CN103965206A - New crystal form and preparation method of asenapine maleate - Google Patents
New crystal form and preparation method of asenapine maleate Download PDFInfo
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- CN103965206A CN103965206A CN201310032793.0A CN201310032793A CN103965206A CN 103965206 A CN103965206 A CN 103965206A CN 201310032793 A CN201310032793 A CN 201310032793A CN 103965206 A CN103965206 A CN 103965206A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
The present invention relates to a new crystal form and a preparation method of an asenapine maleate, wherein the new crystal form is asenapine maleate crystal form C.
Description
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, relate to new crystal of Org 5222 and preparation method thereof, be specifically related to the crystal C of Org 5222 and prepare the preparation method of this crystal formation.
Background technology
A Sena product are that one is treated central nervous system disorder, especially schizoid bulk drug.A Sena virtue chemical name is trans-5-chloro-2-methyl-2,3,3a, and also [4,5-c] pyrroles of 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxepin, its preparation method is disclosed in US Patent No. 4145434.
Document (Drugs ofthe Future1993,18 (12), trans-5-chloro-2-methyl-2 1117-1123), are annotated, 3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] also [4,5-c] pyrroles's pharmacological characteristic of oxepin, its kinetics and metabolic mechanism.Safety and the efficacy outcomes of carrying out with it human volunteer and schizophreniac, show that A Sena product have CNS and suppress active and anti-Dopamine HCL and serotonin activity.
In view of the drug effect of this compound, wish it to mix various pharmaceutical compositions, giving with the form of slow release type formulation is that those suffer from clothes for patients use mentally disabled, to reduce medicining times.Therefore,, for better realizing the research and development of medicine, the different crystal forms of finding Org 5222 is essential.
Document (Arzneim.-Forsch./Drug Res.40 (1999), 536-539) has been described the physicochemical property of Org 5222, and the fusing point of the Org 5222 monoclinic form of crystallization is 141-145 DEG C.The Org 5222 monoclinic form of preparing according to U.S. US4145434, its powder diffraction spectrum demonstration, 2 θ are 9.6 °, 20.4 °, 22.0 °, 23.4 °, 25.2 °, 26.1 °, 26.7 °, 26.8 °, locate to there is characteristic peak for 29.1 ° and 30.0 °, have more the peak of feature at 9.6 °, 20.4 °, 22.0 °, 23.4 °, 25.2 °, locate for 26.8 °.
Patent CN1861604A has reported another crystal formation of Org 5222, and this crystal is iris shape, and melting range is 138-142 DEG C, and its powder diffraction spectrum shows, 2 θ are 10.5 °, 15.7 °, and 18.3 °, 19.0 °, 20.3 °, 20.8 °, 22.2 °, 23.2 °, locate to there is characteristic peak for 25.6 ° and 27.5 °, have more the peak of feature at 10.5 °, 15.7 °, 18.3 °, 19.0 °, 22.2 °, 23.2 °, and 27.5 ° located.
Summary of the invention
A kind of method that C crystal formation of preparing Org 5222 is provided of the present invention.The method comprises by the cooling Virahol that has dissolved Org 5222 that contains makes Org 5222 crystallization.Optionally, in the time can obtaining the crystal formation of C crystal formation, can in the Virahol of Org 5222, add described crystal as crystal seed.Crystallisate can further obtain C crystal formation through long-time insulated and stirred.
The X-ray powder diffraction of the C crystal formation of Org 5222.Collection of illustrative plates is taking the strong peak at a certain particular value place at diffraction angle 2 θ places as feature, C crystal formation locates to have characteristic peak at 6.6 °, 9.4 °, 13.1 °, 16.7 °, 18.2 °, 18.5 °, 18.9 °, 20.0 °, 20.5 °, 21.1 °, 21.6 °, 22.4 °, 24.3 °, 25.4 °, 27.2 °, 27.8 °, and the peak that has more feature is located at 6.6 °, 13.1 °, 16.7 °, 18.5 °, 21.1 °, 22.4 °, 24.3 ° and 27.8 °.
2 shown θ values are typically referred to as particular value ± 0.2.
Crystallization Org 5222 melting range prepared by the present invention is the specific polymorphic of 124.3-128.4 DEG C.
Org 5222 C crystal formation of the present invention can characterize by several method well known in the art, thereby is different from monocline type crystal formation and iris type, for example dsc, X-ray powder diffraction and other method.Described method can be used alone or in combination.
Brief description of the drawings
Fig. 1 illustrates the nucleus magnetic hydrogen spectrum of A Senaping.
Fig. 2 illustrates the powder diffraction spectrum of A Senaping C crystalline substance.
Fig. 3 illustrates the powder diffraction spectrum of A Senaping monoclinic form.
Fig. 4 illustrates the powder diffraction spectrum of A Senaping iris type.
Fig. 5 illustrates the DSC collection of illustrative plates of A Senaping C crystal formation.
Fig. 6 illustrates the TGA collection of illustrative plates of A Senaping C crystalline substance.
Embodiment
Universal method
X-ray powder diffraction (X-PRD) collection of illustrative plates obtains on XPert Pro Panalytical reflection diffraction instrument, configuration Bragg-Brantano assembly, and copper-K alpha-ray, is set as 40KV and 150mA and X ' celerator detector.The slit using is: anti-scatter slit
, divergent slit
, soller slit 0.02rad.Condition determination: sweep limit
.
