CN105399725B - Bent its salt of Ge Lieting compounds, crystal, pharmaceutical composition and purposes - Google Patents
Bent its salt of Ge Lieting compounds, crystal, pharmaceutical composition and purposes Download PDFInfo
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- CN105399725B CN105399725B CN201510749702.4A CN201510749702A CN105399725B CN 105399725 B CN105399725 B CN 105399725B CN 201510749702 A CN201510749702 A CN 201510749702A CN 105399725 B CN105399725 B CN 105399725B
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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 present invention provides a kind of new dipeptidy peptidase in inhibitors song Ge Lieting compounds, hemisuccinic acid salt, hydrate, novel crystal forms medicine, the pharmaceutical composition containing them and the purposes in preparing diabetes conditions drug.Novel crystal forms provided by the invention contain 0.5 succinic acid molecules, reduce the intake of non-active ingredient, and relative toxicity is low and active constituent content higher, apply in the formulation safer, effective, are also more suitable for the clinical application of high dose formulations.Compared with existing song Ge Lieting succinate crystal forms, novel crystal forms stability provided by the invention is good, is conducive to solid pharmaceutical preparation wet granulation or liquid preparation is made, and convenient for drug manufacture, storage, transport；Novel crystal forms purity provided by the invention is high, and medication is safer.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of the hemisuccinic acid salt and its crystal of antidiabetic drug song Ge Lieting
Or crystal form, it further relates to the preparation method of the salt and its crystal or crystal form, its pharmaceutical composition and its treats diabetes preparing
Application in the drug of disease.
Background technology
As living standards of the people constantly improve, the illness rate of diabetes has become serious in trend is gradually increasing
Threaten one of the chronic disease of human health.In recent years, dipeptidyl peptidase-IV inhibitors (DPP-IV inhibitor) are as sugar
The drug for urinating the novel targets of disease, has been to be concerned by more and more people, and be widely used in clinic.DPP-IV inhibitor is first class
The novel diabetes B drug that blood glucose level can be controlled by improving body self-ability, can be used as single medicine, also can be with other mouths
Antidiabetic drug combination is taken, mechanism of action is unique, has and does not generate hypoglycemia, do not cause weight gain and Small side effects etc. solely
Special advantage, while causing the incidence of gastrointestinal side effect also very low.
Bent Ge Lieting (Trelagliptin), entitled 2- [6- (3- amino-piperadine -1- the bases) -3- methyl -2,4- bis- of chemistry
Oxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls] the fluoro- benzonitriles of -4- are the one kind researched and developed by military field (Takeda) and Furiex
Novel super long effective DPP-IV inhibitor, Weekly administration is primary, and similar DPP-IV inhibitor needs to take orally one daily in the market
Secondary, therefore, medication advantage undoubtedly will provide more convenient therapeutic choice for diabetic, be expected to greatly improve patient
Convenience and compliance.The medicine obtains Japanese hygienic workfare portion (MHLW) on March 7th, 2015 and ratifies listing, trade name
For Zafatek, tablet Ge Lieting containing song succinate crystal form A as active constituents of medicine, the specification of tablet have 50mg and
100mg。
Patent document US 20090275750A1 disclose bent Ge Lieting and preparation method thereof, but its solid-state shape is not disclosed
Formula.Bent Ge Lieting belongs to slightly water-soluble compound, generally uses, therefore, is ground to its solid-state form in solid form in the formulation
Study carefully and has a very important significance.
Chinese invention patent CN201310056368.5 (the solid-state forms and preparation method thereof of denomination of invention song Ge Lietingxin
And purposes) disclose bent Ge Lieting in a variety of crystal habits, including crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and without fixed
Form and preparation method thereof.
Patent document ZL200780049086.5 (denominations of invention：2- [6- (3- amino-piperadine -1- bases) -3- methyl -2,4-
Dioxo -3,4- dihydro -2H- pyrimidine -1- ylmethyls] the fluoro- benzonitriles of -4- succinate polymorph and its application method)
Disclose the bent Ge Lieting succinates in a variety of crystal habits, including crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form
F, crystal form G and amorphous state and their preparation method and characterization.
By the further research to bent Ge Lieting succinates solid-state form, it has been found that residual in organic solvent or water
In the case of staying, bent Ge Lieting succinates cannot maintain original crystalline state.Therefore, in order to meet pharmaceutical solid preparation pair
In the strict demand of pharmaceutical activity form, expand the raw material form selected by formulation development, this field needs to develop new bent lattice
The salt and its crystal or crystal form in row spit of fland.
Invention content
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to provide a kind of stability, dissolubility, hygroscopicity, flowing
Phase, purity all have advantage, and are suitable for industrialized large-scaled production bent Ge Lieting salt and its crystal form with long term storage.
The invention discloses a koji Ge Lieting hemisuccinic acid salt, structural formula is as follows：
The invention also discloses the hydrate of a koji Ge Lieting hemisuccinic acid salt, structural formula is as follows：
Wherein n=1.0~2.5.
