CN104974146B - Crystal formation E, crystal formation F of canagliflozin and preparation method thereof - Google Patents
Crystal formation E, crystal formation F of canagliflozin and preparation method thereof Download PDFInfo
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- CN104974146B CN104974146B CN201410467951.XA CN201410467951A CN104974146B CN 104974146 B CN104974146 B CN 104974146B CN 201410467951 A CN201410467951 A CN 201410467951A CN 104974146 B CN104974146 B CN 104974146B
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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 present invention provides two kinds of novel crystal forms of canagliflozin (canagliflozin), crystal formation E and crystal formation F, and preparation method thereof.The novel crystal forms that the present invention is prepared have very big improvement in form and particle diameter, and particle is tiny and dispersed, beneficial to drug solubility and dissolution rate is improved, are easy to formulation development.
Description
Technical field
The present invention relates to chemical medicine, more particularly to the Kan Ge of the hypoglycemic agent available for treatment type II diabetes
Arrange net crystal formation E, crystal formation F and preparation method thereof.
Background technology
Canagliflozin (canagliflozin, the compound shown in formula I), chemical name be 1- (β-D- glycopyranosyls)-
4- methyl -3- [5- (4- fluorophenyls) -2- thienyl methyls] benzene, is by Johnson ＆ Johnson's pharmacy (Johnson＆Johnson) subsidiary
Janssen Pharmaceutica is researched and developed, and FDA is obtained on March 29th, 2013 and ratifies hypoglycemic drug for treating type II diabetes, is FDA
First sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor of approval.SGLT2 inhibitor being capable of specificity suppression kidney pair
The reabsorption of glucose, excessive glucose is set to be discharged from urine so as to directly reduce blood sugar level.The knot of the drug molecule
Structure is as follows：
It is well known that polymorphism is widely present in medicine.The different crystal forms of same medicine are in outward appearance, particle diameter, molten
Xie Du, mobility, fusing point, dissolution rate, biological effectiveness etc. might have it is dramatically different, also can to the stability of medicine,
Bioavilability and curative effect produce different influences.Therefore, comprehensive and systematic screening polymorph is carried out in medicament research and development, selection is most
It is adapted to the crystal formation of exploitation, is one of very important important research content.
Patent CN101573368B discloses the semihydrate crystal formation and its method for crystallising of canagliflozin, and the crystal formation is finally used
In industrialization.
Patent CN101801371B discloses the compound crystal form and its method for crystallising of canagliflozin, described in the document
Method for crystallising step is more, and needs to carry out under conditions of argon gas protection.
Patent CN103889429 A disclose canagliflozin and L-PROLINE, D-PROLINE, L-phenylalanine eutectic with
And amorphous canagliflozin, the patent are mainly the eutectic and its crystallization side that the canagliflozin described is formed with other various assistant agents
Method.
Patent CN103554092A discloses the crystal formation B of canagliflozin, is volatilized from the in the mixed solvent of second alcohol and water
Arrive.Its X-ray powder diffraction figure 2theta values be 6.3 ° ± 0.2 °, 9.4 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.6 ° ±
There is characteristic peak at 0.2 °, 16.9 ° ± 0.2 ° and 18.2 ° ± 0.2 °.
Patent CN103588762A discloses crystal formation C, D of canagliflozin.Crystal formation C is molten from the mixing of tetrahydrofuran and water
Volatilization obtains in agent, and crystal formation C is in N2Under protection crystal formation D is obtained after 80 degree of heating.
Patent CN103980261A, CN103980262A and CN103936725A and A crystal formations, the B for disclosing canagliflozin
Crystal formation, C crystal form, in terms of patent data, A, B crystal form are laminated structure, and mobility is bad；C crystal form crystallinity is bad, and baseline is uneven
Surely and it is nearly all broad peak, there is mixed crystal, stability needs further textual criticism.
