CN104693190B - Crystal form B of compound as well as preparation method and application thereof - Google Patents
Crystal form B of compound as well as preparation method and application thereof Download PDFInfo
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- CN104693190B CN104693190B CN201310665375.5A CN201310665375A CN104693190B CN 104693190 B CN104693190 B CN 104693190B CN 201310665375 A CN201310665375 A CN 201310665375A CN 104693190 B CN104693190 B CN 104693190B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines and particularly discloses a crystal form B of a deoxyC-glucoside SGLT2 inhibitor 4-(6-deoxy-beta-D-glucopyranosyl)-2-[5-(4-fluorophenyl)thiophene-2-methyl]-1-methylbenzene (CD-6) as well as a preparation method and application thereof. The values of the characteristic absorption peaks (2theta) of powder X-ray diffraction of the crystal form are 3.30, 5.34, 6.04, 6.58, 8.10, 8.90, 10.76, 11.60, 12.08, 13.18, 13.90, 14.74, 16.18, 16.88, 18.10, 19.38, 20.52, 21.14, 22.02, 23.36 and 24.50, wherein the measuring error of 2theta is +/-0.2. The crystal form has the characteristics of stable apparent condition, capability of further improving the purity of the compound, stability in preservation, and the like, and has the characteristic of direct supply of active pharmaceutical ingredients. A chemical structural formula of the compound is as shown in the specification.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of phenyl C- glucosides containing deoxyglucose structure and derives
The crystal formation of thing, and in particular to a kind of 4- (6- deoxidation-β-D- glucopyranosyls) -2- [5- (4- fluorophenyls) thiophene -2- methyl] -
The crystal formation B of 1- methylbenzene, and the preparation method and application of the crystal formation.
Background technology
The present inventor with regard to 4- (6- deoxidation-β-D- glucopyranosyls) -2- [5- (4- fluorophenyls) thiophene -2- methyl] -
1- methylbenzene (for convenience of description, hereinafter referred to as CD-6) is used as Na+- glucose cotransporter 2（Or referred to as 2 type sodium glucoses
Cotransport son, sodium-dependent glucose cotransporter2, is abbreviated as SGLT2）Inhibitor have submitted invention
Patent application (CN201310213608.8).The compound can be used to prepare the pharmaceutical composition for the treatment of diabetes, its chemistry knot
Structure formula is as follows：
In research process, the inventors discovered that, the later stage for preparing the final step of above-claimed cpd CD-6 is from solution
In by solvent evaporated isolated product, its form is a kind of solids between white foam and white solid
Matter, and the state fluctuate between each batch it is indefinite, it is difficult to keep constant apparent condition, be not suitable for being made directly as crude drug
With.Simultaneously as the compound often presents certain foam characteristic, so as to increase the difficulty of further purification, to system
Standby highly purified crude drug brings certain difficulty.
The content of the invention
Therefore, it is an object of the invention to overcome drawbacks described above, there is provided a kind of crystal formation B of CD-6, the crystal formation has steady
Fixed apparent condition, contributes to further improving the purity of CD-6, and improves storage stability, and system can be stably supplied
Standby crude drug, and also there is provided the preparation method and application of the crystal formation.
The invention provides a kind of 4- (6- deoxidation-β-D- glucopyranosyls) -2- [5- (4- fluorophenyls) thiophene -2- first
Base] -1- methylbenzene (CD-6) crystal formation B, X-ray powder diffraction (PXRD, the Powder X-ray represented with 2 θ angles
Diffraction) 3.30,5.34,6.04,6.58,8.10,8.90,10.76,11.60,12.08,13.18,13.90,
14.74th, 16.18,16.88,18.10,19.38,20.52,21.14,22.02,23.36,24.50 ° of vicinity have diffraction maximum.
Crystal formation B of the invention, wherein, its X-ray powder diffraction interplanar distance d value be 26.75,16.54,
14.62、13.42、10.91、9.93、8.22、7.62、7.32、6.71、6.37、6.00、5.47、5.25、4.90、4.58、
4.32、4.20、4.03、3.80、Position vicinity there is diffraction maximum.Preferably, the interplanar distance d value and 2 θ angles
There is corresponding relation as shown in table 1 between degree.
Corresponding relation between the interplanar distance d value of table 1 and 2 θ
Crystal formation B of the invention, wherein, its differential thermal analysis（DTA, Differential Thermal Analysis）
Collection of illustrative plates can have endothermic peak at 141 DEG C.