TGA method.Measure the material mass of Org 5222 and the relation of temperature with thermogravimetric analyzer Q50, contribute to study the variation of crystalline nature, as the physical phenomenon of the materials such as fusing, evaporation, distillation and absorption; Also contribute to study material dehydration, dissociate, be oxidized, the chemical phenomenon of the material such as reduction.
DSC method.Measure the fusing point (starting temperature) of Org 5222 by dsc (DSC).DSC instrument comprise have ceramic sensor the measuring cell based on hot-fluid principle and can temperature range be at 0-300 DEG C use heating plant.Heating rate is at least 1-20 DEG C/min.Purified gas is that coutroi velocity is the nitrogen of 50ml/min.With aluminum sample disc accurate weighing Org 5222 (2-5mg).The heating rate using is 10 DEG C/min, and the linear temperature program of 0-180 DEG C.
Embodiment 1: prepare Org 5222 C crystal formation by Org 5222 crystallisate
By trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxepin also [4,5-c] pyrroles (Z)-20 grams of (E)-butenedioic acid salt are placed in the single port bottle of 100 milliliters, add 60 milliliters of ethyl acetate, under magnetic agitation, be warming up to 65 degree, after approximately 30 minutes, dissolve completely.After being cooled to 20 degree, continue to stir 4 hours, and then continue to be cooled to-20 DEG C ± 5 degree, stir 30 minutes, filter.Solid is used 10 milliliters of (20 ± 5 DEG C) ethyl acetate washings again.By the crystal of gained at 60 DEG C of vacuum-drying 4-6 hour.Productive rate: 90%.
Embodiment 2: prepare Org 5222 C crystal formation by Org 5222 crystallisate
By trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxepin also [4,5-c] pyrroles (Z)-20 grams of (E)-butenedioic acid salt are placed in the single port bottle of 100 milliliters, add 60 milliliters of Virahols, under magnetic agitation, be warming up to 65 degree, after approximately 30 minutes, dissolve completely.After being cooled to 20 degree, continue to stir 4 hours, and then continue to be cooled to-20 DEG C ± 5 degree, stir 30 minutes, filter.Solid is used 10 milliliters of (20 ± 5 DEG C) washed with isopropyl alcohol again.By the crystal of gained at 60 DEG C of vacuum-drying 4-6 hour.Productive rate: 96%.
Claims (7)
1. Org 5222 crystal C, is characterized in that: the position that its X-ray powder diffraction is about 6.6 °, 13.1 °, 16.7 °, 18.5 °, 21.1 °, 22.4 °, 24.3 ° and 27.8 ° in 2 θ values is to there being characteristic diffraction peak;
2. according to outside claim 1 crystal C institute tool characteristic diffraction peak, the position that is also further included in 2 θ values and is 9.4 °, 18.2 °, 18.9 °, 20.0 °, 20.5 °, 21.6 °, 25.4 °, 27.2 ° has feature diffraction;
3. according to the crystal C of claim 1, the DSC characteristic peak of Org 5222 crystal C is 128.43 DEG C;
4. a method of preparing the Org 5222 crystal C of claim 1-3, is characterized in that Org 5222 to start crystallize out in certain temperature in organic solvent, and maintains stirring certain hour;
5. according to the method for claim 4, also comprise following process:
1) Org 5222 is suspended in suitable organic solvent at ambient temperature, then heating is dissolved it completely and is obtained Org 5222 solution;
2) the Org 5222 solution of upper step is cooled to suitable temperature and stirs, and maintain certain hour by its crystallize out;
3) crystal of separating out is filtered or centrifugation;
4) crystal separation being obtained carries out vacuum-drying under 60 degree.
6. according to the method for claim 5, step 1) said suitable organic solvent comprises ethyl acetate, Virahol;
7. according to the method for claim 5, step 2) said suitable temperature is 10-40 degree, preferably temperature is 10-30 degree, most preferably 20 degree; Step 2) said certain hour is for being more than or equal to 1 hour, is preferably 2 hours, most preferably is 4 hours.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7741358B2 (en) * | 2005-04-14 | 2010-06-22 | N.V. Organon | Crystal form of asenapine maleate |
| CN1861604B (en) * | 2005-04-07 | 2011-08-31 | 欧加农股份有限公司 | Crystal form of asenapine maleate |
| EP2468750A1 (en) * | 2010-12-13 | 2012-06-27 | Chemo Ibérica, S.A. | Polymorphic forms of asenapine maleate and processes for their preparation |
-
2013
- 2013-01-29 CN CN201310032793.0A patent/CN103965206A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1861604B (en) * | 2005-04-07 | 2011-08-31 | 欧加农股份有限公司 | Crystal form of asenapine maleate |
| US7741358B2 (en) * | 2005-04-14 | 2010-06-22 | N.V. Organon | Crystal form of asenapine maleate |
| EP2468750A1 (en) * | 2010-12-13 | 2012-06-27 | Chemo Ibérica, S.A. | Polymorphic forms of asenapine maleate and processes for their preparation |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US10980753B2 (en) | 2016-12-20 | 2021-04-20 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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Application publication date: 20140806 |