Its structure chart is shown in that Fig. 2, hydrogen bond structure figure are shown in Fig. 3.
The invention also discloses a koji Ge Lieting hemisuccinic acid salt hydrates crystal form I, the structural formula such as following formula institutes
Show：
N=2.0~2.5 therein, preferably 2.25.
The bent Ge Lieting hemisuccinic acids salt hydrate crystal form I, belongs to anorthic system, P1 space groups, cell parameter is：α=85.87~85.89 °, β=
87.30~87.32 °, γ=83.36~83.38 °,
The X-ray powder diffraction figure (CuK α radiation) of the crystal form I has feature at 2 θ ± 0.2 ° of the following angle of diffraction
Peak：4.7,9.5,11.3,11.8,12.5,15.8,17.0.
Preferably, the X-ray powder diffraction figure (CuK α radiation) of the crystal form I further can 2 θ of the following angle of diffraction ±
There is characteristic peak at 0.2 °：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, the crystal form I has X-ray powder diffraction figure substantially as shown in.
Further, bent I thermogravimetic analysis (TGA) figure of Ge Lieting hemisuccinic acids salt hydrate crystal form of the invention include 4.1%~
5.1% mass loss, thermogravimetic analysis (TGA) when Fig. 4 is n=2.25.
Further, the DSC figures of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I of the invention show (Fig. 5), Qu Gelie
The fusing point (summit value) of spit of fland hemisuccinic acid salt hydrate crystal form I is 189.5 DEG C.
The invention also discloses the preparation methods of the bent Ge Lieting hemisuccinic acids salt hydrate crystal form I, by Qu Gelie
Spit of fland is added in solvent, is heated to reflux dissolving, is added succinic acid, the song quality g of Ge Lieting and the volume of solvent in reaction system
The ratio of ml is 1:The molar ratio of 3~20, bent Ge Lieting and succinic acid is 2:1, the reflux temperature is 30~80 DEG C, stirring 15
~120min is filtered after going to stirring 1 after room temperature~for 24 hours, is dried in vacuo at a temperature of 40~50 DEG C, obtains bent Ge Lieting
Hemisuccinic acid salt hydrate crystal form I.
Preferably, the method that succinic acid is added is：Succinic acid is dissolved in after forming solution in solvent and is added to bent Ge Lieting
Solution system, or solid succinic acid is directly added to bent Ge Lieting solution systems.
The wherein described solvent is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, ethyl acetate, methyl acetate, Ethyl formate, second
Acid butyl ester, acetone, butanone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, dichloromethane, 1,4- dioxane, dimethyl sulfoxide (DMSO), water
One or more of with arbitrary proportion mix solvent.
Preferably, the solvent is a kind of or more in normal propyl alcohol, isopropanol, ethyl acetate, acetone, tetrahydrofuran
The solvent that kind is mixed with arbitrary proportion.
It is highly preferred that the solvent is the one or two kinds of with the molten of arbitrary proportion mixing of isopropanol and tetrahydrofuran
Agent.
Preferably, the volume ml ratios of the weight g of song Ge Lieting and solvent are 1 in reaction:10~15.
Preferably, the temperature being heated to reflux is 40~70 DEG C.
Preferably, the recrystallization temperature is room temperature, and the crystallization time is 2~3 hours.
The invention also discloses bent Ge Lieting hemisuccinic acids salt hydrate crystal forms II, and the structural formula is shown below：
The bent Ge Lieting hemisuccinic acids salt hydrate crystal form II, belongs to monoclinic system, P21 space groups, and cell parameter is：α=90.00 °, β=100.404 (27) °, γ
=90.00 °,
The X-ray powder diffraction figure (CuK α radiation) of the crystal form II has feature at 2 θ ± 0.2 ° of the following angle of diffraction
Peak：4.6,9.3,12.7,13.2,14.3,15.5,16.8.
Preferably, the X-ray powder diffraction figure (CuK α radiation) of the crystal form I further can 2 θ of the following angle of diffraction ±
There is characteristic peak at 0.2 °：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, the crystal form II has X-ray powder diffraction figure substantially as shown in FIG. 6.
The bent Ge Lieting hemisuccinic acids salt hydrate crystal form II of the present invention, thermogravimetic analysis (TGA) figure is shown, includes 2.3% matter
Amount loss.
The DSC figures of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II of the present invention show (Fig. 8), half ambers of bent Ge Lieting
The fusing point (summit value) of hydrochloride hydrates crystal form II is 190.6 DEG C.
The invention also discloses the preparation methods of the bent Ge Lieting hemisuccinic acids salt hydrate crystal form II：
Bent Ge Lieting is added in solvent, is heated to reflux dissolving, is added succinic acid, the matter of song Ge Lieting in reaction system
The ratio for measuring the volume ml of g and solvent is 1:The molar ratio of 3~20, bent Ge Lieting and succinic acid is 2:1, the reflux temperature is
30~80 DEG C, 15~120min is stirred, after going to stirring 1 after room temperature~for 24 hours, is filtered, vacuum is dry at a temperature of 40~50 DEG C
It is dry, obtain bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
Preferably, the method that succinic acid is added is：Succinic acid is dissolved in after forming solution in solvent and is added to bent Ge Lieting
Solution system, or solid succinic acid is directly added to bent Ge Lieting solution systems.
