CN106831741B - A kind of preparation method of Iloperidone superfine powder - Google Patents
A kind of preparation method of Iloperidone superfine powder Download PDFInfo
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- CN106831741B CN106831741B CN201611236110.3A CN201611236110A CN106831741B CN 106831741 B CN106831741 B CN 106831741B CN 201611236110 A CN201611236110 A CN 201611236110A CN 106831741 B CN106831741 B CN 106831741B
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- iloperidone
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- superfine powder
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of preparation methods of Iloperidone superfine powder, and the method, steps are as follows: 1) in proportion by 0.8-1.2g Iloperidone be suspended in 10~100ml water and organic solvent in the mixed solvent；2) acetic acid is added dissolves Iloperidone；3) at 15~30 DEG C, the lower aqueous solution that alkali is added dropwise is stirred, pH value of solution=4-4.5 is adjusted；4) it precipitates crystal, places；5) Iloperidone superfine powder is directly obtained in 40~100 DEG C of drying to constant weights.
Description
Technical field
The invention patent relates to chemical medicines, more particularly to a kind of preparation side of Iloperidone bulk pharmaceutical chemicals superfine powder
Method.
Background technique
Iloperidone (iloperidone), 3- methoxyl group -4- [3- [4- (fluoro- 1, the 2- benzo isoxazole -3- base of 6-) piperidines
Base] propoxyl group] acetophenone, structure is shown in formula I.Iloperidone piece (trade name: Fanapt) is opened by Vanda company, the U.S.
Hair, and be divided into 7 kinds of specifications in U.S.'s listing in acquisitions FDA on May 6th, 2009 approval: 1,2,4,6,8,10,12mg, auxiliary material is
Lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose, crospovidone, magnesium stearate, superfine silica gel powder and purified water (were prepared
It goes out in journey).
As a kind of atypical antipsychotic, Iloperidone is to the positive symptom and yin for mitigating schizophreniac
Property symptom has positive effect.Compared with anti-semen antibody used at present, the adverse reaction of Iloperidone is less, patient's constitution
It is smaller to measure increasing degree, will not induce patient that diabetes occur, patient's extrapyramidal symptom is also less.
Iloperidone, the solubility 0.012mg/ml in water are insoluble drug, are prepared into tablet, the dissolution rate of drug
It will receive the influence of solubility.For such slightly solubility material, drug-eluting becomes the pass for limiting its absorption and bioavilability
Key factor.According to Noyes-Whimey equation, drug granule granularity is reduced, its specific surface and wetability are increased, to reach
The rapidly-soluble purpose of grain.Therefore, the micronization of bulk pharmaceutical chemicals becomes the important channel for solving the problems, such as insoluble drug dissolution rate
One of.
Wherein the micronization of bulk pharmaceutical chemicals includes recrystallization, mechanical crushing, vibromill crushing and air-flow crushing etc..
Official reports that Iloperidone is single crystal form, the experimental study that we are recrystallized also by a large amount of single solvents
It is confirmed, the product is without polymorphism and is easy to crystallize, and basic granularity is at 50 μm or more, self-control amplification product
Granularity close to 150 μm, be detailed in attached drawing 1.Afterwards by being mechanically pulverized and the processing such as air-flow crushing, crystal form is without significant change, but
Phenomena such as in the presence of dispersion, Electrostatic Absorption, active ingredient loss is big, the loss more than nearly 10% or more；Simultaneously in physical crushing spy
When being not air-flow crushing, due to high temperature exothermic, the impurity especially oxidative degradation impurity of Iloperidone is caused to increase, to make to make
Agent product is unable to reach medicinal standard.
In addition, CN104324008A, which is reported, carries out precipitating micronization using binary solvent (readily soluble solvent and anti-solvent)
Method prepares superfine powder Iloperidone, and the technological operation is simple, but has been all made of a large amount of organic solvents, and this method is unfavorable for ring
It protects.
We follow the principle of Green Chemistry, adopt water as main solvent, pass through the plan of acid-base neutralization and adjusting pH crystallization
Slightly (quick crystallization is carried out using the extremely low feature of the degree of supersaturation of Iloperidone in water) and carried out a large amount of experiment discovery, greatly
Salt (such as hydrochloride, sulfate, nitrate, oxalates, tartrate, citrate, the fumarate of most Iloperidones
Deng) in water solubility not very well, dissolubility is good only in the acetic acid salt water of Iloperidone, and can by adjust pH reach
To the product for controlling ultra-fine powder granularity.