Patent CN103936726A discloses the crystal formation III and crystal formation IV of canagliflozin.Crystal formation III is that one and half n-octyl alcohols are molten
Agent compound, in the case of available, typically not directly as medicinal crystal-form, and crystal formation IV needs to remove solvent by crystal formation III
Change and prepare.
Based on problem of the prior art, 1- (β-D- glycopyranosyls) -4- methyl -3- [5- (4- fluorophenyls) -2- thiophenes are developed
Fen ylmethyl] benzene novel crystal forms, for the exploitation of Subsequent pharmacological, to provide new selection very necessary.
The content of the invention
It is an object of the invention to provide the two of canagliflozin kind crystal formation E and crystal formation F and its Pharmaceutical composition, preparation side
Method.Stability of crystal form provided by the invention is good, and particle is tiny and dispersed, is more beneficial for formulation development, is adapted to industrial metaplasia
Production.
It is an object of the present invention to provide a kind of crystal formation E of canagliflozin.
The crystal formation E of canagliflozin provided by the invention, it is characterised in that in 2theta values in its X-ray powder diffraction figure
To have at 19.3 ° ± 0.2 °, 18.4 ° ± 0.2 °, 9.6 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.7 ° ± 0.2 °, 17.5 ° ± 0.2 °
There is characteristic peak.
Further, the crystal formation E of canagliflozin provided by the invention, is further characterized in that, its X-ray powder diffraction figure
It is that there is characteristic peak at 14.6 ° ± 0.2 °, 21.2 ° ± 0.2 °, 22.4 ° ± 0.2 ° also in 2theta values.
Further, the crystal formation E of canagliflozin provided by the invention, is further characterized in that, its X-ray powder diffraction
(XRPD) figure is substantially consistent with Fig. 1.
Further, the crystal formation E of canagliflozin provided by the invention, it is characterised in that be heated to 72.5 DEG C and nearby go out
Existing endothermic peak, its differential scanning calorimetric analysis (DSC) figure are substantially consistent with Fig. 2.
Further, the crystal formation E of canagliflozin provided by the invention, it is characterised in that being heated to 82 DEG C has about
7.1% weightlessness, its thermogravimetric analysis (TGA) figure are substantially consistent with Fig. 3.
Further, the crystal formation E of canagliflozin provided by the invention, it is characterised in that crystal formation E is that the solvent of acetic acid closes
Thing.
It is a further object of the invention to provide canagliflozin crystal formation E preparation method.
Further, canagliflozin crystal formation E provided by the invention preparation method, it is characterised in that including following step
Suddenly：
(1) powder of canagliflozin is dissolved in the in the mixed solvent of acetic acid and liquid alkane；
(2) stir and be cooled to crystal precipitation, the crystallization that filter collection separates out is crystal formation E；
Step (1) described operation, can be the powder of canagliflozin is directly dissolved in acetic acid and liquid alkane mixing it is molten
Agent or the powder of canagliflozin is first dissolved in acetic acid, then liquid alkane is added in acetic acid solution.
Further, the mixed solvent of described acetic acid and liquid alkane, it is characterised in that the acetic acid and liquid alkane
The ratio of hydrocarbon is less than 2:1, more preferably 2:1 to 1:10.
Further, the preferred pentane of described liquid alkane, hexane or heptane, further preferred heptane.
It is a further object to provide a kind of the crystal formation E and pharmaceutic adjuvant of the canagliflozin comprising effective therapeutic dose
Pharmaceutical composition.Usually the crystal formation E of the canagliflozin of therapeutically effective amount is mixed or connect with one or more pharmaceutic adjuvants
Touch and pharmaceutical composition or preparation is made, the pharmaceutical composition or preparation are prepared in a manner of well known in pharmaceutical field.
In pharmaceutical composition of the present invention, the crystal formation E of canagliflozin, available for the drop for preparing treatment type II diabetes
Purposes in hypoglycemic medicament preparation.
It is a further object of the invention to provide a kind of crystal formation F of canagliflozin.
