CN102344442A - Novel crystal form of tandospirone citrate and preparation method and application thereof - Google Patents
Novel crystal form of tandospirone citrate and preparation method and application thereof Download PDFInfo
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- CN102344442A CN102344442A CN2011102224427A CN201110222442A CN102344442A CN 102344442 A CN102344442 A CN 102344442A CN 2011102224427 A CN2011102224427 A CN 2011102224427A CN 201110222442 A CN201110222442 A CN 201110222442A CN 102344442 A CN102344442 A CN 102344442A
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a novel crystal form of tandospirone citrate and a preparation method and an application thereof. The novel crystal form of the tandospirone citrate is capable of improving the dissolubility and the stability of a primary product, is beneficial to the preparations and the use of a product and improving the safety of the product.
Description
Technical field
The present invention relates to the new crystal of SM-3997, and the preparation method of crystal formation and purposes.
Background technology
Tandospirone be the 3rd generation anxiolytic medicament and 5-HT
1AAcceptor portion agonist, high selectivity ground combine and exciting postsynaptic 5-HT
1AAcceptor, this receptor mainly concentrate on hippocampus, in cerebral limbic system such as separated, interpeduncular nucleus, amygdala and the seam gland nuclear, suppresses hyperfunction serotonin ability nervous activity, thereby brings into play effect antianxity; Simultaneously, through the autoreceptor negative feedback mechanism, make 5-HT quantity normalizing, and do not have influence on the 5-HT concentration of synaptic cleft, so do not produce the side reaction such as of flaccid muscles, anticonvulsion of benzodiazepines anxiolytic medicament.
Existing research shows; Tandospirone has the more angst resistance effect of highly selective than its same analog derivative (like azaspiro ketone, buspirone etc.); And its angst resistance effect and diazepam are suitable, but toxic side effect such as the nervimotion sexual function infringement due to it, drug abuse are littler than diazepam.Tandospirone also has certain antidepressant effect, can bring into play therapeutic action better for being mixed with anxiety with depressed patient.At present, SM-3997 (be the Tandospirone citrate, structure is suc as formula shown in 1) has been widely used in the control of clinical anxiety and relative disease thereof, and market outlook are very good.
At present; To the existing more research of the preparation method of SM-3997; Like US4507303, US4818756, JP60087262, CN101362751A, CN101880274A etc.; Disclose the preparation method of Tandospirone and SM-3997 respectively, but also do not seen relevant report the crystal formation of SM-3997.
Summary of the invention
The object of the present invention is to provide the new crystal of SM-3997, and the preparation method of new crystal and purposes.
The invention provides the crystal formation I of SM-3997, in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 20.7 ± 0.2,19.8 ± 0.2,16.3 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 24.6 ± 0.2,22.4 ± 0.2,12.1 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 14.9 ± 0.2,14.6 ± 0.2,14.1 ± 0.2 degree places.
Wherein, the fusing point of this crystal formation is 167.5-168.5 ℃.
Wherein, this crystal formation is at 3442 ± 3cm
-1, 1692 ± 3cm
-1, 1724 ± 3cm
-1, 1739 ± 3cm
-1There is infrared absorption at the place.
Wherein, the differential scanning calorimetric endothermic peak of this crystal formation is respectively at 162 ℃-177 ℃ and 177 ℃-220 ℃.
Wherein, in this crystal form X ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is:
Further preferably, this crystal form X ray powder diffraction as shown in Figure 1.
The present invention also provides a kind of method for preparing above-mentioned crystal formation I, and its operation steps is following:
A, SM-3997 is dissolved in the solvent, makes SM-3997 solution; Wherein, any of the mixing solutions, acetone that said solvent is selected from the aqueous solution, alcohol of the aqueous solution, the acetone of water, alcohol, alcohol and acetone and pure mixed aqueous solution is preferably water, pure any or its combination;
B, cooling crystallization; Perhaps
C, adding xenogenesis solvent, cooling crystallization; Wherein, said xenogenesis solvent is poorer than A step solvent for use to the solubleness of SM-3997;
D, isolation of crystalline, drying promptly gets;
Wherein, in the crystallization process of step B, C, need to stir.
Further, alcohol described in the steps A is selected from any or its combination of methyl alcohol, ethanol, Virahol, is preferably methyl alcohol.
Further, the solvent load of steps A (volume) is 3-20 a times of SM-3997 quality, is preferably 4-10 doubly.