The wherein described solvent is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, ethyl acetate, methyl acetate, Ethyl formate, second
Acid butyl ester, acetone, butanone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, dichloromethane, 1,4- dioxane, dimethyl sulfoxide (DMSO), water
In it is one or more with arbitrary proportion mix solvents.
Preferably, the one kind or more of the solvent in acetonitrile, isopropanol, ethyl acetate, acetone, tetrahydrofuran, water
The solvent that kind is mixed with arbitrary proportion.It is highly preferred that the solvent is the solvent that acetonitrile and water are mixed with arbitrary proportion.
Preferably, the volume ml ratios of the weight g of song Ge Lieting and solvent are 1 in reaction:10~1:15.
Preferably, the temperature being heated to reflux is 40~70 DEG C.
Preferably, the recrystallization temperature is room temperature, and the crystallization time is 2~3 hours.
The present inventor has found in the course of the research, by bent Ge Lieting hemisuccinic acids salt hydrate crystal form I and song Ge Lieting half
Succinate hydrate crystal forms II, after being heat-treated 30~90 minutes at a temperature of 100 DEG C~120 DEG C, hydrate crystal forms can be dehydrated
It is transformed into anhydrous crystal forms, however the anhydrous crystal forms easily absorb water, and in temperature-fall period, are transformed into half ambers of bent Ge Lieting again quickly
Amber hydrochloride hydrates crystal form II.Therefore, bent Ge Lieting hemisuccinic acids salt anhydrous crystal forms are difficult to exist at ambient temperature.
In 25 DEG C, relative humidity 92% (saturation KNO3 solution) environment, by the bent Ge Lieting hemisuccinic acids salt of the present invention
Hydrate crystal forms I and crystal form II are placed 5 days, and bent Ge Lieting hemisuccinic acids salt hydrate crystal form I can be stabilized.
It is compared by stability competitive assay, the bent Ge Lieting succinates of patent document ZL200780049086.5 reports
Organic solvent (such as：Dimethyl sulfoxide (DMSO), acetonitrile, methanol, ethyl alcohol, acetone etc.) or organic solvent and water, especially in ethyl alcohol, water
Or the magma of the in the mixed solvent of ethyl alcohol and water, it cannot maintain original crystal habit, but the Qu Gelie of transition cost invention
The mixture of spit of fland hemisuccinic acid salt hydrate crystal form I or crystal form II or two kind of crystal form illustrates the bent Ge Lieting of the present invention
Hemisuccinic acid salt hydrate has better stability.This property makes the bent Ge Lieting hemisuccinic acids salt hydrate of the present invention
It is more suitable for the wet granulation technology of solid pharmaceutical preparation or liquid preparation is made, is conducive to during drug manufacture, storage, transport etc.
It keeps stablizing, to make product quality keep stablizing.
The invention discloses a kind of compositions containing bent Ge Lieting hemisuccinic acids salt, wherein song Ge Lieting hemisuccinic acid salt
Exist in the form of crystal form I and/or crystal form II to be selected from.It should be pointed out that other of song Ge Lieting hemisuccinic acid salt crystallize and without fixed
Shape form can also exist in composition.Described pharmaceutical composition may include with 0.005%~95% (w/w)
Range is present in composition.
Wherein the pharmaceutical composition further includes the conventional pharmaceutical carrier in addition to bent Ge Lieting hemisuccinic acids salt；Figuration
Agent；Diluent；Lubricant；Adhesive；Wetting agent；Disintegrant；Glidant；Sweetener；Flavoring agent；Emulsifier；Solubilizer；PH is slow
Electuary；Aromatic；Surface stabilizer；Suspending agent；And other conventional pharmaceutically inactive reagents.Particularly, the drug
Composition may include lactose, mannitol, glucose, sucrose, Dicalcium Phosphate, calcium carbonate, saccharin sodium, carboxymethyl cellulose, hard
Fatty acid magnesium, calcium stearate, cross-linked carboxymethyl cellulose sodium, talcum, starch, natural natural gum, molasses, polyvinylpyrrolidone, fibre
Dimension element and its derivative, povidone, Crospovidone acetic acid esters, sodium citrate, cyclodextrine derivatives, mono laurate sorbitol anhydride
Ester, triethanolamine sodium acetate, triethanolamine oleate, the polymer of bio-compatible, ethylene vinyl acetate, polyanhydride, polyglycolic acid,
Polyorthoester, polylactic acid and other this kind of reagents.
The wherein described pharmaceutical composition can be prepared into the tablet of oral administration, capsule, granule, powder, pill,
The aqueous or non-aqueous injection solution or lotion of pulvis, pastille, syrup, suspension or suitable parenteral administration；It is preferred that
Ground, the pharmaceutical composition are selected from tablet, capsule or the granule for being prepared as being suitble to oral administration；It is highly preferred that described
The tablet or capsule for being suitble to oral administration are prepared by wet granulation technology.