The crystal formation F of canagliflozin provided by the invention, it is characterised in that in 2theta values in its X-ray powder diffraction figure
To have at 17.2 ° ± 0.2 °, 19.9 ° ± 0.2 °, 16.7 ° ± 0.2 °, 23.1 ° ± 0.2 °, 15.8 ° ± 0.2 °, 20.9 ° ± 0.2 °
There is characteristic peak.
Further, the crystal formation F of canagliflozin provided by the invention, is further characterized in that, its X-ray powder diffraction figure
It is that there is characteristic peak at 26.6 ° ± 0.2 °, 14.0 ° ± 0.2 °, 28.6 ° ± 0.2 ° also in 2theta values.
Further, the crystal formation F of canagliflozin provided by the invention, is further characterized in that, its X-ray powder diffraction
(XRPD) figure is substantially consistent with Fig. 4.
Further, the crystal formation F of canagliflozin provided by the invention, it is characterised in that be heated to 54.1 DEG C and nearby go out
Existing endothermic peak, its differential scanning calorimetric analysis (DSC) figure are substantially consistent with Fig. 5.
Further, the crystal formation F of canagliflozin provided by the invention, it is characterised in that being heated to 78 DEG C has about
11.9% weightlessness, its thermogravimetric analysis (TGA) figure are substantially consistent with Fig. 6.
Further, the crystal formation F of canagliflozin provided by the invention, it is characterised in that crystal formation F is the third of canagliflozin
Ketone solvates.
It is a further object of the invention to provide canagliflozin crystal formation F preparation method.
Canagliflozin crystal formation F provided by the invention preparation method, it is characterised in that comprise the following steps：
(1) powder of canagliflozin is dissolved in the in the mixed solvent of acetone and liquid alkane；
(2) stir and be cooled to crystal precipitation, the crystallization that filter collection separates out is crystal formation F；
Step (1) described operation, can be the powder of canagliflozin is directly dissolved in acetone and liquid alkane mixing it is molten
Agent or the powder of canagliflozin is first dissolved in acetone, then liquid alkane is added in acetone soln.
Further, the mixed solvent of described acetone and liquid alkane, it is characterised in that the acetic acid and liquid alkane
The ratio of hydrocarbon is less than 2:1, more preferably 2:1 to 1:2.
Further, the preferred pentane of described liquid alkane, hexane or heptane, further preferred heptane.
Beneficial effects of the present invention are：
Crystal formation provided by the invention has good physical and chemical stability, and the lower 90 days crystal formations of room temperature condition do not change
Become；
Crystal formation provided by the invention is compared with the semihydrate (CN101573368B) of final industrialization, in form and particle diameter
On have very big improvement, particle is tiny and dispersed, beneficial to drug solubility and dissolution rate is improved, is easy to preparation to open
Hair；
Crystal formation preparation method provided by the invention is simple, process control, solvent safety and conventional is easy to get；
Solvate crystal formation provided by the invention, is easy to desolvation, and it is amorphous to prepare pure canagliflozin, the preparation
Method is simple, cost is low, environment-friendly, and compared with routinely preparing unbodied method, the amorphous purity of preparation greatly improves,
It is particularly suited for industrialized production.
Brief description of the drawings
The XRPD figures that Fig. 1 is the crystal formation E of canagliflozin
The DSC figures that Fig. 2 is the crystal formation E of canagliflozin
The TGA figures that Fig. 3 is the crystal formation E of canagliflozin
The XRPD figures that Fig. 4 is the crystal formation F of canagliflozin
The DSC figures that Fig. 5 is the crystal formation F of canagliflozin
The TGA figures that Fig. 6 is the crystal formation F of canagliflozin
Fig. 7 be canagliflozin crystal formation E stability test XRPD comparison diagrams (upper figure be crystal formation E place 90 days before
XRPD schemes, and figure below is the XRPD figures after crystal formation E is placed 90 days)
Fig. 8 be canagliflozin crystal formation F stability test XRPD comparison diagrams (upper figure be crystal formation F place 90 days before
XRPD schemes, and figure below is the XRPD figures after crystal formation F is placed 90 days)
Fig. 9 is the petrographic microscope figure of the semihydrate crystal formation (CN101573368B) of canagliflozin
Figure 10 is the crystal formation E of canagliflozin petrographic microscope figure
Figure 11 is the crystal formation F of canagliflozin petrographic microscope figure
Embodiment
The raw materials used semihydrate crystal formation for canagliflozin in the present invention, is obtained by the mode of commercially available purchase.
Used abbreviation is explained as follows in the present invention：
XRPD：X-ray powder diffraction
DSC：Differential scanning calorimetric analysis
TGA：Thermogravimetric analysis
D10：(volume distributed median) accounts for the particle diameter corresponding to 10% in expression particle diameter distribution
D50：(volume distributed median) accounts for the particle diameter corresponding to 50%, also known as meso-position radius in expression particle diameter distribution
D90：(volume distributed median) accounts for the particle diameter corresponding to 90% in expression particle diameter distribution
X-ray powder diffraction figure in the present invention described in embodiment is in Panalytical Empyrean X ray
Gathered on powder diffractometer.The method parameter of described X-ray powder diffraction is as follows：
X ray reflection parameter：Cu,Kα
Kα1()：1.540598；Kα2()：1.544426
The intensities of K α 2/K α 1：0.50
Voltage：45 KVs (kV)
Electric current：40 milliamperes (mA)
Divergent slit：Automatically
Scan pattern：Continuously
Scanning range：From 3.0 to 40.0 degree
Sampling step length：0.013 degree
Differential scanning calorimetric thermogram in the present invention described in embodiment gathers on TA Q200.Described difference
Show that the method parameter of scanning thermometric analysis is as follows：
Temperature range/DEG C：Room temperature is to 300 DEG C
Sweep speed/DEG C/min：10 DEG C/min
Protective gas：The ml/min of nitrogen 50
Thermogravimetric analysis figure in the present invention described in embodiment gathers on TA Q5000.Described thermogravimetric analysis
Method parameter is as follows：
Temperature range：Room temperature is to 300 DEG C
Sweep speed：10 DEG C/min
Protective gas：The ml/min of nitrogen 25
Particle diameter distribution result in the present invention described in embodiment is the S3500 type laser in Microtrac companies
Gathered on Particle Size Analyzer.Microtrac S3500 are equipped with SDC (Sample Delivery Controller) sampling system.
This test uses wet method, and test decentralized medium is Isopar G.The method parameter of described laser particle size analyzer is as follows：
*：Flow velocity 60% is the 60% of 65 milliliters/seconds.
Embodiment 1：The crystal formation E of canagliflozin preparation
The powder of 499.5mg canagliflozins is dissolved in 13.25mL acetic acid：Normal heptane=1:3(v:V) in mixed system,
Then stirred 20 hours under the conditions of being placed on -20 DEG C rapidly, gained solid is crystal formation E.Its XRPD figure is shown in Fig. 1, and its DSC figure is shown in
Fig. 2, its TGA figure are shown in Fig. 3.
