CN102344442B - 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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- CN102344442B CN102344442B CN201110222442.7A CN201110222442A CN102344442B CN 102344442 B CN102344442 B CN 102344442B CN 201110222442 A CN201110222442 A CN 201110222442A CN 102344442 B CN102344442 B CN 102344442B
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- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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 a kind of new crystal of SM-3997 compound, and crystal formation preparation method and the purposes of this compound.
Background technology
Tandospirone be the 3rd generation anxiolytic medicament and 5-HT
1Aacceptor portion agonist, high selectivity ground combination and exciting postsynaptic 5-HT
1Aacceptor, this receptor mainly concentrate on hippocampus, in the cerebral limbic systems such as, interpeduncular nucleus, amygdala and seam gland core, suppress hyperfunction serotonin energy nervous activity, thereby bring into play effect antianxity; Meanwhile, by autoreceptor negative feedback mechanism, make 5-HT quantity normalizing, and do not have influence on the 5-HT concentration of synaptic cleft, therefore do not produce the side reaction such as of flaccid muscles, anticonvulsion of benzodiazepines anxiolytic medicament.
There are some researches show, Tandospirone has the more angst resistance effect of highly selective compared with its same analog derivative (as azaspiro ketone, buspirone etc.), and its angst resistance effect and diazepam are suitable, but the toxic side effect such as nervimotion Sexual dysfunction, drug abuse due to it is less than diazepam.Tandospirone also has certain antidepressant effect, for being mixed with anxiety and depressed patient can bring into play therapeutic action better.At present, SM-3997 (be Tandospirone citrate, structure as shown in Equation 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, as US4507303, US4818756, JP60087262, CN101362751A, CN101880274A etc., disclose respectively the preparation method of Tandospirone and SM-3997, but yet there are no the relevant report of the crystal formation to 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 crystalline form 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 DEG C.
Wherein, this crystal formation is at 3442 ± 3cm
-1, 1692 ± 3cm
-1, 1724 ± 3cm
-1, 1739 ± 3cm
-1there is infrared absorption at place.
Wherein, the differential scanning calorimetric endothermic peak of this crystal formation is respectively at 162 DEG C-177 DEG C and 177 DEG C-220 DEG C.
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 of preparing above-mentioned crystalline form I, and its operation steps is as follows:
A, SM-3997 is dissolved in solvent, makes SM-3997 solution; Wherein, described solvent is selected from any of mixed aqueous solution of mixing solutions, acetone and the alcohol of the aqueous solution, alcohol and the acetone of the aqueous solution, the acetone of water, alcohol, alcohol, is preferably any or its combination of water, alcohol;
B, cooling crystallization; Or
C, add xenogenesis solvent, cooling crystallization; Wherein, described xenogenesis solvent is poorer than A step solvent for use to the solubleness of SM-3997;
D, isolation of crystalline, dry, to obtain final product;
Wherein, in the Crystallization Process of step B, C, need to stir.
Further, alcohol described in 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 times of SM-3997 quality, is preferably 4-10 doubly.
Further, the dissolution process of steps A suitably heats, and preferably Heating temperature is that room temperature is to solvent boiling point.
The present invention also provide above-mentioned crystalline form I at preparation treatment and serotonin or/and the purposes in the medicine of norepinephrine (NA) re-uptake relative disease.
Wherein, described medicine is the medicine for the treatment of central nervous system disease, be preferably Cure of depression, 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, fat, 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, Raynaud syndrome, the medicine of Parkinson's disease or epilepsy.
Further, crystalline form I is in the purposes of preparing in serotonin conditioning agent.
Wherein, described serotonin conditioning agent is the medicine for the treatment of 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 crystalline form I, adds the preparation that pharmaceutically acceptable auxiliary material 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 DEG C.
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 place.
Wherein, the differential scanning calorimetric endothermic peak of this crystal formation is respectively at 108 DEG C-127 DEG C, 162 DEG C-177 DEG C and 177 DEG C-220 DEG C.
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 of preparing above-mentioned crystal form II, and its operation steps is as follows:
A) SM-3997 is dissolved in to aqueous acetone solution, makes the aqueous acetone solution of SM-3997;
B) cooling crystallization;
C) isolation of crystalline, dry, to obtain final product;
Wherein, in step Crystallization Process b), need to leave standstill.