Crystal formation B of the invention, wherein, its X-ray powder diffraction collection is as shown in Figure 2.
Present invention also offers the method for preparing above-mentioned crystal formation B, the method includes：By 4- (6- deoxidation-β-D- glucopyras
Glycosyl) -2- [5- (4- fluorophenyls) thiophene -2- methyl] -1- methylbenzene is dissolved in a kind of good solvent, can subsequently heat this molten
Liquid, is slowly added to a kind of poor solvent, and then slowly cooling crystallization, collected by suction crystallization under agitation, is then dried, and obtains crystalline substance
Type B.
The method according to the invention, wherein, good solvent is selected from ethyl acetate, n-propyl acetate, isopropyl acetate, acetic acid
N-butyl, isopropyl acetate, poor solvent is normal hexane, hexamethylene, diisopropyl ether, ether, petroleum ether.
The method according to the invention, wherein, 4- (6- deoxidation-β-D- glucopyranosyls) -2- [5- (4- fluorophenyls)
Thiophene -2- methyl] quality-volume-volume ratio (g/mL/mL) of -1- methylbenzene and good solvent and poor solvent is 1：5~
10：3~30, preferably 1：7：7.
Preferably, operation is dried using vacuum oil pump, drying time is 4~8 hours, preferably 5 hours.
Present invention also offers a kind of pharmaceutical composition, of the invention crystal formation B of the described pharmaceutical composition comprising effective dose
With one or more pharmaceutically acceptable adjuvant.The pharmaceutically acceptable adjuvant can be to maintain the substrate of pharmaceutical dosage form
Or adjuvant, by being selected according to different medicaments or compositionss are used, be optionally included with carrier, excipient, diluent,
Filler, binding agent, disintegrating agent, lubricant, fluidizer, effervescent, correctivess, preservative, coating material etc..Excipient includes
For example Microcrystalline Cellulose, Lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, Mannitol, Sorbitol,
The combination of one or more in glucose, Fructose, water, Polyethylene Glycol, Propylene Glycol, glycerol, cyclodextrin, cyclodextrin derivative
Thing.Filler includes such as Lactose, sucrose, dextrin, starch, pregelatinized Starch, Mannitol, Sorbitol, calcium hydrogen phosphate, sulphuric acid
The compositionss of one or more of calcium, Calcium Carbonate, Microcrystalline Cellulose.Binding agent includes such as sucrose, starch, polyvidone, carboxylic first
Base sodium cellulosate, hypromellose, hydroxypropylcellulose, methylcellulose, Polyethylene Glycol, medicinal alcohol, one kind of water or several
The compositionss planted.Disintegrating agent includes such as starch, crosslinking polyvidone, Croscarmellose Sodium, low substituted hydroxy-propyl fiber
The compositionss of one or more of element, carmethose, gas-producing disintegrant.
Pharmaceutical composition of the invention, wherein, described pharmaceutical composition can be solid orally ingestible, liquid oral
Preparation or injection.Preferably, the solid orally ingestible include dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, capsule or
Granule；The liquid oral medicine includes oral solution；The injection include injection liquid drugs injection, injection freeze-dried powder,
Big transfusion or primary infusion.
Present invention also offers crystal formation B or the crystal formation B prepared according to the method for the present invention are being prepared for treating diabetes
Pharmaceutical composition in purposes.The inventor has discovered that CD-6 has the inhibitory action of SGLT2, can be used for as effective ingredient
Prepare the medicine in terms of diabetes.And model card is drained by suppression in vitro to humanization SGLT2 and rat glucose in urine
Real, the crystal formation B of the present invention has higher SGLT2 inhibitory activity.
The crystal formation B of CD-6 of the present invention is effective in comparatively wide dosage range.The agent for example taken daily
Amount is divided into and once or being for several times administered about in the range of 1mg~500mg/ people.Actually take the crystal formation B of CD-6 of the present invention
Dosage can be determined according to relevant situation by doctor.These situations include：The condition of patient, route of administration,
Age, body weight, the individual reaction to medicine, order of severity of symptom etc..
