CN103910710A - Alogliptin novel crystal form and preparation method thereof - Google Patents
Alogliptin novel crystal form and preparation method thereof Download PDFInfo
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- CN103910710A CN103910710A CN201310728432.XA CN201310728432A CN103910710A CN 103910710 A CN103910710 A CN 103910710A CN 201310728432 A CN201310728432 A CN 201310728432A CN 103910710 A CN103910710 A CN 103910710A
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- 239000013078 crystal Substances 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 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 title abstract description 3
- 229960001667 alogliptin Drugs 0.000 title abstract description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 63
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 32
- 238000004090 dissolution Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 51
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an alogliptin novel crystal form and a preparation method thereof. The crystal form presents in a substantially pure crystal morphology, has good performance in aspects such as stability, is helpful for storing, is beneficial to operate in a production process, can be used for preparing drugs for treating diabetes, and can also be used for preparing a pharmaceutically acceptable salt thereof.
Description
Technical field
The present invention relates to new crystal of Egelieting and preparation method thereof, belong to pharmacy field.
Background technology
Egelieting (Alogliptin), chemistry 2-[[6-[(3R by name)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene, its structural formula is suc as formula shown in (1):
PCT application WO2005095381 discloses its structure, and its benzoate is used to treat diabetes B as medicinal forms.
Medicine polymorphic is the common phenomenon in drug research and development, is the important factor that affects drug quality.The different crystal forms of same medicine may have difference at aspects such as outward appearance, fusing point, mobility, dissolution rate, bioequivalences, and stability to medicine, bioavailability, curative effect etc. also can exert an influence.Therefore,, in drug research and development, need to consider the polymorphic problem of medicine comprehensively.
PCT applies for WO2007035372, WO2010072680 etc. disclose the salt of Egelieting or the part crystal formation of free alkali, although these Patent Application Publications multiple crystal formation, but because there is material impact in the physico-chemical property of different crystal forms to compound etc., therefore still there is the necessary crystal formation of studying Egelieting, there is the stable new crystal that is easy to storage, better mobility and low viscosity, is easy to be processed into the superior physico-chemical properties such as medicine to find.
Summary of the invention
Summary of the invention
First aspect provides a kind of new crystal of Egelieting.
Second aspect provides a kind of preparation method of new crystal of Egelieting.
Term definition
" crystal formation " refers to unique ordered arrangement and/or the conformation of the molecule of compound in lattice.
" substantially pure " refers to that a kind of crystal formation does not basically contain another or multiple crystal formation, be the purity at least 60% of its crystal formation, 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 formation, the per-cent of described other crystal formation in cumulative volume or the gross weight of crystal formation is less than 20%, or be less than 10%, or be less than 5%, or be less than 3%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.
" do not basically contain " one or more other crystal formations and refer to that the per-cent of other crystal formation in cumulative volume or the gross weight of crystal formation is less than 20%, or be less than 10%, or be less than 5%, or be less than 4%, or be less than 3%, or be less than 2%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.
X-ray powder diffraction " substantially as shown in the figure " refers in X-ray powder diffraction pattern to have 50% at least, 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 shows in the drawings.
" relative intensity " refers to when the intensity at the last the first peak in all diffraction peaks of X-ray powder diffraction pattern (XRPD) is 100%, the ratio of the intensity at the intensity at other peak and the last the first peak.
In the time mentioning spectrogram or occur data in the drawings, " peak " refers to the characteristic peak that can not belong to background noise that those skilled in the art can identify.
In the context of the present invention, 2 θ values in X-ray powder diffraction pattern all take degree (°) as unit.
" dissolution solvent " refers in this solvent, the solubleness of Egelieting is greater than 1 grams per liter, or be greater than 2 grams per liters, or be greater than 3 grams per liters, or be greater than 4 grams per liters, or be greater than 5 grams per liters, or be greater than 6 grams per liters, or be greater than 7 grams per liters, or be greater than 8 grams per liters, or be greater than 9 grams per liters, or be greater than 10 grams per liters, or be greater than 15 grams per liters, or be greater than 20 grams per liters, or be greater than 30 grams per liters, or be greater than 40 grams per liters, or be greater than 50 grams per liters, or be greater than 60 grams per liters, or be greater than 70 grams per liters, or be greater than 80 grams per liters, or be greater than 90 grams per liters, or be greater than 100 grams per liters.
" poor solvent " refers to the solvent that can promote solution supersaturation and/or crystallization.In some embodiments, the solubleness of Egelieting in poor solvent is less than 0.001 grams per liter, is less than 0.1 grams per liter, is less than 0.0 grams per liter, be less than 0.3 grams per liter, be less than 0.4 grams per liter, be less than 0.5 grams per liter, be less than 0.6 grams per liter, be less than 0.7 grams per liter, be less than 0.8 grams per liter, be less than 1 grams per liter, be less than 2 grams per liters, be less than 3 grams per liters, be less than 4 grams per liters, be less than 5 grams per liters, be less than 6 grams per liters, be less than 7 grams per liters, be less than 8 grams per liters, be less than 9 grams per liters, or be less than 10 grams per liters.
In some embodiments, the solubleness of Egelieting in dissolution solvent is greater than its solubleness in poor solvent.In certain embodiments, take the solubleness in dissolution solvent as calculating basis, it is about 10% that the solubleness of Egelieting in dissolution solvent and poor solvent differs, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%.In certain embodiments, the solubleness of Egelieting in dissolution solvent is approximately higher by 10% than the solubleness in poor solvent, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%.
" envrionment temperature " refers to things present position natural temperature around, and described envrionment temperature can be different according to their location, season of living in, time of living in, generally between-20 ℃ to 45 ℃.
Gradient cooling refers to and system temperature is reduced to a certain value within for some time, insulation maintains this temperature for some time, and then temperature is reduced within for some time to a certain value, and insulation maintains this temperature for some time, repeat operation, until reach target temperature.
Continuity ground cooling refer to by system temperature continuity be reduced to target temperature.
In the context of the present invention, when using or while no matter whether using the wording such as " approximately " or " approximately ", represent that each digital numerical value likely there will be the difference such as 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%.Whenever disclosing one while having N value digital, any have N+/-1%, N+/-2%, and N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, the numeral of N+/-15% or N+/-20% value can be by open clearly, and wherein " +/-" refers to and adds deduct.A lower limit in disclosing a numerical range, RL, and a upper limit, RU, time, any in the disclosure scope within numerical value can be by open clearly.Particularly, comprised the following numerical value within the scope of this: R=RL+K* (RU-RL), wherein K is a variable of from 1% to 100% increasing by 1% increment; As: 1%, 2%, 3%, 4%, 5%, 50%, 51%, 52%...95%, 96%, 97%, 98%, 99% or 100%.In addition, also comprised especially the above-mentioned numerical range with the definition of two R numerals disclosing at this.
Detailed Description Of The Invention
First aspect, contriver is by having researched and developed the new crystal I of Egelieting, and it exists with substantially pure crystal habit.
Crystal formation I is characterised in that, there is peak the position that is 18.05 degree about 2 θ greatly in its X-ray powder diffraction pattern, is the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, there is peak the place or the many places that in the X-ray powder diffraction pattern of crystal formation I, are the position of 11.55,16.33,18.05,19.34 degree greatly about 2 θ.
In some embodiments, there is peak the place or the many places that in the X-ray powder diffraction pattern of crystal formation I, are the position of 11.55,16.33,18.05,19.34 degree greatly about 2 θ, are the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 11.55,13.63,16.33,18.05 about 2 θ greatly, there is peak a place or the many places of the position of 19.34,22.60,26.00 degree.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 11.55,13.63,16.33,18.05 about 2 θ greatly, there is peak a place or the many places of the position of 19.34,22.60,26.00 degree, are the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 7.36,11.55,13.63,14.75 about 2 θ greatly, 15.26,16.33,18.05,19.34,20.70, there is peak one place or the many places of the position of 21.79,22.22,23.38,26.00,29.56 degree.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 7.36,11.55 about 2 θ greatly, 13.63,14.75,15.26,16.33,18.05,19.34,20.70,21.79,22.22,23.38, there is peak one place or the many places of the position of 26.00,29.56 degree, are the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 7.36,10.45,11.55 about 2 θ greatly, 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 one place or the many places of the position of 23.38,26.00,29.56 degree.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 7.36,10.45,11.55 about 2 θ greatly, 11.86,13.63,14.75,15.26,16.33,18.05,19.02,19.34,20.70,21.79,22.22,22.60,23.38, there is peak one place or the many places of the position of 26.00,29.56 degree, are the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, there is peak the position that is 18.05 degree about 2 θ greatly in the X-ray powder diffraction pattern of crystal formation I, and diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or are greater than 90%, or are greater than 95%, or are greater than 99%.
In some embodiments, there is peak the position that is 18.05 degree about 2 θ greatly in the X-ray powder diffraction pattern of crystal formation I, and diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or be greater than 90%, or being greater than 95%, or being greater than 99%, is the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 11.55 about 2 θ greatly, 16.33,18.05, there is peak one place or the many places of positions of 19.34 degree, and wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or are greater than 90%, or be greater than 95%, or be greater than 99%.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 11.55 about 2 θ greatly, 16.33, there is peak one place or the many places of positions of 18.05,19.34 degree, and wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or be greater than 90%, or being greater than 95%, or being greater than 99%, is the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 11.55,13.63 about 2 θ greatly, 16.33,18.05,19.34,22.60, there is peak one place or the many places of the position of 26.00 degree, wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or are greater than 90%, or are greater than 95%, or being greater than 99%, is the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, in the X-ray powder diffraction pattern of crystal formation I, be 7.36,10.45,11.55 about 2 θ greatly, 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 one place or the many places of positions of 23.38,26.00,29.56 degree, and wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or being greater than 90%, or being greater than 95%, or be greater than 99%, is the position Wu Feng of 12.1-13.1 degree at 2 θ.
In some embodiments, substantially as shown in Figure 1, wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 50% to the X-ray powder diffraction pattern of crystal formation I, or be greater than 60%, or be greater than 70%, or be greater than 80%, or be greater than 90%, or be greater than 99%.
In some embodiments, the X-ray powder diffraction pattern of crystal formation I substantially as shown in Figure 1, wherein, be the position Wu Feng of 12.1-13.1 degree at 2 θ, diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 50%, or are greater than 60%, or be greater than 70%, or be greater than 80%, or be greater than 90%, or be greater than 99%.
In some embodiments, the X-ray powder diffraction pattern of crystal formation I substantially as shown in Figure 1, wherein, is the position Wu Feng of 12.1-13.1 degree at 2 θ, and diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or are greater than 90%, or are greater than 99%.
Crystal formation I can also otherwise characterize, and for example, in some embodiments, its means of differential scanning calorimetry is measured (DSC) and located to have endotherm(ic)peak at 125 ℃-132 ℃, and endotherm(ic)peak peak value is greatly about 131.69 ℃.
In the present invention, X-ray powder diffraction testing conditions is: Cu target k α, and wavelength 1.54, sweep limit is 2 ° to 40 ° of 2 θ values; In X-ray powder diffraction pattern, ordinate zou for counting (counts) represent diffracted intensity, X-coordinate be expenditure (°) represent diffraction angle 2 θ.DSC testing conditions: under nitrogen atmosphere, 10 degrees/min of heat-up rates, experimental temperature scope: from 40 ℃ to 300 ℃.
