CN103910710B - Egelieting novel crystal forms and preparation method thereof - Google Patents
Egelieting novel crystal forms and preparation method thereof Download PDFInfo
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- CN103910710B CN103910710B CN201310728432.XA CN201310728432A CN103910710B CN 103910710 B CN103910710 B CN 103910710B CN 201310728432 A CN201310728432 A CN 201310728432A CN 103910710 B CN103910710 B CN 103910710B
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- 239000013078 crystal Substances 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 62
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 abstract description 10
- 238000005516 engineering process Methods 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 238000005755 formation reaction Methods 0.000 description 50
- 239000002904 solvent Substances 0.000 description 22
- 238000004090 dissolution Methods 0.000 description 12
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- -1 filtered Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Novel crystal forms the present invention relates to Egelieting and preparation method thereof, the crystal formation exists with essentially pure crystal habit, has good performance at aspects such as stability, is conducive to storage, is conducive to being operated in production technology；Can be used for preparing the medicine for the treatment of diabetes, it is also possible to for preparing its pharmaceutically useful salt.
Description
Technical field
Novel crystal forms the present invention relates to Egelieting and preparation method thereof, belong to pharmaceutical field.
Background technology
Egelieting (Alogliptin), chemical entitled 2- [[6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3-
Methyl -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl] benzonitrile, shown in its structural formula such as formula (1)：
PCT application WO2005095381 discloses its structure, and its benzoate is used for treatment 2 types sugar as medicinal forms
Urine disease.
Polymorph in pharmaceuticals is the common phenomenon in drug research and development, is the key factor for influenceing drug quality.Same medicine
Different crystal forms might have difference at aspects such as outward appearance, fusing point, mobility, dissolution rate, bioequivalences, to the stabilization of medicine
Property, bioavilability, curative effect etc. can also produce influence.Therefore, it is necessary to consider that the polymorphic of medicine is asked comprehensively in drug research and development
Topic.
PCT application WO2007035372, WO2010072680 etc. disclose the salt of Egelieting or the part crystalline substance of free alkali
Type, although these patent applications disclose various crystal formations, but because different crystal forms have important shadow to physicochemical property of compound etc.
Ring, therefore the necessary crystal formation to study Egelieting is still present, storage, preferable mobility and low are stable and easy to find to have
Viscosity, the novel crystal forms for being easily processed into the superior physicochemical property such as medicine.
The content of the invention
Summary of the invention
First aspect provides a kind of novel crystal forms of Egelieting.
Second aspect provides a kind of preparation method of the novel crystal forms of Egelieting.
Term is defined
" crystal formation " refers to unique ordered arrangement and/or conformation of molecule of the compound in lattice.
" essentially pure " refers to the purity that a kind of crystal formation is substantially free of another or various crystal formations, i.e. its crystal formation
At least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least
98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or
In crystal formation contain other crystal formations, percentage of described other crystal formations in the cumulative volume or gross weight of crystal formation be less than 20%, or less than
10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
One or more other crystal formation of substantially free refers to other crystal formations in the cumulative volume or gross weight of crystal formation
Percentage is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than
0.5%, or less than 0.1%, or less than 0.01%.
X-ray powder diffraction " substantially as shown in the figure " refers at least 50% in X-ray powder diffraction figure, or at least
60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% peak is displayed in figure.
" relative intensity " refer to X-ray powder diffraction figure (XRPD) all diffraction maximums in the intensity at the last the first peak be
When 100%, the ratio of the intensity at other peaks and the intensity at the last the first peak.
When the data in referring to spectrogram or appearing in figure, " peak " refers to that what those skilled in the art were capable of identify that will not belong to
In a characteristic peak of background noise.
In the context of the present invention, 2 θ values in X-ray powder diffraction figure with spend (°) be unit.
" dissolution solvent " refers to that in the solvent, the solubility of Egelieting is more than 1 g/l, or more than 2 g/l, or
Person is more than 3 g/l, or more than 4 g/l, or more than 5 g/l, or more than 6 g/l, or more than 7 g/l, or
More than 8 g/l, or more than 9 g/l, or more than 10 g/l, or more than 15 g/l, or more than 20 g/l, or
Person is more than 30 g/l, or more than 40 g/l, or more than 50 g/l, or more than 60 g/l, or more than 70 grams/
Rise, or more than 80 g/l, or more than 90 g/l, or more than 100 g/l.
" poor solvent " is the solvent for referring to promote solution supersaturation and/or crystallization.In some embodiments, Ah
Solubility of the Ge Lieting in poor solvent be less than 0.001 g/l, less than 0.1 g/l, less than 0.0 g/l, less than 0.3 gram/
Rise, less than 0.4 g/l, less than 0.5 g/l, less than 0.6 g/l, less than 0.7 g/l, less than 0.8 g/l, less than 1 gram/
Rise, less than 2 g/l, less than 3 g/l, less than 4 g/l, less than 5 g/l, less than 6 g/l, less than 7 g/l, less than 8 grams/
Rise, less than 9 g/l, or less than 10 g/l.
In some embodiments, solubility of the Egelieting in dissolution solvent is more than its dissolving in poor solvent
Degree.In certain embodiments, it is to calculate basis with the solubility in dissolution solvent, Egelieting is in dissolution solvent and bad molten
Solubility difference about 10% in agent, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%.At certain
In a little embodiments, solubility of the Egelieting in dissolution solvent is about higher by 10% than the solubility in poor solvent, or 20%,
Or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%.
" environment temperature " refers to the natural temperature around things present position, and the environment temperature can be according to residing
Area, residing season, residing time are different, typically between -20 DEG C to 45 DEG C.
Gradient cooling refers to that system temperature is reduced into a certain value within a period of time, when insulation maintains one section of this temperature
Between, temperature is then reduced to a certain value within a period of time again, insulation maintains this temperature for a period of time, repeats operation,
Until reaching target temperature.
The cooling of continuity ground refers to that system temperature continuity is reduced into target temperature.
In the context of the present invention, when using or regardless of whether use " about " or during the wording such as " about ", represent every
The numerical value of one numeral is possible to that the difference such as 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20% occurs.There is N whenever disclosing one
Value it is digital when, it is any with N+/- 1%, N+/- 2%, N+/- 3%, N+/- 5%, N+/- 7%, N+/- 8%, N+/- 10%, N+/- 15%
Or the numeral of the value of N+/- 20% can be specifically disclosed, wherein " +/- " refers to add deduct.In a number range is disclosed
One lower limit, RL, and a upper limit, RU, when, any numerical value within the scope of the disclosed can be specifically disclosed.
Particularly, the values below in the range of this is contained：R=RL+K* (RU-RL), wherein K be one by 1% increment it is increased from
1% to 100% variable；Such as：1%th, 2%, 3%, 4%, 5%, 50%, 51%, 52%...95%, 96%, 97%, 98%, 99% or 100%.Separately
Outward, be disclosed that above-mentioned with two number ranges of R definitions is also especially contained.
Detailed description of the invention
In a first aspect, inventor passes through to have researched and developed the novel crystal forms I of Egelieting, it is with essentially pure crystalline
State is present.
Crystal formation I is characterised by about thering is peak in the position that 2 θ are 18.05 degree in its X-ray powder diffraction figure, in 2 θ
It is the position Wu Feng of 12.1-13.1 degree.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 11.55,16.33,
At the one of 18.05,19.34 degree of position or there is peak many places.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 11.55,16.33,
It is the position Wu Feng of 12.1-13.1 degree in 2 θ at the one of 18.05,19.34 degree of position or there is peak many places.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 11.55,13.63,
At the one of 16.33,18.05,19.34,22.60,26.00 degree of position or there is peak many places.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 11.55,13.63,
It is the position of 12.1-13.1 degree in 2 θ at the one of 16.33,18.05,19.34,22.60,26.00 degree of position or there is peak many places
Without peak.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 7.36,11.55,13.63,
The one of 14.75,15.26,16.33,18.05,19.34,20.70,21.79,22.22,23.38,26.00,29.56 degree of position
There is peak place or many places.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 7.36,11.55,13.63,
The one of 14.75,15.26,16.33,18.05,19.34,20.70,21.79,22.22,23.38,26.00,29.56 degree of position
There is peak place or many places, are the position Wu Feng of 12.1-13.1 degree in 2 θ.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 7.36,10.45,11.55,
11.86,13.63,14.75,15.26,16.33,18.05,19.02,19.34,20.70,21.79,22.22,22.60,
At the one of 23.38,26.00,29.56 degree of position or there is peak many places.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 7.36,10.45,11.55,
11.86,13.63,14.75,15.26,16.33,18.05,19.02,19.34,20.70,21.79,22.22,22.60,
It is the position Wu Feng of 12.1-13.1 degree in 2 θ at the one of 23.38,26.00,29.56 degree of position or there is peak many places.