But using the single solvent system of pure water, it is too fast meticulous that product is precipitated, be easily formed the agglomeration of part fine particle and
The problem of group, still needs to the preparation by that could be used for formulation products after pulverizing and sieving after dry.
Whens in addition using common inorganic base such as sodium bicarbonate, sodium carbonate etc., gas is also generated, production operation is unfavorable for,
Therefore the inorganic bases such as selection sodium hydroxide, potassium hydroxide.Comprehensively consider the basic principle of Green Chemistry, the present invention does not increase introducing phase
Organic base is closed, therefore does not do related further investigation.
Subsequently through the experiment of a large amount of process optimizations, it has been surprisingly found that by supplementing a small amount of organic solvent, sufficiently
Using the appropriate speed of acetate crystallization, the more stable size distribution that reliably directly obtains is than more uniform superfine powder Yi Panli
Ketone bulk pharmaceutical chemicals, the product can be directly used for the preparation of preparation.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation method of Iloperidone bulk pharmaceutical chemicals superfine powder, the technique green rings
It protects, safety easy to operate, process stabilizing, loss is less and at low cost, is easy to industrialization production, is particularly suitable for being directly used in Yi Panli
The exploitation of ketone preparation uses, and can also substantially reduce controlling risk for its oxidative degradation impurity.
Detailed technology plan explanation of the invention is as follows:
A kind of preparation method of Iloperidone raw material superfine powder, comprising the following steps:
1) in proportion by 0.8-1.2g Iloperidone be suspended in 10~100ml water and organic solvent in the mixed solvent；
2) acetic acid is added dissolves Iloperidone；
3) at 15~30 DEG C, the lower aqueous solution that alkali is added dropwise is stirred, pH value of solution=4-4.5 is adjusted；
4) it precipitates crystal, places；
5) Iloperidone superfine powder is directly obtained in 40~100 DEG C of drying to constant weights.
Preparation method of the present invention, the organic solvent in the step (1) are methanol, ethyl alcohol, acetone, butanone, second
The ratio of nitrile and their mixture, volume and water volume is 1-4:20.
Preparation method of the present invention, the step (2) be added acetic acid mole be Iloperidone quality 1~
5 times.
Preparation method of the present invention, the alkali in step (2) are selected from sodium hydroxide, potassium hydroxide.
Preparation method of the present invention, the standing time in step (4) are 30min~12h.
Preparation method of the present invention, the granularity in step (5) are D (90)≤20 μm.
The present invention is suspended in Iloperidone in water and a certain proportion of organic solvent mixed system, is added a certain amount of
After acetate dissolution, then at a certain temperature, it is sufficiently stirred down and a certain amount of aqueous alkali is gradually added dropwise, precipitate crystal, using
After the ageing of certain time, filtered, it is dry after without crushing, to directly obtain the relatively uniform Iloperidone of distribution of particles ultra-fine
Powder product, granularity is at 20 μm or less.Method of the invention, technique is environmentally protective, safety easy to operate, process stabilizing, damage
Consumption is less and at low cost, is easy to industrialization amplification production, and the exploitation for being particularly suitable for being directly used in Iloperidone preparation uses, also can be big
Controlling risk for its oxidative degradation impurity is reduced greatly.
The preparation method is that obtained by screening, screening process of the invention is as follows:
1) firstly, the chemical stabilities such as soda acid of Iloperidone are fine and stable crystal form, this paper initial option pass through soda acid
The mode that reaction is granulated prepares its superfine powder API.
2) the solubility 0.012mg/ml of Iloperidone in water is water-soluble, and adopting water as main solvent is optimal selection.
3) salt of a large amount of Iloperidones, such as acetate, hydrochloride, sulfate, nitrate, oxalates, winestone have been made by oneself
Hydrochlorate, citrate, fumarate etc., wherein the soluble,very slightly in water such as hydrochloride, sulfate, nitrate of Iloperidone,
The slightly soluble in water such as its oxalates, tartrate, citrate, fumarate, only acetate is readily soluble in water, therefore selects its work
Subsequent development is carried out for suitable acid group.