2 θ of the X-ray powder diffraction of described crystal formation or diffraction peak measured experimental error, and between a machine and another machine and between a sample and another sample, 2 θ of X-ray powder diffraction or diffraction peak measure slightly difference, the numerical value of described experimental error or difference may be 1 unit of about +/-, approximately 0.8 unit of +/-, approximately 0.5 unit of +/-, approximately 0.3 unit of +/-or approximately 0.1 unit of +/-, therefore the numerical value of described 2 θ or diffraction peak can not be considered as absolute.
The means of differential scanning calorimetry figure (DSC) of described crystal formation has experimental error, between a machine and another machine and between a sample and another sample, slightly difference of the position of endotherm(ic)peak and peak value, the numerical value of experimental error or difference may be 5 units of about +/-, approximately 4 units of +/-, approximately 3 units of +/-, approximately 2 units of +/-or approximately 1 unit of +/-, therefore the peak position of described DSC endotherm(ic)peak or the numerical value of peak value can not be considered as absolute.
Second aspect, also provides the preparation method of crystal formation I here, and described preparation method can change above-mentioned crystal formation into the Egelieting of arbitrary form, and the crystal formation that described preparation method obtains exists with substantially pure crystal formation I.
The method of preparing crystal formation I comprises: Egelieting is dissolved in to dissolution solvent, reduces system temperature or reduce dissolution solvent, and crystallize out, and collect crystal.In some embodiments, in crystallize out process, in order further to improve quality or the productive rate of crystallize out, Egelieting solution is mixed with poor solvent; In some embodiments, in the solution of Egelieting, add poor solvent; In some embodiments, Egelieting solution is joined in poor solvent.
In some embodiments, Egelieting is dissolved in dissolution solvent under certain solvent temperature, described solvent temperature can be the arbitrary value of envrionment temperature to solvent boiling point temperature; In some embodiments, Egelieting is dissolved in dissolution solvent under dissolution solvent boiling temperature.
In some embodiments, thus adopt the cooling of continuity ground or gradient cooling to reduce system temperature.
In some embodiments, reduce dissolution solvent by underpressure distillation.
In some embodiments, described dissolution solvent is ethanol, and described poor solvent is water.
In some embodiments, obtain in crystallization process, system temperature is reduced to lower 10 ℃ than solvent temperature, or 20 ℃, or 30 ℃, or 40 ℃, or 50 ℃, or 60 ℃, or 70 ℃, or 80 ℃, or 90 ℃.
Described pure Egelieting crystal formation I substantially can directly be prepared into and be used for the treatment of the medicine of diabetes or for the preparation of becoming the pharmacy acceptable salts such as Egelieting benzoate.
Experimental result shows, the above-mentioned Egelieting existing with substantially pure crystal formation I has good performance aspect stability, be conducive to operate in production technique, can be for the preparation of preparation or pharmaceutical salts.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffraction pattern of Egelieting crystal formation I.
Fig. 2 shows means of differential scanning calorimetry mensuration (DSC) figure of Egelieting crystal formation I.
Embodiment
In order to make those skilled in the art understand better technical scheme of the present invention, below further disclose some unrestricted embodiment the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can obtain by method preparation described in the invention.
Egelieting is made by compound (2) Deprotection as shown in the formula shown in (2), and compound (2) can apply for that method or other known method in WO2010109468 prepare according to PCT,
Embodiment 1
Digest compound (2) by 4.40 and be dissolved in 45 milliliters of methylene dichloride at approximately 25 ℃, stir, be cooled to approximately 10 ℃, drip 10 milliliters of concentrated hydrochloric acids, react 1 hour; Add water 20 milliliters, separatory, organic layer water extraction 2 times, each 15 milliliters, combining water layer, adds 20% aqueous sodium hydroxide solution in water layer, regulate pH to pH=10, stir 2 hours, separate out a large amount of solids, filter water washing, solid drying, obtain 3.21 grams of Egelietings, detect as crystal formation I, see Fig. 1, Fig. 2.
