CN103130658A - Dapoxetine hydrochlorate crystal form A and preparation method thereof - Google Patents
Dapoxetine hydrochlorate crystal form A and preparation method thereof Download PDFInfo
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- CN103130658A CN103130658A CN2011103722716A CN201110372271A CN103130658A CN 103130658 A CN103130658 A CN 103130658A CN 2011103722716 A CN2011103722716 A CN 2011103722716A CN 201110372271 A CN201110372271 A CN 201110372271A CN 103130658 A CN103130658 A CN 103130658A
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Abstract
The invention relates to a crystal form A of dapoxetine hydrochlorate which is a drug for treating male premature ejaculation, and a preparation method thereof; the crystal form A is characterized in that the crystal form A has characteristic diffraction peaks corresponding to positions with 2theta values of about 8.9 degrees, 14.4 degrees, 15.1 degrees, 16.3 degrees, 16.6 degrees, 18.9 degrees, 20.7 degrees, 22.7 degrees, 23.8 degrees, 25.3 degrees, 29.0 degrees, and 29.5 degrees on an X-ray powder diffraction pattern, and the new crystal form has the characteristics of high purity, good stability, and the like.
Description
Technical field:
The present invention relates to organic chemistry filed and pharmaceutical field, be specifically related to a kind of new crystal A that treats prospermia of males medicine dapoxetine hydrochloride and preparation method thereof, the pharmaceutical composition that contains this new crystal, and this new crystal 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 a 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, this stable crystal form, be suitable for use in 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 A.
In one embodiment, the X-ray powder diffraction of dapoxetine hydrochloride crystal form A of the present invention is about the position of 8.9 °, 14.4 °, 15.1 °, 16.3 °, 16.6 °, 18.9 °, 20.7 °, 22.7 °, 23.8 °, 25.3 °, 29.0 °, 29.5 ° to characteristic diffraction peak should be arranged in 2 θ values.
Further, in above-mentioned embodiment, be about the position of 16.9 °, 17.8 °, 19.3 °, 21.2 °, 21.8 °, 26.7 °, 27.8 °, 31.2 °, 33.0 °, 33.6 °, 35.2 °, 36.0 °, 38.8 ° etc. also to diffraction peak should be arranged in 2 θ values.
Further, above-mentioned dapoxetine hydrochloride crystal form A also can have the feature of X-ray powder diffraction representative as shown in Figure 1.
Preferably, the X-ray powder diffraction of dapoxetine hydrochloride crystal form A of the present invention is about the position of 8.9 °, 14.4 °, 15.1 °, 16.3 °, 16.6 °, 16.9 °, 17.8 °, 18.9 °, 19.3 °, 20.7 °, 21.2 °, 21.8 °, 22.7 °, 23.8 °, 25.3 °, 26.7 °, 27.8 °, 29.0 °, 29.5 °, 31.2 °, 33.0 °, 33.6 °, 35.2 °, 36.0 °, 38.8 ° to characteristic diffraction peak should be arranged in 2 θ values.
The X-ray powder diffraction test of dapoxetine hydrochloride crystal form A 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 A of the present invention is listed in accompanying drawing 1." 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 A of the present invention, the experimental error of its diffraction peak 2 θ values be generally ± 0.2 °.
Dapoxetine hydrochloride crystal form A 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 A 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 A 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 a kind of preparation method of dapoxetine hydrochloride crystal form A, the method comprises dapoxetine hydrochloride is dissolved in hydrophilic organic solvent, then mixes crystallization with lower boiling lipotropy organic solvent.
Described hydrophilic organic solvent is selected from alcohols, amides, ketone, nitrile, ethers, sulfone class etc. or their mixture.Wherein, alcohols particular methanol, ethanol, Virahol, ethylene glycol etc.; The preferred DMF of amides (DMF), N,N-dimethylacetamide (DMAC), N-Methyl pyrrolidone etc.; The preferred acetone of ketone etc.; The preferred acetonitrile of nitrile etc.; The preferred tetrahydrofuran (THF) of ethers, Isosorbide-5-Nitrae-dioxane etc.; The preferred methyl-sulphoxide of sulfone class etc.
Described lower boiling lipotropy organic solvent is selected from hydro carbons, ethers, ester class etc. or their mixture.Wherein, the preferred sherwood oil of hydro carbons, Skellysolve A, normal hexane, hexanaphthene etc.; The preferred ether of ethers, isopropyl ether, methyl tertiary butyl ether etc.; The preferred methyl acetate of ester class, ethyl acetate etc.
In one embodiment, the preparation method of dapoxetine hydrochloride crystal form A of the present invention comprises the following steps:
(a) dapoxetine hydrochloride (comprising dry product or wet product) is dissolved in hydrophilic organic solvent, this hydrophilic organic solvent is selected from methyl alcohol, ethanol, Virahol, ethylene glycol, N, dinethylformamide, N, in N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or methyl-sulphoxide one or more;
(b) gained solution is mixed with lower boiling lipotropy organic solvent, this lower boiling lipotropy organic solvent is selected from one or more in sherwood oil, Skellysolve A, normal hexane, hexanaphthene, ether, isopropyl ether, methyl tertiary butyl ether, methyl acetate or ethyl acetate;
(c) crystallization, the terminal temperature general control of crystallization are at crystallization below 50 ℃, and preferred below 30 ℃, crystallization can be standing, also can stir;
(d) separate, comprise the solid that filtration or centrifugal collection are separated out;
(e) optional, the solid that separates is carried out drying, drying temperature is generally 20～100 ℃, preferred 25～80 ℃; Can constant pressure and dry, also can drying under reduced pressure, during decompression, vacuum tightness is generally 300～760mmHg, preferred 600～760mmHg.
In above-mentioned specific embodiments step (a), optional after hydrophilic organic solvent dissolving dapoxetine hydrochloride, solution is filtered.
In above-mentioned specific embodiments step (b), the hybrid mode of the dapoxetine hydrochloride solution of step (a) gained or filtrate and lower boiling lipotropy organic solvent comprises dapoxetine hydrochloride solution or filtrate is added in lower boiling lipotropy organic solvent, or lower boiling lipotropy organic solvent is added in dapoxetine hydrochloride solution or filtrate.
In above-mentioned specific embodiments step (c), the terminal temperature of crystallization refers to that crystallization finishes, the temperature of the crystallization system before the gained crystal is prepared to separate.
Another purpose of the present invention is to provide with the application of dapoxetine hydrochloride crystal form A 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 that contains the dapoxetine hydrochloride crystal form A.
In order to realize this purpose, the invention provides a kind of pharmaceutical composition, contain dapoxetine hydrochloride crystal form A and the pharmaceutical excipient of effective therapeutic dose.Its preparation method is generally that the dapoxetine hydrochloride crystal form A of effective therapeutic dose is mixed or contacts with one or more pharmaceutical excipients
, this drug regimenThing is to adopt mode well known in the art to be prepared.Described pharmaceutical excipient is all pharmaceutical excipients of this area routine.
The pharmaceutical composition of the dapoxetine hydrochloride crystal form A 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 A 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 silicon-dioxide, pregelatinized Starch, starch, lactose, maltodextrin, N.F,USP MANNITOL, Microcrystalline Cellulose, Xylitol, sorbyl alcohol, glucose, micropowder silica gel etc., they can use separately also can mix use, wherein preferred silicon-dioxide, pregelatinized Starch, starch, lactose.
Described disintegrating agent generally comprises sodium starch glycolate, cross-linked polyvinylpyrrolidone, starch, polyvinylpyrrolidone, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Xylo-Mucine, agar, calcium carbonate and sodium bicarbonate etc., they can use separately also can mix use, wherein is preferably sodium starch glycolate, cross-linked polyvinylpyrrolidone.
Described tackiness agent generally comprises the ethanolic soln of Vltra tears, Microcrystalline Cellulose, hydroxypropylcellulose, polyvidone, starch slurry, polyvinyl alcohol, alginate, water, various concentration, they can use separately also can mix use, wherein preferred Vltra tears, Microcrystalline Cellulose, hydroxypropylcellulose.
Described lubricant generally comprises Magnesium Stearate, stearic acid, calcium stearate, palmitinic acid, pure aluminium silicate, stearylamide, talcum powder, solid polyethylene glycol.They can use separately also can mix use, wherein preferred Magnesium Stearate, stearic acid, calcium stearate.
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.
Experiment shows, dapoxetine hydrochloride crystal form A physicochemical property provided by the invention are stable, are suitable for long-term storage, and the composition (preparation) that comprises the dapoxetine hydrochloride crystal form A also has satisfactory stability with active in preparation with in storing.
In sum, dapoxetine hydrochloride crystal form A preparation method of the present invention is easy, has the advantages such as satisfactory stability and preparation adaptability, has the industrialization practicality.
Description of drawings
Fig. 1 is the X-ray powder diffraction of dapoxetine hydrochloride crystal form A.
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 A
2g dapoxetine hydrochloride solid is dissolved in the 20ml Virahol, the dissolving clarification is heated to reflux, the standing room temperature that is cooled to, add under stirring in the 150ml hexanaphthene, finish, stir about 50min under room temperature, filter, with filter cake dry dapoxetine hydrochloride crystal form A under 40 ~ 50 ℃ of vacuum conditions, its X-ray powder diffraction is seen Fig. 1, main test data values such as following table (listing relative intensity more than or equal to 4% test data).
| 2 θ angles (°) measured value | D() measured value | Relative intensity (%) |
| 8.88540 | 9.94422 | 14 |
| 14.3676 | 6.15980 | 30 |
| 15.0761 | 5.87188 | 39 |
| 16.3200 | 5.42702 | 20 |
| 16.6400 | 5.32337 | 14 |
| 16.9600 | 5.22364 | 4 |
| 17.7987 | 4.97934 | 10 |
| 18.8786 | 4.69688 | 57 |
| 19.2600 | 4.60472 | 8 |
| 20.6811 | 4.29140 | 25 |
| 21.2000 | 4.18752 | 5 |
| 21.7666 | 4.07978 | 4 |
| 22.7207 | 3.91507 | 100 |
| 23.7986 | 3.73583 | 27 |
| 25.2693 | 3.52164 | 31 |
| 26.6677 | 3.34006 | 10 |
| 27.7733 | 3.20956 | 8 |
| 29.0128 | 3.07520 | 17 |
| 29.5179 | 3.02371 | 36 |
| 31.2307 | 2.86168 | 7 |
| 33.0073 | 2.71159 | 4 |
| 33.6166 | 2.66383 | 5 |
| 35.2416 | 2.54463 | 4 |
| 36.0025 | 2.49258 | 4 |
| 38.7660 | 2.32101 | 4 |
Embodiment 2:
The preparation of dapoxetine hydrochloride crystal form A
2g dapoxetine hydrochloride solid is dissolved in the 16ml dehydrated alcohol, the dissolving clarification is heated to reflux, filter, filtrate is under agitation added in the 100ml ether, finish, stir about 30min under room temperature, be cooled to 5 ℃ of stir about 30min, filter, with filter cake dry dapoxetine hydrochloride crystal form A that gets under 40 ~ 50 ℃ of vacuum, the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 3
5g dapoxetine hydrochloride sample is dissolved in 50ml methyl alcohol, the dissolving clarification is heated to reflux, 200ml Skellysolve A/methyl acetate (volume ratio 3:1) mixed solution is added in reaction solution, finish, be cooled to approximately 60min of 0 ~ 5 ℃ of standing crystallization, filter, 50 ~ 60 ℃ of vacuum-dryings of filter cake are got the dapoxetine hydrochloride crystal form A, its X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 4
The preparation of dapoxetine hydrochloride A crystal formation
3g dapoxetine hydrochloride solid is dissolved in 27ml N, in dinethylformamide, be heated to 80 ℃ of dissolving clarifications, the standing room temperature that is cooled to adds to 180ml n-hexane/ethyl acetate (volume ratio 2:1) mixed solution in reaction solution under stirring, finishes, be cooled to 0 ~ 5 ℃ of stir about 45min, filter, 50 ~ 60 ℃ of vacuum-dryings of filter cake are got the dapoxetine hydrochloride crystal form A, its X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 5:
The preparation of dapoxetine hydrochloride crystal form A
2g dapoxetine hydrochloride sample is dissolved in 30ml acetone, the dissolving clarification is heated to reflux, the standing room temperature that is cooled to, add under stirring in the 120ml sherwood oil, finish, be cooled to approximately 40min of 5 ~ 10 ℃ of standing crystallizatioies, filter, get the dapoxetine hydrochloride crystal form A, its X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 6:
The preparation of dapoxetine hydrochloride crystal form A
3g dapoxetine hydrochloride sample is dissolved in the 90ml tetrahydrofuran (THF), the dissolving clarification is heated to reflux, filter, under stirring, the 100ml isopropyl ether is added in filtrate, finish, continue stir about 60min under room temperature, filter, get the dapoxetine hydrochloride crystal form A, its X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 7:
The preparation of dapoxetine hydrochloride crystal form A
4g dapoxetine hydrochloride sample is dissolved in the 100ml acetonitrile, the dissolving clarification is heated to reflux, under stirring, the 120ml methyl acetate is added in reaction solution, finish, be cooled to 0 ~ 5 ℃ of stir about 2h, filter, 50 ~ 60 ℃ of vacuum-dryings of filter cake are got the dapoxetine hydrochloride crystal form A, its X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 8:
5g dapoxetine hydrochloride solid is dissolved in the 40ml methyl-sulphoxide, be heated to 100 ℃ of dissolving clarifications, under stirring, the 150ml ethyl acetate is added in reaction solution, finish, the standing approximately 2h of 0 ~ 5 ℃ of crystallization that is cooled to, filter, with filter cake dry dapoxetine hydrochloride crystal form A that gets under 70 ~ 80 ℃ of vacuum, the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 9
2g dapoxetine hydrochloride solid is dissolved in 50ml 1, in the 4-dioxane, be heated to 100 ℃ of dissolving clarifications, add under stirring in the 80ml methyl tertiary butyl ether, finish, be cooled to 5 ~ 10 ℃ of stir about 1h, filter, with filter cake dry dapoxetine hydrochloride crystal form A that gets under 50 ~ 60 ℃ of vacuum, the X-ray powder diffraction pattern is consistent with Fig. 1 in limit of error.
Embodiment 10
Dapoxetine hydrochloride crystal form A pharmaceutical composition
The prescription of 1000 tablets of tablets of preparation, every dosage that contains 60mg:
The dapoxetine hydrochloride crystal form A ... 60g
Pregelatinized Starch ... 135g
Vltra tears ... 6g
Starch ... 45g
Magnesium Stearate ... 1.2g
Silicon-dioxide ... 2.6g
Sodium starch glycolate ... 9.2g
Above-mentioned prescription is namely got dapoxetine hydrochloride crystal form A 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 (7)
1. dapoxetine hydrochloride crystal form A, it is characterized in that: its X-ray powder diffraction is about the position of 8.9 °, 14.4 °, 15.1 °, 16.3 °, 16.6 °, 18.9 °, 20.7 °, 22.7 °, 23.8 °, 25.3 °, 29.0 °, 29.5 ° to characteristic diffraction peak should be arranged in 2 θ values.
2. the preparation method of a dapoxetine hydrochloride crystal form A, is characterized in that dapoxetine hydrochloride is dissolved in hydrophilic organic solvent, then mixes crystallization with lower boiling lipotropy organic solvent.
3. method as claimed in claim 2, wherein, hydrophilic organic solvent is selected from methyl alcohol, ethanol, Virahol, ethylene glycol, N, dinethylformamide, N, in N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane and methyl-sulphoxide one or more.
4. method as claimed in claim 2, wherein, lower boiling lipotropy organic solvent is selected from one or more in sherwood oil, Skellysolve A, normal hexane, hexanaphthene, ether, isopropyl ether, methyl tertiary butyl ether, methyl acetate and ethyl acetate.
5. method as claimed in claim 2, wherein, the terminal temperature of crystallization is controlled at below 50 ℃.
6. a pharmaceutical composition, comprise dapoxetine hydrochloride new crystal A and pharmaceutical excipient.
Dapoxetine hydrochloride new crystal A 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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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2011
- 2011-11-22 CN CN2011103722716A patent/CN103130658A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (3)
| Title |
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| 尹玲丽，等: "盐酸达泊西汀的合成工艺研究", 《中国药物化学杂志》, vol. 21, no. 1, 28 February 2011 (2011-02-28), pages 37 - 39 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN110903203B (en) * | 2018-09-14 | 2022-11-18 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
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Application publication date: 20130605 |