The invention also discloses bent Ge Lieting hemisuccinic acids salt, hydrate, the crystal forms I of song Ge Lieting hemisuccinic acid salt
And/or crystal form II, and containing their pharmaceutical composition in the drug for preparing the disease that treatment is mediated by dipeptidyl peptidase IV
In purposes, the preferably described disease be type II diabetes.
The bent Ge Lieting hemisuccinic acids salt hydrate and its crystal of the present invention has the advantages that：
1, hemisuccinic acid salt：Compared with known song Ge Lieting succinates, bent Ge Lieting hemisuccinic acids salt of the invention
0.5 succinic acid molecules is contained only, reduces the intake of non-active ingredient, relative toxicity is low and active constituent content higher,
Using safer, more efficient in preparation, the clinic for being also more suitable for high dose medicament is applicable in.
2, hydrate：Purity detecting, compared with known song Ge Lieting succinates, song of the invention are carried out by HPLC
Ge Lieting hemisuccinic acid salt hydrates have higher purity, play a good role to the purifying of impurity in sample.
3, crystal form：Crystal form I disclosed by the invention, the stability of II two kinds of crystal forms of crystal form in the solution are substantially better than and disclose
Bent Ge Lieting succinates various crystal forms.Be conducive to solid pharmaceutical preparation wet granulation or liquid preparation is made, and is convenient for medicine
Object manufacture, storage, transport；And when purity it is high, medication is safer.
Description of the drawings
Fig. 1 is bent Ge Lieting hemisuccinic acids salt hydrate crystal form I X-ray powder diffraction (PXRD) figure.
Fig. 2 is the crystal structure figure of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I.
Fig. 3 is the hydrogen bond connection figure of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I.
Fig. 4 is thermogravimetric analysis (TG) figure of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I.
Fig. 5 is differential scanning analysis (DSC) figure of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I.
Fig. 6 is bent Ge Lieting hemisuccinic acids salt hydrate crystal form II X-ray powder diffraction (PXRD) figure.
Fig. 7 is thermogravimetric analysis (TG) figure of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
Fig. 8 is differential scanning analysis (DSC) figure of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
Fig. 9 is that bent Ge Lieting hemisuccinic acids salt hydrate crystal form I is heat-treated front and back comparison diagram (a be the XRD before being heat-treated
Figure；B is the XRD diagram after heat treatment, is anhydrous crystal forms).
Figure 10-1 is that (a is high humidity treatment for comparison diagram before and after bent I high humidity treatment of Ge Lieting hemisuccinic acids salt hydrate crystal form
Preceding XRD diagram；B is the XRD diagram after high humidity treatment).
Figure 10-2 be before and after bent II high humidity treatment of Ge Lieting hemisuccinic acids salt hydrate crystal form comparison diagram (a be high humidity at
XRD diagram before reason；B is the XRD diagram after high humidity treatment).
Figure 11 be bent Ge Lieting succinates A crystal forms be suspended in ethanol front and back comparison diagram (a be the XRD diagram before suspension,
B is the XRD diagram after being suspended；Wherein b is consistent with song Ge Lieting hemisuccinic acid salt hydrates crystal form I).
Figure 12 is bent Ge Lieting succinates A crystal forms is suspended that (a is front and back comparison diagram in the in the mixed solvent of second alcohol and water
XRD diagram before suspension；B is the XRD diagram after being suspended；Wherein b is consistent with song Ge Lieting hemisuccinic acid salt hydrates crystal form I).
Figure 13 is that bent Ge Lieting hemisuccinic acids salt hydrate crystal form II is suspended that (a is to be suspended to front and back comparison diagram in ethanol
Preceding XRD diagram, b are the XRD diagram after being suspended；Wherein b has part consistent with bent Ge Lieting hemisuccinic acids salt hydrate crystal form I).
Figure 14 is bent Ge Lieting hemisuccinic acids salt hydrate crystal form II before and after the in the mixed solvent of second alcohol and water is suspended
(a is the XRD diagram before being suspended to comparison diagram, and b is the XRD diagram after being suspended；Wherein b and song Ge Lieting hemisuccinic acid salt hydrates crystal form I
Unanimously).
Specific implementation mode
Detecting instrument and method：
Single crystal diffraction：Rigaku R-AXIS-RAPID single crystal diffractometers, using MoK αRay is used
SHELXS97 and SHELXL97 carries out structure elucidation and amendment.Structure chart is obtained using Diamond and Mercury softwares.
Powder x-ray diffraction (XRD) characterizes：Instrument：Rigaku D/Max-2550PC, CuK α radiation, power 40kV ×
250mA, 3~40 ° of 2 θ of scanning range, 0.02 ° of step width (step width), 5 °/min of sweep speed.
Thermogravimetric analysis (TG) characterizes:Instrument：TA companies SDT Q600, purge gass：Nitrogen 120ml/min, heating rate：10
DEG C/min, temperature range：Room temperature~380 DEG C.