Embodiment 2
1.01 grams of reflux of Egelieting are dissolved in 4 milliliters of ethanol, are cooled to 25 ℃, join in 40 ml waters, and 0 ℃-5 ℃ stirrings of temperature control 1 hour, filter, and drying solid, obtains 0.85 gram of product, and X-ray powder diffraction detects as crystal formation I.
Embodiment 3: water absorbability detects
Detection method: the sample of crystal formation I is placed 24 hours in the climatic chamber of relative humidity 92%, then detects, and the changes in weight situation of comparative sample is calculated moisture absorption percentage.Wb refers to that bottle is heavy, and W (b+s) refers to the gross weight of bottle and sample, and unit is gram.Detected result is as following table:
Embodiment 4: Detection of Stability
High temperature experiment: get the sample of appropriate crystal formation I, pack in weighing bottle, be paved into thin layer (≤5mm), be then positioned in 60 ℃ of thermostat containers, detect XRPD after 15 days;
Look after experiment: get the sample of appropriate crystal formation I, pack in weighing bottle, be paved into thin layer (≤5mm), uncovered being placed in lighting box (band ultraviolet) placed 15 days under illumination 4500 ± 500lx condition, then detects XRPD; Detected result shows that the XRPD of crystal formation I is unchanged, and crystal formation is unchanged.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and apply the technology of the present invention.Those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.
Claims (6)
1. Egelieting crystal formation I, there is peak the position that is approximately 18.05 degree at 2 θ in the X-ray powder diffraction pattern of described crystal formation I, is the position Wu Fengs of 12.1 degree to 13.1 degree at 2 θ.
2. Egelieting crystal formation I claimed in claim 1, is approximately 11.55,16.33 at 2 θ in the X-ray powder diffraction pattern of described crystal formation I, and there is peak a place or the many places of the position of 18.05,19.34 degree; Or in the X-ray powder diffraction pattern of described crystal formation I, be approximately 11.55,13.63 at 2 θ, there is peak a place or the many places of the position of 16.33,18.05,19.34,22.60,26.00 degree; Or in the X-ray powder diffraction pattern of described crystal formation I, be approximately 7.36,11.55 at 2 θ, there is peak a place or the many places of the position of 13.63,14.75,15.26,16.33,18.05,19.34,20.70,21.79,22.22,23.38,26.00,29.56 degree; Or in the X-ray powder diffraction pattern of described crystal formation I, be approximately 7.36,10.45 at 2 θ, 11.55,11.86,13.63,14.75,15.26,16.33,18.05,19.02,19.34,20.70, there is peak one place or the many places of the position of 21.79,22.22,22.60,23.38,26.00,29.56 degree; Or the X-ray powder diffraction pattern of described crystal formation I substantially as shown in Figure 1, wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 80%, or are greater than 90%, or are greater than 99%.
3. Egelieting crystal formation I claimed in claim 1, in the X-ray powder diffraction pattern of described crystal formation I, be approximately 11.55,16.33 at 2 θ, 18.05, there is peak one place or the many places of positions of 19.34 degree, and wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 99%; Or be approximately 11.55,13.63 at 2 θ in the X-ray powder diffraction pattern of described crystal formation I, there is peak a place or the many places of positions of 16.33,18.05,19.34,22.60,26.00 degree, wherein diffraction angle 2 θ are that the relative intensity at the peak of 18.05 degree is greater than 99%.
4. a method of preparing the arbitrary described Egelieting crystal formation I of claim 1-3, comprising: Egelieting is dissolved in to dissolution solvent, reduces system temperature or reduce dissolution solvent, crystallization, collects crystal.
5. method according to claim 4, described crystallization comprises with poor solvent and mixing.
6. method according to claim 5, described dissolution solvent is ethanol, poor solvent is water.
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 |
|---|---|---|---|
| CN201210591927.8 | 2012-12-29 | ||
| CN2012105919278 | 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)
| Publication Number | Publication Date |
|---|---|
| CN103910710A true CN103910710A (en) | 2014-07-09 |
| CN103910710B CN103910710B (en) | 2017-06-16 |
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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 |
| 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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