CN103936726A - Crystal, preparation method and applications of crystal - Google Patents
Crystal, preparation method and applications of crystal Download PDFInfo
- Publication number
- CN103936726A CN103936726A CN201410155712.0A CN201410155712A CN103936726A CN 103936726 A CN103936726 A CN 103936726A CN 201410155712 A CN201410155712 A CN 201410155712A CN 103936726 A CN103936726 A CN 103936726A
- Authority
- CN
- China
- Prior art keywords
- methyl
- glucopyranosyl
- fluorophenyl
- benzene
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses crystal forms III and IV of 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene. In an X-ray powder diffraction diagram, the crystal forms III and IV at least have characteristic peaks at 2q values being 6.61+/-0.2, 3.92+/-0.2 and 19.68+/-0.2, as well as 17.40+/-0.2, 15.35+/-0.2 and 14.91+/-0.2, respectively. The invention further discloses a preparation method and medical applications of the crystal. The crystal form III is an octanol complex and has more obvious action effect on the diabetes treatment effect. The crystal form IV is an anhydrous complex, and is high in purity; the drying process for preparing the anhydrous complex is simple; on the aspect of preparation technology, the anhydrous complex has obvious advantages compared with the hydrous complex.
Description
Technical field
The present invention relates to 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] novel crystal of benzene and its production and use.
Background technology
Diabetes are one group of internal secretion-metabolic troubles, and the hyperglycemia of take indicates jointly as it.Water, the metabolic disturbance of electrolyte of or sugar, protein, fat and secondary that relative hyposecretion cause absolute because of Regular Insulin.It can relate to each system of whole body particularly chronic lesion, the dysfunction of eye, kidney, heart, blood vessel, nerve, even brings out many mortality complication.Along with the aging of world population, diabetes have become a kind of common disease, frequently-occurring disease, are a kind of diseases of serious harm human health.Data shows, global diabetic subject by 2000 1.5 hundred million be increased to 2.8 hundred million, expecting the year two thousand thirty whole world will have nearly 500,000,000 people to suffer from diabetes.
Human body, under standard state, regulates and what control glucose metabolism balance is glucose transporter.Sodium glucose co-transporter 2 white (SGLT) is a kind of known glucose transporter.SGLT comprises SGLT1 and SGLT2, and wherein SGLT1 is expressed in small intestine and kidney proximal tubule compared with in the S3 sections of far-end, absorbs approximately 10% sugar; SGLT2 is mainly expressed in the front SI sections of kidney proximal tubule, and the SGLT2 that more than 90% glucose heavily absorbs by this place is responsible for.Therefore suppress SGLT, particularly suppress the heavily absorption that SGLT2 can and then suppress sugar, thereby sugar is discharged through urine, reduce the concentration of sugar in blood.
Canagliflozin(Ka Gelie is clean, 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene) be the oral antidiabetic drug that medicine that U.S. FDA has been ratified is used for the treatment of diabetes B.This medicine is sodium dependent glucose transporter (SGLT2) inhibitor optionally.The clean molecular formula of Ka Gelie is C24H25FO5S, and its molecular weight is 444.52.The clean chemical structural formula of Ka Gelie is as follows:
Generally speaking, for the operability of bulk drug and preparation production, the object of the stability that medicine is preserved and raising curative effect of medication, need to make medicine the state of crystal.
The clean existing crystal formation of Ka Gelie has following several.In US 2008/0146515 A1 patent, disclosed the clean semihydrate structure of Ka Gelie as follows, the X-ray powder diffraction figure of this crystal formation comprises following 2q value (recording with Cu Ka): 4.36 ± 0.2,13.54 ± 0.2,16.00 ± 0.2,19.32 ± 0.2 and 20.80 ± 0.2.Semihydrate XRPD figure, as shown in Fig. 3, has also disclosed the preparation method of this semihydrate crystal formation simultaneously.
In US 2009/0233874 A1 patent, also disclosed the clean another kind of crystal formation of Ka Gelie, Fig. 4 has shown the XRPD figure of this crystal formation, the diffraction peak of XRPD figure is listed in the table below:
The clean five kinds of eutectic crystal formations of Ka Gelie in WO2013064909 A2 patent, have been disclosed, comprise Ka Gelie clean-L-PROLINE eutectic and Ka Gelie clean-eutectic of D-PROLINE-ethanol compound, Ka Gelie is clean-L-Phe monohydrate eutectic crystal formation, Ka Gelie is clean-L-Phe eutectic crystal formation and Ka Gelie clean-D-PROLINE eutectic crystal formation.