Compared with by the CD-6 samples being directly evaporated obtained in the modes such as solution between cystose and normal solid,
CD-6 crystal formation B prepared by the present invention have good appearance stability between batch（It is white solid, rather than with certain journey
The cystose feature of degree）And repeatability, and purity further improves.For example, the present inventor is found by experiment that, crystal formation B
In the range of the continuous batch for preparing 15 batches, its outward appearance is stable, is normally white solid, and through PXRD and DTA
Analysis is stable crystal formation B per criticizing.In addition, each batch through HPLC analyses, the purity of crystal formation B is 99.60%~99.70%,
It is significantly higher than the purity 98.33% of CD-6 raw materials.
Additionally, the crystal formation B of the present invention also has good storage stability.For example, the present inventor, should by experimental verification
Crystal formation B two weeks by a definite date to light, heat, the stability experiment of vapor in, its impurity is not significantly increased, thus with good
Bin stability.
Based on above-mentioned characteristic, the crystal formation B of the present invention can be more suitable for industrialization as the stable supplying source of CD-6 crude drug
Production.
Description of the drawings
Hereinafter, with reference to accompanying drawing describing embodiment of the present invention in detail, wherein：
Fig. 1 shows differential thermal analyses (DTA) collection of illustrative plates of obtained crystal formation B in embodiment 1；
Fig. 2 shows the PXRD collection of illustrative plates of obtained crystal formation B in embodiment 1.
Specific embodiment
The present invention is further illustrated below by specific embodiment, it should be understood, however, that, these embodiments are only
It is used for specifically describing in more detail, and is not to be construed as limiting the present invention in any form.
This part to the present invention test used in material and test method carry out general description.Although being
But realize that many materials that the object of the invention used and operational approach are it is known in the art that the present invention still here is use up
May describe in detail.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour
It is well known in the art as method.
With the following Examples, the present invention is as follows to the condition determination of crystal formation B：
X-ray powder diffraction（PXRD）Condition：
Instrument：Rigaku D/Max-2500 types 18kW
Diffractometer：Polycrystal powder diffractometer
Target：Cu-K α are radiated,2 θ=3~50 °
Pipe pressure：40KV
Pipe flow：100mA
Scanning speed：8℃/min
Crystalline graphite monochromator
DS/SS=1°
RS：0.3mm
Differential thermal analyses (DTA) condition：
Instrument：Rigaku PTC-10A TG-DTA analysers
Heating rate：10℃/min
Scanning temperature range：0~300 DEG C
Reference substance：Al2O3
Sample size：The crystal formation B to be measured of 5.8mg
High performance liquid chromatography (HPLC) condition：
Chromatographic column：C18, 150mm × 4.6mm, 5 μm
Mobile phase：Methanol/water/acetic acid=70/30/0.25
Wavelength：230nm
Flow velocity：0.8ml/min
Sample size：10μL
Column temperature：35℃
Instrument：It is general to analyse general L6 chromatograph of liquid
Hitachi's L-7250 automatic samplers
It is general to analyse general LC Win chromatographic work stations
Embodiment 1
The present embodiment is used to illustrate the crystal formation B and its preparation process of CD-6 of the present invention.
CD-6 is prepared as raw material.It is referred to following reaction scheme：
Specifically preparation process can be：
The THF for being dried addition 36.1g (0.1mol) compound I-1 and 600mL dryings in round-bottomed flask of one 2L, adds
Magneton, is sealed after nitrogen purging with rubber cork.Flask is placed in liquid nitrogen-ethanol system and is cooled to -78 DEG C, starts electromagnetism and stirs
Mix.Slowly with the n-BuLi of syringe Deca 62.5mL (0.1mmol) 1.6M, continue at such a temperature to stir after completion of dropping
Half an hour, then by syringe, slowly Deca 43.3g (10mmol) II is dissolved in solution made by the THF that 200mL is dried.Deca
After finishing, reactant mixture continues at such a temperature stirring 1 hour.Under ice-water bath cooling, by Dropping funnel slowly Deca
28.8g (0.3mol) methanesulfonic acid is dissolved in solution made by 200mL methanol, is stirred overnight under room temperature after completion of dropping.Reaction mixing
Thing is poured in 4000mL frozen water, stirring, uses saturation NaHCO3Solution adjusts pH=4-6, the dichloromethane extraction of 500mL × 3.
Merge organic faciess, weak brine washing, anhydrous sodium sulfate drying is evaporated on a rotary evaporator, and residue is the crude product of III.
