CN106699689A - Cariprazine trihydrate compound - Google Patents
Cariprazine trihydrate compound Download PDFInfo
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- CN106699689A CN106699689A CN201510773565.8A CN201510773565A CN106699689A CN 106699689 A CN106699689 A CN 106699689A CN 201510773565 A CN201510773565 A CN 201510773565A CN 106699689 A CN106699689 A CN 106699689A
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- Prior art keywords
- cariliprazine
- trihydrate
- composition
- crystal
- weight
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
The invention belongs to the technical field of medicines and particularly relates to a cariprazine trihydrate compound. The obtained cariprazine trihydrate compound contains three crystallization waters and has the advantages as follows: the purity is high, the stability is good and moisture-absorption weight gain is not remarkable under the high-humidity condition.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to Cariliprazine trihydrate and preparation method thereof, the invention further relates to the schizoid application of composition treatment using this hydrate.
Background technology
Schizophrenia is to make one to lose the insanity of ability throughout one's life, wherein whole world incidence according to reports is about 1 %.The illness is generally showed during the manhood of puberty or youth；Cardinal symptom is divided into three kinds of scopes：Positive symptom, such as vain hope and illusion；Negative symptoms, cannot such as drive and social withdrawal；With cognitive symptom, there is problem in such as notice and memory.They cause society and occupational dysfunctions, are inevitably had a significant effect by the individual presence place of infringement to family and widely in society.In addition to psychotic symptoms, in the risk with schizoid patient also in the medical science comorbidities bigger than general groups.
Schizoid symptom antipsychotic drug treatment, is mainly worked by blocking dopamine D 2 acceptor.
Cariprazine hydrochloride shown in following formula is D3/D2 receptor antagonists, can be used as treating the medicine of such as schizoid disease.
In actual production process, it has been found that there are problems that purification difficult, impurity content are higher in Cariliprazine preparation technology and have certain moisture absorption.
The Cariliprazine trihydrate crystal that the present inventor obtains on the basis of many experiments, has the advantage that：Purity is high, and maximum contaminant is less than 1 ‰；Good stability, even if moisture absorption weightening is not also obvious under high humidity conditions.
The content of the invention
One object of the present invention, discloses a kind of Cariliprazine trihydrate.
Another object of the present invention, discloses the preparation method of Cariliprazine trihydrate.
A further object of the present invention, discloses the pharmaceutical composition comprising Cariliprazine trihydrate.
Treatment use is being prepared the invention also discloses Cariliprazine trihydrate.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of Cariliprazine trihydrate（Shown in formula I）,
（Formulas I）
Thermogravimetry be it is a kind of determine material in moisture chemical method in, the most single-minded to water, the most accurate method has been listed in the standard method of determination of moisture in many materials, especially organic compound, reliable results.Determined through multiple batches, the moisture that described invention compound contains is between 9.52%-14.12% (percentage by weight).The theoretical content of Cariliprazine trihydrate reclaimed water is 11.2%, it can be assumed that invention compound contains a hypocrystalline water.
The measurement result of wherein 6 batches is as follows：
The Cariliprazine trihydrate crystal, is determined, condition determination using D/Max-2500.9161 types x-ray diffractometer：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）, D values and relative intensity it is as follows,
The measure of 2 θ values uses light source in the present invention, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allowed certain rational error range, and its error range is ± 0.2 °.
Fusing point test：According to Pharmacopoeia of People's Republic of China（2010 editions, two）The first methods of C of annex VI determine fusing point, and the fusing point for measuring is 169-172 DEG C.
Another object of the present invention, discloses the preparation method of Cariliprazine trihydrate crystal, is dissolved in n-hexyl alcohol-furans-heated in water solution by by Cariliprazine, naturally cools to room temperature, then is incubated a period of time and obtains.
Specifically include the following steps：Cariliprazine adds 9-11 times（Weight or measurement (WM) ratio）Tetrahydrofuran-ethyl acetate-water=4.2-4.5：0.6-0.8：In the mixed liquor of 4.8-7.2, dissolving is heated to, filtrate naturally cools to 25 DEG C -30 DEG C, then stands insulation 3-5 hours, separates out crystallization, filtering, through being dried to obtain.
A further object of the present invention, there is provided the composition comprising Cariliprazine trihydrate crystal and one or more Cariliprazine trihydrate of pharmaceutically acceptable carrier composition.
Pharmaceutical composition of the invention prepares as follows：Using standard and conventional technique, the compounds of this invention is combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.Said composition is used to prepare oral formulations.
The active ingredient contained in pharmaceutical composition and unit dosage form（The compounds of this invention）Amount can be specifically applied according to the state of an illness of patient, the situation of diagnosis, the amount or concentration of compound used are adjusted in a scope wider, and the amount scope of reactive compound is the 1%~40% of composition（Weight）.
Present invention also offers application of the Cariliprazine trihydrate in schizoid medicine is treated.
Stability test
Inventor is studied the stability of crystal formation of the invention, and investigation condition is high temperature（60℃ ±2℃）, strong illumination（5000Lx±500lx）, high humidity（92.5%±5%）Inspection target is outward appearance, content and relevant material.
As a result：From 0-15 days under high light, high temperature, super-humid conditions, outward appearance, relevant material, content do not change, and illustrate that chemical stability is good, are adapted to the manufacture and long term storage of pharmaceutical preparation.
Specific embodiment
With reference to embodiment, the present invention is described further, professional and technical personnel in the field is better understood from the present invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention by any way.
Embodiment
1
In 100L reactors, 6 kilograms of Cariliprazine trihydrates are added to 10 times（Weight or measurement (WM) ratio）Tetrahydrofuran-ethyl acetate-water=4.3：0.8：In 5 mixed liquor, 70 DEG C are heated to, are incubated 30 minutes, filtered while hot.47 DEG C of filtrate, is incubated 1 hour；35 DEG C are naturally cooled to again, 10 hours are incubated, the crystallization for separating out is filtered, through natural drying at room temperature, 6.02 kilograms of white crystal is obtained, and purity 99.92%, dissolvent residual detection meets the requirements.The moisture measured with Karl_Fischer method is 0.89%.
Using standard and conventional technique, the compounds of this invention is combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.Said composition is used to prepare oral formulations, injection.Only citing is illustrated, and is in no way intended to it and limits the scope of the present invention by any way.
Embodiment
2
Tablet containing Cariliprazine trihydrate:Cariliprazine trihydrate weight compares 25%, appropriate lactose, microcrystalline cellulose 30%, pregelatinized starch 18%, low-substituted hydroxypropyl cellulose 8%, lauryl sodium sulfate 1%, magnesium stearate 0.8%, appropriate PVP.
Technique：The preparation of label:Main ingredient is well mixed with auxiliary material by identified prescription, is pelletized, particle aeration-drying below 40 DEG C, with l6 mesh sieve whole grains, adds magnesium stearate and remaining starch, compressing tablet to obtain final product.
Spacer layer coating:During talcum powder added into 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, be configured to 20% suspension as spacer layer coating liquid.It is coated in fluid bed, its process conditions is as follows：Atomisation pressure 0.3 MPa, feed speed 5mL/min, 37 DEG C of inlet temperature, 31 DEG C of outlet temperature, dry air flow 200m3/ h, separation layer weightening is the 9% of essence piece piece weight.
Enteric layers are coated:No. II resin is dissolved in absolute ethyl alcohol, clothing liquid concentration is 10% (w/v), and in addition to spray speed is for 4mL/min,, with spacer layer coating condition, enteric layers weightening is the 6% of bag isolation synusia weight to its process conditions for remaining.
Claims (6)
1. the trihydrate of Cariliprazine shown in formula I,
（Ⅰ）
Determined with DTG, the hydrate contains the moisture of percentage by weight 1.89%-2.21%；The crystal of the Cariliprazine trihydrate, in being determined as characteristic X-ray powder with CuKa rays, its collection of illustrative plates has the following 2 θ angles of diffraction, interplanar distance (d values) and relative intensity（I/I0）,
The error of the 2 θ angles of diffraction is ± 0.2.
2. the preparation method of Cariliprazine trihydrate crystal described in claim 1, dissolves, natural cooling by by Cariliprazine in tetrahydrofuran-ethyl acetate-heated in water solution, then is incubated a period of time and obtains.
3. according to the method for claim 2, it is characterised in that comprise the following steps：Cariliprazine adds 9-11 times（Weight or measurement (WM) ratio）Tetrahydrofuran-ethyl acetate-water=4.2-4.5：0.6-0.8：In the mixed liquor of 4.8-7.2, dissolving is heated to, filtrate naturally cools to 35 DEG C -40 DEG C, then stands insulation 9-11 hours, separates out crystallization, filtering, through being dried to obtain.
4. a kind of Cariliprazine trihydrate crystal containing described in claim 1 and one or more pharmaceutically acceptable carrier constitute the composition of Cariliprazine trihydrate.
5. the composition of the Cariliprazine trihydrate described in claim 4, it is characterised in that said composition is used to prepare oral formulations.
6. application of the Cariliprazine trihydrate described in claim 1 in schizoid medicine is treated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510773565.8A CN106699689A (en) | 2015-11-13 | 2015-11-13 | Cariprazine trihydrate compound |
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| CN201510773565.8A CN106699689A (en) | 2015-11-13 | 2015-11-13 | Cariprazine trihydrate compound |
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| CN106699689A true CN106699689A (en) | 2017-05-24 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586389A (en) * | 2018-06-29 | 2018-09-28 | 成都福柯斯医药技术有限公司 | A kind of new method of synthesis Cariliprazine |
| CN114099512A (en) * | 2020-08-26 | 2022-03-01 | 上海博志研新药物技术有限公司 | Carilazine pharmaceutical composition, preparation method and application |
-
2015
- 2015-11-13 CN CN201510773565.8A patent/CN106699689A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586389A (en) * | 2018-06-29 | 2018-09-28 | 成都福柯斯医药技术有限公司 | A kind of new method of synthesis Cariliprazine |
| CN114099512A (en) * | 2020-08-26 | 2022-03-01 | 上海博志研新药物技术有限公司 | Carilazine pharmaceutical composition, preparation method and application |
| WO2022042642A1 (en) * | 2020-08-26 | 2022-03-03 | 上海博志研新药物技术有限公司 | Cariprazine pharmaceutical composition, preparation method and application thereof |
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Application publication date: 20170524 |