CN104447771A - Stable asenapine maleate sublingual compound - Google Patents
Stable asenapine maleate sublingual compound Download PDFInfo
- Publication number
- CN104447771A CN104447771A CN201310413292.7A CN201310413292A CN104447771A CN 104447771 A CN104447771 A CN 104447771A CN 201310413292 A CN201310413292 A CN 201310413292A CN 104447771 A CN104447771 A CN 104447771A
- Authority
- CN
- China
- Prior art keywords
- toxilic acid
- hydrate
- acid asenapine
- asenapine
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 Clc(cc1C(C2)[C@]3CN2*=I)ccc1Oc1c3cccc1 Chemical compound Clc(cc1C(C2)[C@]3CN2*=I)ccc1Oc1c3cccc1 0.000 description 2
Classifications
-
- 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
Belongs to the technical field of medicines, the invention in particular relates to an asenapine maleate sublingual hydrate and a preparation method thereof. The asenapine maleate sublingual hydrate obtained by the invention contains a crystal water, and has the advantages of: high purity, good stability, and non-obvious moisture absorption weight gain under a high humidity condition.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of toxilic acid asenapine hydrate and preparation method thereof, the invention still further relates to the composition using this hydrate, and the application in the medicine manufacturing treatment schizophrenia and bipolar affective disorder relative disease.
Background technology
Toxilic acid asenapine (Asenapine Maleate Sublingual), researched and developed by ORGANON SUB MERCK company, in August, 2009 goes on the market in the U.S., trade(brand)name: SAPHRIS, specification is 5mg and 10mg, clinically for the acute treatment of the manic of schizophrenia and bipolar affective disorder and mixing outbreak.The same year is multinational listing in Europe, only for the manic of bipolar affective disorder and the acute treatment mixing outbreak.
Schizophrenia and bipolar affective disorder are the pernicious mental disorderes having a strong impact on human normal life, are a kind of multifactorial diseases.Although at present still not bery clear and definite to the understanding of its cause of disease, the effect that the susceptible quality of individual mind and the undesirable element of outside social environment develop the generation of disease know together by everybody.It is susceptible quality or outside undesirable element all can cause disease generation by inherent biological factor acting in conjunction.
This product chemistry (3aR by name, 12bR)-trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-also [4,5-c] pyrroles (2Z)-(E)-butenedioic acid hydrogen ester (1:1), molecular formula: C17H16ClNOC4H4O4, molecular weight: 401.84.Its structural formula is:
In research process, repeat the method that existing document is recorded, the toxilic acid asenapine impurity number obtained is more, and total impurities is higher.The toxilic acid asenapine that the present invention obtains, containing a crystal water, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions.
Summary of the invention
One object of the present invention, discloses a kind of toxilic acid asenapine hydrate.
Another object of the present invention, discloses the preparation method of toxilic acid asenapine hydrate.
Another object of the present invention, discloses the pharmaceutical composition comprising toxilic acid asenapine hydrate.
The invention also discloses toxilic acid asenapine hydrate and manufacture the application in treatment schizophrenia and bipolar affective disorder relative disease medicine.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of bilastine hydrate (shown in formula I),
（Ⅰ）
Karl_Fischer method (Karl Fischer method) a kind ofly measures in all kinds of chemical processes of moisture in material, and, method the most accurately the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.
After sample constant weight, through 6 batches of mensuration, the moisture that described invention compound contains is between 4.17%-4.39% (weight percent).In toxilic acid asenapine monohydrate, the theoretical content of water is 4.29%, can assert that invention compound contains a crystal water.
This toxilic acid asenapine monohydrate crystal, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ), d value and relative intensity as follows,
| Spectral line number | 2 θ (degree) | Spacing (d) | I/I 0 |
| 1 | 5.030 | 8.7542 | 4 |
| 2 | 7.160 | 7.6011 | 4 |
| 3 | 9.240 | 7.4512 | 99 |
| 4 | 10.270 | 6.0156 | 7 |
| 5 | 12.460 | 5.8623 | 8 |
| 6 | 14.520 | 4.7946 | 3 |
| 7 | 17.690 | 4.5162 | 4 |
| 8 | 18.220 | 3.9113 | 15 |
| 9 | 21.300 | 3.4532 | 23 |
| 10 | 23.460 | 3.1320 | 11 |
| 11 | 25.150 | 3.0016 | 2 |
| 12 | 27.350 | 2.8901 | 2 |
| 13 | 31.440 | 2.7463 | 2 |
| 14 | 32.530 | 2.6602 | 4 |
| 15 | 34.760 | 2.5836 | 4 |
| 16 | 35.880 | 2.4359 | 1 |
| 17 | 37.420 | 2.2113 | 3 |
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Another object of the present invention, the preparation method of toxilic acid asenapine hydrate crystal.