Wherein, step a) described in aqueous acetone solution the volume ratio of acetone and water be 10:1-1:6, be preferably 6:1-1:4, more preferably 3:1.
Wherein, step a) in the consumption (volume) of aqueous acetone solution be SM-3997 solid weight 2-20 doubly, be preferably 4-10 times.
Wherein, the dissolution process of step in a) suitably heats, and preferably Heating temperature is that room temperature is to solvent boiling point.
The present invention also provide above-mentioned crystal form II at preparation treatment and serotonin or/and the purposes in the medicine of norepinephrine (NA) re-uptake relative disease.
Wherein, described medicine is the medicine for the treatment of central nervous system disease, be preferably Cure of depression, 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, fat, 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, Raynaud syndrome, the medicine of Parkinson's disease or epilepsy.
Further, crystal form II is in the purposes of preparing in serotonin conditioning agent.
Wherein, described serotonin conditioning agent is the medicine for the treatment of 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 pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
The present invention also provides the crystalline form III 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 DEG C.
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 place.
Wherein, the differential scanning calorimetric endothermic peak of this crystal formation is respectively at 108 DEG C-127 DEG C, 162 DEG C-177 DEG C and 177 DEG C-220 DEG C.
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 of preparing above-mentioned crystalline form III, and its operation steps is as follows:
A) SM-3997 is dissolved in the water, makes the SM-3997 aqueous solution;
B) leave standstill cooling crystallization;
C) isolation of crystalline, dry, to obtain final product;
Wherein, in step Crystallization Process b), need to leave standstill.
Wherein, in the described SM-3997 aqueous solution consumption (volume) of water be SM-3997 solid weight 3-15 doubly, be preferably 4-8 doubly, most preferably be 6 times.
Wherein, step a) described dissolution process suitably heats, and preferably Heating temperature is that room temperature is to solvent boiling point.
The present invention also provide above-mentioned crystalline form III at preparation treatment and serotonin or/and the purposes in the medicine of norepinephrine (NA) re-uptake relative disease.
Wherein, described medicine is the medicine for the treatment of central nervous system disease, be preferably Cure of depression, 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, fat, 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, Raynaud syndrome, the medicine of Parkinson's disease or epilepsy.
Further, crystalline form III is in the purposes of preparing in serotonin conditioning agent.
Wherein, described serotonin conditioning agent is the medicine for the treatment of 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 crystalline form III, adds the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
Pharmaceutically acceptable carrier of the present invention is the usual excipients for the preparation of above-mentioned preparation well known in the art or auxiliary material.The vehicle that oral preparations or external preparation are conventional or auxiliary material 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, such as syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, Mierocrystalline cellulose and derivative thereof (as Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose or HPMC etc.), gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Weighting agent, such as lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, inorganic calcium salt (as 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, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyoxyethylene glycol; Disintegrating agent, such as starch and derivative thereof (as sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch, W-Gum etc.), polyvinylpyrrolidone or Microcrystalline Cellulose; Wetting agent, such as sodium lauryl sulphate, water or alcohol etc.
Vehicle or auxiliary material that injection of the present invention is conventional include but are not limited to: oxidation inhibitor, such as 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, such as 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, such as 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 retarding agent dressing or by making again micropill after active principle microcapsules, comprise sustained release pellet or controlled release micro pill etc.; 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 of mixing agent and be selected from glyceryl monostearate, hydrogenated castor oil, Dormant oils, polysiloxane or dimethyl siloxane; 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 preferred technical solution of the present invention, the dosage form of described composition is selected from any of 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, solidifying paste.