Crystal formation E 2theta values and the respective value of intensity are as shown in table 1 in the present embodiment：
The crystal formation E of table 1 2theta values and the respective value of intensity
| 2theta | D intervals | Intensity % |
| 6.66 | 13.27 | 35.21 |
| 7.86 | 11.24 | 7.84 |
| 9.58 | 9.23 | 78.13 |
| 9.71 | 9.11 | 68.56 |
| 12.70 | 6.97 | 34.00 |
| 14.60 | 6.07 | 46.08 |
| 15.83 | 5.60 | 35.48 |
| 17.09 | 5.19 | 29.69 |
| 17.45 | 5.08 | 67.90 |
| 18.18 | 4.88 | 32.58 |
| 18.44 | 4.81 | 87.70 |
| 18.91 | 4.69 | 27.78 |
| 19.25 | 4.61 | 100.00 |
| 19.92 | 4.46 | 52.56 |
| 20.14 | 4.41 | 75.18 |
| 20.70 | 4.29 | 72.38 |
| 21.19 | 4.19 | 44.95 |
| 21.43 | 4.15 | 26.74 |
| 22.39 | 3.97 | 42.47 |
| 22.88 | 3.89 | 10.85 |
| 23.24 | 3.83 | 10.50 |
| 23.87 | 3.73 | 12.78 |
| 24.11 | 3.69 | 22.33 |
| 24.49 | 3.63 | 25.63 |
| 24.69 | 3.61 | 37.60 |
| 25.06 | 3.55 | 30.39 |
| 26.48 | 3.37 | 21.81 |
| 27.51 | 3.24 | 10.66 |
| 27.98 | 3.19 | 11.41 |
| 29.08 | 3.07 | 9.49 |
| 29.48 | 3.03 | 13.61 |
| 29.89 | 2.99 | 18.40 |
| 30.16 | 2.96 | 41.06 |
| 31.94 | 2.80 | 9.83 |
| 32.59 | 2.75 | 4.79 |
| 34.52 | 2.60 | 12.19 |
| 35.16 | 2.55 | 8.01 |
| 35.85 | 2.51 | 6.14 |
| 37.36 | 2.41 | 4.98 |
| 38.53 | 2.34 | 4.64 |
| 38.89 | 2.32 | 6.04 |
Embodiment 2：The crystal formation E of canagliflozin preparation
The powder of 19.6mg canagliflozin is dissolved in 0.20mL acetic acid：Normal heptane=1:1(v:V) in the mixed solvent,
Then stirred 20 hours under the conditions of being placed on -20 DEG C rapidly, gained solid is crystal formation E.
Crystal formation E 2theta values and the respective value of relative intensity are as shown in table 2 in the present embodiment：
The crystal formation E of table 2 2theta values and the respective value of relative intensity
| 2theta | D intervals | Intensity % |
| 6.65 | 13.29 | 26.49 |
| 9.67 | 9.14 | 100.00 |
| 12.69 | 6.97 | 11.84 |
| 14.57 | 6.08 | 45.47 |
| 15.83 | 5.60 | 14.67 |
| 17.45 | 5.08 | 35.69 |
| 18.15 | 4.89 | 21.63 |
| 18.46 | 4.81 | 38.71 |
| 19.24 | 4.61 | 57.65 |
| 20.16 | 4.41 | 36.65 |
| 20.72 | 4.29 | 33.18 |
| 21.18 | 4.19 | 26.97 |
| 22.40 | 3.97 | 15.64 |
| 24.46 | 3.64 | 25.11 |
| 25.21 | 3.53 | 12.00 |
| 26.50 | 3.36 | 8.82 |
| 27.84 | 3.20 | 2.49 |
| 29.46 | 3.03 | 14.63 |
| 30.20 | 2.96 | 14.80 |
| 32.03 | 2.79 | 6.37 |
| 34.49 | 2.60 | 5.18 |
| 35.14 | 2.55 | 5.83 |
Embodiment 3：The crystal formation E of canagliflozin preparation
The powder of 21.1mg canagliflozin is dissolved in 0.40mL acetic acid solvents, it is normal then to add 0.50mL normal heptanes
Temperature stirring 5 days, gained solid is crystal formation E.