The present inventor is by a large amount of experiments, explore refining solvent and the relation of toxilic acid asenapine crystal obtained, by toxilic acid asenapine is dissolved in acetone-heated in water solution, then lower the temperature stage by stage, obtain the preparation method of toxilic acid asenapine hydrate crystal of the present invention.
Specifically comprise the following steps:: toxilic acid asenapine adds in the mixed solution of 7-9 times of (weight or measurement (WM) ratio) acetone-water=1.5-2:3-6, be heated to 60 DEG C-80 DEG C, filtered while hot, be cooled to 35-40 DEG C, insulation 3-4 hour, and then be cooled to 20 DEG C-25 DEG C, insulation 2-3 hour, crystallization, filter, drying obtains.
The method is reproducible, is amplified to pilot scale, and optical purity and crystal formation all can reappear very well.
Another object of the present invention, provides the composition comprising the toxilic acid asenapine hydrate that toxilic acid asenapine hydrate crystal and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 20%(weight of composition).
Present invention also offers the application of toxilic acid asenapine hydrate in the medicine manufacturing treatment schizophrenia and bipolar affective disorder relative disease.
stability test
The chemical stability of contriver to crystal formation of the present invention is studied, and investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), and high humidity (92.5%, RH) inspection target is outward appearance, content and related substance.
Result: from 0-10 days under high light, high temperature, super-humid conditions, outward appearance, related substance, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate crystal of the present invention:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
In the 3000ml reaction flask that stirring, thermometer, condenser are housed, add acetone-water (2:6) mixed solution of 300 grams of toxilic acid asenapines and 2400ml, start stirring, be heated to 75 DEG C, treat whole clearly molten, filtered while hot.Be cooled to 35 DEG C, be incubated 3 hours; Then, be cooled to 20 DEG C, be incubated 2 hours, crystallization, filter, drying obtains high purity above-mentioned toxilic acid asenapine hydrate crystal 276.1 grams, optical purity 99.88%.Dissolvent residual detects and meets the requirements.
Measure through Karl_Fischer method, the moisture containing 4.30% (weight percent).
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 2
Tablet containing toxilic acid asenapine hydrate
Prescription: toxilic acid asenapine monohydrate 10 grams, lactose 50 grams, Microcrystalline Cellulose 260 grams, sodium starch glycolate 50 grams, Magnesium Stearate 5 grams, distilled water is appropriate, makes 10000.
Technique: pulverized by toxilic acid asenapine monohydrate, crosses 60 mesh sieves, and with distilled water softwood after mix with unclassified stores, 16 mesh sieves granulations, put in 40-45 DEG C of drying in loft drier, Magnesium Stearate adds in dry particle and mixes, compressing tablet.
Claims (6)
1. the hydrate of toxilic acid asenapine shown in formula I,
（Ⅰ）
Measure with Karl_Fischer method, described hydrate contains the moisture of 4.17%-4.39%;
The crystal of described toxilic acid asenapine hydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and relative intensity I/I
0:
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of toxilic acid asenapine hydrate crystal described in claim 1, by being dissolved in acetone-heated in water solution by toxilic acid asenapine, then cooling obtains stage by stage.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that toxilic acid asenapine adds in the mixed solution of 7-9 times of (weight or measurement (WM) ratio) acetone-water=1.5-2:3-6, be heated to 60 DEG C-80 DEG C, filtered while hot, be cooled to 35-40 DEG C, insulation 3-4 hour, and then be cooled to 20 DEG C-25 DEG C, insulation 2-3 hour, crystallization, filter, drying obtains.
4. the composition of the toxilic acid asenapine hydrate formed containing toxilic acid asenapine hydrate crystal according to claim 1 and one or more pharmaceutically acceptable carriers.
5. the composition of toxilic acid asenapine hydrate according to claim 4, is characterized in that said composition is for the preparation of oral preparations.