Brief description of the drawings
The X-ray powder diffraction of Fig. 1 SM-3997 crystalline form I;
The DSC collection of illustrative plates of Fig. 2 SM-3997 crystalline form I;
The infared spectrum of Fig. 3 SM-3997 crystalline form 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 crystalline form III;
The DSC collection of illustrative plates of Fig. 8 SM-3997 crystalline form III;
The infared spectrum of Fig. 9 SM-3997 crystalline form III;
Figure 10 prepares the X-ray powder diffraction of gained SM-3997 according to the open method of document (CN101362751B embodiment 4, CN101880274A);
The X-ray powder diffraction (water dissolution, stirring and crystallizing) of Figure 11 SM-3997 crystalline form I;
The X-ray powder diffraction (dissolve with methanol, stirring and crystallizing) of Figure 12 SM-3997 crystalline form I;
The X-ray powder diffraction (80% aqueous ethanolic solution dissolves, stirring and crystallizing) of Figure 13 SM-3997 crystalline form I;
The X-ray powder diffraction (60% aqueous acetone solution dissolves, stirring and crystallizing) of Figure 14 SM-3997 crystalline form I;
The X-ray powder diffraction (methanol/acetone mixing solutions dissolves, stirring and crystallizing) of Figure 15 SM-3997 crystalline form I;
The X-ray powder diffraction (water dissolution, acetone stirring and crystallizing) of Figure 16 SM-3997 crystalline form I;
The X-ray powder diffraction (dissolve with methanol, acetone stirring and crystallizing) of Figure 17 SM-3997 crystalline form I;
The X-ray powder diffraction (acetone: water=6:1 mixing solutions dissolves, leaves standstill crystallization) of Figure 18 SM-3997 crystal form II;
In accompanying drawing of the present invention, the X-coordinate of X-ray powder diffraction is 2 θ scales, and ordinate zou is peak intensity; The X-coordinate of DSC collection of illustrative plates is temperature, and ordinate zou is heat flux.
Embodiment
The preparation of embodiment 1 SM-3997 crystalline form I
SM-3997 500g is placed in to the mixing solutions of acetone (2700ml) and water (900ml), stirs, reflux, be heated to dissolve; As required, add the gac processing of decolouring; After filtration, the cooling lower stirring crystallize out of mother liquor; Filter and collect crystal, drying under reduced pressure, makes white SM-3997 I N-type waferN, and yield is 95%.
In the present invention, preferably the add-on of gac is the 1wt.%-5wt.% of SM-3997 weight.
The detection method of crystal of the present invention comprises:
1, X powder diffraction test
1) sample preparation: directly take sample and make X diffraction experiment.
2) test apparatus: X ' Pert Pro MPD Philips X-ray powder diffraction instrument
(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, 2 θ sweep limit 5-50 °, 9 °/point of sweep velocitys, 0.03 ° of step-length.Slit condition: transmitting slit is 0.5 °, and accepting slit is 1mm.
2, melting point test
Use Tianjin within huge day, to send out YRT-3 type drug melting point instrument; Test conditions is: 155 DEG C of pre-temperature, 1 DEG C/min of heat-up rate.
3, differential scanning calorimetry (DSC) test
Use DSC Q100 analyser, initial temperature is set to 30 DEG C, and final temperature is set to 260 DEG C, and temperature rise rate is set to 10 DEG C/min (10K/min).
4, infrared measurement test
Use instrument is ThermoFisher Nicolet6700 Fourier transformation infrared spectrometer, and uses paraffin oil to stick with paste the detection of legal system sheet.
Detect according to the method described above the SM-3997 crystalline form I that embodiment 1 prepares, its fusing point is 167.5-168.5 DEG C, and powder X-ray diffraction is shown in Fig. 1, and diffraction related data is referring to table 1, and DSC is shown in Fig. 2, and IR is shown in Fig. 3.
The X-ray powder diffraction data of the I N-type waferN of table 1 SM-3997
In the present invention, the preparation method of SM-3997 used is as follows:
Prepare SM-3997 with reference to existing document (CN101362751B embodiment 4, CN101880274A):
Method 1: by Tandospirone alkali 300g, Citric Acid 164g, ethanol 3600ml adds in reactor, is warmed up to 80 DEG C, refluxes 30 minutes, lets cool to room temperature, leave standstill, suction filtration, with absolute ethanol washing, dry, obtain SM-3997 430g.Recording its fusing point according to fusing point test method of the present invention is 169-170 DEG C, and salify productive rate is 95%, and X powder diffraction collection of illustrative plates as shown in figure 10.
