CN105399725A - Salt, crystal and pharmaceutical composition of trelagliptin compound and applications thereof - Google Patents
Salt, crystal and pharmaceutical composition of trelagliptin compound and applications thereof Download PDFInfo
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- CN105399725A CN105399725A CN201510749702.4A CN201510749702A CN105399725A CN 105399725 A CN105399725 A CN 105399725A CN 201510749702 A CN201510749702 A CN 201510749702A CN 105399725 A CN105399725 A CN 105399725A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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 provides a novel dipeptidyl peptidase IV inhibitor trelagliptin compound, hemi-succinate, hydrates and novel crystal-form drugs thereof, a pharmaceutical composition containing them and applications thereof in preparing medications for treating diabetic diseases. A novel crystal form provided by the invention contains 0.5 succinate molecule, so that the intake of inactive ingredients is reduced, then the relative toxicity is low, and the effective composition content is high, therefore, the novel crystal-form is safer and more effective when applied to preparations, and more applicable to the clinical application of high-dose preparations. Compared with the succinate crystal form of existing trelagliptin, the novel crystal form provided by the invention is good in stability and conducive to the wet granulation of solid preparations or the preparation of liquid preparations, and facilitates the manufacturing, storage and transportation of medications; and the novel crystal form provided by the invention is high in purity and safer in usage of medication.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to the hemisuccinic acid salt of the bent Ge Lieting of a kind of antidiabetic drug and crystal thereof or crystal formation, also relate to the preparation method of described salt and crystal or crystal formation, its pharmaceutical composition and the application in the medicine of preparation treatment diabetes conditions thereof.
Background technology
Along with living standards of the people constantly improve, the morbidity of diabetes, in ascendant trend gradually, has become one of chronic disease of serious threat human health.In recent years, dipeptidyl peptidase-IV inhibitors (DPP-IV inhibitor), as the medicine of the novel targets for diabetes, more and more receives the concern of people, and is widely used in clinical.DPP-IV inhibitor is first class controls glucose level novel diabetes B medicine by improving body self-ability, can be used as single medicine, also can with other oral antidiabetic drug coupling, its mechanism of action is unique, have and do not produce hypoglycemia, do not cause body weight to increase, and the unique advantage such as side effect is little, cause the incidence of gastrointestinal side effect also very low simultaneously.
Bent Ge Lieting (Trelagliptin), chemistry 2-[6-(3-amino-piperadine-1-base)-3-methyl-2 by name, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl] the fluoro-benzonitrile of-4-, it is a kind of novel super long effective DPP-IV inhibitor researched and developed by military field (Takeda) and Furiex, Weekly administration once, and similar DPP-IV inhibitor needs every day once oral on market, therefore, its medication advantage provides more convenient therapeutic choice by for diabetic subject undoubtedly, is expected to convenience and the compliance of significantly improving patient.This medicine obtains Japanese health workfare portion (MHLW) approval listing on March 7th, 2015, and commodity are called Zafatek, and its tablet is containing bent Ge Lieting succinate crystal form A as active constituents of medicine, and the specification of tablet has 50mg and 100mg.
Patent documentation US20090275750A1 discloses bent Ge Lieting and preparation method thereof, but its solid-state form unexposed.Bent Ge Lieting belongs to slightly water-soluble compound, generally uses in solid form in the formulation, therefore, is of great significance its solid-state form research tool.
Chinese invention patent CN201310056368.5 (solid-state form of the bent Ge Lietingxin of denomination of invention and its production and use) discloses the bent Ge Lieting in multiple crystal habit, comprises crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E and amorphous state and preparation method thereof.
Patent documentation ZL200780049086.5 (denomination of invention: 2-[6-(3-amino-piperadine-1-base)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl] polymorphic form of succinate of the fluoro-benzonitrile of-4-and using method thereof) disclose bent Ge Lieting succinate in multiple crystal habit, comprise crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F, crystal formation G and amorphous state and their preparation method and sign.
Through the further research to bent Ge Lieting succinate solid-state form, we find, when organic solvent or water remain, bent Ge Lieting succinate can not maintain original crystalline state.Therefore, in order to meet the strict demand of pharmaceutical solid preparation for pharmaceutical activity form, expand raw material form selected by formulation development, this area needs to develop the salt of new bent Ge Lieting and crystal thereof or crystal formation.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, provide a kind of stability, solvability, water absorbability, moving phase, purity all to have advantage, and be suitable for bent Ge Lieting salt and the crystal formation thereof of industrialized production and standing storage.
The invention discloses a kind of bent Ge Lieting hemisuccinic acid salt, its structural formula is as follows:
The invention also discloses a kind of hydrate of bent Ge Lieting hemisuccinic acid salt, its structural formula is as follows:
Wherein n=1.0 ~ 2.5.
Fig. 2 is shown in by its structure iron, and hydrogen bond structure figure is shown in Fig. 3.