The crude product is directly used in next step reaction without purification.
The crude product of the compound III of above-mentioned preparation is dissolved in the dichloromethane of 500mL dryings in the round-bottomed flask of 2L, plus
Enter 23.3g (0.2mol) Et3SiH, stirs under -30 DEG C of coolings.By Dropping funnel slowly Deca 14.2g (0.1mmol) three
Fluorination borate ether is dissolved in solution made by the dichloromethane that 50mL is dried.After completion of dropping, reactant mixture continues at -30 DEG C
Stirring is then gradually heating to room temperature for 1 hour, and continues to stir 5 hours at room temperature, and TLC shows that reaction is completed.Toward reactionization
200mL saturated sodium bicarbonate solutions are carefully added in compound, continue to be poured in 2000mL frozen water after stirring half an hour, stirred,
The dichloromethane extraction of 500mL × 3.Merge organic faciess, weak brine washing, anhydrous sodium sulfate drying is steamed on a rotary evaporator
Dry, residue column chromatography purification obtains the sterling of IV, white foam solid,1H NMR(DMSO-d6,400MHz),δ7.26-
7.37(m,14H),7.13-7.20(m,4H),6.93-6.98(m,5H),6.63(d,1H,J=3.6Hz),4.88-4.94(m,
2H),4.70(d,1H,J=10.8Hz),4.37(d,1H,J=10.4Hz),4.21(d,1H,J=9.6Hz),4.16(d,1H,J=
12.0Hz),4.09(d,1H,J=12.0Hz),3.90(d,1H,J=10.4Hz),3.76(t,1H,J=9.0Hz),3.53-3.60
(m,2H),3.32(t,1H,J=9.0Hz),2.33(s,3H),1.34(d,3H,J=6.0Hz).
34.9g (50mmol) compound IV is dissolved in the methyl phenyl ethers anisole of 200mL dryings, stirring under -10 DEG C of coolings, is slowly added into
The anhydrous AlCl of 33.3g (0.25mol)3, room temperature is slowly raised to after adding, it is stirred for 1 hour, TLC shows that reaction is completed.Reaction is mixed
It is poured in 2000mL frozen water after compound is slightly cold, stirs, the ethyl acetate extraction of 500mL × 3.Merge organic faciess, weak brine is washed
Wash, anhydrous sodium sulfate drying is evaporated on a rotary evaporator, residue through short column chromatography after purification gained white solid,
It is dried and is CD-6.The white solid has certain foam property.1H NMR(DMSO-d6,400MHz),δ7.56-7.60(m,
2H),7.26(d,1H,J=3.6Hz),7.17-7.21(m,3H),7.10-7.12(m,2H),6.78(d,1H,J=3.6Hz),
4.92(d,1H,J=5.2Hz),4.86(d,1H,J=4.0Hz),4.68(d,1H,J=5.2Hz),4.14(d,1H,J=16.0Hz),
4.09(d,1H,J=16.0Hz),3.96(d,1H,J=9.2Hz),3.14-3.31(m,3H),2.90-2.95(m,1H),2.25
(s,3H),1.15(d,3H,J=6.0Hz);13C NMR(DMSO-d6,100MHz),δ162.54,160.12,143.57,
140.19,138.23,137.37,134.85,130.47,129.64,128.85,126.94,126.86,126.31,126.05,
123.34,115.93,115.72,81.32,78.16,75.71,75.59,74.81,33.35,18.75,18.23.
Products C D-6 obtained in taking 1.00g said methods is placed in the round-bottomed flask of 100mL, adds ethyl acetate 7mL, is stirred
Mix, with 50 DEG C of hot water heating, obtain the solution of a clarification.Then the slowly Deca 7mL normal hexane into round-bottomed flask, Deca
After finishing, heating source (hot water) is removed, be stirred overnight under Temperature fall, obtain a white magma shape system.Collected by suction is crystallized,
And 30 DEG C in the vacuum oil pump at be dried 5 hours, obtain the white solid 0.67g of CD-6 of the present invention, the response rate is 67%.
Differential thermal analyses (DTA) collection of illustrative plates and X-ray diffraction (PXRD) collection of illustrative plates of the CD-6 crystal formation B is respectively such as Fig. 1 and Fig. 2 institutes
Show, it may be determined that CD-6 crystal formations obtained in the present embodiment are crystal formation B.
Embodiment 2-10
With reference to the operational approach of embodiment 1, using 1.00g CD-6 as raw material, related experiment parameter is converted, still may be used
To prepare the crystal formation B (table 2) of CD-6.
The crystal formation B of CD-6 is prepared under the different experiments parameter of table 2.
| Embodiment | Good solvent and its volume | Poor solvent and its volume | Temperature (DEG C) when solvent mixes | Yield (%) |
| 2 | Ethyl acetate 5mL | Hexamethylene 5mL | 40 | 71 |
| 3 | N-propyl acetate 7mL | Normal hexane 3mL | 45 | 64 |
| 4 | Isopropyl acetate 8mL | Diisopropyl ether 8mL | 50 | 65 |
| 5 | N-butyl acetate 9mL | Ether 10mL | 50 | 68 |
| 6 | Isopropyl acetate 10mL | Petroleum ether 15mL | 50 | 67 |
| 7 | Ethyl acetate 10mL | Petroleum ether 18mL | 50 | 72 |
| 8 | Ethyl acetate 7mL | Petroleum ether 20mL | 50 | 68 |
| 9 | Ethyl acetate 7mL | Petroleum ether 25mL | 50 | 78 |
| 10 | Ethyl acetate 7mL | Petroleum ether 30mL | 50 | 82 |
Determine that the white solid in above-described embodiment is the crystal formation B of CD-6 by DTA and PXRD.
Embodiment 11
The present embodiment is used for the preparation of the tablet of CD-6 crystal formation B of the explanation containing the present invention.
Sample crystal formation B, pregelatinized Starch and Microcrystalline Cellulose obtained in embodiment 1 are sieved, are sufficiently mixed with recipe quantity,
The solution containing recipe quantity polyvinylpyrrolidone, mixing, soft material processed is added to sieve, wet granular processed, in 50~60 DEG C of dryings；
Then Sodium carboxymethyl starch, magnesium stearate and Pulvis Talci are sieved in advance, above-mentioned dried granule is added to recipe quantity
In, tabletting obtains final product the tablet containing CD-6 crystal formation B.
Embodiment 12According to the side that document (Meng, W.et al, J.Med.Chem., 2008,51,1145-1149) is recorded
Method determines the IC that the crystal formation B of CD-6 obtained in embodiment 1 suppresses to SGLT2 and SGLT150Value.Measurement result is as shown in table 3 below：
The IC that the crystal formation B of table 3.CD-6 suppresses to SGLT2 and SGLT150Value
According to IC in upper table50The measurement result of value understands that the crystal formation B of CD-6 is strong selective SGLT2 inhibitor.
Embodiment 13
The purity of crystal formation B obtained in embodiment 1 is determined using HPLC, its purity is 99.65%.And be used to prepare crystal formation B's
CD-6 raw materials measure purity for 98.33%.It can thus be appreciated that the purity of crystal formation B is significantly improved, the batch life of medicine is particularly suited for
Produce.
Embodiment 14CD-6 crystal formations B obtained in embodiment 1 is carried out into influence factor's test with CD-6 raw materials as a comparison,
Respectively in illumination (natural sunlight, averagely about 80000Lx), high temperature (60 DEG C) and high humidity (80% relative humiditys at 40 DEG C)
Under conditions of place two weeks (14 days), outward appearance, impurity number and impurity level (determining with HPLC) were compared with the 0th day.Result of the test
4~6 are shown in Table respectively.
The light durability test data of table 4.
The thimble test data of table 5.
The high humidity stability test data of table 6.
From table 4~6, in the stability test under the illumination of two weeks, high temperature, super-humid conditions by a definite date, the present invention is brilliant
There is no visible change in the outward appearance of type B, crystal formation keeps stable, while by HPLC measure, its impurity number and total impurities
It is not apparent from increasing, thus compared with CD-6 raw materials, crystal formation B has more preferable bin stability, can be used as CD-6 crude drug
Stable source.
Embodiment 15
Rejection abilities of the model determination CD-6 crystal formations B to SGLT2 is drained by rat glucose in urine.
