CN105218522A - A kind of dextrorotation lY 81149 compound and pharmaceutical composition thereof - Google Patents
A kind of dextrorotation lY 81149 compound and pharmaceutical composition thereof Download PDFInfo
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- CN105218522A CN105218522A CN201410294728.XA CN201410294728A CN105218522A CN 105218522 A CN105218522 A CN 105218522A CN 201410294728 A CN201410294728 A CN 201410294728A CN 105218522 A CN105218522 A CN 105218522A
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Abstract
The invention provides a kind of dextrorotation lY 81149 compound of new crystalline form, and the preparation method of this new crystal and containing the pharmaceutical composition of this crystal formation.The dextrorotation lY 81149 compound of crystalline form of the present invention is basicly stable under high temperature, high humidity and illumination condition; Accelerated test condition stability inferior with draw moist also without noticeable change, draw simultaneously and moistly meet medicinal requirements.
Description
Technical field
The invention belongs to medicinal chemistry arts, relate to a kind of dextrorotation lY 81149 compound of crystalline form and pharmaceutical composition thereof and preparation method particularly.
Background technology
LY 81149 (Ilaprazole), systematic naming method is 5-(1 hydrogen-pyrroles-1-base)-2-[[(4-methoxyl group-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1 hydrogen-benzoglyoxaline; Its enteric coated tablet can be used for treating duodenal ulcer.
Dextrorotation lY 81149 chemical structure, such as formula shown in I, is R configuration.The Acidinhibitor disclosing the lY 81149 of left-handed or dextrorotation in CN101098867A is all strong than raceme.
The crystal Form A form of dextrorotation lY 81149 is disclosed in WO2008/083319A1, and the FormA of left-handed lY 81149, FormO, amorphous forms.
Summary of the invention
The invention provides a kind of dextrorotation lY 81149 compound of new crystalline form, and the preparation method of this new crystal and containing the pharmaceutical composition of this crystal formation.
Can the present invention be realized by following technical solution:
Structure, such as formula the dextrorotation lY 81149 compound shown in I, is crystalline form, and its X-ray powder diffraction figure has diffraction peak at following spacing place: 11.21,8.91,7.32,4.83,4.16,4.10,3.63.
Its X-ray powder diffraction figure has diffraction peak at following spacing place: 5.90,5.58,5.46,3.90,3.10.Spacing also can be represented by d value, and its unit is dust.
Further preferably, the dextrorotation lY 81149 compound of described crystalline form, has X-ray powder diffraction figure substantially as shown in Figure 1; In Fig. 1,2 θ angles, d value and Relative intensity data are as shown in table 1.According to Bragg equation 2dsin θ=n λ; Wherein λ is the wavelength of X-ray, and n is diffraction progression; In the present invention, Fig. 1 is obtained by Cu target diffraction, and wavelength X is 1.5406 dusts.There is error in the mensuration at 2 θ angles; Generally speaking the limit of error at 2 θ angles can regard as measuring error ± 0.2.
Table 1
Further preferably, the dextrorotation lY 81149 compound of described crystalline form, has DSC collection of illustrative plates substantially as shown in Figure 2, has an endotherm(ic)peak at about 180 DEG C of places.The temperature rise rate of the DSC collection of illustrative plates shown in Fig. 2 is 10 DEG C/min, and temperature elevating range is 50 ~ 300 DEG C, and in collection of illustrative plates, endotherm(ic)peak upwards (Endoup).
Present invention also offers a kind of method preparing described crystalline form dextrorotation lY 81149 compound, comprising: dextrorotation lY 81149 is dissolved in methylene dichloride, drip methyl tertiary butyl ether, stirring and crystallizing, filter and obtain described dextrorotation lY 81149 compound.
Preferably, dissolve and at room temperature carry out with the process of crystallization, described room temperature refers to 15 ~ 30 DEG C.
Preferably the volume ratio of methylene dichloride and methyl tertiary butyl ether is 1:(0.5 ~ 10); Be further preferably 1:(1 ~ 5).
Preferably every 1 gram of dextrorotation lY 81149 is dissolved in (3 ~ 15) mL methylene dichloride; Further preferably be dissolved in (3 ~ 8) mL methylene dichloride for every 1 gram of dextrorotation lY 81149.
Present invention also offers a kind of pharmaceutical composition of the dextrorotation lY 81149 compound containing described crystalline form.Preferably, the dosage form of described composition can be oral solid formulation (including but not limited to enteric coated tablet, enteric coated capsule) or parenteral formulations agent (as freeze dried injection).
According to the present invention, described composition also comprises pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier normally those of ordinary skill in the art specifically can be selected according to concrete form of medication.Available well known technology is as manufacture technics pharmaceutical compositions of the present invention such as conventional granulation, mixing, dissolving, formation capsule, freeze-drying.The present composition can be made the form for various route of administration, such as, oral administration, intravenously etc.
The present invention also provides the dextrorotation lY 81149 compound of described crystalline form preparing the application in proton pump inhibitor medicine.
The present invention has investigated the factors such as high temperature, high humidity and illumination to the impact of the dextrorotation lY 81149 compound stability of crystalline form of the present invention, under also having investigated accelerated test condition the dextrorotation lY 81149 compound of crystalline form of the present invention stability with draw moist.Result shows that new crystal of the present invention is basicly stable under high temperature, high humidity and illumination condition; Under accelerated test condition new crystal of the present invention stability with draw moist also without noticeable change, simultaneously according to " Chinese Pharmacopoeia " 2010 editions two annex XIXJ, new crystal of the present invention is slightly draw moist, meets medicinal requirements.
Accompanying drawing explanation
The X-ray powder diffraction pattern of the dextrorotation lY 81149 compound of Fig. 1 crystalline form of the present invention
The DSC collection of illustrative plates of the dextrorotation lY 81149 compound of Fig. 2 crystalline form of the present invention
The dextrorotation lY 81149 A crystal formation that Fig. 3 is prepared according to WO2008/083319A1 embodiment 2
Embodiment
Mode below by embodiment further illustrates, but those skilled in the art understand, and following embodiment is not limiting the scope of the invention, and any improvement of making on basis of the present invention and change, all within protection scope of the present invention.
Embodiment 1
Get dextrorotation lY 81149 crude product (1.0g) and be dissolved in methylene dichloride (5mL), under room temperature, slowly drip methyl tertiary butyl ether (15mL), stirring at room temperature 30 minutes, filter, filter cake methyl tertiary butyl ether washs, and 30 DEG C of vacuum-dryings, obtain white solid 0.78g.
Substantially as shown in Figure 1, its DSC collection of illustrative plates substantially as shown in Figure 2 for the X-ray powder diffraction of gained white solid.
Embodiment 2
Get dextrorotation lY 81149 crude product (1.0g) and be dissolved in methylene dichloride (3mL), under room temperature, slowly drip methyl tertiary butyl ether (15mL), stirring at room temperature 20 minutes, filter, filter cake methyl tertiary butyl ether washs, and 30 DEG C of vacuum-dryings, obtain white solid.The X-ray powder diffraction of gained white solid substantially as shown in Figure 1.
Embodiment 3
Get dextrorotation lY 81149 crude product (1.0g) and be dissolved in methylene dichloride (8mL), under room temperature, slowly drip methyl tertiary butyl ether (15mL), stirring at room temperature 40 minutes, filter, filter cake methyl tertiary butyl ether washs, and 30 DEG C of vacuum-dryings, obtain white solid.The X-ray powder diffraction of gained white solid substantially as shown in Figure 1.
Embodiment 4
Get dextrorotation lY 81149 crude product (1.0g) and be dissolved in methylene dichloride (10mL), under room temperature, slowly drip methyl tertiary butyl ether (15mL), stirring at room temperature 50 minutes, filter, filter cake methyl tertiary butyl ether washs, and 30 DEG C of vacuum-dryings, obtain white solid.The X-ray powder diffraction of gained white solid substantially as shown in Figure 1.
Embodiment 5
Get dextrorotation lY 81149 crude product (1.0g) and be dissolved in methylene dichloride (15mL), under room temperature, slowly drip methyl tertiary butyl ether (15mL), stirring at room temperature 1 hour, filter, filter cake methyl tertiary butyl ether washs, and 30 DEG C of vacuum-dryings, obtain white solid.The X-ray powder diffraction of gained white solid substantially as shown in Figure 1.
Embodiment 6
Prepare dextrorotation lY 81149 A crystal formation according to WO2008/083319A1 embodiment 2, investigate illumination, relative humidity (temperature is 25 DEG C), temperature (relative humidity is 65 ± 5%) to the impact of dextrorotation lY 81149 A crystal formation and new crystal of the present invention.Result is as shown in table 1.(0d represents initial time, after 5d and 10d represents 5 days respectively with 10 days after)
Table 1
From influence factor test, no matter under high temperature, high humidity or light conditions, new crystal of the present invention is obviously than A stable crystal form.Outward appearance aspect, relative to new crystal of the present invention, A crystal formation is more easy to change, is become faint yellow to brown from off-white color.
Embodiment 7
Dextrorotation lY 81149 A crystal formation has been prepared according to WO2008/083319A1 embodiment 2, under having investigated accelerated test condition (30 DEG C ± 2 DEG C, RH65 ± 5%), dextrorotation lY 81149 A crystal formation and new crystal stability of the present invention.The results are shown in Table 2.