The invention also discloses a kind of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I, described structural formula is shown below:
N=2.0 ~ 2.5 wherein, are preferably 2.25.
Described bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I, belong to triclinic(crystalline)system, P1 spacer, unit cell parameters is:
α=85.87 ~ 85.89 °, β=87.30 ~ 87.32 °, γ=83.36 ~ 83.38 °,
The X-ray powder diffraction pattern (CuK α radiation) of described crystal formation I has characteristic peak at a ° place, following diffraction angle 2 θ ± 0.2: 4.7,9.5,11.3,11.8,12.5,15.8,17.0.
Preferably, the X-ray powder diffraction pattern (CuK α radiation) of described crystal formation I can have characteristic peak at a ° place, following diffraction angle 2 θ ± 0.2 further: 4.7,9.5,11.3,11.8,12.5,15.8,17.0,18.8,19.1,19.7,21.3,21.8,22.6,25.1,25.6,26.8.
Without limitation, described crystal formation I has X-ray powder diffraction pattern as shown in Figure 1 substantially.
Further, bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I thermogravimetic analysis (TGA) figure of the present invention comprises the mass loss of 4.1% ~ 5.1%, thermogravimetic analysis (TGA) when Fig. 4 is n=2.25.
Further, the DSC figure of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I of the present invention shows (Fig. 5), and the fusing point (summit value) of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I is 189.5 DEG C.
The invention also discloses the preparation method of described bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I, bent Ge Lieting is joined in solvent, reflux is dissolved, add succsinic acid, in reaction system, the quality g of bent Ge Lieting is 1:3 ~ 20 with the ratio of the volume ml of solvent, the mol ratio of bent Ge Lieting and succsinic acid is 2:1, described reflux temperature is 30 ~ 80 DEG C, stir 15 ~ 120min, after stirring 1 ~ 24h after going to room temperature, suction filtration, vacuum-drying at the temperature of 40 ~ 50 DEG C, obtains bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
Preferably, the method adding succsinic acid is: be dissolved in by succsinic acid in solvent after forming solution and join bent Ge Lieting solution system, or directly solid-state succsinic acid is joined bent Ge Lieting solution system.
One or more in wherein said solvent selected from methanol, ethanol, n-propyl alcohol, Virahol, ethyl acetate, methyl acetate, ethyl formate, butylacetate, acetone, butanone, methyl ethyl ketone, acetonitrile, tetrahydrofuran (THF), methylene dichloride, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide (DMSO), water are with the solvent of arbitrary proportion mixing.
Preferably, described solvent is selected from one or more solvents mixed with arbitrary proportion in n-propyl alcohol, Virahol, ethyl acetate, acetone, tetrahydrofuran (THF).
More preferably, described solvent is a kind of or two kinds of solvents mixed with arbitrary proportion of Virahol and tetrahydrofuran (THF).
Preferably, in reaction, the weight g of bent Ge Lieting and the volume ml ratio of solvent are 1:10 ~ 15.
Preferably, the temperature of described reflux is 40 ~ 70 DEG C.
Preferably, described recrystallization temperature is room temperature, and the crystallization time is 2 ~ 3 hours.
The invention also discloses bent Ge Lieting hemisuccinic acid salt hydrate crystal form II, described structural formula is shown below:
Described bent Ge Lieting hemisuccinic acid salt hydrate crystal form II, belong to oblique system, P21 spacer, unit cell parameters is:
α=90.00 °, β=100.404 (27) °, γ=90.00 °,
The X-ray powder diffraction pattern (CuK α radiation) of described crystal form II has characteristic peak at a ° place, following diffraction angle 2 θ ± 0.2: 4.6,9.3,12.7,13.2,14.3,15.5,16.8.
Preferably, the X-ray powder diffraction pattern (CuK α radiation) of described crystal formation I can have characteristic peak at a ° place, following diffraction angle 2 θ ± 0.2 further: 4.6,9.3,12.7,13.2,14.3,15.5,16.8,18.7,20.5,21.8,22.4,23.5.
Without limitation, described crystal form II has X-ray powder diffraction pattern as shown in Figure 6 substantially.
Bent Ge Lieting hemisuccinic acid salt hydrate crystal form II of the present invention, thermogravimetic analysis (TGA) figure shows, and comprises the mass loss of 2.3%.
The DSC figure of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II of the present invention shows (Fig. 8), and the fusing point (summit value) of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II is 190.6 DEG C.
The invention also discloses the preparation method of described bent Ge Lieting hemisuccinic acid salt hydrate crystal form II:
Bent Ge Lieting is joined in solvent, reflux is dissolved, add succsinic acid, in reaction system, the quality g of bent Ge Lieting is 1:3 ~ 20 with the ratio of the volume ml of solvent, and the mol ratio of bent Ge Lieting and succsinic acid is 2:1, described reflux temperature is 30 ~ 80 DEG C, stir 15 ~ 120min, after stirring 1 ~ 24h after going to room temperature, suction filtration, vacuum-drying at the temperature of 40 ~ 50 DEG C, obtains bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
Preferably, the method adding succsinic acid is: be dissolved in by succsinic acid in solvent after forming solution and join bent Ge Lieting solution system, or directly solid-state succsinic acid is joined bent Ge Lieting solution system.
One or more in wherein said solvent selected from methanol, ethanol, n-propyl alcohol, Virahol, ethyl acetate, methyl acetate, ethyl formate, butylacetate, acetone, butanone, methyl ethyl ketone, acetonitrile, tetrahydrofuran (THF), methylene dichloride, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide (DMSO), water are with the solvent of arbitrary proportion mixing.
Preferably, described solvent is selected from one or more solvents mixed with arbitrary proportion in acetonitrile, Virahol, ethyl acetate, acetone, tetrahydrofuran (THF), water.More preferably, described solvent is the solvent that acetonitrile and water mix with arbitrary proportion.
Preferably, in reaction, the weight g of bent Ge Lieting and the volume ml ratio of solvent are 1:10 ~ 1:15.
Preferably, the temperature of described reflux is 40 ~ 70 DEG C.
Preferably, described recrystallization temperature is room temperature, and the crystallization time is 2 ~ 3 hours.
The present inventor finds in research process, by bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I and bent Ge Lieting hemisuccinic acid salt hydrate crystal form II, at 100 DEG C ~ 120 DEG C temperature, thermal treatment is after 30 ~ 90 minutes, hydrate crystal forms can dewater and be transformed into anhydrous crystal forms, but this anhydrous crystal forms very easily absorbs water, in temperature-fall period, be transformed into again bent Ge Lieting hemisuccinic acid salt hydrate crystal form II very soon.Therefore, bent Ge Lieting hemisuccinic acid salt anhydrous crystal forms is difficult to existence at ambient temperature.
25 DEG C, in relative humidity 92% (saturated KNO3 solution) environment, bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I of the present invention and crystal form II are placed 5 days, bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I energy stable existence.
Contrasted by stability competitive assay, the bent Ge Lieting succinate that patent documentation ZL200780049086.5 reports is at organic solvent (such as: dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, ethanol, acetone etc.) or organic solvent and water, especially the magma in the mixed solvent of ethanol, water or ethanol and water, original crystal habit can not be maintained, but be transformed into the mixture of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I of the present invention or crystal form II or two kinds of crystal formations, illustrate that bent Ge Lieting hemisuccinic acid salt hydrate of the present invention has better stability.This character makes bent Ge Lieting hemisuccinic acid salt hydrate of the present invention be more suitable for the wet granulation technology of solid preparation or make liquid preparation, is conducive to keeping stable in the processes such as medicine manufacture, storage, transport, thus makes quality product keep stable.
The invention discloses a kind of composition containing bent Ge Lieting hemisuccinic acid salt, wherein bent Ge Lieting hemisuccinic acid salt is to be selected from crystal formation I and/or the existence of crystal form II form.Be to be noted that other crystallizations and the amorphous form of bent Ge Lieting hemisuccinic acid salt also may reside in composition.Described pharmaceutical composition can comprise and being present in composition with the scope of 0.005% ~ 95% (w/w).
Wherein said pharmaceutical composition also comprises the conventional pharmaceutical carrier except bent Ge Lieting hemisuccinic acid salt; Vehicle; Thinner; Lubricant; Tackiness agent; Wetting agent; Disintegrating agent; Glidant; Sweeting agent; Seasonings; Emulsifying agent; Solubilizing agent; PH buffer reagent; Perfume compound; Surface stabilizer; Suspending agent; And the reagent of the pharmaceutically non-activity of other routine.Especially, this pharmaceutical composition can comprise lactose, N.F,USP MANNITOL, glucose, sucrose, Si Liaodengji dicalcium phosphate feed grade, calcium carbonate, soluble saccharin, carboxymethyl cellulose, Magnesium Stearate, calcium stearate, cross-linked carboxymethyl cellulose sodium, talcum, starch, natural natural gum, molasses, polyvinylpyrrolidone, cellulose and its derivates, polyvidone, Crospovidone acetic ester, Trisodium Citrate, cyclodextrin derivative, Sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, biocompatible polymkeric substance, ethylene vinyl acetate, polyanhydride, polyglycolic acid, poe, poly(lactic acid) and other this kind of reagent.
Wherein said pharmaceutical composition can be prepared into peroral administration tablet, capsule, granule, powder, pill, pulvis, lozenge, syrup, suspensoid, or the water-based of applicable administered parenterally or nonaqueous injection solution or emulsion; Preferably, described pharmaceutical composition is selected from and is prepared as applicable peroral administration tablet, capsule or granule; More preferably, described applicable peroral administration tablet or capsule are prepared by wet granulation technology.
The invention also discloses bent Ge Lieting hemisuccinic acid salt, the hydrate of bent Ge Lieting hemisuccinic acid salt, described crystalline form I and/or crystal form II, and the pharmaceutical composition containing them is preparing the purposes in the medicine for the treatment of the disease mediated by dipeptidyl peptidase IV, preferred described disease is being type II diabetes.
Bent Ge Lieting hemisuccinic acid salt hydrate of the present invention and crystal thereof have following beneficial effect:
1, hemisuccinic acid salt: compared with known bent Ge Lieting succinate, bent Ge Lieting hemisuccinic acid salt of the present invention is only containing 0.5 succinic acid molecules, decrease the absorption of non-active ingredient, relative toxicity is low and active constituent content is higher, apply safer, more effective in the formulation, be also more suitable for the clinical of high dose medicament and be suitable for.
2, hydrate: carry out purity detecting by HPLC, compared with known bent Ge Lieting succinate, bent Ge Lieting hemisuccinic acid salt hydrate of the present invention has higher purity, plays a good role to the purifying of impurity in sample.
3, crystal formation: crystalline form I disclosed by the invention, crystal form II two kinds of crystal formations stability in the solution are obviously better than the various crystal formations of published bent Ge Lieting succinate.Be conducive to solid preparation wet granulation or make liquid preparation, and being convenient to medicine manufacture, storage, transport; And time purity high, medication is safer.
Accompanying drawing explanation
Fig. 1 is bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I X-ray powder diffraction (PXRD) figure.
Fig. 2 is the crystalline structure figure of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
Fig. 3 is the hydrogen bond interface chart of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
Fig. 4 is thermogravimetric analysis (TG) figure of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
Fig. 5 is differential scanning analysis (DSC) figure of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
Fig. 6 is bent Ge Lieting hemisuccinic acid salt hydrate crystal form II X-ray powder diffraction (PXRD) figure.
Fig. 7 is thermogravimetric analysis (TG) figure of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
Fig. 8 is differential scanning analysis (DSC) figure of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
Fig. 9 is that (a is the XRD figure before thermal treatment for comparison diagram before and after the thermal treatment of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I; B is the XRD figure after thermal treatment, is anhydrous crystal forms).
Figure 10-1 is that (a is the XRD figure before high humidity treatment for comparison diagram before and after the high humidity treatment of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I; B is the XRD figure after high humidity treatment).
Figure 10-2 is that (a is the XRD figure before high humidity treatment for comparison diagram before and after the high humidity treatment of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II; B is the XRD figure after high humidity treatment).
Figure 11 is that (a is the XRD figure before suspendible to the comparison diagram of bent Ge Lieting succinate A crystal formation in ethanol before and after suspendible, and b is the XRD figure after suspendible; Wherein b is consistent with bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I).
Figure 12 is that (a is the XRD figure before suspendible to the comparison diagram of bent Ge Lieting succinate A crystal formation in the mixed solvent of second alcohol and water before and after suspendible; B is the XRD figure after suspendible; Wherein b is consistent with bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I).
Figure 13 is that (a is the XRD figure before suspendible to the comparison diagram of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II in ethanol before and after suspendible, and b is the XRD figure after suspendible; Wherein b has partly consistent with bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I).
Figure 14 is that (a is the XRD figure before suspendible to the comparison diagram of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II in the mixed solvent of second alcohol and water before and after suspendible, and b is the XRD figure after suspendible; Wherein b is consistent with bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I).
Embodiment
Detecting instrument and method:
Single crystal diffraction: RigakuR-AXIS-RAPID single crystal diffractometer, adopts MoK α
ray, carries out structure elucidation and correction with SHELXS97 and SHELXL97.Diamond and Mercury software is used to obtain structure iron.
Powder x-ray diffraction (XRD) characterizes: instrument: RigakuD/Max-2550PC, CuK α radiation, power 40kV × 250mA, sweep limit 2 θ 3 ~ 40 °, walk wide (stepwidth) 0.02 °, sweep velocity 5 °/min.
Thermogravimetric analysis (TG) characterizes: instrument: TA company SDTQ600, sweep gas: nitrogen 120ml/min, heat-up rate: 10 DEG C/min, temperature range: room temperature ~ 380 DEG C.
Differential scanning calorimetric analysis (DSC) characterizes: instrument: TA company DSCQ100, sweep gas: nitrogen 50ml/min, heat-up rate: 10 DEG C/min, temperature range: room temperature ~ 300 DEG C.
To contribute to understanding the present invention further by subordinate's embodiment, but be not used in restriction the present invention.Described embodiment describes the preparation method and application of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I of the present invention and bent Ge Lieting hemisuccinic acid salt hydrate crystal form II in detail.It will be apparent for a person skilled in the art that the many changes for both materials and methods can be implemented without departing from the present invention.
Embodiment 1: bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I and preparation thereof
Get 15.00g (41.97mmol) bent Ge Lieting and be placed in round-bottomed flask, add 200mL tetrahydrofuran (THF) and 100mL Virahol, be stirred and heated to 40 DEG C, in heat-processed, solid dissolves gradually; Take succsinic acid 2.47g (20.91mmol) to join in bent Ge Lieting solution, add rear adularescent solid and separate out, continue to stir 60min, stop heating, naturally cool to room temperature and stir 2h.Filter, filter cake washed with isopropyl alcohol 2 times, drains, vacuum-drying at 40 DEG C, obtains bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
By by the bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I prepared above, the triclinic cell via spacer P1 is differentiated, the feature of these triclinic cells be by under 296K by the following parameter that Single Crystal X-ray structural analysis measures:
α=85.883 (2) °, β=87.312 (3) °, γ=83.373 (2) °,
molecule number Z=2 in structure cell, molecular formula: 2 (C
18h
21fN
5o
2) C
4h
4o
42 (H
2o) 0.25 (H
2o); Atomic coordinate is in table 1.
Prove according to these crystallographic datas: containing 2 bent Ge Lieting molecules, 1 succinic acid molecules and 2.25 water moleculess in the structure of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I, succsinic acid is transferred in the primary amine groups in 2 bent Ge Lieting molecules on piperidine ring as the hydrogen ion on two carboxyl of di-carboxylic acid respectively, form salt form and connected by intramolecular hydrogen bond, its crystalline structure as shown in Figure 2.Structural analysis shows in bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I and there is abundant hydrogen bond network, bent Ge Lieting molecule, succinic acid molecules and water molecules are linked together closely, Fig. 3 is hydrogen bond interface chart, therefore, the water molecules comprised in crystal has higher stability, also shows that it is hydrate crystal forms.
The atomic coordinate of each atom of table 1 bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I and temperature factor
The feature diffract spectral line of table 2 bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I X-ray powder diffraction
Embodiment 2: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I
Get 15.0g (41.97mmol) bent Ge Lieting and be placed in round-bottomed flask, add 150mL tetrahydrofuran (THF), be stirred and heated to 50 DEG C, in heat-processed, solid dissolves gradually; Taking succsinic acid 2.47g (20.91mmol) is dissolved in 50mL Virahol; Joined by succinic acid solution in bent Ge Lieting solution, in adition process, adularescent solid is separated out, and continues to stir 20min, stops heating, naturally cool to room temperature and stir 2h.Filter, filter cake washed with isopropyl alcohol 2 times, drains, vacuum-drying at 50 DEG C, obtains bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
After testing, the feature diffract spectral line etc. of X-ray powder diffraction is all identical with embodiment 1.
Embodiment 3: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I
Get 15.0g (41.97mmol) bent Ge Lieting and be placed in round-bottomed flask, add 100mL tetrahydrofuran (THF) and 50mL Virahol, be stirred and heated to 70 DEG C, in heat-processed, solid dissolves gradually; Taking succsinic acid 2.47g (20.91mmol) joins in bent Ge Lieting solution, and adularescent solid is separated out, and continues to stir 30min, stops heating, naturally cool to room temperature and stir 2h.Filter, filter cake washed with isopropyl alcohol 2 times, drains, vacuum-drying at 50 DEG C, obtains bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
After testing, the feature diffract spectral line etc. of X-ray powder diffraction is all identical with embodiment 1.
Embodiment 4: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I
Get 1100g (3.08mol) bent Ge Lieting and be placed in round-bottomed flask, add 8400mL tetrahydrofuran (THF) and 4200mL Virahol, be stirred and heated to 60 DEG C, in heat-processed, solid dissolves gradually; Taking succsinic acid 183g (1.55mol) joins in bent Ge Lieting solution, and adularescent solid is separated out, and continues to stir 30min, stops heating, naturally cool to room temperature and stir 2h.Filter, filter cake washed with isopropyl alcohol 2 times, drains, vacuum-drying at 50 DEG C, obtains bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
After testing, the feature diffract spectral line etc. of X-ray powder diffraction is all identical with embodiment 1.
Embodiment 5: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I
Get bent Ge Lieting succinate A crystal formation 10g, add in 20ml medicinal alcohol, be stirred and heated to 60 DEG C, in heat-processed, solid dissolves gradually, continues to stir 15min, stop heating, naturally cool to room temperature, crystallization, suction filtration, vacuum-drying at 50 DEG C, obtains bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
After testing, the feature diffract spectral line etc. of X-ray powder diffraction is all identical with embodiment 1.
Embodiment 6: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II
Get 15.0g (41.97mmol) bent Ge Lieting and be placed in round-bottomed flask, add in 270mL acetonitrile and 27mL water, be stirred and heated to 40 DEG C, in heat-processed, solid dissolves gradually; Take succsinic acid 2.47g (20.91mmol), in bent Ge Lieting solution, add rear continuation and stir 20min, stop heating, naturally cool to room temperature and stir 2h.Filter, drain, vacuum-drying at 50 DEG C, obtain bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
The feature diffract spectral line of the X-ray powder diffraction of table 3 bent Ge Lieting hemisuccinic acid salt hydrate crystal form II
Embodiment 7: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II
Get 15.0g (41.97mmol) bent Ge Lieting and be placed in round-bottomed flask, add 150mL acetonitrile and 10mL water, be stirred and heated to 70 DEG C, in heat-processed, solid dissolves gradually; Taking succsinic acid 2.47g (20.91mmol) joins in bent Ge Lieting solution, continues to stir 20min, stops heating, naturally cools to room temperature and stir 2h.Filter, drain, vacuum-drying at 50 DEG C, obtain bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
After testing, the feature diffract spectral line of its X-ray powder diffraction is identical with embodiment 6.
Embodiment 8: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II
Get 15.0g (41.97mmol) bent Ge Lieting and be placed in round-bottomed flask, add 150mL acetonitrile, be stirred and heated to 70 DEG C, in heat-processed, solid dissolves gradually; Taking succsinic acid 2.47g (20.91mmol) is dissolved in 10mL water, is joined by amber aqueous acid in bent Ge Lieting solution, continues to stir 30min, stops heating, naturally cools to room temperature and stir 2h.Filter, drain, vacuum-drying at 50 DEG C, obtain bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
After testing, the feature diffract spectral line of its X-ray powder diffraction is identical with embodiment 6.
Embodiment 9: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II
Get 15g (41.97mmol) bent Ge Lieting and be placed in round-bottomed flask, add 200mL acetonitrile and 15mL water, be stirred and heated to 60 DEG C, in heat-processed, solid dissolves gradually; Take succsinic acid 2.47g (20.91mol), join in bent Ge Lieting solution, continue to stir 30min, stop heating, naturally cool to room temperature and stir 2h.Filter, drain, vacuum-drying at 50 DEG C, obtain bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
After testing, the feature diffract spectral line of its X-ray powder diffraction is identical with embodiment 6.
Embodiment 10: the preparation of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II
Get 20g bent Ge Lieting succinate A crystal formation and be placed in round-bottomed flask, add 100mL acetonitrile, be stirred and heated to 70 DEG C, in heat-processed, solid loses clearly molten, drips water gradually and is about 11mL, dissolve completely to solid, under being placed in room temperature, and crystallization 4h.Filter, drain, vacuum-drying at 50 DEG C, obtain bent Ge Lieting hemisuccinic acid salt hydrate crystal form II.
After testing, the feature diffract spectral line of its X-ray powder diffraction is identical with embodiment 6.
Embodiment 11: the preparation of bent Ge Lieting hemisuccinic acid salt anhydrous crystal forms
Get bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I or crystal form II appropriate, shakeout on watch-glass, put into 120 DEG C of baking ovens, 40 ~ 60min, take out and carry out PXRD sign immediately, be bent Ge Lieting hemisuccinic acid salt anhydrous crystal forms.
Fig. 9 is comparison diagram before and after the thermal treatment of bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I, and wherein collection of illustrative plates a is the XRD figure before thermal treatment; Collection of illustrative plates b is the XRD figure after thermal treatment, is anhydrous crystal forms.
Embodiment 12: for the high humidity stability test of the present invention's bent Ge Lieting hemisuccinic acid salt hydrate crystal formation
By the bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I prepared by the embodiment of the present invention 1 and by the crystal form II that embodiment 6 prepares be placed on 25 DEG C, carry out high humidity stability test in relative humidity 92% (saturated KNO3 solution) environment.Test-results shows, crystalline form I energy stable existence (Figure 10-1), and crystal form II then changes crystalline form I (Figure 10-2) gradually into.
Figure 10-1 is comparison diagram before and after placing under bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I super-humid conditions.Wherein collection of illustrative plates a is the XRD figure before high humidity treatment; Collection of illustrative plates b is the XRD figure after high humidity treatment.Both are identical.
Figure 10-2 is comparison diagram before and after placing under bent Ge Lieting hemisuccinic acid salt hydrate crystal form II super-humid conditions.Wherein collection of illustrative plates a is the XRD figure before high humidity treatment; Collection of illustrative plates b is the XRD figure after high humidity treatment.Crystal form II then changes crystalline form I into substantially.
Embodiment 13: for the bent Ge Lieting hemisuccinic acid salt hydrate crystal formation of the present invention and known bent Ge Lieting succinate, carry out stability competitive assay.
Described stability competitive assay is: get respectively equivalent by the bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I prepared by the embodiment of the present invention 1, the crystal form II prepared by embodiment 6 and prepare bent Ge Lieting succinate crystal form A by patent documentation ZL200780049086.5, be placed in ethanol respectively, the mixed solvent of second alcohol and water forms suspension liquid, at room temperature, jolting, after 5 days, carries out PXRD sign.The figure of bent Ge Lieting succinate A crystal formation in above-mentioned solvent before and after suspendible is shown in Figure 11, Figure 12, and the figure of crystal form II in above-mentioned solvent before and after suspendible is shown in Figure 13, Figure 14.
Test-results is as following table:
Figure 11 is the comparison diagram of bent Ge Lieting succinate A crystal formation in ethanol before and after suspendible, and wherein collection of illustrative plates a is the XRD figure before suspendible, and collection of illustrative plates b is the XRD figure after suspendible.Show in figure: collection of illustrative plates b is consistent with bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
Figure 12 is the comparison diagram of bent Ge Lieting succinate A crystal formation in the mixed solvent of second alcohol and water before and after suspendible, and wherein collection of illustrative plates a is the XRD figure before suspendible, and collection of illustrative plates b is the XRD figure after suspendible.Show in figure: collection of illustrative plates b is consistent with bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I.
Figure 13 is the comparison diagram of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II in ethanol before and after suspendible, and wherein collection of illustrative plates a is the XRD figure before suspendible, and collection of illustrative plates b is the XRD figure after suspendible.Part crystal form II is had to be transformed into crystalline form I after showing suspendible in figure.
Figure 14 is the comparison diagram of bent Ge Lieting hemisuccinic acid salt hydrate crystal form II in the mixed solvent of second alcohol and water before and after suspendible, and wherein collection of illustrative plates a is the XRD figure before suspendible, and collection of illustrative plates b is the XRD figure after suspendible.Bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I is transformed into after showing suspendible in figure.
Embodiment 14: bent Ge Lieting hemisuccinic acid salt crystal formation I tablet
The prescription of bent Ge Lieting hemisuccinic acid salt crystal formation I (weight of free alkali form) of every sheet 50mg:
Bent Ge Lieting hemisuccinic acid salt (crystal formation I) 58.3mg
Lactose 24.6mg
Microcrystalline Cellulose 33.3mg
Cross-linked carboxymethyl cellulose 3.0mg
Hydroxypropylcellulose 5.0mg
Hypromellose 4.0mg
Silicon-dioxide 4.0mg
Magnesium Stearate 1.5mg
Opadry 85F6400302.3mg
Prepare tablet in conventional manner.
Embodiment 15: bent Ge Lieting hemisuccinic acid salt crystal form II tablet
The prescription of the bent Ge Lieting hemisuccinic acid salt crystal form II (weight of free alkali form) of every sheet 25mg
Bent Ge Lieting hemisuccinic acid salt (crystal formation I) 29.2mg
Lactose 12.3mg
Microcrystalline Cellulose 16.7mg
Cross-linked carboxymethyl cellulose 1.5mg
Hydroxypropylcellulose 2.5mg
Hypromellose 2.0mg
Silicon-dioxide 2.0mg
Magnesium Stearate 0.8mg
Opadry 85F6400301.2mg
Prepare tablet in conventional manner.
Claims (17)
1. bent Ge Lieting hemisuccinic acid salt, has structural formula such as formula (I):
2. the hydrate of bent Ge Lieting hemisuccinic acid salt, has structural formula such as formula (II):
Wherein n=1.0 ~ 2.5.
3. bent Ge Lieting hemisuccinic acid salt hydrate crystalline form I according to claim 2, it is characterized in that, described crystalline form I is triclinic(crystalline)system, P1 spacer, and unit cell parameters is:
α=85.87 ~ 85.89 °, β=87.30 ~ 87.32 °, γ=83.36 ~ 83.38 °,
molecule number Z=2 in structure cell;
Wherein n=2.0 ~ 2.5, preferably 2.25.
4. crystalline form I according to claim 3, is characterized in that, described crystal formation uses Cu-K α radiation, has the X-ray powder diffraction pattern represented with 2 θ ± 0.2 °, has characteristic peak: 4.7,9.5,11.3,11.8,12.5,15.8,17.0 with upper/lower positions.
5. crystalline form I according to claim 4, is characterized in that having characteristic peak with upper/lower positions: 4.7,9.5,11.3,11.8,12.5,15.8,17.0,18.8,19.1,19.7,21.3,21.8,22.6,25.1,25.6,26.8.
6. crystalline form I according to any one of claim 3 ~ 5, is characterized in that, has X-ray powder diffraction pattern as shown in Figure 1.
7. crystalline form I according to any one of claim 3 ~ 5, is characterized in that, has DSC differential thermal analysis curve as shown in Figure 5, comprises the mass loss of 4.1% ~ 5.1%.
8. bent Ge Lieting hemisuccinic acid salt hydrate crystal form II according to claim 2, it is characterized in that, described crystal form II is oblique system, P2
1spacer, unit cell parameters is:
α=90.00 °, β=100.404 (27) °, γ=90.00 °,
Wherein n=1.