Patent CN103641822A also discloses the clean semihydrate crystal formation of Ka Gelie, and according to the comparison of XRPD figure and the comparison of diffraction peak data, the disclosed crystal formation of patent CN103641822A is identical in fact with crystal formation in US 2009/0233874 A1 patent.Patent CN103588762A and patent CN103554092A have disclosed clean 3 new crystal of Ka Gelie called after crystal form B respectively, C, D.Wherein crystal form B and C are hydrate or solvate, in Aquo System, volatilize and obtain, and preparation method is difficult to amplify.In aqueous solvent system, easily obtain in addition semihydrate crystal form A (US 2008/0146515 A1 crystal formation), crystal form B and C preparation are produced to interference.Crystal formation D is from crystal C, and heating obtains.
As mentioned above, 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl has only been proposed] semihydrate, hydrate and the eutectic crystal formation of benzene, for the crystal formation of other types, whether exist both without recording also without enlightening.
Summary of the invention
Main purpose of the present invention is to provide a kind of 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] new crystal of benzene and preparation method thereof and pharmaceutical usage.
1-of the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene, in its X-ray powder diffraction figure, in 2q value, be at least 6.61 ± 0.2, 3.92 ± 0.2 and 19.68 ± 0.2 places have characteristic peak, can also comprise and be positioned at 21.35 ± 0.2, 10.46 ± 0.2, 18.72 ± 0.2, 20.00 ± 0.2, 9.60 ± 0.2, 4.90 ± 0.2, 17.14 ± 0.2, 11.62 ± 0.2, 14.41 ± 0.2, 17.50 ± 0.2, 6.13 ± 0.2, 21.89 ± 0.2, 19.35 ± 0.2, 9.86 ± 0.2, the characteristic peak at 29.23 ± 0.2 places.
1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene is octanol solvate.
1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl wherein] in the octanol solvate of crystal form II I of benzene, octanol and 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] mol ratio of benzene is 0.5:1 ~ 3:1, crystal form II I is carried out to magnetic resonance detection, result is: 1H NMR (d6-DMS0, 400MHz): δ 0.86 (1.5H, t, J=8.0Hz), 1.25 (5H, br), 1.36-1.43 (1H, m), 2.26 (3H, s), 3.13-3.28 (4H, m), 3.37 (1H, q, J=7.0 Hz), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.2Hz), 4.10, 4.15 (each 1H, d, J=16.0Hz), 4.32 (0.5H, t, J=5.2Hz), 4.44 (1H, t, J=5.6Hz), 4.73 (1H, d, J=6.0Hz), 4.92 (2H, d, J=4.8Hz), 6.80 (1H, d, J=3.56Hz), 7.11-7.16 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.6Hz), 7.59 (2H, dd, J=8.8, 5.4Hz), from above result, octanol and 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] mol ratio of benzene is the most stable while being 0.5:1.
1-of the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] form IV of benzene, in its X-ray powder diffraction figure, in 2q value, be at least 17.40 ± 0.2, 15.35 ± 0.2 and 14.91 ± 0.2 places have characteristic peak, can also comprise and be positioned at 31.72 ± 0.2, 30.03 ± 0.2, 28.04 ± 0.2, 24.41 ± 0.2, 23.47 ± 0.2, 22.43 ± 0.2, 20.57 ± 0.2, 18.32 ± 0.2, 16.18 ± 0.2, 7.42 ± 0.2, 10.26 ± 0.2, the characteristic peak at 13.23 ± 0.2 places, form IV is without hydrate, fusing point is 120 degrees Celsius of left and right.
In medical composition, comprising 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene and form IV be as effective constituent.
Prepare 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] method of benzene crystal form II I, in octanol or the solution that contains octanol, supersaturation precipitation or recrystallization are prepared crystal form II I, 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl from crude product, amorphous or other crystal formations] benzole soln, by adding the method for anti-solvent or intensification-cooling, separate out solid, then after solid-liquid separation, obtain crystal form II I.
Preparation 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] method of form IV of benzene, wherein method is for take 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene is a starting raw material, the octanol in crystal form II I sloughed and obtained described form IV.
Preparation 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the another kind of method of form IV of benzene, at oversaturated 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] add the crystal seed of form IV in benzole soln, by precipitation or recrystallization, prepare described form IV.
1-of the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene or form IV and one or more antidiabetics, antihyperglycemic agents and/or other diseases therapeutic combination use.
1-of the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene or the purposes of form IV and medical composition thereof: be used for the treatment of or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing postpones, Regular Insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, fat, hypertriglyceridemia, X syndrome, the complication of diabetes, atherosclerosis or hypertension, loss of weight, hyperuricemia.
Compared with prior art beneficial effect of the present invention is: crystal form II I is 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the octanol solvate of benzene, this solvate itself just can be regarded as a kind of pharmaceutical composition existing with crystalline forms, because connecting blocker itself as gap, octanol there is the effect that reduces diabetic complication, as pharmacological action and the neuroprotective of anti-myocardial oedema hypertrophy, therefore be compared to 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] other crystal formation of benzene, crystal form II I is in treating diabetes effect, especially in early days in the prevention of diabetic subject's cardiovascular complication, there is more significantly action effect.
Form IV is 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene without hydrate crystal forms, be in lattice, except drug molecule, not comprise the crystal formation of other molecule, make drug crystal forms purer, under identical metering, reduce the quality of compound, such as, at present FDA ratifies 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl clinically] the semihydrate crystal formation of benzene, the metering of using is 300 mg, if to replace semihydrate crystal formation only to need 294 mg without hydrate crystal forms, thereby reduced to a certain extent the content of main component in preparation, reduce the difficulty of formulation development.In addition, the hydrate crystal forms (crystal formation I and crystal form II) of anhydrous crystal forms invention relatively is before relative simple in preparation technology, because hydrate crystal forms is easily dehydration in drying process, need rehydrated step, to generate the good hydrate crystal forms of quality homogeneous, or be dried and remove the residual of organic solvent under certain humidity condition, these two kinds of modes all need strict process regulation, more complicated, without hydrate, drying process is simple in preparation, do not need to consider the problem of water content, therefore aspect preparation technology, without the relative hydrate of hydrate, have a clear superiority in.
Accompanying drawing explanation
Fig. 1 is 1-of the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the X-ray powder diffraction figure of benzene crystal form II I, the longitudinal axis represents peak intensity (cps), transverse axis represents diffraction angle (2 θ [°]);
Fig. 2 is 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the X-ray powder diffraction figure of benzene form IV, the longitudinal axis represents peak intensity (cps), transverse axis represents diffraction angle (2 θ [°]);
Fig. 3 is 1-in prior art (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the X-ray powder diffraction figure of benzene semihydrate (crystal formation I), the longitudinal axis represents peak intensity (cps), and transverse axis represents diffraction angle (2 θ [°]);
Fig. 4 is 1-in prior art (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the X-ray powder diffraction figure of benzene crystal form II, the longitudinal axis represents peak intensity (cps), and transverse axis represents diffraction angle (2 θ [°]);
Fig. 5 is 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is without the DSC figure of hydrate (form IV), and the longitudinal axis represents hot-fluid (mW), and upwards, transverse axis represents temperature (° C) to endotherm(ic)peak;
Fig. 6 is 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is without the TGA figure of hydrate (form IV), and the longitudinal axis represents quality change percentage ratio (%), and transverse axis represents temperature (° C);
Fig. 7 is 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is without the DVS figure of hydrate (form IV), the longitudinal axis represents quality change percentage ratio (%), and transverse axis represents target relative humidity (%);
Fig. 8 is 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene without hydrate (form IV) through before and after DVS test, X-ray powder diffraction comparison diagram, top is the front sample of test, the XRPD figure that bottom is the rear sample of test, the longitudinal axis represents peak intensity (cps), and transverse axis represents diffraction angle (2 θ [°]).
Embodiment
Below in conjunction with drawings and Examples, the specific embodiment of the present invention is described in further detail.Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Taking about 10mg 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene adds in vial, under room temperature condition, add 0.4mL n-Octanol that sample dissolution is extremely clear, then sample is placed on to standing over night (12h) under 5 ℃ of conditions, separate out and obtain solid, suspension liquid is placed in to filtering centrifuge tube, 4000rpm centrifuging 3 minutes, obtain solid and according to the method for this patent regulation, carry out crystal formation detection with XRPD, and detect octanol and 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl with 1H nuclear-magnetism] molar ratio of benzene.By XRPD result, showing that gained solid position is crystal form II I, octanol and 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] mol ratio of benzene is 0.5:1.X-ray powder diffraction in this patent, operation and analytical procedure are as follows:
In Cu K α radiation (1.54 A), on the Bruker D8 Discover x-ray powder diffraction instrument of the GADDS operating in reflection mode (general area diffraction detector system) CS, gather X-ray powder diffraction figure, tube voltage and the magnitude of current are set to respectively 40kV and 40mA, the 2 θ scope interscan sample times of 180 seconds of 3.0 ° to 40.0 °, the peak position representing for 2 θ, use corundum standard substance calibration diffractometer, normally under the room temperature of 20 ℃-30 ℃, implement all analyses, the GADDS that uses 4.1.14T version WNT software, gathers and integration data.Use has 5.0.37 version JADE XRD diffractogram process software (Materials Data, Inc) and evaluates diffractogram.