Further, the dissolution process of steps A suitably heats, and preferred Heating temperature is that room temperature is to solvent boiling point.
The present invention also provides above-mentioned crystal formation I preparing treatment and serotonin or/and the purposes in the medicine of norepinephrine (NA) re-uptake relative disease.
Wherein, said medicine is preferably the treatment dysthymia disorders for the medicine of treatment central nervous system disease; Anxiety disorder, Phobias, agoraphobia; Post-traumatic stress disorder, premenstrua anxiety disorder, fibromyalgia; ADHD (Attention Deficit Hyperactivity Disorder), obsessional idea and behavior integration disease, autism; Autism, schizophrenia, obesity; Bulimia nervosa or shortage, Tourette syndrome, vasomotion sexflush; Cocaine or alcohol addiction, sexual dysfunction, border personality disorder; Chronic fatigue syndrome; The urinary incontinence, pain, Shy Drager syndromes; The Reynolds syndromes, the medicine of Parkinson's disease or epilepsy.
Further, the purposes of crystal formation I in preparation serotonin conditioning agent.
Wherein, said serotonin conditioning agent is the medicine of treatment anxiety disorder, dysthymia disorders or insomnia.
The present invention also provides a kind of pharmaceutical composition, and it is to be activeconstituents by above-mentioned crystal formation I, adds the preparation that acceptable accessories or complementary composition are prepared from.
The present invention also provides the crystal form II of SM-3997, and in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 27.2 ± 0.2,25.2 ± 0.2,21.9 ± 0.2,18.0 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 37.4 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 27.0 ± 0.2,20.8 ± 0.2,15.0 ± 0.2,13.6 ± 0.2 degree places.
Wherein, the fusing point of this crystal formation is 167.0-168.0 ℃.
Wherein, this crystal formation is at 3485 ± 3cm
-1, 3442 ± 3cm
-1, 3215 ± 3cm
-1, 1678 ± 3cm
-1, 1691 ± 3cm
-1, 1735 ± 3cm
-1There is infrared absorption at the place.
Wherein, the differential scanning calorimetric endothermic peak of this crystal formation is respectively at 108 ℃-127 ℃, 162 ℃-177 ℃ and 177 ℃-220 ℃.
Further, in this crystal form X ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is:
Further preferably, this crystal form X ray powder diffraction as shown in Figure 4.
The present invention also provides a kind of method for preparing above-mentioned crystal form II, and its operation steps is following:
A) SM-3997 is dissolved in aqueous acetone solution, makes the aqueous acetone solution of SM-3997;
B) cooling crystallization;
C) isolation of crystalline, drying promptly gets;
Wherein, in the crystallization process of step b), need leave standstill.
Wherein, described in the step a) in the aqueous acetone solution volume ratio of acetone and water be 10: 1-1: 6, be preferably 6: 1-1: 4, more preferably 3: 1.
Wherein, in the step a) consumption of aqueous acetone solution (volume) be the SM-3997 solid weight 2-20 doubly, be preferably 4-10 doubly.
Wherein, the dissolution process in the step a) suitably heats, and preferred Heating temperature is that room temperature is to solvent boiling point.
The present invention also provides above-mentioned crystal form II preparing treatment and serotonin or/and the purposes in the medicine of norepinephrine (NA) re-uptake relative disease.
Wherein, said medicine is preferably the treatment dysthymia disorders for the medicine of treatment central nervous system disease; Anxiety disorder, Phobias, agoraphobia; Post-traumatic stress disorder, premenstrua anxiety disorder, fibromyalgia; ADHD (Attention Deficit Hyperactivity Disorder), obsessional idea and behavior integration disease, autism; Autism, schizophrenia, obesity; Bulimia nervosa or shortage, Tourette syndrome, vasomotion sexflush; Cocaine or alcohol addiction, sexual dysfunction, border personality disorder; Chronic fatigue syndrome; The urinary incontinence, pain, Shy Drager syndromes; The Reynolds syndromes, the medicine of Parkinson's disease or epilepsy.
Further, the purposes of crystal form II in preparation serotonin conditioning agent.
Wherein, said serotonin conditioning agent is the medicine of treatment anxiety disorder, dysthymia disorders or insomnia.
The present invention also provides a kind of pharmaceutical composition, and it is to be activeconstituents by above-mentioned crystal form II, adds the preparation that acceptable accessories or complementary composition are prepared from.
The present invention also provides the crystal form II I of SM-3997, and in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 40.3 ± 0.2,33.4 ± 0.2,11.3 ± 0.2,6.8 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 29.8 ± 0.2,22.9 ± 0.2,18.2 ± 0.2,13.7 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 27.3 ± 0.2,24.3 ± 0.2,22.2 ± 0.2,21.3 ± 0.2,18.0 ± 0.2,15.3 ± 0.2 degree places.
Wherein, the fusing point of this crystal formation is 167.0-168.0 ℃.
Wherein, this crystal formation is at 3489 ± 3cm
-1, 3425 ± 3cm
-1, 3218 ± 3cm
-1, 1734 ± 3cm
-1, 1678 ± 3cm
-1There is infrared absorption at the place.
Wherein, the differential scanning calorimetric endothermic peak of this crystal formation is respectively at 108 ℃-127 ℃, 162 ℃-177 ℃ and 177 ℃-220 ℃.
Further, in this crystal form X ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is:
Further preferably, this crystal form X ray powder diffraction as shown in Figure 7.
The present invention also provides a kind of method for preparing above-mentioned crystal form II I, and its operation steps is following:
A) SM-3997 is dissolved in the water, makes the SM-3997 aqueous solution;
B) leave standstill cooling crystallization;
C) isolation of crystalline, drying promptly gets;
Wherein, in the crystallization process of step b), need leave standstill.
Wherein, in the said SM-3997 aqueous solution consumption (volume) of water be the SM-3997 solid weight 3-15 doubly, be preferably 4-8 doubly, most preferably be 6 times.
Wherein, the said dissolution process of step a) suitably heats, and preferred Heating temperature is that room temperature is to solvent boiling point.
The present invention also provides above-mentioned crystal form II I preparing treatment and serotonin or/and the purposes in the medicine of norepinephrine (NA) re-uptake relative disease.
Wherein, said medicine is preferably the treatment dysthymia disorders for the medicine of treatment central nervous system disease; Anxiety disorder, Phobias, agoraphobia; Post-traumatic stress disorder, premenstrua anxiety disorder, fibromyalgia; ADHD (Attention Deficit Hyperactivity Disorder), obsessional idea and behavior integration disease, autism; Autism, schizophrenia, obesity; Bulimia nervosa or shortage, Tourette syndrome, vasomotion sexflush; Cocaine or alcohol addiction, sexual dysfunction, border personality disorder; Chronic fatigue syndrome; The urinary incontinence, pain, Shy Drager syndromes; The Reynolds syndromes, the medicine of Parkinson's disease or epilepsy.
Further, the purposes of crystal form II I in preparation serotonin conditioning agent.
Wherein, said serotonin conditioning agent is the medicine of treatment anxiety disorder, dysthymia disorders or insomnia.
The present invention also provides a kind of pharmaceutical composition, and it is to be activeconstituents by above-mentioned crystal form II I, adds the preparation that acceptable accessories or complementary composition are prepared from.
Pharmaceutically acceptable carrier according to the invention is usual excipients or the auxiliary material that is used to prepare above-mentioned preparation well known in the art.Vehicle or auxiliary material that oral preparations or external preparation are commonly used include but are not limited to weighting agent (thinner), lubricant (glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, disintegrating agent etc.Tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, Mierocrystalline cellulose and derivative thereof (like Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose or HPMC etc.), gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Weighting agent, for example lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, inorganic calcium salt (like calcium sulfate, calcium phosphate, secondary calcium phosphate, precipitated calcium carbonate etc.), sorbyl alcohol or glycine; Lubricant, for example micropowder silica gel, Magnesium Stearate, talcum powder, white lake, boric acid, hydrogenated vegetable oil, polyoxyethylene glycol; Disintegrating agent, for example starch and derivative thereof (like sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch, W-Gum etc.), polyvinylpyrrolidone or Microcrystalline Cellulose; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.
Vehicle or auxiliary material that injection according to the invention is commonly used include but are not limited to: oxidation inhibitor, for example S-WAT, sodium bisulfite, Sodium Pyrosulfite, dibutyl benzoic acid etc.; Fungistat, for example 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; Conditioning agent, for example hydrochloric acid, Citric Acid, potassium hydroxide (sodium), Sodium Citrate and buffer reagent (comprising phosphoric acid dioxy sodium and Sodium phosphate dibasic etc.); Emulsifying agent, for example Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, fabaceous lecithin; Solubilizing agent, for example tween-80, bile, glycerine etc.