Method 2: by Tandospirone alkali 100g, Citric Acid 55g, ethyl acetate 800ml adds in reactor, reacts 2 hours, suction filtration, washing, dry, obtain SM-3997 143g.Recording its fusing point according to fusing point test method of the present invention is 169-171 DEG C, and salify productive rate is 95%, and X powder diffraction collection of illustrative plates as shown in figure 10.
The preparation method of embodiment 2 SM-3997 crystalline form Is
Prepare SM-3997 crystal formation according to the method for embodiment 1, its condition is referring to table 2.Under each condition, the crystal of gained, through powder X-ray diffraction, determines that it is SM-3997 crystalline form I, and the representative X diffracting spectrum of part is shown in Figure 11 to Figure 17.From each X diffracting spectrum, 2 θ angle of diffraction of this crystalline form I have 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 crystalline form I
The preparation of embodiment 3 SM-3997 crystal form IIs
SM-3997 500g is placed in to the mixing solutions of acetone (1950ml) and water (650ml), is heated to 60 DEG C, stirring and dissolving; As required, add activated carbon decolorizing processing; After filtration, the cooling lower standing crystallize out of mother liquor.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 to crystalline form I, but difference is also, needs to stir in the Crystallization Process of crystalline form I, and crystal form II needs to leave standstill.
Detect the SM-3997 crystal form II making according to the method for the invention, recording its fusing point is 167.0-168.0 DEG C, and powder X-ray diffraction is shown in Fig. 4, and diffraction related data is referring to table 3, and DSC is shown in Fig. 5, and IR is shown in 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
Prepare SM-3997 crystal formation according to the method for embodiment 3, its condition is referring to table 4.Under each condition, the crystal of gained, through powder X-ray diffraction, determines that it is SM-3997 crystal form II, and the representative X diffracting spectrum of part is shown in Figure 18.From each X diffracting spectrum, 2 θ angle of diffraction of this crystal form II have 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 in to 3000ml water, is heated to 80 DEG C of dissolvings; As required, add the gac processing of decolouring; After filtration, the cooling lower standing crystallize out of mother liquor.Filter and collect crystal, drying under reduced pressure, makes white SM-3997 III N-type waferN, and yield is 91%.
The preparation method of crystalline form III is similar to crystalline form I, but difference is also, needs to stir in the Crystallization Process of crystalline form I, and crystalline form III needs to leave standstill.
Detect the SM-3997 crystalline form III making according to the method for the invention, recording its fusing point is 166.5-167.5 DEG C, and powder X-ray diffraction is shown in Fig. 7, and diffraction related data is referring to table 5, and DSC is shown in Fig. 8, and IR is shown in Fig. 9.
The X-ray powder diffraction data of table 5 SM-3997 crystalline form III
The preparation of embodiment 6 SM-3997 III N-type waferNs
Prepare SM-3997 crystal formation according to the method for embodiment 5, its condition is referring to table 6.Under each condition, the crystal of gained, through powder X-ray diffraction, determines that it is SM-3997 crystalline form III, and adopting fusing point test method of the present invention to record its fusing point is 166.5-167.5 DEG C.
The preparation of table 6 crystalline form III
Prove beneficial effect of the present invention by concrete test example below.
The solvability comparative studies of test example 1 SM-3997 crystalline form I of the present invention, crystal form II, crystalline form III and currently available products
Take trial-product 2g, be placed in the 20ml water of 25 ± 2 DEG C, in 10 seconds of powerful jolting every 1 minute, observe the dissolving situation in 3 minutes.As without visual visible particles of solute, be considered as dissolving completely; If there is visual visible particles of solute, add 5 times of water gagings, repeat aforementioned operation, until dissolve completely.Record total water amount and time.The results are shown in Table 7.
Wherein, SM-3997 crystalline form I, crystal form II, crystalline form III are prepared by the embodiment of the present invention 1,3,5 respectively, SM-3997 currently available products prepares with reference to the existing disclosed method of document (CN101362751B embodiment 4, CN101880274A).
The solvability comparative studies of table 7 crystalline form I, crystal form II, crystalline form III and currently available products
From table 7, compared with SM-3997, the water-soluble that I N-type waferN tool has clear improvement, the solvability of III N-type waferN makes moderate progress equally.
The study on the stability of test example 2 SM-3997 crystalline form I of the present invention, crystal form II, crystalline form III and currently available products
Study on the stability condition comprises:
1. thermal destruction: get the about 200mg of trial-product, be placed in 60 DEG C of loft drier and place;
2. photodegradation: get the about 200mg of trial-product, the environment that is placed in illumination and is 4500 ± 500lx is placed;
3. high humidity degraded: get trial-product 200mg, be placed in and be placed with KNO
3in the moisture eliminator of saturated solution, room temperature is placed.Study on the stability the results are shown in Table 8.
Wherein, SM-3997 crystalline form I, crystal form II, crystalline form III are prepared by the embodiment of the present invention 1,3,5 respectively, SM-3997 currently available products prepares with reference to the existing disclosed method of document (CN101362751B embodiment 4, CN101880274A).
The study on the stability of table 8 crystalline form I, crystal form II, crystalline form III and currently available products
From table 8, the less stable of SM-3997 currently available products to light, heat, particularly, under strong illumination, in product, impurity significantly increases: irradiate 5 days, dopant species is increased to 13, purity drop 0.3%; Irradiate 10 days, dopant species is increased to 14, purity drop 0.63%; Compared with SM-3997 currently available products, the stability of crystalline form I, II, III is better, and wherein, crystalline form I is under accelerated stability test, and dopant species is without obvious increase; Crystal form II and crystalline form III are under accelerated stability test, and dopant species is without obvious increase, and purity is without obvious reduction, shows that crystal form II and crystalline form III have significantly improved the stability of SM-3997,
In sum, SM-3997 new crystal of the present invention, can improve solvability and the stability of original product, is more conducive to preparation, the use of product, the security that has improved product.
Claims (21)
1. the crystalline form I of a SM-3997 compound, it is characterized in that: in this compound crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 24.6 ± 0.2,22.4 ± 0.2,20.7 ± 0.2,19.8 ± 0.2,16.3 ± 0.2,14.9 ± 0.2,14.6 ± 0.2,14.1 ± 0.2,12.1 ± 0.2 degree places.
2. the crystalline form I of SM-3997 compound according to claim 1, is characterized in that: in this compound crystal form X ray powder diffraction, have X-ray powder diffraction figure feature substantially as shown in Figure 1.
3. according to the crystal I of the SM-3997 compound described in claim 1-2 any one, it is characterized in that: the fusing point of described compound crystal I is 167.5 DEG C-168.5 DEG C.
4. the crystal I of SM-3997 compound according to claim 3, is characterized in that: described compound crystal I has DSC collection of illustrative plates substantially as shown in Figure 2.
5. according to the crystal I of the SM-3997 compound described in claim 1-2 any one, it is characterized in that: the infared spectrum of described compound crystal I is at 3442 ± 3cm
-1, 1739 ± 3cm
-1, 1724 ± 3cm
-1, 1692 ± 3cm
-1there is infrared absorption at place.
6. according to the crystal I of the SM-3997 compound described in claim 1-2 any one, it is characterized in that: described compound crystal I has infared spectrum feature substantially as shown in Figure 3.
7. according to the preparation method of the crystal I of the SM-3997 compound described in claim 1-6 any one, it is characterized in that, operation steps is as follows:
A) SM-3997 is dissolved in solvent, makes SM-3997 solution;
B) stir cooling crystallization; Or
C) add xenogenesis solvent, stir cooling crystallization; Wherein, described xenogenesis solvent to the solubleness of SM-3997 than a) step solvent for use is poor;
D) isolation of crystalline, dry, to obtain final product,
Wherein, step b), need in step Crystallization Process c) to stir;
Wherein, step a) described in solvent be selected from any or its combination of the mixed aqueous solution of mixing solutions, acetone and the alcohol of the aqueous solution, alcohol and the acetone of the aqueous solution, the acetone of water, alcohol, alcohol, described alcohol is selected from any one of methyl alcohol, ethanol, Virahol;
Wherein, step a) described in solvent load volume be SM-3997 quality 3-20 doubly;
Wherein, suitably heating in step dissolution process a), Heating temperature is that room temperature is to solvent boiling point.
8. preparation method according to claim 7, step a) described in solvent be any or its combination of water, alcohol, described alcohol is selected from any one of methyl alcohol, ethanol, Virahol.
9. preparation method according to claim 8, is characterized in that, described alcohol is methyl alcohol.
10. preparation method according to claim 7, is characterized in that: step a) described in solvent load volume be SM-3997 quality 4-10 doubly.
11. 1 kinds of pharmaceutical compositions, is characterized in that: it be crystal I by the SM-3997 compound described in claim 1-6 any one as activeconstituents, add the preparation that pharmaceutically acceptable auxiliary material is prepared from.
12. pharmaceutical compositions according to claim 11, is characterized in that: the dosage form of described composition is selected from any of tablet, suspension, capsule, granule, pill, powder, syrup, injection, gelifying agent, lotion, suppository, basting agent, paste.
13. pharmaceutical compositions according to claim 12, wherein said pill is selected from pill.
14. pharmaceutical compositions according to claim 12, wherein said tablet is selected from effervescent.
15. pharmaceutical compositions according to claim 12, wherein said basting agent is selected from any of emulsion, creme, liniment.
16. pharmaceutical compositions according to claim 12, described paste is selected from any of emplastrum, solidifying paste, ointment.
17. pharmaceutical compositions according to claim 11, is characterized in that: the dosage form of described composition is selected from mixture.
18. pharmaceutical compositions according to claim 17, is characterized in that: described mixture is selected from distillate medicinal water.
The crystal I of the SM-3997 compound described in 19. claim 1-6 any one at preparation treatment and serotonin or/and the application in the medicine of norepinephrine reuptake relative disease.
20. application according to claim 19, is characterized in that: described medicine is the medicine for the treatment of central nervous system disease.
21. application according to claim 20, described central nervous system disease is dysthymia disorders, anxiety disorder, Phobias, post-traumatic stress disorder, premenstrua anxiety disorder, ADHD (Attention Deficit Hyperactivity Disorder), obsessional idea and behavior integration disease, autism, schizophrenia, fat, 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, Raynaud syndrome, Parkinson's disease or epileptic condition.
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| CN201310394951.7A CN103641818B (en) | 2011-08-04 | 2011-08-04 | A kind of SM-3997 compound and its production and use |
| CN201110222442.7A CN102344442B (en) | 2011-08-04 | 2011-08-04 | Novel crystal form of tandospirone citrate and preparation method and application thereof |
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| CN201310394951.7A Division CN103641818B (en) | 2011-08-04 | 2011-08-04 | A kind of SM-3997 compound and its production and use |
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| CN103755687B (en) * | 2013-12-25 | 2015-10-21 | 四川科瑞德制药有限公司 | Hydrochloric acid Tandospirone crystalline form I and preparation method thereof |
| CN105218528A (en) * | 2014-06-06 | 2016-01-06 | 四川科瑞德制药有限公司 | A kind of L-TARTARIC ACID Tandospirone compound |
| CN105175398A (en) * | 2014-06-06 | 2015-12-23 | 四川科瑞德制药有限公司 | Tandospirone oxalate compound |
| CN106397412A (en) * | 2015-07-30 | 2017-02-15 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonists, a preparing method thereof and uses of the receptor agonists |
| CN106397410B (en) * | 2015-07-30 | 2021-03-26 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonist and preparation method and application thereof |
| CN106397413B (en) * | 2015-07-30 | 2021-03-26 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonist and preparation method and application thereof |
| CN106397411B (en) * | 2015-07-30 | 2021-03-26 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonist and preparation method and application thereof |
| CN106749196B (en) * | 2015-11-25 | 2020-07-03 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonist |
| CN106905302B (en) * | 2015-12-22 | 2020-07-31 | 四川科瑞德制药股份有限公司 | Azaspiroanone compound and preparation method thereof |
| CN113121507A (en) * | 2019-12-30 | 2021-07-16 | 北大医药股份有限公司 | Stable crystal form of tandospirone citrate and preparation method thereof |
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| CN103641818A (en) | 2014-03-19 |
| CN102344442A (en) | 2012-02-08 |
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