9. crystal form II according to claim 8, is characterized in that, described crystal formation uses Cu-K α radiation, has the X-ray powder diffraction pattern represented with 2 θ ± 0.2 °, has characteristic peak: 4.6,9.3,12.7,13.2,14.3,15.5,16.8 with upper/lower positions.
10. crystal form II according to claim 9, is characterized in that, has characteristic peak: 4.6,9.3,12.7,13.2,14.3,15.5,16.8,18.7,20.5,21.8,22.4,23.5 with upper/lower positions.
Crystal form II according to any one of 11. according to Claim 8 ~ 10, is characterized in that, has X-ray powder diffraction pattern as shown in Figure 6.
Crystal form II according to any one of 12. according to Claim 8 ~ 10, is characterized in that, has DSC differential thermal analysis curve as shown in Figure 8, comprises the mass loss of about 2.3%.
The method of 13. crystalline form Is of preparation according to any one of claim 3 ~ 5 or the crystal form II described in 8 ~ 10 any one, comprises the steps:
Bent Ge Lieting is joined in solvent, reflux is dissolved, add succsinic acid, in reaction system, the quality of bent Ge Lieting is 1:3 ~ 20g/ml with the ratio of the volume of solvent, and the mol ratio of bent Ge Lieting and succsinic acid is 2:1, and described reflux temperature is 30 ~ 80 DEG C, stir 15 ~ 120min, after stirring 1 ~ 24h after going to room temperature, suction filtration, vacuum-drying at the temperature of 40 ~ 50 DEG C.
14. preparation methods according to claim 13, the wherein said solvent preparing crystalline form I is selected from one or more solvents mixed with arbitrary proportion in n-propyl alcohol, Virahol, ethyl acetate, acetone, tetrahydrofuran (THF), water, the solvent that preferred Virahol and tetrahydrofuran (THF) mix with arbitrary proportion, more preferably Virahol and tetrahydrofuran (THF) volume ratio are 1:2 ~ 3; The solvent preparing crystal form II is one or more solvents mixed with arbitrary proportion be selected from acetonitrile, Virahol, ethyl acetate, acetone, tetrahydrofuran (THF), water, the solvent that preferred acetonitrile and water mix with arbitrary proportion, more preferably the volume ratio of acetonitrile and water is 10 ~ 15:1.
15. 1 kinds of pharmaceutical compositions, comprise hydrate, the crystalline form I described in any one of claim 3 ~ 5, the crystal form II described in any one of claim 8 ~ 10 of bent Ge Lieting hemisuccinic acid salt according to claim 1, bent Ge Lieting hemisuccinic acid salt according to claim 2.
16. pharmaceutical compositions according to claim 15, it is characterized in that, described pharmaceutical composition is prepared into applicable peroral administration tablet, capsule, granule, powder, pill, pulvis, lozenge, syrup, suspensoid, or the water-based of applicable administered parenterally or nonaqueous injection solution or emulsion; Preferably, described pharmaceutical composition is prepared into applicable peroral administration tablet, capsule or granule; More preferably, described applicable peroral administration tablet or capsule are prepared by wet granulation technology.
Crystalline form I described in the hydrate of 17. bent Ge Lieting hemisuccinic acid salt according to claim 1, bent Ge Lieting hemisuccinic acid salt according to claim 2, any one of claim 3 ~ 5, crystal form II described in any one of claim 8 ~ 10 are preparing the purposes prevented and/or treated in the medicine of the disease mediated by dipeptidyl peptidase IV, and wherein said disease is type II diabetes.
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| CN112480075A (en) * | 2020-12-22 | 2021-03-12 | 山东永丞制药有限公司 | Refining method of trelagliptin succinate |
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| CN101573351A (en) * | 2006-11-29 | 2009-11-04 | 武田药品工业株式会社 | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| WO2015149270A1 (en) * | 2014-04-01 | 2015-10-08 | 杭州普晒医药科技有限公司 | Crystal of trelagliptin semi-succinate and preparation method and pharmaceutical composition thereof |
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| CN1926128A (en) * | 2004-03-15 | 2007-03-07 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| CN101573351A (en) * | 2006-11-29 | 2009-11-04 | 武田药品工业株式会社 | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| WO2015149270A1 (en) * | 2014-04-01 | 2015-10-08 | 杭州普晒医药科技有限公司 | Crystal of trelagliptin semi-succinate and preparation method and pharmaceutical composition thereof |
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| CN112480075A (en) * | 2020-12-22 | 2021-03-12 | 山东永丞制药有限公司 | Refining method of trelagliptin succinate |
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Application publication date: 20160316 Assignee: Hangzhou Huadi Pharmaceutical Technology Co.,Ltd. Assignor: Hangzhou Huadong Medicine Group Biopharmaceutical Co.,Ltd. Contract record no.: X2021330000100 Denomination of invention: Trogliptin compounds, salts, crystals, pharmaceutical compositions and uses thereof Granted publication date: 20180907 License type: Common License Record date: 20210820 |