In addition; Also activeconstituents can be mixed by its preparation requirement with pharmaceutically acceptable slow-released carrier or controlled release carrier; Again according to the preparation method of sustained-release preparation well known in the art; As add the retarding agent dressing or, comprise sustained release pellet or controlled release micro pill etc. processing micropill after the active principle microcapsulesization again; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the dressing retarding agent etc. of mixing, described oil any or its combination that agent is selected from glyceryl monostearate, hydrogenated castor oil, Dormant oils, polysiloxane or dimethyl siloxane of mixing; Described hydrophilic colloid is selected from any or its combination of Xylo-Mucine, hydroxypropylcellulose, Vltra tears, PVP, gum arabic, tragacanth or carbopol; Described dressing retarding agent is selected from any or its combination of ethyl cellulose (EC), HPMC (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin.
Wherein, In the optimal technical scheme of the present invention, the dosage form of said composition is selected from tablet, suspension, capsule, granule, pill, powder, pill, syrup, mixture, distillate medicinal water, effervescent, paste, emulsion, medicinal tea, pulvis, injection (injection), transfusion, gelifying agent, emplastrum, plaster, creme, ointment, liniment, lotion, suppository, basting agent, paste, coagulate any of paste.
Description of drawings
The X-ray powder diffraction of Fig. 1 SM-3997 crystal formation I;
The DSC collection of illustrative plates of Fig. 2 SM-3997 crystal formation I;
The infared spectrum of Fig. 3 SM-3997 crystal formation I;
The X-ray powder diffraction of Fig. 4 SM-3997 crystal form II;
The DSC collection of illustrative plates of Fig. 5 SM-3997 crystal form II;
The infared spectrum of Fig. 6 SM-3997 crystal form II;
The X-ray powder diffraction of Fig. 7 SM-3997 crystal form II I;
The DSC collection of illustrative plates of Fig. 8 SM-3997 crystal form II I;
The infared spectrum of Fig. 9 SM-3997 crystal form II I;
(CN101362751B embodiment 4 CN101880274A) discloses the X-ray powder diffraction that method prepares the gained SM-3997 to Figure 10 according to document;
The X-ray powder diffraction (water dissolution, stirring and crystallizing) of Figure 11 SM-3997 crystal formation I;
The X-ray powder diffraction (dissolve with methanol, stirring and crystallizing) of Figure 12 SM-3997 crystal formation I;
The X-ray powder diffraction of Figure 13 SM-3997 crystal formation I (dissolving of 80% aqueous ethanolic solution, stirring and crystallizing);
The X-ray powder diffraction of Figure 14 SM-3997 crystal formation I (dissolving of 60% aqueous acetone solution, stirring and crystallizing);
The X-ray powder diffraction of Figure 15 SM-3997 crystal formation I (dissolving of methanol/acetone mixing solutions, stirring and crystallizing);
The X-ray powder diffraction of Figure 16 SM-3997 crystal formation I (water dissolution, acetone stirring and crystallizing);
The X-ray powder diffraction of Figure 17 SM-3997 crystal formation I (dissolve with methanol, acetone stirring and crystallizing);
The X-ray powder diffraction of Figure 18 SM-3997 crystal form II (acetone: water=mixing solutions dissolving in 6: 1, leave standstill crystallization);
In the accompanying drawing of the present invention, the X-coordinate of X-ray powder diffraction is 2 θ scales, and ordinate zou is a peak intensity; The X-coordinate of DSC collection of illustrative plates is a temperature, and ordinate zou is a heat flux.
Embodiment
The preparation of embodiment 1 SM-3997 crystal formation I
SM-3997 500g is placed the mixing solutions of acetone (2700ml) and water (900ml), stir, reflux, be heated to dissolving; As required, add the gac processing of decolouring; After the filtration, the mother liquor cooling is stirred down and is separated out crystal; Filter and collect crystal, drying under reduced pressure makes white SM-3997 I N-type waferN, and yield is 95%.
Among the present invention, the add-on of preferred gac is the 1wt.%-5wt.% of SM-3997 weight.
Crystalline detection method of the present invention comprises:
1, X powder diffraction test
1) sample preparation: directly take by weighing sample and make the X diffraction experiment.
2) test apparatus: X ' Pert Pro MPD Philips X-ray powder diffraction appearance (penetrating source CuK α, graphite monochromator, useful range: 5-50 ° of 2 θ).
3) test conditions: CuK α radiation, graphite monochromator, pipe is pressed 40KV, pipe stream 35mA, 5-50 ° of 2 θ sweep limit, 9 °/minute of sweep velocitys, 0.03 ° of step-length.The slit condition: the emission slit is 0.5 °, and accepting slit is 1mm.
2, melting point test
Use Tianjin to send out YRT-3 type drug melting point appearance in huge day; Test conditions is: temperature is 155 ℃ in advance, 1 ℃/min of heat-up rate.
3, differential scanning calorimetry (DSC) test
Use DSC Q100 analyser, initial temperature is set to 30 ℃, and final temperature is set to 260 ℃, and temperature rise rate is set to 10 ℃/minute (10K/min).
4, infrared measurement test
Use instrument to be ThermoFisher Nicolet 6700 Fourier transformation infrared spectrometers, and use Yellow Protopet 2A to stick with paste the legal system sheet and detect.
Detect the SM-3997 crystal formation I that embodiment 1 prepares according to the method described above, its fusing point is 167.5-168.5 ℃, and the powder X-ray diffraction is seen Fig. 1, and the diffraction related data is referring to table 1, and DSC sees Fig. 2, and IR sees Fig. 3.
The X-ray powder diffraction data of the I N-type waferN of table 1 SM-3997
The preparation method of used SM-3997 is following among the present invention:
The existing document of reference (CN101362751B embodiment 4, CN101880274A) preparation SM-3997:
Method 1: with Tandospirone alkali 300g, Citric Acid 164g, ethanol 3600ml adds in the reaction kettle, is warmed up to 80 ℃, refluxes 30 minutes, puts and is chilled to room temperature, leaves standstill, and suction filtration is used absolute ethanol washing, and drying gets SM-3997 430g.Recording its fusing point according to fusing point test method of the present invention is 169-170 ℃, and the salify productive rate is 95%, and the X powder diffraction collection of illustrative plates as shown in Figure 4.
Method 2: with Tandospirone alkali 100g, Citric Acid 55g, ethyl acetate 800ml adds in the reaction kettle, reacted 2 hours, suction filtration, washing, drying gets SM-3997 143g.Recording its fusing point according to fusing point test method of the present invention is 169-171 ℃, and the salify productive rate is 95%, and the X powder diffraction collection of illustrative plates as shown in figure 10.
The preparation method of embodiment 2 SM-3997 crystal formation I
Method according to embodiment 1 prepares the SM-3997 crystal formation, and its condition is referring to table 2.The crystal of gained is measured through the powder X-ray diffraction under each condition, determines that it is SM-3997 crystal formation I, and the representative X diffracting spectrum of part is seen Figure 11 to Figure 17.Can know that by each X diffracting spectrum the 2 θ angle of diffraction of this crystal formation I have the common characteristic peak at 20.7 ± 0.2,19.8 ± 0.2,16.3 ± 0.2 degree places.
The preparation of table 2 SM-3997 crystal formation I
The preparation of embodiment 3 SM-3997 crystal form IIs
SM-3997 500g is placed the mixing solutions of acetone (1950ml) and water (650ml), be heated to 60 ℃, stirring and dissolving; As required, adding activated carbon decolorizing handles; After the filtration, leave standstill under the mother liquor cooling and separate out crystal.Filter and collect crystal, drying under reduced pressure makes white SM-3997 crystal form II, and yield is 95%.
The preparation method of crystal form II is similar with crystal formation I, but difference is that also need in the crystallization process of crystal formation I to stir, crystal form II then need leave standstill.
Detect the SM-3997 crystal form II that makes according to the method for the invention, recording its fusing point is 167.0-168.0 ℃, and the powder X-ray diffraction is seen Fig. 4, and the diffraction related data is referring to table 3, and DSC sees Fig. 5, and IR sees Fig. 6.
The X-ray powder diffraction data of the crystal form II of table 3 SM-3997
The preparation of embodiment 4 SM-3997 crystal form IIs
Method according to embodiment 3 prepares the SM-3997 crystal formation, and its condition is referring to table 4.The crystal of gained is measured through the powder X-ray diffraction under each condition, determines that it is the SM-3997 crystal form II, and the representative X diffracting spectrum of part is seen Figure 18.Can know that by each X diffracting spectrum 2 θ angle of diffraction of this crystal form II have the common characteristic peak at 27.2 ± 0.2,25.2 ± 0.2,21.9 ± 0.2,18.0 ± 0.2 degree places.
The preparation of table 4 crystal form II
The preparation of embodiment 5 SM-3997 III N-type waferNs
SM-3997 500g is placed 3000ml water, be heated to 80 ℃ of dissolvings; As required, add the gac processing of decolouring; After the filtration, leave standstill under the mother liquor cooling and separate out crystal.Filter and collect crystal, drying under reduced pressure makes white SM-3997 III N-type waferN, and yield is 91%.
The preparation method of crystal form II I is similar with crystal formation I, but difference is that also need in the crystallization process of crystal formation I to stir, crystal form II I then need leave standstill.
Detect the SM-3997 crystal form II I that makes according to the method for the invention, recording its fusing point is 166.5-167.5 ℃, and the powder X-ray diffraction is seen Fig. 7, and the diffraction related data is referring to table 5, and DSC sees Fig. 8, and IR sees Fig. 9.
The X-ray powder diffraction data of table 5 SM-3997 crystal form II I
The preparation of embodiment 6 SM-3997 III N-type waferNs
Method according to embodiment 5 prepares the SM-3997 crystal formation, and its condition is referring to table 6.The crystal of gained is measured through the powder X-ray diffraction under each condition, determines that it is SM-3997 crystal form II I, and adopting fusing point test method of the present invention to record its fusing point is 166.5-167.5 ℃.
The preparation of table 6 crystal form II I
Below prove beneficial effect of the present invention through concrete Test Example.
The solvability comparative studies of Test Example 1 SM-3997 crystal formation I of the present invention, crystal form II, crystal form II I and currently available products
Take by weighing trial-product 2g, place 25 ± 2 ℃ 20ml water, every at a distance from 1 minute 10 seconds of powerful jolting, observe the dissolving situation in 3 minutes.As do not have visual visible particles of solute, promptly be considered as dissolving fully; If visual visible particles of solute is arranged, add 5 times of water gagings, repeat aforementioned operation, until dissolving fully.Record total water amount and time.The result sees table 7.
Wherein, SM-3997 crystal formation I, crystal form II, crystal form II I are prepared by the embodiment of the invention 1,3,5 respectively; (CN101362751B embodiment 4, CN101880274A) disclosed method prepares the SM-3997 currently available products with reference to existing document.
The solvability comparative studies of table 7 crystal formation I, crystal form II, crystal form II I and currently available products
Visible by table 7, to compare with SM-3997, the I N-type waferN has the water-soluble of obvious improvement, and the solvability of III N-type waferN makes moderate progress equally.
The study on the stability of Test Example 2 SM-3997 crystal formation I of the present invention, crystal form II, crystal form II I and currently available products
The study on the stability condition comprises:
1. thermal destruction: get the about 200mg of trial-product, place 60 ℃ of loft drier to place;
2. photodegradation: get the about 200mg of trial-product, placing illumination is that the environment of 4500 ± 500lx is placed;
3. high humidity degraded: get trial-product 200mg, place to be placed with KNO
3In the moisture eliminator of saturated solution, room temperature is placed.The study on the stability result sees table 8.
Wherein, SM-3997 crystal formation I, crystal form II, crystal form II I are prepared by the embodiment of the invention 1,3,5 respectively; (CN101362751B embodiment 4, CN101880274A) disclosed method prepares the SM-3997 currently available products with reference to existing document.
The study on the stability of table 8 crystal formation I, crystal form II, crystal form II I and currently available products
Visible by table 8, the SM-3997 currently available products is to the less stable of light, heat, and particularly under strong illumination, impurity significantly increases in the product: shone 5 days, dopant species increases to 13, purity drop 0.3%; Shone 10 days, dopant species increases to 14, purity drop 0.63%; Compare with the SM-3997 currently available products, the stability of crystal formation I, II, III is better, and wherein, crystal formation I is under accelerated stability test, and dopant species does not have obvious increase; Crystal form II and crystal form II I are under accelerated stability test, and dopant species does not have obvious increase, and purity do not have obvious reduction, show that crystal form II and crystal form II I have significantly improved the stability of SM-3997,
In sum, SM-3997 new crystal of the present invention can improve the solvability and the stability of original product, helps preparation, the use of product more, has improved security of products.