In some embodiments, about have in the position that 2 θ are 18.05 degree in the X-ray powder diffraction figure of crystal formation I
Peak, the θ of the angle of diffraction 2 is that the relative intensity at 18.05 degree of peak is more than 80%, or more than 90%, or more than 95%, or be more than
99%。
In some embodiments, about have in the position that 2 θ are 18.05 degree in the X-ray powder diffraction figure of crystal formation I
Peak, the θ of the angle of diffraction 2 is that the relative intensity at 18.05 degree of peak is more than 80%, or more than 90%, or more than 95%, or be more than
99%, it is the position Wu Feng of 12.1-13.1 degree in 2 θ.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 11.55,16.33,
There is peak at the one of 18.05,19.34 degree of position or many places, and the wherein θ of the angle of diffraction 2 is that the relative intensity at 18.05 degree of peak is more than
80%, or more than 90%, or more than 95%, or more than 99%.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 11.55,16.33,
There is peak at the one of 18.05,19.34 degree of position or many places, and the wherein θ of the angle of diffraction 2 is that the relative intensity at 18.05 degree of peak is more than
80%, or more than 90%, or more than 95%, or be the position Wu Feng of 12.1-13.1 degree in 2 θ more than 99%.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 11.55,13.63,
There is peak at the one of 16.33,18.05,19.34,22.60,26.00 degree of position or many places, and the wherein θ of the angle of diffraction 2 is 18.05 degree
The relative intensity at peak is more than 80%, or more than 90%, or more than 95%, or be the position of 12.1-13.1 degree in 2 θ more than 99%
Put without peak.
In some embodiments, in the X-ray powder diffraction figure of crystal formation I about 2 θ be 7.36,10.45,11.55,
11.86,13.63,14.75,15.26,16.33,18.05,19.02,19.34,20.70,21.79,22.22,22.60,
There is peak at the one of 23.38,26.00,29.56 degree of position or many places, and the wherein θ of the angle of diffraction 2 is the relative intensity at 18.05 degree of peak
It is the position Wu Feng of 12.1-13.1 degree in 2 θ more than 80%, or more than 90%, or more than 95%, or more than 99%.
In some embodiments, the X-ray powder diffraction figure of crystal formation I substantially as shown in, the wherein θ of the angle of diffraction 2
For the relative intensity at 18.05 degree of peaks is more than 50%, or more than 60%, or more than 70%, or more than 80%, or it is more than
90%, or more than 99%.
In some embodiments, the X-ray powder diffraction figure of crystal formation I substantially as shown in, wherein, be in 2 θ
The position Wu Feng of 12.1-13.1 degree, the θ of the angle of diffraction 2 are that the relative intensity at 18.05 degree of peak is more than 50%, or more than 60%, or
More than 70%, or more than 80%, or more than 90%, or more than 99%.
In some embodiments, the X-ray powder diffraction figure of crystal formation I substantially as shown in, wherein, be in 2 θ
The position Wu Feng of 12.1-13.1 degree, the θ of the angle of diffraction 2 are that the relative intensity at 18.05 degree of peak is more than 80%, or more than 90%, or
More than 99%.
Crystal formation I can also be characterized otherwise, for example, in some embodiments, its means of differential scanning calorimetry is determined
(DSC) there is endothermic peak at 125 DEG C -132 DEG C, endotherm peak is about at 131.69 DEG C.
In the present invention, X-ray powder diffraction testing conditions are：Cu target k α, wavelength 1.54, sweep limits arrives for 2 ° of 2 θ values
40°；In X-ray powder diffraction figure, ordinate is the diffracted intensity represented with counting (counts), and abscissa is expenditure (°)
The θ of the angle of diffraction 2 of expression.DSC testing conditions：Under blanket of nitrogen, 10 degrees/min of programming rate, experimental temperature scope：From 40 DEG C to
300℃。
2 θ of the X-ray powder diffraction collection of the crystal formation or diffraction maximum have measured experimental error, and in a machine
Between device and another machine and between a sample and another sample, 2 θ or diffraction maximum of X-ray powder diffraction collection
Measure and may slightly have difference, the numerical value of the experimental error or difference is probably about +/- 1 unit, about +/- 0.8
Individual unit, about +/- 0.5 unit, about +/- 0.3 unit or about +/- 0.1 unit, therefore 2 θ or diffraction maximum
Numerical value can not be considered as it is absolute.