Differential scanning calorimetric analysis (DSC) characterizes：Instrument：TA companies DSC Q100, purge gass：Nitrogen 50ml/min rises
Warm speed：10 DEG C/min, temperature range：Room temperature~300 DEG C.
It will be helpful to further understand the present invention by subordinate's embodiment, but be not used in the limitation present invention.The implementation
Example detailed description of the present invention song Ge Lieting hemisuccinic acid salt hydrates crystal form I and song Ge Lieting hemisuccinic acid salt hydrate crystal forms
II preparation method and application.It will be apparent for a person skilled in the art that many changes for both material and method
It can implement without departing from the present invention.
Embodiment 1：Bent Ge Lieting hemisuccinic acids salt hydrate crystal form I and its preparation
It takes 15.00g (41.97mmol) songs Ge Lieting to be placed in round-bottomed flask, 200mL tetrahydrofurans is added and 100mL is different
Propyl alcohol is stirred and heated to 40 DEG C, and solid gradually dissolves in heating process；It weighs succinic acid 2.47g (20.91mmol) and is added to song
There is white solid precipitation in Ge Lieting solution, after addition, continues to stir 60min, stop heating, naturally cool to room temperature and stir
2h.Filtering, filter cake are washed 2 times with isopropanol, are drained, be dried in vacuo at 40 DEG C, obtain bent Ge Lieting hemisuccinic acids salt hydration
Object crystal form I.
It is tiltedly brilliant via the three of space group P1 by by obtained bent Ge Lieting hemisuccinic acids salt hydrate crystal form I made above
Born of the same parents differentiate that these triclinic cells are characterized in the parameters described below by using Single Crystal X-ray structural analysis to measure at 296K：α=85.883 (2) °, β=87.312
(3) °, γ=83.373 (2) °,Molecular number Z=2 in structure cell, molecular formula：2(C18H21F
N5O2)·C4H4O4·2(H2O)·0.25(H2O)；Atomic coordinates is shown in Table 1.
It is proved according to these crystallographic datas：Contain 2 songs in the structure of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I
Ge Lieting molecules, 1 succinic acid molecules and 2.25 hydrones, succinic acid is as the hydrogen ion on dicarboxylic acids two carboxyl
It is transferred in the primary amine groups in 2 song Ge Lieting molecules on piperidine ring, forms salt form and is connected by intramolecular hydrogen bond respectively,
Crystal structure is as shown in Figure 2.Structural analysis shows that there is abundant hydrogen bonds in song Ge Lieting hemisuccinic acid salt hydrates crystal form I
Network closely links together bent Ge Lieting molecules, succinic acid molecules and hydrone, and Fig. 3 is hydrogen bond connection figure, therefore,
The hydrone for including in crystal has higher stability, also indicates that it is hydrate crystal forms.
The atomic coordinates and temperature factor of 1 song Ge Lieting hemisuccinic acid salt hydrates crystal form of table, I each atom
The feature diffraction spectral line of 2 song Ge Lieting hemisuccinic acid salt hydrates crystal form of table, I X-ray powder diffraction
Embodiment 2：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I
It takes 15.0g (41.97mmol) songs Ge Lieting to be placed in round-bottomed flask, 150mL tetrahydrofurans is added, are stirred and heated to
50 DEG C, solid gradually dissolves in heating process；Succinic acid 2.47g (20.91mmol) is weighed to be dissolved in 50mL isopropanols；By amber
Acid solution is added in bent Ge Lieting solution, there is white solid precipitation in adition process, is continued to stir 20min, is stopped heating, from
So it is cooled to room temperature and stirs 2h.Filtering, filter cake are washed 2 times with isopropanol, are drained, be dried in vacuo at 50 DEG C, obtain bent lattice
Arrange spit of fland hemisuccinic acid salt hydrate crystal form I.
After testing, feature diffraction spectral line of X-ray powder diffraction etc. is same as Example 1.
Embodiment 3：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I
It takes 15.0g (41.97mmol) songs Ge Lieting to be placed in round-bottomed flask, 100mL tetrahydrofurans and 50mL isopropyls is added
Alcohol is stirred and heated to 70 DEG C, and solid gradually dissolves in heating process；It weighs succinic acid 2.47g (20.91mmol) and is added to bent lattice
It arranges in the solution of spit of fland, there is white solid precipitation, continue to stir 30min, stop heating, naturally cool to room temperature and stir 2h.Filtering,
Filter cake is washed 2 times with isopropanol, is drained, and is dried in vacuo at 50 DEG C, and bent Ge Lieting hemisuccinic acids salt hydrate crystal form I is obtained.
After testing, feature diffraction spectral line of X-ray powder diffraction etc. is same as Example 1.
Embodiment 4：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I
It takes 1100g (3.08mol) songs Ge Lieting to be placed in round-bottomed flask, 8400mL tetrahydrofurans and 4200mL isopropyls is added
Alcohol is stirred and heated to 60 DEG C, and solid gradually dissolves in heating process；It weighs succinic acid 183g (1.55mol) and is added to Qu Gelie
In the solution of spit of fland, there is white solid precipitation, continues to stir 30min, stop heating, naturally cool to room temperature and stir 2h.Filtering, filter
Cake is washed 2 times with isopropanol, is drained, and is dried in vacuo at 50 DEG C, and bent Ge Lieting hemisuccinic acids salt hydrate crystal form I is obtained.
After testing, feature diffraction spectral line of X-ray powder diffraction etc. is same as Example 1.
Embodiment 5：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form I
Bent Ge Lieting succinates A crystal form 10g are taken, is added in 20ml medicinal alcohols, is stirred and heated to 60 DEG C, heating process
Middle solid gradually dissolves, and continues to stir 15min, stops heating, naturally cools to room temperature, and crystallization filters, and vacuum is dry at 50 DEG C
It is dry, obtain bent Ge Lieting hemisuccinic acids salt hydrate crystal form I.
After testing, feature diffraction spectral line of X-ray powder diffraction etc. is same as Example 1.
Embodiment 6：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II
It takes 15.0g (41.97mmol) songs Ge Lieting to be placed in round-bottomed flask, is added in 270mL acetonitriles and 27mL water, stirring
40 DEG C are heated to, solid gradually dissolves in heating process；Succinic acid 2.47g (20.91mmol) is weighed, song Ge Lieting solution is arrived
In, continue to stir 20min after addition, stops heating, naturally cool to room temperature and stir 2h.Filtering, is drained, the vacuum at 50 DEG C
It is dry, obtain bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
The feature diffraction spectral line of the X-ray powder diffraction of 3 song Ge Lieting hemisuccinic acid salt hydrates crystal form II of table
Embodiment 7：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II
It takes 15.0g (41.97mmol) songs Ge Lieting to be placed in round-bottomed flask, 150mL acetonitriles and 10mL water is added, stirring adds
Heat is to 70 DEG C, and solid gradually dissolves in heating process；It weighs succinic acid 2.47g (20.91mmol) and is added to bent Ge Lieting solution
In, continue to stir 20min, stops heating, naturally cool to room temperature and stir 2h.Filtering, drains, is dried in vacuo at 50 DEG C,
Obtain bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
After testing, the feature diffraction spectral line of X-ray powder diffraction is same as Example 6.
Embodiment 8：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II
It takes 15.0g (41.97mmol) songs Ge Lieting to be placed in round-bottomed flask, 150mL acetonitriles is added, are stirred and heated to 70
DEG C, solid gradually dissolves in heating process；It weighs succinic acid 2.47g (20.91mmol) to be dissolved in 10mL water, by the water of succinic acid
Solution is added in bent Ge Lieting solution, is continued to stir 30min, is stopped heating, naturally cool to room temperature and stir 2h.Filtering,
It drains, is dried in vacuo at 50 DEG C, obtain bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
After testing, the feature diffraction spectral line of X-ray powder diffraction is same as Example 6.
Embodiment 9：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II
It takes 15g (41.97mmol) songs Ge Lieting to be placed in round-bottomed flask, 200mL acetonitriles and 15mL water, agitating and heating is added
To 60 DEG C, solid gradually dissolves in heating process；Succinic acid 2.47g (20.91mol) is weighed, is added in bent Ge Lieting solution,
Continue to stir 30min, stops heating, naturally cool to room temperature and stir 2h.Filtering, drains, is dried in vacuo, obtains at 50 DEG C
Bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
After testing, the feature diffraction spectral line of X-ray powder diffraction is same as Example 6.
Embodiment 10：The preparation of bent Ge Lieting hemisuccinic acids salt hydrate crystal form II
It takes 20g song Ge Lieting succinate A crystal forms to be placed in round-bottomed flask, 100mL acetonitriles is added, are stirred and heated to 70
DEG C, solid loses dissolved clarification in heating process, and water about 11mL is gradually added dropwise and is placed at room temperature until solid is completely dissolved, crystallization 4h.
Filtering, drains, is dried in vacuo at 50 DEG C, obtain bent Ge Lieting hemisuccinic acids salt hydrate crystal form II.
After testing, the feature diffraction spectral line of X-ray powder diffraction is same as Example 6.
Embodiment 11：The preparation of bent Ge Lieting hemisuccinic acids salt anhydrous crystal forms
It takes bent Ge Lieting hemisuccinic acids salt hydrate crystal form I or crystal form II appropriate, shakeouts on surface plate, be put into 120
DEG C baking oven, 40~60min take out progress PXRD characterizations, as song Ge Lieting hemisuccinic acid salt anhydrous crystal forms immediately.
Fig. 9 is that song Ge Lieting hemisuccinic acid salt hydrates crystal form I is heat-treated front and back comparison diagram, and wherein collection of illustrative plates a is heat treatment
Preceding XRD diagram；Collection of illustrative plates b is the XRD diagram after heat treatment, is anhydrous crystal forms.
Embodiment 12：For the high humidity stability test of song Ge Lieting hemisuccinic acid salt hydrate crystal forms of the invention
It is made by the bent Ge Lieting hemisuccinic acids salt hydrate crystal form I being prepared by the embodiment of the present invention 1 and by embodiment 6
Standby obtained crystal form II is placed on carries out high humidity stability test in 25 DEG C, relative humidity 92% (saturation KNO3 solution) environment.
Test result shows that crystal form I can be stabilized (Figure 10-1), and crystal form II is then gradually converted into crystal form I (Figure 10-2).
Figure 10-1 is that front and back comparison diagram is placed under I super-humid conditions of song Ge Lieting hemisuccinic acid salt hydrates crystal form.Wherein scheme
It is the XRD diagram before high humidity treatment to compose a；Collection of illustrative plates b is the XRD diagram after high humidity treatment.The two is identical.
Figure 10-2 is that front and back comparison diagram is placed under II super-humid conditions of song Ge Lieting hemisuccinic acid salt hydrates crystal form.Wherein scheme
It is the XRD diagram before high humidity treatment to compose a；Collection of illustrative plates b is the XRD diagram after high humidity treatment.Crystal form II then substantially has been converted to crystal form I.
Embodiment 13：For song Ge Lieting hemisuccinic acid salt hydrate crystal forms of the invention and known song Ge Lieting succinic acids
Salt carries out stability competitive assay.
The stability competitive assay is：The Qu Gelie that will be prepared by the embodiment of the present invention 1 of equivalent is taken respectively
Spit of fland hemisuccinic acid salt hydrate crystal form I, the crystal form II being prepared by embodiment 6 and by patent document ZL200780049086.5
Bent Ge Lieting succinates crystal form A is prepared, is respectively placed in the in the mixed solvent formation suspension of ethyl alcohol, second alcohol and water,
At room temperature, after shaking 5 days, PXRD characterizations are carried out.Figure before and after bent Ge Lieting succinates A crystal forms are suspended in above-mentioned solvent is shown in
Figure 11, Figure 12, the figure before and after crystal form II is suspended in above-mentioned solvent are shown in Figure 13, Figure 14.
Test result such as following table：
Figure 11 is the comparison diagram before and after bent Ge Lieting succinates A crystal forms are suspended in ethanol, and wherein collection of illustrative plates a is before being suspended
XRD diagram, collection of illustrative plates b be suspended after XRD diagram.It is shown in figure：Collection of illustrative plates b and song Ge Lieting hemisuccinic acid salt hydrates crystal form I 1
It causes.
Figure 12 is comparison diagram of the bent Ge Lieting succinates A crystal forms before and after the in the mixed solvent of second alcohol and water is suspended,
Middle collection of illustrative plates a is the XRD diagram before being suspended, and collection of illustrative plates b is the XRD diagram after being suspended.It is shown in figure：Collection of illustrative plates b and song Ge Lieting hemisuccinic acids
Salt hydrate crystal form I is consistent.
Figure 13 is the comparison diagram before and after bent Ge Lieting hemisuccinic acids salt hydrate crystal form II is suspended in ethanol, wherein collection of illustrative plates
A is the XRD diagram before being suspended, and collection of illustrative plates b is the XRD diagram after being suspended.Show there is part crystal form II to be transformed into crystal form I after being suspended in figure.
Figure 14 is bent Ge Lieting hemisuccinic acids salt hydrate crystal form II before and after the in the mixed solvent of second alcohol and water is suspended
Comparison diagram, wherein collection of illustrative plates a are the XRD diagram before being suspended, and collection of illustrative plates b is the XRD diagram after being suspended.Show to be transformed into bent lattice after being suspended in figure
Arrange spit of fland hemisuccinic acid salt hydrate crystal form I.
Embodiment 14：Bent Ge Lieting hemisuccinic acids salt crystal form I tablets
The prescription of the bent Ge Lieting hemisuccinic acids salt crystal form I (weight of free alkali form) of every 50mg：
Bent Ge Lieting hemisuccinic acids salt (crystal form I) 58.3mg
Lactose 24.6mg
Microcrystalline cellulose 33.3mg
Cross-linked carboxymethyl cellulose 3.0mg
Hydroxypropylcellulose 5.0mg
Hydroxypropyl methylcellulose 4.0mg
Silica 4.0mg
Magnesium stearate 1.5mg
Opadry 85F640030 2.3mg
Tablet is prepared in conventional manner.
Embodiment 15：Bent Ge Lieting hemisuccinic acids salt crystal form II tablets
The prescription of the bent Ge Lieting hemisuccinic acids salt crystal form II (weight of free alkali form) of every 25mg
Bent Ge Lieting hemisuccinic acids salt (crystal form I) 29.2mg
Lactose 12.3mg
Microcrystalline cellulose 16.7mg
Cross-linked carboxymethyl cellulose 1.5mg
Hydroxypropylcellulose 2.5mg
Hydroxypropyl methylcellulose 2.0mg
Silica 2.0mg
Magnesium stearate 0.8mg
Opadry 85F640030 1.2mg
Tablet is prepared in conventional manner.
Claims (20)
1. song Ge Lieting hemisuccinic acid salt hydrates crystal form I, which is characterized in that the crystal form I be anorthic system, P1 space groups,
Cell parameter is： α=85.87~85.89 °, β
=87.30~87.32 °, γ=83.36~83.38 °, Molecular number Z=2 in structure cell；
Wherein the bent Ge Lieting hemisuccinic acids salt hydrate structure is as follows：
Wherein n=2.0~2.5.
2. song Ge Lieting hemisuccinic acid salt hydrates crystal form I according to claim 1, it is characterized in that the n=2.25.
3. crystal form I according to claim 1, which is characterized in that the crystal form is radiated using Cu-K α, have with 2 θ ±
The X-ray powder diffraction figure of 0.2 ° of expression has characteristic peak in following position：4.7,9.5,11.3,11.8,12.5,15.8,
17.0。
4. crystal form I according to claim 3, which is characterized in that there is characteristic peak in following position：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.
5. crystal form I according to claim 1, which is characterized in that have X-ray powder diffraction figure as shown in Figure 1.
6. crystal form I according to claim 1, which is characterized in that there is DSC differential thermal analysis curves as shown in Figure 5, including
4.1%~5.1% mass loss.
7. song Ge Lieting hemisuccinic acid salt hydrates crystal form II, which is characterized in that the crystal form II is monoclinic system, P21Space
Group, cell parameter are： α=90.00 °, β=
100.404 (27) °, γ=90.00 °,
Wherein the bent Ge Lieting hemisuccinic acids salt hydrate structure is as follows：
Wherein n=1.
8. crystal form II according to claim 7, which is characterized in that the crystal form is radiated using Cu-K α, have with 2 θ ±
The X-ray powder diffraction figure of 0.2 ° of expression has characteristic peak in following position：4.6,9.3,12.7,13.2,14.3,15.5,
16.8。
9. crystal form II according to claim 8, which is characterized in that there is characteristic peak in following position：4.6,9.3,12.7,
13.2,14.3,15.5,16.8,18.7,20.5,21.8,22.4,23.5.
10. crystal form II according to claim 7, which is characterized in that have X-ray powder diffraction figure as shown in FIG. 6.
11. crystal form II according to claim 7, which is characterized in that there is DSC differential thermal analysis curves as shown in Figure 8, including
2.3% mass loss.
12. the method according to I or 7~11 any one of them crystal form II of claim 1~6 any one of them crystal form is prepared,
Include the following steps：
Bent Ge Lieting is added in solvent, is heated to reflux dissolving, is added succinic acid, in reaction system the quality of song Ge Lieting and
The ratio of the volume of solvent is 1:The molar ratio of 3~20g/mL, bent Ge Lieting and succinic acid is 2:1, the reflux temperature is 30
~80 DEG C, 15~120min is stirred, after going to stirring 1 after room temperature~for 24 hours, filters, is dried in vacuo at a temperature of 40~50 DEG C.
13. preparation method according to claim 12, wherein the solvent for preparing crystal form I is selected from normal propyl alcohol, isopropyl
One or more solvents mixed with arbitrary proportion in alcohol, ethyl acetate, acetone, tetrahydrofuran, water；Prepare the molten of crystal form II
Agent is one or more with the molten of arbitrary proportion mixing in acetonitrile, isopropanol, ethyl acetate, acetone, tetrahydrofuran, water
Agent.
14. preparation method according to claim 13, wherein I solvent of crystal form for preparing is selected from isopropanol and tetrahydrochysene furan
It mutters the solvent mixed with arbitrary proportion；The solvent for preparing crystal form II is selected from the solvent that acetonitrile and water are mixed with arbitrary proportion.
15. preparation method according to claim 14, wherein the solvent for preparing crystal form I is isopropanol and tetrahydrochysene furan
Volume ratio of muttering is 1:2~3；The solvent for preparing crystal form II is that the volume ratio of acetonitrile and water is 10~15:1.
16. a kind of pharmaceutical composition, including any one of claim 1~6 any one of them crystal form I, claim 7~11 institute
The crystal form II stated.
17. pharmaceutical composition according to claim 16, which is characterized in that the pharmaceutical composition is prepared into suitable warp
Tablet, capsule, granule, powder, pill, pulvis, pastille, syrup, suspension or the suitable parenteral administration of mouth administration
Aqueous or non-aqueous injection solution or lotion.
18. pharmaceutical composition according to claim 17, it is characterised in that the pharmaceutical composition is prepared into suitable warp
Tablet, capsule or the granule of mouth administration.
19. pharmaceutical composition according to claim 18, it is characterised in that the tablet or capsule of the suitable oral administration
Agent is prepared by wet granulation technology.
20. any one of claim 1~6 crystal form I, claim 7~11 any one of them crystal form II are preparing prevention
And/or the purposes in the drug of disease that is mediated by dipeptidyl peptidase IV for the treatment of, wherein the disease is type II diabetes.
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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 |
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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 |
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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 |