4) in the screening of different alkali, common organic base such as triethylamine or ammonium hydroxide etc. are not likely to produce precipitating, and newly-increased have
Machine reagent does not meet the basic principle of Green Chemistry.Inorganic base such as sodium carbonate, potassium carbonate etc. then easily generates gas, is unfavorable for
The stability and safety of technological operation.Using the unitary highly basic such as sodium hydroxide, potassium hydroxide, stable product quality and technique
Operability meets the requirements.
It is 5) too high to the control requirement of rate of addition when carrying out acid-base reaction granulation using single pure aquatic system,
Chang Yinwei particle is too small and agglomerate is agglomerated, after centrifugation and drying, it is still necessary to use after pulverization process for preparation.Here I
Attempt several frequently seen miscible with water and not solvent such as methanol, ethyl alcohol, acetone, butanone, the acetonitrile with Iloperidone dissolution
Deng effect is fairly obvious.In view of the excessive crystallization of organic solvent content is slow, particle increases, therefore has carried out correlative study.
With the comparative experiments of the prior art:
1) we are crushed using air-flow, and particle is meticulous, and are lost 15% or so, and relevant control is improper, oxidation
Impurity is easy to increase, and is not suitable for the preparation process of existing Iloperidone.
2) related process of CN104324008A is repeated in we, in suitable process parameters range, product granularity etc.
Correlated quality can reach our requirement substantially, but organic solvent type is too many, and granularity is partially thin and residual molten amount is bigger than normal.
By screening and the comparative experiments with the prior art, the present invention is found surprisingly that, excellent below presence of the invention
Point:
1) environmentally protective, molten residual is extremely low
2) product actual recovery is 90% or more, no especial equipment requirements, and cost is relatively low
3) product granularity non-agglomerate is evenly distributed, and can be directly used for preparation production
4) safety easy to operate is easily-controllable, is conducive to industrialized production
5) controls such as reliable in quality, degradation impurity and residual solvent are very reasonable
Detailed description of the invention
The particle size distribution figure of Fig. 1 pilot scale self-control Iloperidone bulk pharmaceutical chemicals
The particle size distribution figure of Iloperidone bulk pharmaceutical chemicals in Fig. 2 embodiment 1
Specific embodiment
Granulometry is acquired by Malvern SM2000 type laser particle analyzer: it is former to weigh about 120mg Iloperidone
Expect medicine, set in the measuring bottle of 50ml, 5% lecithin soln of 3.0ml and the Iloperidone Isopar G saturated solution of 30ml is added,
Ultrasonic 6min.After running background measurement, takes solution to be added in sample cell and measure, particle refractive index 1.430, granule absorbance
0.8, obscurity 5~20%, mixing speed 1600rpm, background and sample time of measuring are 10s.
The present invention can be further described by the following examples, however there is no offices for the scope of the present invention
It is limited to following embodiments.
The Iloperidone API that the present invention uses self-control to amplify is raw material, testing graininess such as Fig. 1, partial size D90=142.9 μm.
Embodiment 1
(1) 100g (0.234mol) Iloperidone is suspended in 1500ml water and 100ml ethyl alcohol mixed system in proportion；
(2) after acetic acid (1.2eq) dissolution being added；
(3) then at 15~30 DEG C, the aqueous solution that a certain amount of alkali is gradually added dropwise is sufficiently stirred down, adjusts pH=4 or so；
(4) it precipitates crystal, after the ageing of certain time；
(5) 96.2g, yield 96.2%, D are directly obtained in 40~100 DEG C of drying to constant weights90=13.7 μm.Granularity is surveyed
Examination is as shown in Figure 2.
Embodiment 2
With example 1, ethyl alcohol volume is only changed to 250ml from 100ml, obtains solid product 92.6g, yield 92.6%, D90
=15.2 μm.
Embodiment 3:
With example 1, only organic solvent is changed to acetone, obtains solid product 95.1g, yield 95.1%, D90=11.2 μm.
Embodiment 4:
With example 1, only organic solvent is changed to acetonitrile, obtains solid product 96.7g, yield 96.7%, D90=9.2 μm.
Embodiment 5:
With example 1, the 50ml ethyl alcohol in wherein 100ml is only changed to 50ml acetonitrile, obtains solid product 96.3g, yield
96.3%, D90=10.8 μm.