Crystal formation E 2theta values and intensity respective value are as shown in table 3 in the present embodiment：
The crystal formation E of table 3 2theta values and the respective value of intensity
| 2theta | D intervals | Intensity % |
| 6.57 | 13.46 | 7.82 |
| 9.56 | 9.25 | 100.00 |
| 14.45 | 6.13 | 44.37 |
| 15.71 | 5.64 | 8.62 |
| 17.33 | 5.12 | 29.48 |
| 18.02 | 4.92 | 22.90 |
| 18.33 | 4.84 | 28.20 |
| 19.13 | 4.64 | 50.71 |
| 20.03 | 4.43 | 24.10 |
| 21.06 | 4.22 | 24.78 |
| 22.25 | 4.00 | 9.83 |
| 24.34 | 3.66 | 24.31 |
| 29.35 | 3.04 | 13.73 |
| 29.98 | 2.98 | 8.34 |
| 31.90 | 2.81 | 7.12 |
Embodiment 4：The crystal formation F of canagliflozin preparation
The powder of 500.9mg canagliflozins is dissolved in 10.00mL acetone：Normal heptane=2:3(v:V) in mixed system,
Then stirred 20 hours under the conditions of being placed on -20 DEG C rapidly, gained solid is crystal formation F after testing.
Crystal formation F 2theta values and the respective value of relative intensity are as shown in table 4 in the present embodiment：
The crystal formation F of table 4 2theta values and the respective value of relative intensity
| 2theta | D intervals | Intensity % |
| 8.81 | 10.04 | 5.67 |
| 11.51 | 7.69 | 20.19 |
| 11.69 | 7.57 | 20.13 |
| 12.01 | 7.37 | 14.36 |
| 13.28 | 6.67 | 23.68 |
| 14.00 | 6.33 | 18.72 |
| 15.84 | 5.60 | 30.56 |
| 16.69 | 5.31 | 68.12 |
| 17.17 | 5.16 | 100.00 |
| 17.45 | 5.08 | 28.58 |
| 17.73 | 5.00 | 27.34 |
| 19.95 | 4.45 | 83.34 |
| 20.85 | 4.26 | 28.85 |
| 21.85 | 4.07 | 12.45 |
| 22.23 | 4.00 | 15.91 |
| 23.07 | 3.86 | 37.80 |
| 23.55 | 3.78 | 10.50 |
| 24.19 | 3.68 | 15.60 |
| 24.55 | 3.63 | 7.29 |
| 26.61 | 3.35 | 24.03 |
| 27.57 | 3.24 | 7.18 |
| 28.65 | 3.12 | 17.64 |
| 29.22 | 3.06 | 14.32 |
| 29.96 | 2.98 | 16.53 |
| 31.29 | 2.86 | 13.55 |
| 33.29 | 2.69 | 7.82 |
| 34.48 | 2.60 | 7.20 |
| 35.86 | 2.50 | 2.54 |
| 37.73 | 2.38 | 4.25 |
| 38.41 | 2.34 | 3.76 |
| 39.10 | 2.30 | 4.44 |
Embodiment 5：The crystal formation F of canagliflozin preparation
The powder of 20.7mg canagliflozin is dissolved in 0.55mL acetone：Normal heptane=4:7(v:V) mixed system
In, stirred 20 hours under the conditions of being then placed on -20 DEG C rapidly, gained solid is crystal formation F.Its XRPD figure is shown in Fig. 4, its DSC
Figure is shown in Fig. 5, and its TGA figure is shown in Fig. 6.
Crystal formation F 2theta values and the respective value of intensity are as shown in table 5 in the present embodiment：
The crystal formation F of table 5 2theta values and the respective value of intensity
| 2theta | D intervals | Intensity % |
| 14.06 | 6.30 | 15.62 |
| 15.89 | 5.58 | 40.76 |
| 16.68 | 5.31 | 58.45 |
| 17.18 | 5.16 | 97.47 |
| 19.94 | 4.45 | 100.00 |
| 20.87 | 4.26 | 40.76 |
| 21.89 | 4.06 | 43.91 |
| 23.10 | 3.85 | 42.17 |
| 24.18 | 3.68 | 33.63 |
| 24.61 | 3.62 | 22.38 |
| 26.62 | 3.35 | 32.53 |
| 28.65 | 3.12 | 31.37 |
| 29.20 | 3.06 | 32.09 |
| 29.96 | 2.98 | 26.11 |
| 31.28 | 2.86 | 27.29 |
| 33.27 | 2.69 | 10.48 |
Embodiment 6：The crystal formation F of canagliflozin preparation
The powder of 20.4mg canagliflozin is dissolved in 0.40mL acetone solvents, it is normal then to add 0.30mL normal heptanes
Temperature stirring 5 days, gained solid is crystal formation F.