6. the application of toxilic acid asenapine hydrate described in claim 1 in the medicine manufacturing treatment schizophrenia and bipolar affective disorder relative disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310413292.7A CN104447771A (en) | 2013-09-12 | 2013-09-12 | Stable asenapine maleate sublingual compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310413292.7A CN104447771A (en) | 2013-09-12 | 2013-09-12 | Stable asenapine maleate sublingual compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104447771A true CN104447771A (en) | 2015-03-25 |
Family
ID=52894588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310413292.7A Pending CN104447771A (en) | 2013-09-12 | 2013-09-12 | Stable asenapine maleate sublingual compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104447771A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018039190A1 (en) * | 2016-08-22 | 2018-03-01 | Navinta Ii Llc | Pharmaceutical solution of asenapine for sublingual or buccal use |
| 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 (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1861604A (en) * | 2005-04-07 | 2006-11-15 | 奥格诺爱尔兰有限公司 | Crystal form of asenapine maleate |
| WO2012066565A2 (en) * | 2010-11-16 | 2012-05-24 | Cadila Healthcare Limited | Asenapine maleate amorphous and crystalline form and process for preparation thereof |
| WO2012123325A1 (en) * | 2011-03-11 | 2012-09-20 | Medichem S.A. | NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID |
| CN102952144A (en) * | 2011-08-29 | 2013-03-06 | 上海华拓医药科技发展股份有限公司 | Crystal forms of asenapine maleate, and preparation method and medical composition thereof |
| US20130211099A1 (en) * | 2010-06-18 | 2013-08-15 | Dr. Reddy's Laboratories, Inc. | Asenapine maleate |
-
2013
- 2013-09-12 CN CN201310413292.7A patent/CN104447771A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1861604A (en) * | 2005-04-07 | 2006-11-15 | 奥格诺爱尔兰有限公司 | Crystal form of asenapine maleate |
| US20130211099A1 (en) * | 2010-06-18 | 2013-08-15 | Dr. Reddy's Laboratories, Inc. | Asenapine maleate |
| WO2012066565A2 (en) * | 2010-11-16 | 2012-05-24 | Cadila Healthcare Limited | Asenapine maleate amorphous and crystalline form and process for preparation thereof |
| WO2012123325A1 (en) * | 2011-03-11 | 2012-09-20 | Medichem S.A. | NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID |
| CN102952144A (en) * | 2011-08-29 | 2013-03-06 | 上海华拓医药科技发展股份有限公司 | Crystal forms of asenapine maleate, and preparation method and medical composition thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018039190A1 (en) * | 2016-08-22 | 2018-03-01 | Navinta Ii Llc | Pharmaceutical solution of asenapine for sublingual or buccal use |
| US10085971B2 (en) | 2016-08-22 | 2018-10-02 | Navinta Iii Inc | Pharmaceutical solution of asenapine for sublingual or buccal use |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104447771A (en) | Stable asenapine maleate sublingual compound | |
| CN106543072A (en) | Mo Fanselin compounds | |
| CN106543124A (en) | dapagliflozin compound | |
| CN105646520A (en) | Stable Halaven compound | |
| CN104447683A (en) | Stable Bilastine compound | |
| CN106554315A (en) | Stable olaparib compound | |
| CN105669673A (en) | Stable Ticagrelor compound | |
| CN106699630A (en) | Brivaracetam sesquihydrate compound | |
| CN107663173A (en) | Miscellaneous Shandong amine of grace and its production and use | |
| CN107663166A (en) | Lome Tapai and its production and use | |
| CN107778295A (en) | Mai Rui replaces Buddhist nun's compound | |
| CN106543256A (en) | Stable shellfish cholic acid compound difficult to understand | |
| CN107344955A (en) | A kind of dexamethasone hydrate compound | |
| CN105646320A (en) | Stable Vernakalant compound | |
| CN104650065A (en) | Teneligliptin compound | |
| CN106543137A (en) | Stable glug row purification compound | |
| CN106543250A (en) | A kind of stable tofogliflozin hydrate compound | |
| CN102408375A (en) | Ozagrel sodium compound | |
| CN105566210A (en) | Perampanel compound | |
| CN105646583A (en) | Stable ceftaroline compound | |
| CN107663198A (en) | Olmesartan medoxomil and its production and use | |
| CN105646653A (en) | Stable telaprevir compound | |
| CN105330659A (en) | Rivaroxaban compound | |
| CN107141253A (en) | A kind of Aripiprazole sesquialter hydrate compound | |
| CN105622728A (en) | Stable oritavancin compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150325 |
|
| WD01 | Invention patent application deemed withdrawn after publication |