Claims (10)
1. the crystal formation I of SM-3997, it is characterized in that: in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 20.7 ± 0.2,19.8 ± 0.2,16.3 ± 0.2 degree places; Be preferably 2 θ angle of diffraction and also characteristic peak arranged at 24.6 ± 0.2,22.4 ± 0.2,12.1 ± 0.2 degree places; More preferably 2 θ angle of diffraction also have characteristic peak at 14.9 ± 0.2,14.6 ± 0.2,14.1 ± 0.2 degree places.
2. method for preparing the described crystal formation I of claim 1, it is characterized in that: its operation steps is following:
A, SM-3997 is dissolved in the solvent, makes SM-3997 solution;
B, cooling crystallization; Perhaps
C, adding xenogenesis solvent, cooling crystallization; Wherein, said xenogenesis solvent is poorer than A step solvent for use to the solubleness of SM-3997;
D, isolation of crystalline, drying promptly gets;
Wherein, in the crystallization process of step B, C, need to stir.
3. the crystal form II of SM-3997, it is characterized in that: in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 27.2 ± 0.2,25.2 ± 0.2,21.9 ± 0.2,18.0 ± 0.2 degree places; Be preferably 2 θ angle of diffraction and also characteristic peak arranged at 37.4 ± 0.2 degree places; More preferably 2 θ angle of diffraction also have characteristic peak at 27.0 ± 0.2,20.8 ± 0.2,15.0 ± 0.2,13.6 ± 0.2 degree places.
4. method for preparing the described crystal form II of claim 3, it is characterized in that: its operation steps is following:
A) SM-3997 is dissolved in aqueous acetone solution, makes the aqueous acetone solution of SM-3997;
B) cooling crystallization;
C) isolation of crystalline, drying promptly gets;
Wherein, in the crystallization process of step b), need leave standstill.
5. the crystal form II I of SM-3997, it is characterized in that: in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 40.3 ± 0.2,33.4 ± 0.2,11.3 ± 0.2,6.8 ± 0.2 degree places; Be preferably 2 θ angle of diffraction and also characteristic peak arranged at 29.8 ± 0.2,22.9 ± 0.2,18.2 ± 0.2,13.7 ± 0.2 degree places; More preferably 2 θ angle of diffraction also have characteristic peak at 27.3 ± 0.2,24.3 ± 0.2,22.2 ± 0.2,21.3 ± 0.2,18.0 ± 0.2,15.3 ± 0.2 degree places.
6. method for preparing the described crystal form II I of claim 5, it is characterized in that: its operation steps is following:
A) SM-3997 is dissolved in the water, makes the SM-3997 aqueous solution;
B) cooling crystallization;
C) isolation of crystalline, drying promptly gets;
Wherein, in the crystallization process of step b), need leave standstill.
7. claim 1,3,5 any described crystal formations are preparing treatment and serotonin or/and the purposes in the medicine of norepinephrine reuptake relative disease.
8. purposes according to claim 7 is characterized in that: said medicine is preferably the treatment dysthymia disorders for the medicine of treatment central nervous system disease; Anxiety disorder, Phobias, agoraphobia; Post-traumatic stress disorder, premenstrua anxiety disorder, fibromyalgia; ADHD (Attention Deficit Hyperactivity Disorder), obsessional idea and behavior integration disease, autism; Autism, schizophrenia, obesity; Bulimia nervosa or shortage, Tourette syndrome, vasomotion sexflush; Cocaine or alcohol addiction, sexual dysfunction, border personality disorder; Chronic fatigue syndrome; The urinary incontinence, pain, Shy Drager syndromes; The Reynolds syndromes, the medicine of Parkinson's disease or epilepsy.
9. pharmaceutical composition is characterized in that: it is to be activeconstituents by claim 1,3,5 any described crystal formations, adds the preparation that acceptable accessories or complementary composition are prepared from.
10. pharmaceutical composition according to claim 9 is characterized in that: said preparation is oral or injection formulations.
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Also Published As
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| CN103641818A (en) | 2014-03-19 |
| CN102344442B (en) | 2014-08-13 |
| CN103641818B (en) | 2015-08-12 |
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