Crystal formation F 2theta values and the respective value of intensity are as shown in table 6 in the present embodiment：
The crystal formation F of table 6 2theta values and the respective value of relative intensity
| 2theta | D intervals | Intensity % |
| 11.67 | 7.58 | 26.72 |
| 11.98 | 7.38 | 16.10 |
| 13.24 | 6.69 | 8.31 |
| 13.97 | 6.34 | 21.54 |
| 15.81 | 5.61 | 52.21 |
| 16.67 | 5.32 | 43.61 |
| 17.15 | 5.17 | 100.00 |
| 17.42 | 5.09 | 33.69 |
| 17.72 | 5.01 | 22.52 |
| 19.92 | 4.46 | 86.61 |
| 20.83 | 4.27 | 23.21 |
| 21.76 | 4.09 | 18.93 |
| 22.20 | 4.00 | 21.08 |
| 23.04 | 3.86 | 31.90 |
| 23.52 | 3.78 | 13.16 |
| 24.16 | 3.68 | 16.33 |
| 24.69 | 3.61 | 12.38 |
| 25.13 | 3.54 | 10.96 |
| 25.75 | 3.46 | 5.98 |
| 26.58 | 3.35 | 21.78 |
| 27.57 | 3.24 | 7.89 |
| 28.62 | 3.12 | 22.07 |
| 29.20 | 3.06 | 15.78 |
| 29.94 | 2.98 | 19.96 |
| 31.23 | 2.86 | 14.91 |
| 33.24 | 2.70 | 5.95 |
| 33.80 | 2.65 | 5.40 |
| 34.49 | 2.60 | 7.54 |
| 35.78 | 2.51 | 2.95 |
| 37.67 | 2.39 | 2.72 |
| 38.40 | 2.34 | 2.60 |
| 39.09 | 2.30 | 3.89 |
Embodiment 7：Canagliflozin crystal formation E and crystal formation F stability study
By the canagliflozin crystal formation E obtained in embodiment 1 and the canagliflozin crystal formation F obtained in embodiment 4 in room temperature bar
Placed 90 days under part, wherein room temperature scope detects, crystal formation between 15 DEG C -40 DEG C after placing 90 days through x-ray powder diffraction instrument
Do not change.As shown in Figure 7 and Figure 8.In Fig. 7, the XRPD that upper figure is the canagliflozin crystal formation E that embodiment 1 obtains schemes, figure below
Scheme for the XRPD after crystal formation E is placed 90 days.In Fig. 8, the XRPD that upper figure is the canagliflozin crystal formation F that embodiment 4 obtains schemes,
Figure below is that the XRPD after crystal formation F is placed 90 days schemes.
The canagliflozin crystal formation E of table 7 and crystal formation F ambient stable Journal of Sex Research
Pass through contrast, it is seen that the crystal formation E and crystal formation F of canagliflozin have stable physical chemistry at ambient temperature
Matter.
Embodiment 8：Canagliflozin crystal formation E, F and semihydrate crystal formation (CN101573368B) form comparative study
Crystal formation E to the canagliflozin that is prepared in embodiment 1, the canagliflozin being prepared in embodiment 4 respectively
Crystal formation F and in the prior art canagliflozin semihydrate crystal formation (CN101573368B) carry out petrographic microscope shooting,
As shown in figs. 9-11.
The semihydrate crystal formation of canagliflozin is (such as in terms of the shooting result of petrographic microscope, in patent CN101573368B
Fig. 9) into bulk and agglomerating, and the crystal formation E (such as Figure 10) of canagliflozin, crystal formation F (such as Figure 11) frustillatum, good dispersion.