On the Bruker of GADDS CS D8 Discover x-ray powder diffraction instrument, implementing X-ray diffraction measures, conventionally sample is laid on monocrystalline silicon piece, by slide glass or equivalent applying light sample powder, to guarantee that sample powder keeps smooth surface and suitable height, then the monocrystalline silicon piece that is loaded with sample is put on the support of Bruker instrument, and uses above-described instrument parameter to gather x-ray diffractogram of powder.For example, by comprising that following many factors produces the measurement difference relevant to this class X-ray powder diffraction analytical results: (a) error in sample preparation thing (height of specimen), (b) instrumental error, (c) calibration difference, (d) personal error (being included in the error occurring while measuring peak position), and (e) character of material (for example preferred orientation error).Alignment error and height of specimen error often cause the displacement of all peaks in equidirectional.When using flat support, the little difference of height of specimen will cause the large displacement of XRPD peak position.Systematic study shows that the height of specimen difference of 1mm can cause height to the peak shift of 2 θ of 1 °.Can identify these displacements from X-ray diffractogram, and can be by compensating for described displacement (by the system calibration factor for all peak positions value) or again calibration instrument eliminate described displacement.As mentioned above, by application system calibration factor, make peak position consistent, recoverable is from the measuring error of different instruments.
1-prepared by the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene, in its X-ray powder diffraction figure, in 2q value, be 6.61 ± 0.2, 3.92 ± 0.2, 19.68 ± 0.2, 21.35 ± 0.2, 10.46 ± 0.2, 18.72 ± 0.2, 20.00 ± 0.2, 9.60 ± 0.2, 4.90 ± 0.2, 17.14 ± 0.2, 11.62 ± 0.2, 14.41 ± 0.2, 17.50 ± 0.2, 6.13 ± 0.2, 21.89 ± 0.2, 19.35 ± 0.2, 9.86 ± 0.2, 29.23 ± 0.2 places have characteristic peak, diffracting spectrum as shown in Figure 1, the diffraction peak of the XRPD figure of crystal form II I is listed in the table below:
| Position? (2oTheta) | d-spacing (?) |
| 3.92 | 22.5 |
| 4.90 | 18.0 |
| 6.13 | 14.4 |
| 6.61 | 13.4 |
| 7.87 | 11.2 |
| 9.60 | 9.2 |
| 9.86 | 9.0 |
| 10.46 | 8.5 |
| 11.62 | 7.6 |
| 11.82 | 7.5 |
| 12.33 | 7.2 |
| 12.58 | 7.0 |
| 13.29 | 6.7 |
| 13.53 | 6.5 |
| 14.41 | 6.1 |
| 15.15 | 5.8 |
| 15.65 | 5.7 |
| 16.07 | 5.5 |
| 17.14 | 5.2 |
| 17.50 | 5.1 |
| 18.72 | 4.7 |
| 19.35 | 4.6 |
| 19.68 | 4.5 |
| 20.00 | 4.4 |
| 21.35 | 4.2 |
| 21.89 | 4.1 |
| 22.97 | 3.9 |
| 23.88 | 3.7 |
| 26.40 | 3.4 |
| 27.85 | 3.2 |
| 29.23 | 3.1 |
| 30.72 | 2.9 |
| 31.30 | 2.9 |
| 33.70 | 2.7 |
| 34.52 | 2.6 |
| 38.81 | 2.3 |
| 39.04 | 2.3 |
Crystal form II I is octanol solvate, octanol and 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] mol ratio of benzene between 0.5:1 ~ 3:1, in the situation of stability, be generally mol ratio 0.5:1.To 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] solvate of benzene and octanol carries out magnetic resonance detection, result is: 1H NMR (d6-DMS0, 400MHz): δ 0.86 (1.5H, t, J=8.0Hz), 1.25 (5H, br), 1.36-1.43 (1H, m), 2.26 (3H, s), 3.13-3.28 (4H, m), 3.37 (1H, q, J=7.0 Hz), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.2Hz), 4.10, 4.15 (each 1H, d, J=16.0Hz), 4.32 (0.5H, t, J=5.2Hz), 4.44 (1H, t, J=5.6Hz), 4.73 (1H, d, J=6.0Hz), 4.92 (2H, d, J=4.8Hz), 6.80 (1H, d, J=3.56Hz), 7.11-7.16 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.6Hz), 7.59 (2H, dd, J=8.8, 5.4Hz), from above result, octanol and 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] mol ratio of benzene is 0. 5:1.