Table 2
Accelerated test is seen, new crystal stability of the present invention is obviously better than A crystal formation; Draw moist aspect and be slightly better than A crystal formation.
Claims (10)
1. structure is such as formula the dextrorotation lY 81149 compound shown in I, it is characterized in that described dextrorotation lY 81149 compound is crystalline form,
Its X-ray powder diffraction figure has diffraction peak at following spacing place: 11.21,8.91,7.32,4.83,4.16,4.10,3.63.
2. dextrorotation lY 81149 compound according to claim 1, is characterized in that its X-ray powder diffraction figure has diffraction peak at following spacing place: 5.90,5.58,5.46,3.90,3.10.
3. dextrorotation lY 81149 compound according to claim 1, is characterized in that the X-ray powder diffraction figure had substantially as shown in Figure 1.
4. dextrorotation lY 81149 compound according to claim 1, is characterized in that the DSC collection of illustrative plates had substantially as shown in Figure 2.
5. prepare the method for the dextrorotation lY 81149 compound according to any one of Claims 1 to 4 for one kind, it is characterized in that: dextrorotation lY 81149 is dissolved in methylene dichloride, drip methyl tertiary butyl ether, stirring and crystallizing, filter and obtain described dextrorotation lY 81149 compound.
6. method according to claim 5, is characterized in that: every 1 gram of dextrorotation lY 81149 is dissolved in (3 ~ 15) mL methylene dichloride; Be preferably every 1 gram of dextrorotation lY 81149 and be dissolved in (3 ~ 8) mL methylene dichloride.
7. method according to claim 5, is characterized in that: the volume ratio of methylene dichloride and methyl tertiary butyl ether is 1:(0.5 ~ 10); Be preferably 1:(1 ~ 5).
8. the dextrorotation lY 81149 compound according to any one of Claims 1 to 4 is preparing the application in proton pump inhibitor medicine.
9. the pharmaceutical composition containing the dextrorotation lY 81149 compound according to any one of Claims 1 to 4.
10. pharmaceutical composition according to claim 9, is characterized in that described pharmaceutical composition is enteric coated tablet, enteric coated capsule or freeze dried injection.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400120A (en) * | 2017-09-01 | 2017-11-28 | 扬子江药业集团有限公司 | Iprazole N crystal form and preparation method thereof, pharmaceutical composition and purposes |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023140A1 (en) * | 1994-02-28 | 1995-08-31 | Il-Yang Pharm. Co., Ltd. | Novel 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole derivatives |
| CN101098867A (en) * | 2005-03-25 | 2008-01-02 | 丽珠医药集团股份有限公司 | Substituted sulfoxide compound and its preparing method and application |
| WO2008083319A1 (en) * | 2006-12-29 | 2008-07-10 | Il Yang Pharmaceutical Company, Ltd. | Solid state forms of enantiopure ilaprazole |
| WO2009061529A1 (en) * | 2007-11-06 | 2009-05-14 | Tap Pharmaceutical Products, Inc. | (+)-enantiomer of 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole and processing method eor preparing the same |
| CN103073536A (en) * | 2013-01-17 | 2013-05-01 | 丽珠医药集团股份有限公司 | Preparation method of ilaprazole |
| CN103172618A (en) * | 2013-02-27 | 2013-06-26 | 丽珠医药集团股份有限公司 | Ilaprazole crystal form and preparation method thereof |
-
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- 2014-06-25 CN CN201410294728.XA patent/CN105218522B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023140A1 (en) * | 1994-02-28 | 1995-08-31 | Il-Yang Pharm. Co., Ltd. | Novel 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole derivatives |
| CN101098867A (en) * | 2005-03-25 | 2008-01-02 | 丽珠医药集团股份有限公司 | Substituted sulfoxide compound and its preparing method and application |
| WO2008083319A1 (en) * | 2006-12-29 | 2008-07-10 | Il Yang Pharmaceutical Company, Ltd. | Solid state forms of enantiopure ilaprazole |
| WO2009061529A1 (en) * | 2007-11-06 | 2009-05-14 | Tap Pharmaceutical Products, Inc. | (+)-enantiomer of 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole and processing method eor preparing the same |
| CN103073536A (en) * | 2013-01-17 | 2013-05-01 | 丽珠医药集团股份有限公司 | Preparation method of ilaprazole |
| CN103172618A (en) * | 2013-02-27 | 2013-06-26 | 丽珠医药集团股份有限公司 | Ilaprazole crystal form and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400120A (en) * | 2017-09-01 | 2017-11-28 | 扬子江药业集团有限公司 | Iprazole N crystal form and preparation method thereof, pharmaceutical composition and purposes |
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Address after: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |