is to identify with high performance liquid chromatography (HPLC) percentage area, is to measure with the HPLC area normalization method.The numerical value of purity is through the take off data gained that rounds up.Detection method can adopt: Mierocrystalline cellulose-three (3,5-xylyl carbamate) bonded silica gel is weighting agent, and the detection wavelength is 290nm, selects suitable mobile mutual-assistance test to satisfy conventional requirement, records color atlas, uses the area normalization method calculated purity.
The crystal formation content (mass content) of dapoxetine hydrochloride crystal form B of the present invention generally is equal to or greater than 80%, preferably is equal to or greater than 90%.
Another object of the present invention is to provide the preparation method of dapoxetine hydrochloride crystal form B, the method comprises that the mixed solvent that dapoxetine hydrochloride and water or mixed water-soluble organic solvent and water are formed contacts.Preferably, described " mixed water-soluble organic solvent " comprises one or more in methyl alcohol, ethanol, Virahol, DMF, N,N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide etc.
In one embodiment, the preparation method of dapoxetine hydrochloride crystal form B of the present invention comprises the following steps:
(a) mixed solvent that dapoxetine hydrochloride and water or mixed water-soluble organic solvent and water is formed mixes, and gets paste mixture; Wherein, described " mixed water-soluble organic solvent " comprises one or more in methyl alcohol, ethanol, Virahol, DMF, N,N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide; The mass volume ratio of the mixed solvent that described dapoxetine hydrochloride and water or mixed water-soluble organic solvent and water form is generally 1:0.5 ~ 5;
(b) mixture in step (a) is separated, or further cooling rear separation; Separate mode comprises filtration or centrifugal; Described " further cooling temperature " is generally lower than mixing temperature more than 10 ℃, preferably lower than more than 20 ℃; Described cooling can be static, also can carry out under the condition that stirs;
(c) optional, separating obtained solid is carried out drying.
In another embodiment, the preparation method of dapoxetine hydrochloride crystal form B of the present invention comprises the following steps:
(a) water-soluble or mixed water-soluble organic solvent and the mixed solvent of water composition with dapoxetine hydrochloride; Wherein, described " mixed water-soluble organic solvent " comprises one or more in methyl alcohol, ethanol, Virahol, DMF, N,N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide; The mass volume ratio of the mixed solvent that dapoxetine hydrochloride and water or mixed water-soluble organic solvent and water form is generally 1:1 ~ 15, preferred 1:1 ~ 10;
(b) with the solution cooling crystallization in step (a); The temperature of described crystallization is generally lower than mixing temperature more than 10 ℃, preferably lower than more than 20 ℃; Crystallization can be static, also can carry out under the condition that stirs;
(c) separate, comprise the solid that filtration or centrifugal collection are separated out;
(d) optional, separating obtained solid is carried out drying.
Another purpose of the present invention is to provide with the application of dapoxetine hydrochloride crystal form B for the manufacture for the treatment of prospermia of males, the male sexual dysfunction disease medicines such as postponing, the property requirement is low, organism is constrained of ejaculating.
A further object of the present invention is to provide the pharmaceutical composition of the crystal form B that contains dapoxetine hydrochloride.
In order to realize this purpose, pharmaceutical composition of the present invention contains dapoxetine hydrochloride crystal form B and the pharmaceutical excipient of effective therapeutic dose.Its preparation method is generally that the dapoxetine hydrochloride crystal form B of effective therapeutic dose is mixed or contact with one or more pharmaceutical excipients, and this pharmaceutical composition is that employing mode well known in the art is prepared.Described pharmaceutical excipient is all pharmaceutical excipients of this area routine.
The pharmaceutical composition of the dapoxetine hydrochloride crystal form B of the invention described above, its dosage form comprises: tablet, coating tablet, capsule, pill, granule, solution, syrup, suspensoid, powder, sustained release preparation or controlled release preparation etc.Solid orally ingestibles such as preferred capsule, tablet, granule, drinkable suspensoid wherein, wherein more preferably Tablet and Capsula.Can prepare the preferred pharmaceutical composition of the present invention according to any ordinary method that the preparation solid orally ingestible adopts.Can adopt the modes such as wet granule compression tablet, direct powder compression to prepare as tablet, capsule such as can adopt powder directly encapsulated, wet granulation is encapsulated prepare at the mode.
The pharmaceutical composition of dapoxetine hydrochloride crystal form B of the present invention, described conventional pharmaceutical excipient comprises weighting agent, disintegrating agent, tackiness agent, lubricant etc., and is optional during for tablet, and tablet is carried out dressing.
Described weighting agent generally comprises lactose, micropowder silica gel, Microcrystalline Cellulose, silicon-dioxide, maltodextrin, pregelatinized Starch, starch, N.F,USP MANNITOL, Xylitol, sorbyl alcohol, glucose etc., they can use separately also can mix use, wherein preferred lactose, micropowder silica gel, Microcrystalline Cellulose.
Described disintegrating agent generally comprises croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, starch, polyvinylpyrrolidone, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, agar, calcium carbonate and sodium bicarbonate etc., they can use separately also can mix use, wherein is preferably croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone.
Described tackiness agent generally comprises the ethanolic soln of hydroxypropylcellulose, Microcrystalline Cellulose, Vltra tears, polyvidone, starch slurry, polyvinyl alcohol, alginate, water, various concentration, they can use separately also can mix use, wherein preferred hydroxypropylcellulose, Microcrystalline Cellulose, Vltra tears.
Described lubricant generally comprises calcium stearate, Magnesium Stearate, stearic acid, palmitinic acid, pure aluminium silicate, stearylamide, talcum powder, solid polyethylene glycol.They can use separately also can mix use, wherein preferred calcium stearate, Magnesium Stearate, stearic acid.
If necessary, can also add other suitable active ingredients or other auxiliary materials in pharmaceutical composition of the present invention, as sweeting agent, tinting material, odor mask, stablizer etc.
In sum, dapoxetine hydrochloride crystal form B preparation method of the present invention is easy, has the good advantages such as preparation adaptability, has the industrialization practicality.
Description of drawings
Fig. 1 is the X-ray powder diffraction of dapoxetine hydrochloride crystal form B.
Embodiment
The invention will be further described below in conjunction with embodiment, can make those skilled in the art more fully understand the present invention, but the scope that does not limit the present invention in any way.
Embodiment 1
The preparation of dapoxetine hydrochloride crystal form B.
The 5g dapoxetine hydrochloride is placed in reaction vessel, add 5ml water under stirring, finish, be cooled to 5 ~ 10 ℃ of stir about 30min, filter, the dapoxetine hydrochloride crystal form B, its X-ray powder diffraction is seen figure one, main test data values such as following table (listing relative intensity more than or equal to 5% test data).
| 2 θ angles (°) measured value | D() measured value | Relative intensity (%) |
| 9.17060 | 9.63559 | 35 |
| 12.5068 | 7.07178 | 8 |
| 13.8561 | 6.38602 | 6 |
| 14.6749 | 6.03150 | 35 |
| 15.8904 | 5.57276 | 9 |
| 16.2194 | 5.46045 | 19 |
| 16.8657 | 5.25264 | 17 |
| 17.9705 | 4.93212 | 24 |
| 19.8103 | 4.47803 | 14 |
| 20.7525 | 4.27680 | 8 |
| 21.0175 | 4.22347 | 7 |
| 21.8331 | 4.06750 | 100 |
| 22.4313 | 3.96036 | 6 |
| 23.1739 | 3.83511 | 18 |
| 24.9375 | 3.56774 | 17 |
| 25.6766 | 3.46669 | 9 |
| 27.0515 | 3.29354 | 20 |
| 27.5391 | 3.23632 | 8 |
| 28.9919 | 3.07736 | 10 |
| 29.4600 | 3.02952 | 11 |
| 29.6600 | 300955 | 11 |
| 29.9802 | 2.97813 | 12 |
| 30.3000 | 2.94742 | 6 |
| 31.3497 | 2.85108 | 8 |
| 34.1295 | 2.62496 | 11 |
| 36.7788 | 2.44173 | 5 |
Embodiment 2
The preparation of dapoxetine hydrochloride crystal form B
The 3g dapoxetine hydrochloride is placed in reaction vessel, adds 6ml 20% isopropanol water solution under stirring, finish, stirring at room is 50min approximately, filters, and gets the dapoxetine hydrochloride crystal form B, and the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 3
The preparation of dapoxetine hydrochloride crystal form B
The 6g dapoxetine hydrochloride is placed in reaction vessel, adds 24ml 40% tetrahydrofuran aqueous solution under stirring, finish, standingly be cooled to 0 ~ 5 ℃ of approximately 1.5h, filter, get the dapoxetine hydrochloride crystal form B, the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 4
The preparation of dapoxetine hydrochloride crystal form B
Under stirring, the 3.5g dapoxetine hydrochloride is slowly added in the methanol aqueous solution of 5ml 10%, be cooled to 10 ~ 15 ℃ and continue stir about 45min, filter, get the dapoxetine hydrochloride crystal form B, the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 5
The preparation of dapoxetine hydrochloride crystal form B
The 4g dapoxetine hydrochloride is dissolved in the 10ml 15% DMF aqueous solution, is heated to 80 ℃ of dissolving clarifications, be cooled to 5 ~ 10 ℃, stirring and crystallizing is 2h approximately, filters, get the dapoxetine hydrochloride crystal form B, the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 6
The preparation of dapoxetine hydrochloride crystal form B
The 3g dapoxetine hydrochloride is dissolved in the aqueous acetone solution of 20ml 60%, the dissolving clarification that is heated to reflux is cooled to room temperature, and stirring and crystallizing is 2h approximately, filters, and gets the dapoxetine hydrochloride crystal form B, and the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 7
The preparation of dapoxetine hydrochloride crystal form B
The 2g dapoxetine hydrochloride is dissolved in 6ml 30% acetonitrile solution, and the dissolving clarification that is heated to reflux is cooled to 0 ~ 5 ℃, and standing crystallization is 1.5h approximately, filters, and gets the dapoxetine hydrochloride crystal form B, and the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 8
Dapoxetine hydrochloride crystal form B pharmaceutical composition
The prescription of 1000 tablets of tablets of preparation, every dosage that contains 60mg:
The dapoxetine hydrochloride crystal form B ... 60g
Lactose ... 155g
Hydroxypropylcellulose ... 8g
Microcrystalline Cellulose ... 35g
Calcium stearate ... 1.4g
Micropowder silica gel ... 2.8g
Croscarmellose sodium ... 9.5g
Above-mentioned prescription is namely got dapoxetine hydrochloride crystal form B sheet by preparation method's film-making of tablet well known to those skilled in the art.
The front has been described the present invention in detail, comprises its preferred embodiment.But, should be understood that and consider content disclosed by the invention, those skilled in the art can change the present invention in essential scope of the present invention and/or improve, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (5)
1. dapoxetine hydrochloride crystal form B is characterized in that: its X-ray powder diffraction is that the position of 9.2 °, 14.7 °, 16.2 °, 16.9 °, 18.0 °, 21.8 °, 23.2 °, 24.9 °, 27.1 ° is to there being characteristic diffraction peak in 2 θ values.
2. the preparation method of a dapoxetine hydrochloride crystal form B is characterized in that the mixed solvent that dapoxetine hydrochloride and water or mixed water-soluble organic solvent and water form is contacted.
3. method as claimed in claim 2, wherein mixed water-soluble organic solvent is selected from one or more in methyl alcohol, ethanol, Virahol, DMF, N,N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide etc.
4. pharmaceutical composition comprises and reaches hydrochloric acid Bo Xi spit of fland crystal form B and pharmaceutical excipient.
The dapoxetine hydrochloride crystal form B postpone for the manufacture for the treatment of prospermia of males, ejaculation, the property requirement is low, the application of organism in being subjected to constrain disease medicament.
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| CN2011103727156A CN103145569A (en) | 2011-11-22 | 2011-11-22 | Crystal form B of dapoxetine hydrochloride, and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104906069A (en) * | 2015-05-26 | 2015-09-16 | 苗怡文 | Medicinal ranitidine hydrochloride composition capsule for treating gastric ulcer |
| CN106389360A (en) * | 2015-07-31 | 2017-02-15 | 重庆华邦制药有限公司 | Directly-compressed tablet of dapoxetine hydrochloride and preparation method thereof |
| CN108264465A (en) * | 2016-12-30 | 2018-07-10 | 苏州科伦药物研究有限公司 | Dapoxetine hydrochloride monohydrate and its preparation method and application |
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN113456606A (en) * | 2020-03-30 | 2021-10-01 | 北京新领先医药科技发展有限公司 | Preparation method of dapoxetine hydrochloride tablet |
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| CN1821212A (en) * | 2006-03-15 | 2006-08-23 | 上海玛耀化学技术有限公司 | Synthetic method for dapoxetine |
| WO2008035358A2 (en) * | 2006-06-05 | 2008-03-27 | Cadila Healthcare Limited | Process for preparing dapoxetine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104906069A (en) * | 2015-05-26 | 2015-09-16 | 苗怡文 | Medicinal ranitidine hydrochloride composition capsule for treating gastric ulcer |
| CN106389360A (en) * | 2015-07-31 | 2017-02-15 | 重庆华邦制药有限公司 | Directly-compressed tablet of dapoxetine hydrochloride and preparation method thereof |
| CN108264465A (en) * | 2016-12-30 | 2018-07-10 | 苏州科伦药物研究有限公司 | Dapoxetine hydrochloride monohydrate and its preparation method and application |
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN110903203B (en) * | 2018-09-14 | 2022-11-18 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN113456606A (en) * | 2020-03-30 | 2021-10-01 | 北京新领先医药科技发展有限公司 | Preparation method of dapoxetine hydrochloride tablet |
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Application publication date: 20130612 |