Embodiment 2
Taking about 10mg 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene adds in vial, under room temperature condition, add the n-Octanol of 0.5mL that sample dissolution is extremely clear, then add gradually 3.05mL normal heptane, crystallization solid, suspension liquid is placed in to filtering centrifuge tube, 4000rpm centrifuging 3 minutes, obtains solid and detects by the XRPD method described in embodiment 1, is crystal form II I.
Embodiment 3
Taking about 10mg 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is to adding in vial, under room temperature condition, add the n-Octanol of 0.5 mL that sample dissolution is extremely clear, in negate solvent 3mL to 20mL vial, the 1.5mL vial that this compound n-Octanol solution is housed is put into 20mL vial, allow anti-solvent gas diffuse in sample solution, suspension liquid is placed in to filtering centrifuge tube, 4000rpm centrifuging 3 minutes, obtaining solid and detect by the XRPD method described in embodiment 1, is crystal form II I.Herein, anti-solvent also can be used normal hexane, pentane, hexanaphthene, toluene, normal heptane etc.
Embodiment 4
Take about 600 mg 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form II I(is the embodiment of the present invention 1 ~ 3 any one preparation) add in vial, add again 45 mL normal heptanes, then sample is placed under 40 ℃ of conditions and stirs after 24 hours, filtration under diminished pressure obtains solid, with normal heptane, wash again, be placed in vacuum drying oven, during room temperature vacuum 24 hour, obtaining solid and detect by the XRPD method described in embodiment 1, is form IV.
1-prepared by the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] form IV of benzene, in its X-ray powder diffraction figure, in 2q value, be 17.40 ± 0.2,15.35 ± 0.2,14.91 ± 0.2,31.72 ± 0.2,30.03 ± 0.2,28.04 ± 0.2,24.41 ± 0.2,23.47 ± 0.2,22.43 ± 0.2,20.57 ± 0.2,18.32 ± 0.2,16.18 ± 0.2,7.42 ± 0.2,10.26 ± 0.2, the characteristic peak at 13.23 ± 0.2 places, as shown in Figure 2, the diffraction peak of the XRPD figure of form IV is listed in the table below:
| Position (2oTheta) | d-spacing (?) |
| 7.42 | 11.9 |
| 10.26 | 8.6 |
| 13.23 | 6.7 |
| 14.91 | 5.9 |
| 15.35 | 5.8 |
| 16.18 | 5.5 |
| 17.40 | 5.1 |
| 18.32 | 4.8 |
| 20.57 | 4.3 |
| 22.43 | 4.0 |
| 23.47 | 3.8 |
| 24.41 | 3.6 |
| 28.04 | 3.2 |
| 30.03 | 3.0 |
| 31.72 | 2.8 |
Form IV in embodiment 4 is done to poor gesture scanning calorimetric (DSC) and analyze, operation and analytical procedure are as follows:
On Perkin-Elmer DSC, carry out dsc (DSC).By the sample weighing of 1-3 mg is entered to aluminium dish, then use aluminium lid capping.The sample preparing is put into instrument analysis.Instrument condition is since 50 oC tests, and under nitrogen purging (25 ml/min), with 10 oC/ per minutes, sample to be heated to 180 oC.Data Analysis(version for the data that instrument gathers: 10.1.0.0412) software analysis is processed.
On NETZSCH TG instrument, carry out thermogravimetric (TGA) analytical procedure.By the sample of 1-3 mg is added to Al
2o
3crucible, puts into instrument analysis.Instrument condition is since 30 oC tests, and under nitrogen purging (25 ml/min), with 10 oC/ per minutes, sample to be heated to 400 oC.
Dynamically steam absorption (DVS) is analyzed and is carried out on surface measurement system (SMS) DVS Intrinsic moisture absorption analyser.Described instrument is controlled by SMS Analysis Suite software (DVS-Intrinsic Control vl. 0. 0. 30).Use Microsoft Excel 2007 and DVS Standard Analysis Suite to data analysis.Sample temperature is remained on to 25 ° of C and Sample moisture obtains as follows: the overall flow rate with 200ml/min mixes nitrogen wet gas current and nitrogen dry gas stream.Near the calibrated Rotronic probe (dynamicrange is 1-100% relative humidity (RH)) that relative humidity use is positioned at sample is measured.Constantly by microbalance (accuracy is scholar 0.005mg), the example weight as % RH function is changed and monitored.Conventionally, before analysis, carry out XRPD.Then 3-10mg sample is placed in to the stainless steel basket through taring under envrionment conditions.Under 40% relative humidity, start: (typical indoor conditions) load and unloading sample also last 2 cycles and make sample stand gradual DVS scheme, wherein use the parameter shown in following table.By these data, calculate DVS thermoisopleth and after analysis, carry out final XRPD to check the variation of solid-state form.