The means of differential scanning calorimetry figure (DSC) of the crystal formation has experimental error, between a machine and another machine with
And between a sample and another sample, the position of endothermic peak and peak value may slightly have difference, experimental error or difference
Numerical value is probably about +/- 5 units, about +/- 4 units, about +/- 3 units, about +/- 2 units or about
+/- 1 unit, thus the peak position of the DSC endothermic peaks or the numerical value of peak value can not be considered as it is absolute.
Second aspect, there is also provided the preparation method of crystal formation I, the preparation method can be any form of Ah lattice
Row spit of fland is changed into above-mentioned crystal formation, and the crystal formation that the preparation method is obtained exists with essentially pure crystal formation I.
The method for preparing crystal formation I includes：Egelieting is dissolved in dissolution solvent, system temperature is reduced or is reduced and dissolve molten
Agent, separates out crystal, and collect crystal.In some embodiments, in precipitation crystallization process, in order to further improve precipitation crystal
Quality or yield, Egelieting solution is mixed with poor solvent；In some embodiments, in the solution of Egelieting
Add poor solvent；In some embodiments, Egelieting solution is added in poor solvent.
In some embodiments, Egelieting is dissolved in dissolution solvent under certain solution temperature, the dissolving temperature
Degree can be arbitrary value of the environment temperature to solvent boiling point temperature；In some embodiments, Egelieting is boiled in dissolution solvent
It is dissolved in dissolution solvent at a temperature of point.
In some embodiments, lowered the temperature using continuity or gradient cooling is so as to reduce system temperature.
In some embodiments, dissolution solvent is reduced by vacuum distillation.
In some embodiments, the dissolution solvent is ethanol, and the poor solvent is water.
In some embodiments, in obtaining crystallization process, system temperature is reduced to it is lower than solution temperature 10 DEG C, or 20
DEG C, or 30 DEG C, or 40 DEG C, or 50 DEG C, or 60 DEG C, or 70 DEG C, or 80 DEG C, or 90 DEG C.
The essentially pure Egelieting crystal formation I can directly be prepared into the medicine for treating diabetes or be used for
It is prepared into the pharmaceutically acceptable salts such as Egelieting benzoate.
Test result indicate that, the above-mentioned Egelieting existed with essentially pure crystal formation I has good in terms of stability
Good performance, is conducive to being operated in production technology, can be used for preparation of preparation or pharmaceutical salts.
Brief description of the drawings
Fig. 1 shows the X-ray powder diffraction figure of Egelieting crystal formation I.
Fig. 2 shows that the means of differential scanning calorimetry of Egelieting crystal formation I determines (DSC) figure.
Specific embodiment
In order that those skilled in the art more fully understands technical scheme, some are disclosed further below non-
The present invention is described in further detail for limitation embodiment.
Reagent used in the present invention can from the market be bought or can be by method system described in the invention
It is standby and obtain.
Egelieting is obtained as compound (2) Deprotection as shown in following formula (2), and compound (2) can be according to PCT Shens
Method or other known method that please be in WO2010109468 be prepared,
Embodiment 1
4.40 g of compound (2) are dissolved in 45 milliliters of dichloromethane at about 25 DEG C, are stirred, be cooled to about 10 DEG C, be added dropwise 10
Milliliter concentrated hydrochloric acid, reacts 1 hour；Add water 20 milliliters, point liquid, organic layer is extracted 2 times with water, 15 milliliters every time, combining water layer, water
20% sodium hydrate aqueous solution is added in layer, pH to pH=10 is adjusted, stirred 2 hours, separate out a large amount of solids, filtered, water washing, Gu
Soma is dry, obtains 3.21 grams of Egelietings, is detected as crystal formation I, sees Fig. 1, Fig. 2.
Embodiment 2
1.01 grams of Egelieting is heated to reflux being dissolved in 4 milliliters of ethanol, is cooled to 25 DEG C, is added in 40 milliliters of water, temperature control 0
DEG C -5 DEG C stir 1 hour, and filtering, drying solid obtains 0.85 gram of product, and X-ray powder diffraction is detected as crystal formation I.
Embodiment 3：Hygroscopicity is detected
Detection method：The sample of crystal formation I is placed 24 hours in the climatic chamber of relative humidity 92%, is then detected, than
Compared with the weight change situation of sample, Moisture percentage is calculated.Wb refers to bottle weight, and W (b+s) refers to the gross weight of bottle and sample, unit for gram.
Testing result such as following table：
Embodiment 4：Detection of Stability
High temperature is tested：The sample of appropriate crystal formation I is taken, is fitted into measuring cup, be paved into thin layer (≤5mm), be then placed into 60
In DEG C insulating box, XRPD is detected after 15 days；
Look after experiment：The sample of appropriate crystal formation I is taken, is fitted into measuring cup, be paved into thin layer (≤5mm), opening is placed in illumination
In case（With ultraviolet）, placed 15 days under the conditions of 4500 ± 500lx of illumination, then detect XRPD；Testing result shows crystal formation I's
XRPD is unchanged, and crystal formation is unchanged.
The method of the present invention is described by preferred embodiment, related personnel substantially can present invention,
Method described herein and application be modified in spirit and scope or suitably change is realized and using of the invention with combine
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, institute
There is similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (6)
1. Egelieting crystal formation I, in 2 θ is 11.55,13.63,16.33 in the X-ray powder diffraction figure of the crystal formation I,
There is peak 18.05,19.34,22.60,26.00 degree of position, in the position Wu Feng that 2 θ are 12.1 degree to 13.1 degree.
2. Egelieting crystal formation I according to claim 1, be in 2 θ in the X-ray powder diffraction figure of the crystal formation I
7.36,11.55,13.63,14.75,15.26,16.33,18.05,19.34,20.70,21.79,22.22,23.38,26.00,
There is peak 29.56 degree of position.
3. Egelieting crystal formation I according to claim 1, be in 2 θ in the X-ray powder diffraction figure of the crystal formation I
7.36,10.45,11.55,11.86,13.63,14.75,15.26,16.33,18.05,19.02,19.34,20.70,21.79,
There is peak 22.22,22.60,23.38,26.00,29.56 degree of position.
4. the X-ray powder diffraction figure of Egelieting crystal formation I according to claim 1, the crystal formation I is substantially such as Fig. 1
Shown, the wherein θ of the angle of diffraction 2 is that the relative intensity at 18.05 degree of peak is more than 99%.
5. Egelieting crystal formation I according to claim 1, the wherein θ of the angle of diffraction 2 is that the relative intensity at 18.05 degree of peak is big
In 99%.
6. a kind of method for preparing any described Egelieting crystal formation I of claim 1-5, including：Egelieting is dissolved in second
Alcohol, obtains the first system；Reduce the first system temperature or reduce the ethanol, obtain second system；By described second
System mixes with water, separates out crystal, and the crystal is Egelieting crystal formation I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310728432.XA CN103910710B (en) | 2012-12-29 | 2013-12-25 | Egelieting novel crystal forms and preparation method thereof |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105919278 | 2012-12-29 | ||
| CN201210591927.8 | 2012-12-29 | ||
| CN201210591927 | 2012-12-29 | ||
| CN201310117109.9 | 2013-04-04 | ||
| CN201310117109 | 2013-04-04 | ||
| CN2013101171099 | 2013-04-04 | ||
| CN201310728432.XA CN103910710B (en) | 2012-12-29 | 2013-12-25 | Egelieting novel crystal forms and preparation method thereof |
Publications (2)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101360735A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor |
| WO2011041154A1 (en) * | 2009-10-01 | 2011-04-07 | Metabolex, Inc. | Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts |
| CN102264719A (en) * | 2008-12-23 | 2011-11-30 | 桑多斯股份公司 | Crystalline form of an organic compound |
| CN102361557A (en) * | 2009-03-26 | 2012-02-22 | Mapi医药公司 | Process for the preparation of alogliptin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101360735A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor |
| CN102264719A (en) * | 2008-12-23 | 2011-11-30 | 桑多斯股份公司 | Crystalline form of an organic compound |
| CN102361557A (en) * | 2009-03-26 | 2012-02-22 | Mapi医药公司 | Process for the preparation of alogliptin |
| WO2011041154A1 (en) * | 2009-10-01 | 2011-04-07 | Metabolex, Inc. | Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts |
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