Claims (7)
1. a kind of preparation method of Iloperidone superfine powder, which is characterized in that steps are as follows:
1) 0.8-1.2g Iloperidone is suspended in the in the mixed solvent of 10~100ml water and organic solvent in proportion；
2) acetic acid is added dissolves Iloperidone；
3) at 15~30 DEG C, the lower aqueous solution that alkali is added dropwise is stirred, pH value of solution=4-4.5 is adjusted；
4) it precipitates crystal, places；
5) Iloperidone superfine powder is directly obtained in 40~100 DEG C of drying to constant weights,
Wherein, the organic solvent in the step (1) is methanol, ethyl alcohol, acetone, butanone, acetonitrile and their mixture, body
Long-pending and water volume ratio is 1-4:20.
2. preparation method according to claim 1, it is characterised in that: the mole that acetic acid is added in the step (2) is for she
1~5 times of Pan Li ketone quality.
3. preparation method according to claim 1, which is characterized in that the alkali in step (3) is selected from sodium hydroxide, hydroxide
Potassium.
4. preparation method according to claim 1, which is characterized in that the standing time in step (4) is 30min~12h.
5. preparation method as described in claim 1, which is characterized in that the granularity in step (5) is D (90)≤20 μm.
6. a kind of preparation method of Iloperidone superfine powder, which is characterized in that steps are as follows:
(1) 100g Iloperidone is suspended in 1500ml water and 100ml ethyl alcohol mixed system in proportion；
(2) acetate dissolution of 1.2eq is added；
(3) then at 15~30 DEG C, the aqueous solution that a certain amount of alkali is gradually added dropwise is sufficiently stirred down, adjusts pH=4；
(4) it precipitates crystal, after the ageing of certain time；
(5) 96.2g Iloperidone superfine powder, yield 96.2%, D are directly obtained in 40~100 DEG C of drying to constant weights90=
13.7μm。
7. a kind of preparation method of Iloperidone superfine powder, which is characterized in that steps are as follows:
(1) 100g Iloperidone is suspended in 1500ml water and 250ml ethyl alcohol mixed system in proportion；
(2) acetate dissolution of 1.2eq is added；
(3) then at 15~30 DEG C, the aqueous solution that a certain amount of alkali is gradually added dropwise is sufficiently stirred down, adjusts pH=4；
(4) it precipitates crystal, after the ageing of certain time；
(5) 96.2g Iloperidone superfine powder, yield 92.6%, D are directly obtained in 40~100 DEG C of drying to constant weights90=
15.2μm。
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| CN201611236110.3A CN106831741B (en) | 2016-12-28 | 2016-12-28 | A kind of preparation method of Iloperidone superfine powder |
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| CN201611236110.3A CN106831741B (en) | 2016-12-28 | 2016-12-28 | A kind of preparation method of Iloperidone superfine powder |
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| CN106831741B true CN106831741B (en) | 2019-08-23 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004006886A2 (en) * | 2002-07-15 | 2004-01-22 | Novartis Ag | Injectable depot formulation comprising crystals of iloperidone |
| CN102108081A (en) * | 2009-12-25 | 2011-06-29 | 重庆医药工业研究院有限责任公司 | Novel crystal form of Iloperidone and preparation method thereof |
| CN103450169A (en) * | 2013-08-14 | 2013-12-18 | 天津华津制药有限公司 | Refining method of iloperidone |
| CN104324008A (en) * | 2014-09-18 | 2015-02-04 | 山东省药学科学院 | Industrial preparation method of micronized iloperidone |
| WO2016198113A1 (en) * | 2015-06-11 | 2016-12-15 | Alrise Biosystems Gmbh | Process for the preparation of drug loaded microparticles |
-
2016
- 2016-12-28 CN CN201611236110.3A patent/CN106831741B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004006886A2 (en) * | 2002-07-15 | 2004-01-22 | Novartis Ag | Injectable depot formulation comprising crystals of iloperidone |
| CN102108081A (en) * | 2009-12-25 | 2011-06-29 | 重庆医药工业研究院有限责任公司 | Novel crystal form of Iloperidone and preparation method thereof |
| CN103450169A (en) * | 2013-08-14 | 2013-12-18 | 天津华津制药有限公司 | Refining method of iloperidone |
| CN104324008A (en) * | 2014-09-18 | 2015-02-04 | 山东省药学科学院 | Industrial preparation method of micronized iloperidone |
| WO2016198113A1 (en) * | 2015-06-11 | 2016-12-15 | Alrise Biosystems Gmbh | Process for the preparation of drug loaded microparticles |
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