| Parameter | Arrange |
| Absorption-the cycle 1 (% R.H.) | 40-90 |
| Desorption is attached-cycle 1 (% R.H.) | 90-0 |
| Absorption-the cycle 2 (% R.H.) | 0-90 |
| Desorption is attached-cycle 2 (% R.H.) | 90-0 |
| Step-length (% R.H.) | 0.02 |
| dmdt （% min-1） | 5 |
| Sample temperature (0C) | 25 |
Form IV is 120 degrees Celsius of left and right melting heat releases, and fusing point is 122.7 degrees Celsius (peak values), as shown in Figure 5.Form IV is (before 120 degrees Celsius) before melting, and weight loss on heating is only 0.9 %, prove that form IV is without hydrate, as shown in Figure 6.The water absorbability of form IV and the physical stability of humidity is investigated by dynamic water adsorption instrument (DVS).Result is presented under 80% relative humidity, 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the form IV moisture absorption of benzene is 0.56%, illustrates that form IV only has slight water absorbability, is beneficial to pharmacy exploitation.In addition, absorption and desorption additive process are reversible, and absorption and de-adsorption curve are forming back stagnant ring, as shown in Figure 7, even if illustrate the in the situation that of high humidity, do not produce hydrate.Before and after dynamic water adsorption test, form IV does not change, and as shown in Figure 8, illustrates that form IV also has good physical stability under high humidity environment yet.
1-prepared by the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene or form IV and medical composition thereof can be for following purposes: treatment, prevention or diabetes-alleviating (I type and type ii diabetes etc.), diabetic complication is (as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), postprandial hyperglycemia disease, retardance wound healing, Regular Insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid blood level raises, the hemotoncus concentration of glycerine raises, hyperlipidemia, fat, increased TG, X syndrome, atherosclerosis or hypertensive progress or morbidity, can also be used for the treatment of hyperuricemia.
1-prepared by the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene or form IV and pharmaceutically useful auxiliary material or carrier can oral or parenterai administrations, and use with other suitable pharmaceutical preparation form.Suitable solid dosage for oral administration comprises, and such as tablet, granule, capsule, pulvis or solid dispersion etc. comprises oral liquid, suspensoid, emulsion etc. for the suitable liquid dosage form of oral administration.Suitable preparation for parenterai administration comprises, for example suppository, injection, intravenous infusion agent, subcutaneous implant and suction preparation.1-of the present invention (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form II I has the activity that relies on suction pressure inhibitor as sodium, and shows splendid blood sugar decreasing effect.
If desired, time, crystal formation of the present invention can be used with one or more other antidiabetic, antihyperglycemic agents and/or other diseases therapeutic combination.The compounds of this invention can same dosage form or the oral dosage form separating or drug administration by injection with this other treatment agent.
The dosage of this therapeutical agent can be according to, for example age, body weight, illness symptom, route of administration, different from dosage form.People's dosage approximately, approximately 0.01 mg/day/kg body weight to 100 mg/day/kg body weight.
This medical composition can be applied in mammals, comprises the mankind, ape, dog, with for example tablet, capsule, particle, or the dosage form of the injection of parenterai administration or intranasal administration or skin patch.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, do not departing under the prerequisite of the technology of the present invention principle; can also make some improvement and modification, these improve and modification also should be considered as protection scope of the present invention.
Claims (10)
1.1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene, it is characterized in that, be at least that 6.61 ± 0.2,3.92 ± 0.2 and 19.68 ± 0.2 places have characteristic peak in 2q value in its X-ray powder diffraction figure.
2. 1-as claimed in claim 1 (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene, it is characterized in that, described crystal form II I is octanol solvate.
3. 1-as claimed in claim 2 (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene, it is characterized in that octanol and 1-(b-D-glucopyranosyl) in described octanol solvate-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] mol ratio of benzene is 0.5:1 ~ 3:1.
4.1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] form IV of benzene, it is characterized in that, be at least that 17.40 ± 0.2,15.35 ± 0.2 and 14.91 ± 0.2 places have characteristic peak in 2q value in its X-ray powder diffraction figure.
5. medical composition, it contains crystal described in claim 1 ~ 4 any one as effective constituent.
6. 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl described in preparation claim 1 ~ 3 any one] method of benzene crystal form II I, it is characterized in that, in octanol or the solution that contains octanol, supersaturation precipitation or recrystallization are prepared crystal form II I.
7. preparation 1-claimed in claim 4 (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] method of form IV of benzene, it is characterized in that, take 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene is starting raw material, the octanol in crystal form II I sloughed and obtained described form IV.
