CN103910747B - A kind of Olanzapine medicine crystal formation F and preparation method thereof - Google Patents
A kind of Olanzapine medicine crystal formation F and preparation method thereof Download PDFInfo
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- CN103910747B CN103910747B CN201410168531.1A CN201410168531A CN103910747B CN 103910747 B CN103910747 B CN 103910747B CN 201410168531 A CN201410168531 A CN 201410168531A CN 103910747 B CN103910747 B CN 103910747B
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The invention belongs to medicinal chemistry art, be specifically related to a kind of Olanzapine medicine crystal formation F and preparation method thereof.This crystal formation is the hydrate of Olanzapine medicine.Its spacer of crystal of the Olanzapine medicine crystal formation F that the present invention prepares is triclinic(crystalline)system, and four olanzapine molecules and eight water moleculess are by forming the basic structural unit of Olanzapine medicine crystal formation F together with hydrogen bonded.Selected by drug crystal forms F preparation process of the present invention, solvent is ethyl acetate solvent, and employing method is solvent room temperature volatilization method.Drug crystal forms F prepared by the present invention has outside the speciality such as psychotic acute stages treated and maintaining treatment of serious positive symptom or negative symptoms schizophrenia and other inheriting original Olanzapine medicine, and its solvability, stability have obvious change.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of novel olanzapine crystal form F and preparation method thereof.
Background technology
Olanzapine (Olanzapine) chemical name: 2-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazine)-4H-thieno-[2,3-b] [1,5] benzodiazepine, molecular formula: C
17h
20n
4s, olanzapine is applicable to schizophrenia and other has psychotic acute phase and the maintaining treatment of serious positive symptom or negative symptoms; Olanzapine also can alleviate schizophrenia and the common Secondary cases affective symptom of relative disease.Structural formula is as follows:
At present, patent US5229382 discloses olanzapine crystal form I and produces to precipitate and carry out filtration drying by adding methyl tertiary butyl ether after olanzapine and 2-butanols heating for dissolving and obtain; Patent US5736541 discloses after olanzapine crystal form II to be suspended in anhydrous ethyl acetate heating cooling by olanzapine and obtains, and crystal form II is more stable than crystalline form I simultaneously; Patent US6348458 discloses three kinds of new crystal formations of olanzapine, respectively called after III, IV, V, and wherein crystalline form III is dissolved in acetic acid and water by olanzapine, and after adding gac and ammoniacal liquor stirring, filtration drying obtains; Crystalline form IV is dissolved in acetic acid and water by olanzapine, and after adding ammoniacal liquor stirring, filtration drying obtains; Crystalline form V is dissolved in acetic acid and water by olanzapine, and after adding sodium hydroxide solution stirring, filtration drying obtains; It is that add propyl carbinol stirring in olanzapine after, filtration drying obtains that patent WO03091260 discloses olanzapine new crystal VI; It is be dissolved in by olanzapine in methyl ethyl ketone and water that patent WO2006102176 discloses olanzapine new crystal Ⅹ, and after stirring, filtration drying obtains; Patent US7745429 discloses olanzapine new crystal A and is suspended in methylene dichloride and acetonitrile by olanzapine, crystallization of volatilizing after heated and stirred.Patent WO0218390 discloses olanzapine monohydrate I and dihydrate I, wherein monohydrate I is that add olanzapine reflux in DMSO, N methyl piperazine, toluene and water after, filtration drying obtains, and dihydrate I is that the relative proportions by changing each material in monohydrate I obtains; Patent US6020487 discloses olanzapine three kinds of dihydrates B, D, E, wherein dihydrate B obtains about being suspended in water by olanzapine and stirring half a day, olanzapine is suspended in water to stir after 5 days and obtains by dihydrate D, and dihydrate E is that add olanzapine heated and stirred in ethyl acetate, toluene and water after, filtration drying obtains.
Affect a lot of because have of the crystal formation of medicine, different crystal formations is all likely obtained as by change solvent species, temperature, illumination etc., because of the difference of crystalline network, can there is notable difference in same its physical properties of medicine different crystal forms, thus can have an impact to Drug safety, validity.
The hydrate of medicine is a kind of new crystal that active constituents of medicine and water are formed by Intermolecular Forces (as hydrogen bond), and it can improve physico-chemical property and the bioavailability of active constituents of medicine, has more stable feature.
Research shows, relatively large in atmospheric moisture or under having compared with intense light irradiation an environment, along with the prolongation of time, the content of Olanzapine medicine is on a declining curve.
The stability of medicine is vital, especially in commercially available validity period, good stability is kept, reduce medicine and produce impurity (related substance) due to degraded, to guarantee curative effect of medication and security, prevent the generation of adverse drug reaction significant.In order to improve the stability of Olanzapine medicine, the invention provides a kind of new crystal of olanzapine, it has good stability.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of olanzapine crystal form F of novel texture is provided.Drug crystal forms prepared by the present invention has outside the speciality such as psychotic acute stages treated and maintaining treatment of serious positive symptom or negative symptoms schizophrenia and other inheriting original Olanzapine medicine, and its solvability, stability have obvious change.Another object of the present invention is to provide the preparation method of a kind of above-mentioned Olanzapine medicine crystal formation F.
A kind of Olanzapine medicine crystal formation F of the present invention, is characterized in that, use Cu-K α radiation, its Powder XRD pattern data characterization is as follows:
Table 1: Olanzapine medicine crystal formation F Powder XRD pattern data
Described Olanzapine medicine crystal formation F is the hydrate of Olanzapine medicine.
The spacer of described Olanzapine medicine crystal formation F is triclinic(crystalline)system, its axial length a=12.1423 ~ 12.5423, b=13.4972 ~ 13.8972, c=14.0911 ~ 14.3911, α=65.810 ~ 66.210, β=64.024 ~ 64.424, γ=63.022 ~ 63.422.
The infared spectrum of described Olanzapine medicine crystal formation F is at 755.97 ± 0.2cm
-1, 971.96 ± 0.2cm
-1, 1004.75 ± 0.2cm
-1, 1149.38 ± 0.2cm
-1, 1220.74 ± 0.2cm
-1, 1267.02 ± 0.2cm
-1, 1409.73 ± 0.2cm
-1, 1469.52 ± 0.2cm
-1, 1589.08 ± 0.2cm
-1, 2846.46 ± 0.2cm
-1, 2933.24 ± 0.2cm
-1, 3236.02 ± 0.2cm
-1there is absorption peak at place.
In described Olanzapine medicine crystal formation F, four olanzapine molecules pass through N-HO hydrogen bonded with eight water moleculess respectively, pass through O-HO hydrogen bonded in described crystal formation F between eight water moleculess.
The step of the preparation method of described Olanzapine medicine crystal formation F is: be dissolved in by olanzapine in ethyl acetate solvent, stirs, filters, leaves standstill the yellow bulk crystals of separating out in volatilization, collection container, namely obtain described Olanzapine medicine crystal formation F.
Further the step of the preparation method of described Olanzapine medicine crystal formation F is: be dissolved in by olanzapine in ethyl acetate, stirs 30min ~ 60min, filters; Seal the vessel port that olanzapine solution is housed with film, film is established volatilization aperture, leave standstill volatilization after 5-7 days, collect the yellow bulk crystals of separating out, namely obtain described Olanzapine medicine crystal formation F.
Described olanzapine is 3.1 ~ 3.5mmol:40 ~ 50ml with the molecular volume ratio of described treated ethyl acetate.
Moisture in described ethyl acetate Absorbable rod air, in stirring, filtration, leaves standstill in the middle of process, all from air, can introduce moisture in solution system, thus form described Olanzapine medicine crystal formation F with olanzapine; The water molecules contained in described olanzapine molecule and ethyl acetate can form hydrogen bond, makes the water molecules that contains in ethyl acetate and olanzapine point sub-connection and form described Olanzapine medicine crystal formation F by Hyarogen-bonding.
The Olanzapine medicine crystal formation F for preparing of this invention has outside the speciality such as psychotic acute stages treated and maintaining treatment of serious positive symptom or negative symptoms schizophrenia and other inheriting original Olanzapine medicine, and its solvability, stability and bioavailability have obvious change.
Accompanying drawing explanation
Fig. 1 is the crystalline structure cell schematics adopting the Olanzapine medicine crystal formation F that obtains of embodiment 1 to carry out single crystal diffraction to draw.
Fig. 2 be adopt the Olanzapine medicine crystal formation F powder that obtains of embodiment 1 XRD figure spectrum (corresponding data is see table 1).
Fig. 3 is the thermogravimetric collection of illustrative plates of the Olanzapine medicine crystal formation F adopting embodiment 1 to obtain.
Fig. 4 is the IR collection of illustrative plates of the Olanzapine medicine crystal formation F adopting embodiment 1 to obtain.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Following specific embodiment is only further used for the present invention is described, but not for limiting content of the present invention.
The instrument of detection of drugs crystal formation F structure of the present invention and performance thereof is as follows:
1, crystalline structure is measured by X-ray single crystal diffractometer, and full name is aRigakuSCXminidiffractometer.
2, powder diffractometer is produced by German Bruker company, model be D8-Discover, Cu-K α (
), tube voltage 40KV, tube current 30mA, sweep velocity 8 °/min.
3, thermogravimetric curve is produced by METTLERTOLEDO company, and model is STAReSystem, adopts nitrogen atmosphere, temperature rise rate 10 DEG C/min.
4, infrared curve is recorded by Fourier infrared spectrograph, and model is NICOLET5700FT-IR.
The transparent glass instrument that the present invention uses is external import, and capacity is 50ml.
5, samples contg is recorded by Agilent1200 high performance liquid chromatograph, and adopt VenusilASBC18 chromatographic column to analyze, moving phase is damping fluid (pH=2.5): acetonitrile=45:55.
Embodiment 1:
(1) weigh:
Olanzapine 900mg feeds intake, and accurately takes with analytical balance.
(2) bulk drug dissolves:
Accurately measure 40ml ethyl acetate with transfer pipet and be placed in 50ml beaker, add aforementioned load weighted bulk drug olanzapine, stir 30min.
(3) solvent room temperature volatilization method:
After solid dissolves completely, take out stirrer, be filled in a clean 50ml transparent glass bottle with analytical paper, seal bottleneck with preservative film, with the several aperture of pinprick, leave standstill volatilization.After 6 days, have in bottle and separate out yellow bulk crystals.
Adopt the yellow bulk crystals that obtains of embodiment 1 and crystal form II carries out solubility test and stability test obtains following data:
Table 2: olanzapine crystal form F and the crystal form II dissolubility data respectively in water, methyl alcohol, ethanol
The solubleness of olanzapine crystal form F in methyl alcohol, second alcohol and water is better than crystal form II as can be seen from Table 2.
Table 3: olanzapine crystal form F and crystal form II thimble test data
Table 3 be respectively the olanzapine crystal form F of 1.0g and crystal form II are placed in 60 DEG C thermostatic drying chamber in place 10 days, respectively at sampling in the 0th, 5,10 day, the change of observation two samples contgs.Can find out two samples under the condition of high temperature content without obvious change.
Table 4: olanzapine crystal form F and crystal form II high humidity stability test data
Table 4 respectively the olanzapine crystal form F of 1.0g and crystal form II is placed in opening weighing bottle, and be put in comprehensive testing chamber for medicine stability, 25 DEG C, place 10 days under the condition of relative humidity 90% ± 5%, and in sampling in the 0th, 5,10 day, the change of observation two samples contgs.Can find out that olanzapine crystal form II content the 10th day time obviously reduces, and the content of crystal formation F does not significantly change.
Table 5: olanzapine crystal form F and crystal form II light durability testing data
Table 5 respectively the olanzapine crystal form F of 1.0g and crystal form II is placed in opening weighing bottle, and be put in comprehensive testing chamber for medicine stability, be place 10 days under condition under the illumination of 4500 ± 500lx in intensity, and in sampling in the 0th, 5,10 day, the change of observation two samples contgs.Can find out that, under the condition of strong illumination, olanzapine crystal form F is more stable than crystal form II.
The yellow bulk crystals adopting embodiment 1 to obtain carries out single crystal diffraction experiment and obtains Fig. 1.
The yellow bulk crystals adopting embodiment 1 to obtain carries out X-ray powder diffraction experiment and obtains Fig. 2, and corresponding data is see table 1.
The yellow bulk crystals adopting embodiment 1 to obtain carries out thermogravimetric curve experiment and obtains Fig. 3, as can be seen from Figure 3 olanzapine crystal form F is divided into two steps to decompose, the first step is decomposed from 114 DEG C, 147 DEG C of decomposition complete, weightless 7.48%, second step completes to 208 DEG C of decomposition from 183 DEG C, weightless 84.10%.
The yellow bulk crystals adopting embodiment 1 to obtain carries out Infrared spectra adsorption experiment and obtains Fig. 4.
Claims (8)
1. an Olanzapine medicine crystal formation F, is characterized in that, use Cu-K α radiation, its Powder XRD pattern data characterization is as follows:
2. Olanzapine medicine crystal formation F according to claim 1, is characterized in that described Olanzapine medicine crystal formation F is the hydrate of Olanzapine medicine.
3. Olanzapine medicine crystal formation F according to claim 1 and 2, the spacer that it is characterized in that described Olanzapine medicine crystal formation F is triclinic(crystalline)system, its axial length a=12.1423 ~ 12.5423, b=13.4972 ~ 13.8972, c=14.0911 ~ 14.3911, α=65.810 ~ 66.210, β=64.024 ~ 64.424, γ=63.022 ~ 63.422.
4. Olanzapine medicine crystal formation F according to claim 1 and 2, is characterized in that its infared spectrum is at 755.97 ± 0.2cm
-1, 971.96 ± 0.2cm
-1, 1004.75 ± 0.2cm
-1, 1149.38 ± 0.2cm
-1, 1220.74 ± 0.2cm
-1, 1267.02 ± 0.2cm
-1, 1409.73 ± 0.2cm
-1, 1469.52 ± 0.2cm
-1, 1589.08 ± 0.2cm
-1, 2846.46 ± 0.2cm
-1, 2933.24 ± 0.2cm
-1, 3236.02 ± 0.2cm
-1there is absorption peak at place.
5. Olanzapine medicine crystal formation F according to claim 1 and 2, to it is characterized in that in Olanzapine medicine crystal formation F four olanzapine molecules respectively with eight water moleculess by N-HO hydrogen bonded, pass through O-H between eight water moleculess in described crystal formation F ... O hydrogen bonded.
6. a preparation method of Olanzapine medicine crystal formation F as claimed in claim 1 or 2, is characterized in that comprising the steps: ethyl acetate to mix with water, fully stirs, stratification, and removing water layer, obtains treated ethyl acetate; Separately olanzapine is dissolved in described treated ethyl acetate solvent, moisture in described ethyl acetate Absorbable rod air, in stirring, filtration, leave standstill in the middle of process, all from air, moisture can be introduced in solution system, thus form yellow bulk crystals and described Olanzapine medicine crystal formation F with olanzapine.
7. the preparation method of Olanzapine medicine crystal formation F according to claim 6, is characterized in that comprising the steps: olanzapine to be dissolved in described treated ethyl acetate, stirs 30min ~ 60min, filters; Seal the vessel port that olanzapine solution is housed with film, film is established volatilization aperture, leave standstill volatilization after 5-7 days, collect the yellow bulk crystals of separating out, namely obtain described Olanzapine medicine crystal formation F.
8. the preparation method of Olanzapine medicine crystal formation F according to claim 6, is characterized in that olanzapine is 3.1 ~ 3.5mmol:40 ~ 50ml with the molecular volume ratio of described treated ethyl acetate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1729195A (en) * | 2002-12-20 | 2006-02-01 | 阿达梅德公司 | Process for the preparation of a pharmaceutically pure polymorphic form I of olanzapine |
| EP2108651A1 (en) * | 2001-12-24 | 2009-10-14 | Sun Pharmaceuticals Industries Ltd. | Crystalline form I of 2-methyl-4-(4-methyl-1-piperazinyl) 10H thieno[2,3-B][1,5] benzodiazepine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1575962A1 (en) * | 2002-12-24 | 2005-09-21 | Teva Pharmaceutical Industries Limited | Novel crystal forms of olanzapine, methods for their preparation and method for the preparation of known olanzapine crystal forms |
| KR20070113277A (en) * | 2005-03-21 | 2007-11-28 | 닥터 레디스 레보러터리즈 리미티드 | Process for preparing crystalline form i of olanzapine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2108651A1 (en) * | 2001-12-24 | 2009-10-14 | Sun Pharmaceuticals Industries Ltd. | Crystalline form I of 2-methyl-4-(4-methyl-1-piperazinyl) 10H thieno[2,3-B][1,5] benzodiazepine |
| CN1729195A (en) * | 2002-12-20 | 2006-02-01 | 阿达梅德公司 | Process for the preparation of a pharmaceutically pure polymorphic form I of olanzapine |
Non-Patent Citations (3)
| Title |
|---|
| "Anhydrates and Hydrates of Olanzapine: Crystallization, Solid-State Characterization, and Structural Relationships";Susan M. Reutzel-Edens et al.;《Crystal Growth & Design》;20030702;第3卷(第6期);第897-907页 * |
| "奥氮平原料药的制备及质量控制";刘召鹏;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20121015(第10期);全文 * |
| "奥氮平原料药纯化及质量控制研究";方文燕;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20130915(第9期);全文 * |
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Effective date of registration: 20210615 Address after: 225300 No.1, South Batang Road, China medicine city, Taizhou City, Jiangsu Province Patentee after: JIANG SU PHARMAMAXCORP Co.,Ltd. Address before: 210096 No. four archway, 2, Jiangsu, Nanjing Patentee before: SOUTHEAST University |
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Address after: 225300 No.1, South Batang Road, China medicine city, Taizhou City, Jiangsu Province Patentee after: Jiangsu Changtai Pharmaceutical Co.,Ltd. Address before: 225300 No.1, South Batang Road, China medicine city, Taizhou City, Jiangsu Province Patentee before: JIANG SU PHARMAMAXCORP Co.,Ltd. |