After the high sugar of the high fat of normal SD rats is fed one month, with low dose of repeatedly lumbar injection modeling (the 2 types sugar of streptozocin
Urine disease model), determine blood sugar content before and after modeling.It is after modeling success that modeling rat is random according to twenty-four-hour urine sugar amount and body weight
Packet (8/group), respectively one group blank group (giving equal-volume 0.5%CMC sodium solutions) and testing compound group (10mg/
kg).Fasting 16 hours before each group rat experiment.Gavage is given after CD-6 crystal formations B0.5h obtained in experimental rat embodiment 1, then
Gavage gives glucose (2g/kg).The urine of 0~12h time periods after administration is collected, with determination of glucose oxidase each time
The urine sugar value of section.Experiment measures crystal formation B and can induce generation 734mg glucoses in urine/200g body weight in this experiment, illustrates that crystal formation B has
Stronger glucose in urine discharges ability.
Although present invention has been a certain degree of description, it will be apparent that, without departing from the spirit and scope of the present invention
Under the conditions of, the appropriate change of each condition can be carried out.It is appreciated that the invention is not restricted to the embodiment, and it is attributed to right
The scope of requirement, it includes the equivalent of each factor.
Claims (12)
1. a kind of 4- (6- deoxidation-β-D- glucopyranosyls) -2- [5- (4- fluorophenyls) thiophene -2- methyl] -1- methylbenzene
(CD-6) crystal formation B, it is characterised in that crystal formation X-ray powder diffraction characteristic absorption peak (2 θ) value is：3.30、5.34、
6.04、6.58、8.10、8.90、10.76、11.60、12.08、13.18、13.90、14.74、16.18、16.88、18.10、
19.38th, 20.52,21.14,22.02,23.36,24.50,2 θ measurement error are ± 0.2,
2. crystal formation B according to claim 1, it is characterised in that the X-ray powder diffraction characteristic absorption peak (2 θ) with
Interplanar distance d value has following corresponding relation：
3. crystal formation B according to claim 1 and 2, it is characterised in that the X-ray powder diffraction collection such as description figure
Shown in 2.
4. crystal formation B according to claim 1 and 2, it is characterised in that its differential thermal analyses collection of illustrative plates has heat absorption at 141 DEG C
Peak.
5. a kind of 4- as claimed in claim 1 or 2 (6- deoxidation-β-D- glucopyranosyls) -2- [5- (4- fluorophenyls) thiophenes
Fen -2- methyl] -1- methylbenzene crystal formation B preparation method, it is characterised in that by 4- (6- deoxidation-β-D- Glucopyranose .s
Base) -2- [5- (4- fluorophenyls) thiophene -2- methyl] -1- methylbenzene is dissolved in a kind of good solvent, it is slowly added to a kind of bad molten
Agent, the lower crystallize of stirring, collected by suction crystallization is dried, and obtains crystal formation B.
6. method according to claim 5, it is characterised in that the good solvent is ethyl acetate, n-propyl acetate, second
Isopropyl propionate, n-butyl acetate, poor solvent is normal hexane, hexamethylene, diisopropyl ether, ether, petroleum ether.
7. preparation method according to claim 5, it is characterised in that the 4- (6- deoxidation-β-D- glucopyranosyls)-
2- [5- (4- fluorophenyls) thiophene -2- methyl] -1- methylbenzene is with the usage ratio of good solvent and poor solvent：1:5~10:
3~30；The ratio is mass volume ratio；Unit is g/mL/mL.
8. preparation method according to claim 7, it is characterised in that the 4- (6- deoxidation-β-D- glucopyranosyls)-
2- [5- (4- fluorophenyls) thiophene -2- methyl] -1- methylbenzene is with the usage ratio of good solvent and poor solvent：1/7/7.
9. a kind of pharmaceutical composition, it is characterised in that any one of claim 1~2 of the described pharmaceutical composition comprising effective dose
Described crystal formation B and one or more pharmaceutically acceptable adjuvant.
10. pharmaceutical composition according to claim 9, it is characterised in that described pharmaceutical composition be solid orally ingestible,
Liquid oral medicine or injection.
11. pharmaceutical compositions according to claim 10, wherein, the solid orally ingestible include dispersible tablet, enteric coatel tablets,
Chewable tablet, oral cavity disintegration tablet, capsule or granule；The liquid oral medicine includes oral solution；The injection includes injection
With liquid drugs injection, injection freeze-dried powder, big transfusion or primary infusion.
Purposes of the crystal formation B described in 12. claim 1 or 2 in the medicine for treating diabetes is prepared.
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| CN104693190A (en) | 2015-06-10 |
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