8. preparation 1-claimed in claim 4 (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] method of form IV of benzene, it is characterized in that, at oversaturated 1-(b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] add the crystal seed of form IV in benzole soln, by precipitation or recrystallization, prepare described form IV.
9. the 1-as described in claim 1 ~ 4 any one (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene or form IV and one or more antidiabetics, antihyperglycemic agents and/or other diseases therapeutic combination use.
10. the 1-as described in claim 1 ~ 5 any one (b-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene or the purposes of form IV and medical composition thereof: be used for the treatment of or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing postpones, Regular Insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, fat, hypertriglyceridemia, X syndrome, the complication of diabetes, atherosclerosis or hypertension, loss of weight, hyperuricemia.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410155712.0A CN103936726B (en) | 2014-04-18 | 2014-04-18 | Crystal, preparation method and its usage |
| PCT/CN2015/076854 WO2015158298A1 (en) | 2014-04-18 | 2015-04-17 | Crystal, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410155712.0A CN103936726B (en) | 2014-04-18 | 2014-04-18 | Crystal, preparation method and its usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103936726A true CN103936726A (en) | 2014-07-23 |
| CN103936726B CN103936726B (en) | 2016-06-15 |
Family
ID=51184637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410155712.0A Active CN103936726B (en) | 2014-04-18 | 2014-04-18 | Crystal, preparation method and its usage |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103936726B (en) |
| WO (1) | WO2015158298A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530024A (en) * | 2015-02-04 | 2015-04-22 | 上海迪赛诺药业有限公司 | Crystal form of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene and preparation method thereof |
| WO2015158298A1 (en) * | 2014-04-18 | 2015-10-22 | 苏州井然医药科技有限公司 | Crystal, preparation method and use thereof |
| WO2016136830A1 (en) * | 2015-02-27 | 2016-09-01 | 田辺三菱製薬株式会社 | Novel crystal of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene |
| WO2016191173A1 (en) | 2015-05-22 | 2016-12-01 | Janssen Pharmaceutica Nv | Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol |
| WO2017084644A1 (en) | 2015-11-20 | 2017-05-26 | Zentiva, K.S. | A crystalline form of canagliflozin and a method of its preparation |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (belta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate |
| 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 |
| WO2013064909A2 (en) * | 2011-10-31 | 2013-05-10 | Scinopharm Taiwan, Ltd. | Crystalline and non-crystalline forms of sglt2 inhibitors |
| CN103554092A (en) * | 2013-11-11 | 2014-02-05 | 苏州晶云药物科技有限公司 | New crystal form B of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene and preparation method of new crystal form B |
| CN103588762A (en) * | 2013-11-27 | 2014-02-19 | 苏州晶云药物科技有限公司 | Novel crystal form of canagliflozin and its preparation method |
| CN103641822A (en) * | 2013-10-21 | 2014-03-19 | 江苏奥赛康药业股份有限公司 | Canagliflozin compound and pharmaceutical composition thereof |
| CN103694230A (en) * | 2013-12-06 | 2014-04-02 | 江苏奥赛康药业股份有限公司 | High-purity canagliflozin compound and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102648196B (en) * | 2009-10-14 | 2016-04-27 | 詹森药业有限公司 | Can be used as the preparation method of the compound of the inhibitor of SGLT2 |
| CN103936726B (en) * | 2014-04-18 | 2016-06-15 | 王军 | Crystal, preparation method and its usage |
-
2014
- 2014-04-18 CN CN201410155712.0A patent/CN103936726B/en active Active
-
2015
- 2015-04-17 WO PCT/CN2015/076854 patent/WO2015158298A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (belta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate |
| 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 |
| WO2013064909A2 (en) * | 2011-10-31 | 2013-05-10 | Scinopharm Taiwan, Ltd. | Crystalline and non-crystalline forms of sglt2 inhibitors |
| CN103641822A (en) * | 2013-10-21 | 2014-03-19 | 江苏奥赛康药业股份有限公司 | Canagliflozin compound and pharmaceutical composition thereof |
| CN103554092A (en) * | 2013-11-11 | 2014-02-05 | 苏州晶云药物科技有限公司 | New crystal form B of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene and preparation method of new crystal form B |
| CN103588762A (en) * | 2013-11-27 | 2014-02-19 | 苏州晶云药物科技有限公司 | Novel crystal form of canagliflozin and its preparation method |
| CN103694230A (en) * | 2013-12-06 | 2014-04-02 | 江苏奥赛康药业股份有限公司 | High-purity canagliflozin compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 夏玲红，等: "治疗2型糖尿病的新药Canagliflozin", 《中国药师》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015158298A1 (en) * | 2014-04-18 | 2015-10-22 | 苏州井然医药科技有限公司 | Crystal, preparation method and use thereof |
| CN104530024A (en) * | 2015-02-04 | 2015-04-22 | 上海迪赛诺药业有限公司 | Crystal form of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene and preparation method thereof |
| EP3053919A1 (en) | 2015-02-04 | 2016-08-10 | Shanghai Desano Pharmaceuticals Investment Co., Ltd | Crystalline form of 1-(beta-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene and preparation method thereof |
| US10167306B2 (en) | 2015-02-04 | 2019-01-01 | Shanghai Desano Pharmaceuticals Investment Co., Ltd. | Crystalline form of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene and preparation method thereof |
| WO2016136830A1 (en) * | 2015-02-27 | 2016-09-01 | 田辺三菱製薬株式会社 | Novel crystal of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene |
| WO2016191173A1 (en) | 2015-05-22 | 2016-12-01 | Janssen Pharmaceutica Nv | Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol |
| US20180155329A1 (en) * | 2015-05-22 | 2018-06-07 | Janssen Pharmaceutica Nv | Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol |
| JP2018515565A (en) * | 2015-05-22 | 2018-06-14 | ヤンセン ファーマシューティカ エヌ．ベー． | Anhydrous crystalline form of (1S) -1,5-anhydro-1- [3-[[5- (4-fluorophenyl) -2-thienyl] methyl] -4-methylphenyl] -D-glucitol |
| WO2017084644A1 (en) | 2015-11-20 | 2017-05-26 | Zentiva, K.S. | A crystalline form of canagliflozin and a method of its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015158298A1 (en) | 2015-10-22 |
| CN103936726B (en) | 2016-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2728541C (en) | Crystalline forms of thiazolidinedione compound and its manufacturing method | |
| CN103936726A (en) | Crystal, preparation method and applications of crystal | |
| CN106905267A (en) | The crystalline solid and its preparation and application of the inhibitor of METAP 2 | |
| CN109195980B (en) | Novel crystal form of sodium-glucose cotransporter inhibitor drug, preparation method and application thereof | |
| CN104230907B (en) | Method for preparing crystals and application of crystals | |
| CN115385893A (en) | With pyridine acyl piperidine 5-HT 1F Compositions and methods relating to agonists | |
| WO2012147832A1 (en) | Phenyl pyrrole derivative crystal | |
| CN106892900A (en) | A kind of Vonoprazan fumarate and preparation method thereof | |
| CN109476624B (en) | Crystalline forms of a sodium-glucose cotransporter 2 inhibitor | |
| CN109952307A (en) | The solid form and its preparation method and application of 4 '-thio -2 '-fluoro nucleosides phosphamide compounds | |
| CN105315266B (en) | The crystal form of 1- { the fluoro- 4- of 2- [5- (4- isobutyl phenenyl) -1,2,4- oxadiazoles -3- base]-benzyl } -3- azetidinecarboxylic acid | |
| CN103864756B (en) | Fourth disulfonic acid dabigatran etcxilate and its preparation method and application | |
| US20210260046A1 (en) | Pharmaceutical composition containing ilaprazole or salt thereof and preparation method therefor | |
| KR102160093B1 (en) | Polycrystalline form of DPPIV inhibitor maleate and method for preparing same | |
| CN110128305A (en) | The new salt form of melbine-orinase, preparation method and medical usage | |
| EP3315493B1 (en) | Phenyl amino pyrimidine compound or polymorph of salt thereof | |
| CN106478616B (en) | Crystalline form of GPR40 agonist and preparation method thereof | |
| CN104936947A (en) | Lorcaserin salts and crystals thereof, preparation methods and uses thereof | |
| CN114630668B (en) | Aprocitentan crystal form and preparation method and application thereof | |
| CN110128359A (en) | A kind of crystal and its preparation method and application of 1 inhibitor of uric acid transporter body | |
| JP2013184934A (en) | Novel salt of oxadiazolidinedione, and crystal thereof | |
| TW202342414A (en) | Crystal form of cyclohexenone compound | |
| CN106146465A (en) | Dabigatran etexilate methanesulfonate crystal formation VII and its production and use | |
| CN117209480A (en) | Crystal form of thyroid hormone beta receptor regulator, and preparation method and application thereof | |
| CN104860919A (en) | Piperidine-containing benzimidazole derivative, preparation method and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160205 Address after: 300000 Tianjin Heping District Mu South Road No. 103 Applicant after: Wang Jun Address before: Suzhou City, Jiangsu province 215000 Industrial Park Pavilion only road 2, building 514 room 2 Applicant before: SUZHOU JINRAN PHARMACEUTICAL TECHNOLOGY CO., LTD. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |