CN106543168A - A kind of stable Lurasidone HCl hydrate compound - Google Patents
A kind of stable Lurasidone HCl hydrate compound Download PDFInfo
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- CN106543168A CN106543168A CN201510604520.8A CN201510604520A CN106543168A CN 106543168 A CN106543168 A CN 106543168A CN 201510604520 A CN201510604520 A CN 201510604520A CN 106543168 A CN106543168 A CN 106543168A
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- Prior art keywords
- lurasidone hcl
- lurasidone
- hydrate
- hydrate compound
- crystal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, and in particular to Lurasidone HCl hydrate and preparation method thereof, the Lurasidone HCl that the present invention is obtained, containing a water of crystallization, has the advantage that：Purity is high, good stability, even if moisture absorption weightening is not also obvious under high humidity conditions；With good mouldability.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to Lurasidone HCl hydrate compound and preparation method thereof.
Background technology
Lurasidone（lurasidone）For a new atypical antipsychotic agents, on October 28th, 2010 food and medicine Surveillance Authority of the U.S.（FDA）Ratify its listing, trade name Latuda, for treating schizophrenia.
Lurasidone HCl, entitled N- [4- [4- (1,2- benzisothiazole -3- bases) -1- piperazinyls]-(2R, the 3R) -2 of chemistry, 3- tetramethylenes-butyl]-(1 ' R, 2 ' S, 3 ' R, 4 ' S) -2,3- bicyclo- [2,2,1] heptane imidodicarbonic diamide hydrochlorate, structural formula are as follows：
(I) Lurasidone HCl structural formula
Lurasidone HCl has various preparation methoies, and because of preparation method, especially process for purification is different, obtains different crystal formations, and the Lurasidone HCl of WO2012063246A patent reports is amorphous and crystal formation I.
In research process, the method for repeating prior art, the Lurasidone HCl impurity number for obtaining is more, and total impurities are higher, and obtained Lurasidone HCl anhydride moisture absorption weightening is obvious under high humidity conditions.The Lurasidone HCl that the present invention is obtained, containing a water of crystallization, 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；With good mouldability.
The content of the invention
One object of the present invention, discloses a kind of Lurasidone HCl monohydrate compound.
Another object of the present invention, discloses the preparation method of Lurasidone HCl monohydrate compound.
A further object of the present invention, discloses the pharmaceutical composition comprising Lurasidone HCl monohydrate compound.
The invention also discloses application of the Lurasidone HCl monohydrate in the schizoid medicine of manufacture treatment.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of Lurasidone HCl monohydrate（Shown in formula I）,
（II）
Karl_Fischer method（Karl Fischer methods）In being a kind of all kinds of chemical methodes for determining moisture in material, method the most single-minded to water, the most accurate has been listed in the standard method of determination of water in many materials, especially organic compound, reliable results.
10 batches of Jing are determined, and the moisture that described invention compound contains is between 2.54% -4.13% (percentage by weight).In Lurasidone HCl monohydrate, the theoretical content of water is 3.29%, it can be assumed that invention compound contains a water of crystallization.
The Lurasidone HCl monohydrate crystal, is determined using D/Max-2500.9161 types x-ray diffractometer, condition determination：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）It is as follows with D values.
In the present invention, the measure of 2 θ values uses light source, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allowed certain rational range of error, and its range of error is ± 0.2 °.
The crystal formation heat analysis result shows：At 45 DEG C, 129 DEG C, 156 DEG C have significant endothermic peak respectively.
Jing chlorine ion content determinations, as a result show：The ratio of Lurasidone and hydrogen chloride is 1：1, contain a hydrogen chloride in each Lurasidone HCl monohydrate molecule.
Another object of the present invention, discloses the preparation method of Lurasidone HCl monohydrate compound crystal, by Lurasidone HCl in the dissolving of propanol-acetonitrile-heated in water solution, to naturally cool to room temperature, then is incubated a period of time and obtains.
Specifically include the following steps：Lurasidone HCl adds 9-10 times（Weight or measurement (WM) ratio）Propanol-acetonitrile-water=7-6：2-1：In the mixed liquor of 3-1,65 DEG C -70 DEG C are heated to, filtered while hot naturally cools to room temperature, then is incubated 10-15 hours, separate out crystallization, filtered, drying obtains the above-mentioned Lurasidone HCl monohydrate crystal of high-purity.
Lurasidone HCl used, synthesizes according to the method that document EP187371 (1984-12-2) is provided, the chemical constitution Jing proton nmr spectra of the Lurasidone HCl of synthesis, elementary analysiss, it was demonstrated that chemical constitution is correct.
A further object of the present invention, there is provided the compositionss comprising Lurasidone HCl monohydrate crystal and the Lurasidone HCl hydrate of one or more pharmaceutically acceptable carrier composition.
The pharmaceutical composition of the present 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 microgranule or microsphere.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 situation of the state of an illness of patient, diagnosis, the amount or concentration of compound used are adjusted in a wider scope, and the amount scope of reactive compound is the 1%～30% of compositionss（Weight）.
Present invention also offers application of the Lurasidone HCl monohydrate crystal in manufacture treatment osteoporosis agents.
Stability test
Inventor is studied to the chemical stability of the crystal formation of the present invention, and investigation condition is high temperature（60℃±2℃）, strong illumination（4500Lx±500lx）, high humidity（92.5%,RH）Inspection target is outward appearance, content and relevant material.
As a result：From 0-10 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.
At 40 DEG C, different relative humiditys（RH）Condition（75%, 92.5%）Under, Lurasidone HCl one
The measure of moisture in hydrate crystal：
As a result：At 40 DEG C, different relative humiditys（RH）Condition（75%, 92.5%）Under, water tariff collection is constant, and explanation has good stability, and is adapted to the manufacture and long term storage of pharmaceutical preparation.
At 40 DEG C, different relative humiditys（RH）Condition（75%, 92.5%）Under, the measure of moisture in Lurasidone HCl anhydride crystal：
As a result：At 40 DEG C, different relative humiditys（RH）Condition（75%, 92.5%）Under, Lurasidone HCl anhydride crystal has moisture absorption to increase weight, to moist lability.
Under 400kg and 600kg pressing pressures, the hardness (kg) of the tablet of the 3 batches of Lurasidone HCl monohydrate crystals for respectively obtaining：
| Pressure（kg） | NO.1 | NO.2 | NO.3 | Average |
| 400 | 8.1 | 7.8 | 8.3 | 8.1 |
| 600 | 8.4 | 8.3 | 8.5 | 8.4 |
As a result：With good mouldability.
Specific embodiment：
With reference to embodiment, the present invention is described further, makes professional and technical personnel in the field be 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 equipped with stirring, thermometer, the 5000ml reaction bulbs of condenser, the propanol-acetonitrile-water of 300 grams of Lurasidone HCls and 3000ml is added（6：2：2）Mixed liquor, starts stirring, is heated to 65 DEG C -70 DEG C, treats all molten clear, filtered while hot.Filtrate naturally cools to room temperature, then is incubated 12 hours, separates out crystallization, filters, and Jing indoor seasonings obtain final product 273.1 grams of the white crystals of the above-mentioned Lurasidone HCl monohydrate of high-purity.Jing Karl_Fischer methods are determined, the moisture containing 3.29% (percentage by weight).
The X-ray diffractogram instrument model of the crystallization and condition determination：Rigaku D/max
2500 type diffractometers； CuKa
40Kv 100mA;2 θ sweep limitss：0-50°；
Embodiment
2
Granule containing Lurasidone HCl monohydrate
Prescription：45 grams of Lurasidone HCl monohydrate, 690 grams of Lactose, 88 grams of polyvinylpolypyrrolidone, 90 grams of PEG-4000,150 grams of hydroxypropyl methyl cellulose distill appropriate amount of water, make 1000 bags.
Technique：PEG-4000 is crushed jointly with Lurasidone HCl monohydrate, crosses 80 mesh sieves, with being packed as granule after distilled water soft material, granulation, cold drying after mixing with other materials.
Tablet containing Lurasidone HCl monohydrate
Prescription：40 grams of Lurasidone HCl monohydrate, 190 grams of Lactose, 26 grams of PEG-4000,5 grams of magnesium stearate, 28 grams of Povidone K 30,45 grams of Croscarmellose Sodium distill appropriate amount of water, make 1000.
Technique：PEG-4000 is crushed jointly with Lurasidone HCl monohydrate, crosses 80 mesh sieves, and with distilled water soft material after mixing with other materials, the pelleting of 16 mesh sieves is mixed in adding dry particl in 40-45 DEG C of drying, 16 mesh sieve granulate, magnesium stearate in putting drying baker, tabletting.
Claims (6)
1. the hydrate compound of Lurasidone HCl shown in formula I,
（Ⅰ）
Determined with Karl_Fischer method, the hydrate contains the moisture of 2.54% -4.13% (percentage by weight)；
The crystal of the Lurasidone HCl hydrate compound, in being determined as characteristic X-ray powder with CuKa rays, its collection of illustrative plates has the following 2 θ angles of diffraction and D values,
The error of the 2 θ angles of diffraction is ± 0.2.
2. the preparation method of the hydrate compound crystal of Lurasidone HCl described in claim 1, by Lurasidone HCl in propanol-acetonitrile-heated in water solution dissolving, to naturally cool to room temperature, then is incubated a period of time and obtains.
3. according to the method for claim 3, it is characterised in that comprise the following steps：Lurasidone HCl adds 9-10 times（Weight or measurement (WM) ratio）Propanol-acetonitrile-water=7-6：2-1：In the mixed liquor of 3-1,65 DEG C -70 DEG C are heated to, filtered while hot naturally cools to room temperature, then is incubated 10-15 hours, separate out crystallization, filtered, drying is obtained.
4. compositionss of the Lurasidone HCl hydrate of a kind of hydrate compound crystal containing Lurasidone HCl described in claim 1 and one or more pharmaceutically acceptable carrier composition.
5. 5 required by right described in compositionss, it is characterised in that said composition be used for prepare oral formulations.
6. application of the Lurasidone HCl hydrate compound described in claim 1 in the schizoid medicine of manufacture treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510604520.8A CN106543168A (en) | 2015-09-22 | 2015-09-22 | A kind of stable Lurasidone HCl hydrate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510604520.8A CN106543168A (en) | 2015-09-22 | 2015-09-22 | A kind of stable Lurasidone HCl hydrate compound |
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| Publication Number | Publication Date |
|---|---|
| CN106543168A true CN106543168A (en) | 2017-03-29 |
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| CN201510604520.8A Pending CN106543168A (en) | 2015-09-22 | 2015-09-22 | A kind of stable Lurasidone HCl hydrate compound |
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- 2015-09-22 CN CN201510604520.8A patent/CN106543168A/en active Pending
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| PB01 | Publication | ||
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Application publication date: 20170329 |