Embodiment 9：Canagliflozin crystal formation F and semihydrate crystal formation (CN101573368B) particle diameter comparative study
Particle diameter distribution test is carried out to the crystal formation F of canagliflozin and semihydrate crystal formation being prepared in embodiment 4, it is real
It is as shown in table 8 to test result.
The crystal formation F of table 8 and semihydrate crystal formation (CN101573368B) particle diameter comparative study
As a result show, 90% particle is less than 34.70 microns in the crystal formation F samples that the present invention obtains, and 50% particle is less than
6.92 microns, 10% particle is less than 3.10 microns, and volume distributed median average grain diameter is 15.29 microns.With semihydrate crystal formation
(CN101573368B) compare, particle diameter is smaller, and has narrower particle diameter distribution.
Claims (10)
- A kind of 1. crystal formation E of canagliflozin, it is characterised in that its X-ray powder diffraction figure 2theta values be 19.3 ° ± There is characteristic peak at 0.2 °, 18.4 ° ± 0.2 °, 9.6 ° ± 0.2 °, 20.1 ° ± 0.2 °, 20.7 ° ± 0.2 °, 17.5 ° ± 0.2 °.
- 2. the crystal formation E described in claim 1, is further characterized in that, its X-ray powder diffraction figure 2theta values be 14.6 ° ± There is characteristic peak at 0.2 °, 21.2 ° ± 0.2 °, 22.4 ° ± 0.2 °.
- 3. the crystal formation E described in claim 1, it is characterised in that its X-ray powder diffraction figure is substantially consistent with Fig. 1.
- 4. the crystal formation E of the canagliflozin described in a kind of claim 1,2 or 3 preparation method, it is characterised in that including following step Suddenly：(1) powder of canagliflozin is dissolved in the in the mixed solvent of acetic acid and liquid alkane；The body of the acetic acid and liquid alkane Product ratio is between 2:1 to 1:Between 10；The liquid alkane is selected from pentane, hexane or normal heptane；(2) stir and be cooled to crystal precipitation, the crystallization that filter collection separates out is crystal formation E.
- 5. the preparation method described in claim 4, it is characterised in that the liquid alkane is normal heptane.
- A kind of 6. crystal formation F of canagliflozin, it is characterised in that its X-ray powder diffraction figure 2theta values be 17.2 ° ± There is characteristic peak at 0.2 °, 19.9 ° ± 0.2 °, 16.7 ° ± 0.2 °, 23.1 ° ± 0.2 °, 15.8 ° ± 0.2 °, 20.9 ° ± 0.2 °.
- 7. the crystal formation F described in claim 6, is further characterized in that, its X-ray powder diffraction figure 2theta values be 26.6 ° ± There is characteristic peak at 0.2 °, 14.0 ° ± 0.2 °, 28.6 ° ± 0.2 °.
- 8. the crystal formation F described in claim 6, is further characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 4.
- 9. the crystal formation F of the canagliflozin described in a kind of claim 6,7 or 8 preparation method, it is characterised in that including following step Suddenly：(1) powder of canagliflozin is dissolved in the in the mixed solvent of acetone and liquid alkane；The body of the acetone and liquid alkane Product ratio is between 2:1 to 1:Between 2；The liquid alkane is selected from pentane, hexane or normal heptane；(2) stir and be cooled to crystal precipitation, the crystallization that filter collection separates out is crystal formation F.
- 10. the preparation method described in claim 9, it is characterised in that the liquid alkane is normal heptane.
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| CN103936725A (en) * | 2014-04-01 | 2014-07-23 | 天津大学 | C crystal form of canagliflozin and crystal preparation method of canagliflozin |
| CN103980261A (en) * | 2014-04-01 | 2014-08-13 | 天津大学 | Canagliflozin of crystal form A, and crystallization preparation method thereof |
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| CN101801371A (en) * | 2007-09-10 | 2010-08-11 | 詹森药业有限公司 | The preparation method of the chemical compound of useful as inhibitors of sglt |
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