CN107827878A - A kind of preparation method brilliant Vilazodone Hydrochloride IV - Google Patents
A kind of preparation method brilliant Vilazodone Hydrochloride IV Download PDFInfo
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- CN107827878A CN107827878A CN201711163592.9A CN201711163592A CN107827878A CN 107827878 A CN107827878 A CN 107827878A CN 201711163592 A CN201711163592 A CN 201711163592A CN 107827878 A CN107827878 A CN 107827878A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
Abstract
Preparation method brilliant a kind of Vilazodone Hydrochloride IV, comprises the following steps：（1）1 [4 (base of 5 cyanoindole 3) butyl] 4 (base of 2 carbamyl benzofuran 5) piperazines are added in isopropanol, filtered after being heated to reflux；（2）The aqueous isopropanol containing 5% ~ 35% hydrogen chloride is added dropwise into filtrate；（3）Flow back, filter after being added dropwise, drying obtains IV crystalline substances.This method is simple, convenient, unexpectedly solves mixed crystal phenomenon of the IV crystalline substances caused by by lower turn of crystalline substance of other crystal formation solid-states in the prior art, avoids the generation of mixture；The Vilazodone Hydrochloride IV grain sizes of generation are suitable, residual solvent is qualified, and water content is low, is advantageous to the crystal formation stablized and improves the dissolution situation of formulation products, gratifying In Vitro Dissolution curve is drawn, medicine stability, bioavilability and curative effect can be lifted.
Description
Technical field
The present invention relates to a kind of preparation method of Vilazodone Hydrochloride crystal formation, specifically, it is related to Vilazodone Hydrochloride IV
Brilliant preparation method.
Background technology
Vilazodone piece was approved by the fda in the United States for treating severe adult's depression in 2011, was first indolyl
Amine novel antidepressant, double action mechanism：Selective five hydroxytryptamine reuptaking inhibitor and 5-HT1A acceptor portions excitement
Agent, onset time are substantially better than existing SSRIs classes antidepressant, so as to considerably increase the compliance of patient.
The clinical data experiment of vilazodone shows that its curative effect is substantially better than placebo, has rapid-action, responsiveness simultaneously
It is high, compliance is good, does not put on weight, the advantages of also influenceing sexual function unlike many antidepressants, and adverse reaction is small,
Its is common（2 times of incidence >=5% and at least placebo incidence）Adverse reaction be diarrhoea, Nausea and vomiting and insomnia.
Through research, Vilazodone Hydrochloride is polycrystalline medicine, and different crystal forms are seen outside, solubility, fusing point, dissolution rate, life
Thing validity etc. has dramatically different, and so as to have impact on the stability of medicine, bioavilability and curative effect, this phenomenon exists
Show particularly evident in terms of oral solid formulation.
Patent ZL02812226.7（CN100384841C）Disclose the various crystal formations of vilazodone hydrochloride：1）1-[4-
(5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine hydrochloride solvate, crystal formation I：
Acetone solvate；Crystal formation II and XV：With a solvate of tetrahydrofuran；Crystal formation X：With half solvate of tetrahydrofuran；Crystal formation
XI：Methylate；Crystal formation XIV：With a solvate of normal heptane；2）1- [4- (5- cyanoindole -3- bases) butyl] -4- (2-
Carbamyl-benzofuran -5- bases)-piperazine hydrochloride hydrate, crystal formation V：Monohydrate；Crystal formation VI：Times semihydrate；It is brilliant
Type VIII：Semihydrate；3）1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine
The dehydrate of hydrochloride, crystal formation IV, III, VII, IX；4）1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzene
And furans -5- bases)-piperazine dihydrochloride, crystal formation XIII.
Wherein, at a higher temperature, such as>100 DEG C, IV types are most stable of forms；According to description, IV crystalline substances are in solubility
Be processed into solid pharmaceutical preparation in pharmacy in terms of have some superiority, while solubility of the IV types in water is 0.328 μ g/ml, is
Colorless solid substance, it is advantage drug crystal forms for the crystalline forms being able adequately determines.
In this patent that vilazodone Pian Yuanyan Merck ＆ Co., Inc.s declare, inventor points out by exploration, " this specific
Polymorphic form（Turn into herein " IV is brilliant "）Property with better than other crystal habits, more suitable for being included in pharmaceutical preparation
In ".
With reference to ZL200710180229.8（CN101139345B）, it is known that XRD data brilliant IV are：
Patent ZL02812226.7（CN100384841C）Disclosed in the brilliant synthetic methods of IV, comprising：1）By 1- [4- (5- cyanogen
Base indol-3-yl) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is dispersed in tetrahydrofuran；2）20 DEG C with
Aqueous hydrochloric acid is added at a temperature of between 30 DEG C, converts 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzo
Furans -5- bases)-piperazine is hydrochloride；3）V crystalline substances are settled out at room temperature；4）By precipitated 1- [4- (5- cyanogen is recovered by filtration
Base indol-3-yl) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine hydrochloride monohydrate V crystalline substances；5）85 to 90
V-type is dried in DEG C vacuum, obtains IV crystalline substances.
Or XI types 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- ammonia is dried at a temperature of between 55 and 65 DEG C
Formyl-benzofuran -5- bases) one methylate of-piperazine hydrochloride, obtain IV crystalline substances.
The common ground of above two IV crystal formation preparation methods is other crystal formations by Vilazodone Hydrochloride, through different temperatures
Under the conditions of vacuum drying turn brilliant and obtain, this is very easy to the generation for causing mixed crystal phenomenon, and related IV crystal formations preparation technology compares
It is complicated.Such as：Original grinds V crystalline substances and obtains IV crystalline substances in 85-90 DEG C of vacuum drying, and it is well known that the crystalline substance that turns under solid state has bag
It is rolled in the situation generation for not exclusively turning brilliant in particle.Meanwhile it is claimed in above-mentioned patent application document containing IV crystalline substances and V crystalline substances
Composition or mixture, the mol ratio of the two are about 100 to 1 to 10 to 1.
In the prior art, preparation method brilliant the Vilazodone Hydrochloride IV of Merck Patent GmbH's application, brilliant in IV
Aqueous hydrochloric acid has been used in preparation process, the crystallization from water, Vilazodone Hydrochloride water content will have been caused high, through research, High water cut
The dissolution rate measured for Vilazodone Hydrochloride piece generates adverse effect, reduces the stability, bioavilability and treatment of medicine
Effect.
Therefore it is badly in need of a kind of brilliant preparation methods of new Vilazodone Hydrochloride IV, overcomes Vilazodone Hydrochloride in the prior art
The defects of IV is brilliant and mixed crystal is given birth in V trichites, and caused Vilazodone Hydrochloride water content has a negative impact to preparation dissolution rate.
The content of the invention
In order to solve the above-mentioned technical problem of prior art, brilliant the invention provides a kind of new Vilazodone Hydrochloride IV
Preparation method, this method is simple, convenient, unexpectedly solves IV crystalline substances in the prior art and passes through lower turn of other crystal formation solid-states
Mixed crystal phenomenon caused by crystalline substance, avoid the generation of mixture；The Vilazodone Hydrochloride IV grain sizes of generation are suitable, residual solvent
It is qualified, and water content is low, be advantageous to the crystal formation stablized and improve the dissolution situation of formulation products, draw gratifying
In Vitro Dissolution curve, medicine stability, bioavilability and curative effect can be lifted.
It is an object of the invention to provide the preparation method that a kind of Vilazodone Hydrochloride IV is brilliant, the preparation method comprises the following steps：
（1）1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added into isopropyl
In alcohol, filtered after being heated to reflux；
（2）The aqueous isopropanol containing 5% ~ 35% hydrogen chloride is added dropwise into filtrate；
（3）Flow back, filter after being added dropwise, drying obtains IV crystalline substances.
In above-mentioned preparation method, by by 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzo furan
Mutter -5- bases)-piperazine dissolved is in isopropanol solvent, using the aqueous isopropanol containing 5% ~ 35% hydrogen chloride, in water-free condition
Lower generation vilazodone hydrochloride, can directly obtain IV crystalline substances.This method is simple, convenient, does not turn crystalline substance by the way that V crystalline substances or XI are brilliant, especially
The defects of which obviating lower turn of brilliant easy mixed crystal of solid conditions, while water-free environment has been used, the vilazodone salt of generation
Hydrochlorate water content is low, is advantageous to the crystal formation stablized, and improves the stripping curve of formulation products, for medicine stability, life
Thing availability, curative effect are lifted.
Inventor has found simultaneously, in the aqueous isopropanol for the containing hydrogen chloride being added dropwise in reaction, the concentration pair of institute's containing hydrogen chloride
There is considerable influence in reaction system.If isopropanol solution of hydrogen chloride concentration is too low, for example less than 5%, can cause to separate out crystal mistake
Greatly, and part isopropyl alcohol solvent has been wrapped up, has not only caused residual solvent unqualified, it is more difficult to removed by subsequently drying, and not
The raw material granularity needed for follow-up preparation can be reached, cause dissolution rate unqualified, now need subsequently to crush raw material, increase behaviour
Make cost, and easily cause contamination of products.And the aqueous isopropanol of 5% ~ 35% hydrogen chloride is used, it can solve the above problems substantially.
Preferably, in step 1）In, isopropanol and 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzene
And furans -5- bases)-piperazine volume/mass ratio（ml/g）For 50 ~ 150；Wherein it is more preferably 70 ~ 100.
By the exploration of inventor, find isopropanol and 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls -
Benzofuran -5- bases)-piperazine volume/mass ratio（ml/g）Purity for reaction yield and vilazodone hydrochloride and have
Closing material situation has considerable influence.By continuous exploration discovery, the volume/mass ratio（ml/g）Preferably in 50 ~ 150,
Most preferably 70 ~ 100, avoid vilazodone free alkali during the course of the reaction, separated out from reaction system, will improve reaction yield and
The purity of final products, prepare qualified final products.
Preferably, in step 1）In, the time is heated to reflux as 0.5 ~ 2 hour, and it is small for 0.5 ~ 1 to be more preferably heated to reflux the time
When, after filtering, filtrate is heated to 50 ~ 75 DEG C, the filtrate is more preferably heated to 65 ~ 75 DEG C.
1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added into isopropyl
In alcohol, the time being heated to reflux is controlled, it is ensured that it is completely dissolved in isopropanol, less than 0.5 hour, is easily dissolved endless
Entirely, the waste that will also result in cost more than 2 hours；After filtering out insoluble matter, filtrate is heated to specific temperature, can be kept
Vilazodone free alkali continues to be dissolved in filtrate.
Preferably, in step 2）In, the aqueous isopropanol of containing hydrogen chloride, concentration is 10% ~ 15%.
The aqueous isopropanol of the common hydrogen chloride of in the market, concentration are about 25 ~ 35%, about 6.85 ~ 9.60N.By
Inventor furthers investigate, it is found that concentration is more than 15%, titrating solution usage amount will be greatly decreased, and product granularity is smaller, but can make
It is too fast into crystallization, isopropanol parcel is also easily produced, on the one hand more difficult control rate of titration, on the other hand causes product granularity not
Homogeneous, therefore inventor will use after commercially available isopropanol solution of hydrogen chloride dilution, optium concentration during use is 10% ~ 15%.
Preferably, in step 2）In, dropwise addition process maintains the temperature at 50 ~ 75 DEG C, preferably 65 ~ 75 DEG C.
, it is necessary to control dropping temperature during the aqueous isopropanol of containing hydrogen chloride is added dropwise, suitable dropping temperature, a side
Face ensure that reaction speed；On the other hand it ensure that unreacted 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- ammonia first
Acyl-benzofuran -5- bases)-piperazine dissolved in isopropanol, be advantageous to reaction progress, will not be same with vilazodone hydrochloride
When separate out, influence product purity；3rd, through research, the speed of separating out of vilazodone hydrochloride is appropriate at this temperature, crystallization
Grain suitable size, wraps up less isopropanol solvent so that purity, granularity and the residual solvent amount of final products meet preparation
Preparing needs.
Preferably, in step 2）In, dropwise addition process continues 0.2 ~ 2 hour, more preferably 0.5 ~ 1 hour.
Likewise, the duration of the process of dropwise addition also influences whether crystallization speed, product granularity and residual solvent levels etc..
Rate of addition is too fast, easily produces isopropanol parcel, causes product granularity heterogeneity；Rate of addition easily caused more than 1 hour
Product granularity is excessive, and residual solvent is unqualified, and influences the In Vitro Dissolution of follow-up preparation, it is necessary to IV crystalline substance products to being prepared
Crushing operation is carried out, suitable time for adding may further ensure that the brilliant final masss of Vilazodone Hydrochloride IV.
Preferably, in step 3）In, flowed back after being added dropwise 1.5 ~ 6 hours, more preferably 2 ~ 4 hours, in 80- after filtering
100 DEG C, under vacuum -0.09~-0.1Mpa, dry 10 ~ 25 hours, more preferably 12 ~ 18 hours.
Flowed back after being added dropwise 1.5 ~ 6 hours, more preferably 2 ~ 4 hours, can make it that reaction is complete, ensure final products
Purity；Certain drying temperature and drying time, it is ensured that vilazodone hydrochloride IV is brilliant with suitable water content and residual
Solvent is stayed, so as to be advantageous to the crystal formation stablized and improve the dissolution situation of follow-up preparation, obtains gratifying stripping curve.
Preferably, the IV obtained using the preparation method of the present invention is brilliant, and granularity is in 10 ~ 200 μm, preferably D90<It is 50 μm, different
Propanol solvent remains<0.5%.
Study and find during In Vitro Dissolution experiment is carried out to Vilazodone Hydrochloride piece, grain brilliant Vilazodone Hydrochloride IV
The dissolution rate spent for oral tablet produces considerable influence, and Control granularity is in 10 ~ 200 μm, preferably D90<50 μm, isopropanol solvent
Residual<0.5%, the IV obtained using the preparation method of the present invention is brilliant, and granularity is suitable, and dissolvent residual is qualified, is further prepared
Vilazodone Hydrochloride piece can obtain good stripping curve, meet clinical needs.
Brief description of the drawings：
Fig. 1 Vilazodone Hydrochlorides IV is brilliant（07）X diffracting spectrums；
Fig. 2 Vilazodone Hydrochlorides IV is brilliant（02）Granularity collection of illustrative plates；
Fig. 3 Vilazodone Hydrochlorides IV is brilliant（07）Granularity collection of illustrative plates；
Fig. 4 Vilazodone Hydrochlorides IV is brilliant（02）Residual solvent collection of illustrative plates（1）；
Fig. 5 Vilazodone Hydrochlorides IV is brilliant（02）Residual solvent collection of illustrative plates（2）；
Fig. 6 Vilazodone Hydrochlorides IV is brilliant（07）Residual solvent collection of illustrative plates（1）；
Fig. 7 Vilazodone Hydrochlorides IV is brilliant（07）Residual solvent collection of illustrative plates（2）；
Fig. 8 Vilazodone Hydrochlorides IV is brilliant（02）Make the stripping curve of preparation by oneself；
Fig. 9 Vilazodone Hydrochlorides IV is brilliant（07）Make the stripping curve of preparation by oneself.
Embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below.It is pointed out that these embodiments are complete
It is illustrative.The purpose for providing these embodiments is to fully express meaning of the present invention and content, but therefore will not
Limit the invention among described scope of embodiments.
Comparative example 1：Preparation brilliant Vilazodone Hydrochloride IV（01）
To the 32.6g tetra- of 1g 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine
Hydrogen tetrahydrofuran solution adds 2.1g hydrochloric acid（37 weight %）.After stirring, the crystal precipitated is filtered by suction.In room temperature in vacuo
Middle drying obtains 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine to constant weight
Hydrochloride hydrate V is brilliant.
The V crystalline substances prepared are dried in 85 to 90 DEG C of vacuum to constant weight, obtain 1- [4- (5- cyanoindole -3- bases) butyl] -
4- (2- carbamyls-benzofuran -5- bases)-piperazine hydrochloride IV crystalline substance 0.9g, product purity（Noncrystal purity）It is 95.20%, receives
Rate 83.13%.
Comparative example 2：Preparation brilliant Vilazodone Hydrochloride IV（02）
44g 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added to
In 1500ml isopropanols, it is heated to flowing back, backflow is filtered while hot after 20 minutes, and it is molten that the isopropanol containing 4% hydrogen chloride is added dropwise at room temperature
Liquid 92ml, keeping temperature is 45 DEG C during dropwise addition, continues 1.5 hours, is heated to flowing back after being added dropwise, and is flowed back 2 hours, mistake
Filter, is dried 10 hours, rewinding under the conditions of 80-100 DEG C, vacuum -0.09~-0.1Mpa, and it is brilliant that Vilazodone Hydrochloride IV is made
（01）35.7g, purity are 90.79%, yield 74.95%.
Embodiment 3：Preparation brilliant Vilazodone Hydrochloride IV（03）
44g 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added to
In 2200ml isopropanols, it is heated to flowing back, backflow is filtered while hot after 2 hours, filtrate is heated into 50 DEG C, dropwise addition contains 5% hydrogen chloride
Aqueous isopropanol 73ml, during dropwise addition keeping temperature be 50 DEG C, continue 2 hours, be heated to flowing back after being added dropwise, flow back
1.5 hours, filtering, dried 10 hours under the conditions of 80-100 DEG C, vacuum -0.09~-0.1Mpa, rewinding, hydrochloric acid dimension is made
Draw assistant ketone IV brilliant（01）41.0g, purity are 96.55%, yield 86.07%.
Embodiment 4：Preparation brilliant Vilazodone Hydrochloride IV（04）
44g 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added to
In 3080ml isopropanols, it is heated to flowing back, backflow is filtered while hot after 0.5 hour, filtrate is heated into 65 DEG C, dropwise addition contains 10% chlorine
Change the aqueous isopropanol 36.5ml of hydrogen, keeping temperature is 65 DEG C during dropwise addition, continues 1 hour, is heated to back after being added dropwise
Stream, flow back 2 hours, filtering, dried 12 hours under the conditions of 80-100 DEG C, vacuum -0.09~-0.1Mpa, rewinding, salt is made
Sour vilazodone IV is brilliant（02）43.5g, purity are 98.23%, yield 91.32%.
Embodiment 5：Preparation brilliant Vilazodone Hydrochloride IV（05）
44g 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added to
In 4400ml isopropanols, it is heated to flowing back, backflow is filtered while hot after 0.5 hour, filtrate is heated into 75 DEG C, dropwise addition contains 15% chlorine
Change the aqueous isopropanol 24.3ml of hydrogen, keeping temperature is 75 DEG C during dropwise addition, holds 0.5 hour, is heated to back after being added dropwise
Stream, flow back 4 hours, filtering, dried 18 hours under the conditions of 80-100 DEG C, vacuum -0.09~-0.1Mpa, rewinding, salt is made
Sour vilazodone IV is brilliant（03）44.8g, purity are 99.46%, yield 94.05%.
Embodiment 6：Preparation brilliant Vilazodone Hydrochloride IV（06）
44g 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added to
In 6600ml isopropanols, it is heated to flowing back, backflow is filtered while hot after 1 hour, filtrate is heated into 65 DEG C, dropwise addition contains 35% chlorination
The aqueous isopropanol 10.4ml of hydrogen, keeping temperature is 65 DEG C during dropwise addition, continues 0.2 hour, is heated to back after being added dropwise
Stream, flow back 6 hours, filtering, dried 25 hours under the conditions of 80-100 DEG C, vacuum -0.09~-0.1Mpa, rewinding, salt is made
Sour vilazodone IV is brilliant（04）42.0g, purity are 97.89%, yield 88.17%.
Embodiment 7：Preparation brilliant Vilazodone Hydrochloride IV（07）
4.4kg 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added to
In 308L isopropanols, it is heated to flowing back, backflow is filtered while hot after 1 hour, filtrate is heated into 75 DEG C, dropwise addition contains 15% hydrogen chloride
Aqueous isopropanol 2.43L, during dropwise addition keeping temperature be 75 DEG C, continue 1 hour, be heated to flowing back after being added dropwise, return
Stream 2 hours, filtering, is dried 12 hours, rewinding under the conditions of 80-100 DEG C, vacuum -0.09~-0.1Mpa, and hydrochloric acid dimension is made
Draw assistant ketone IV brilliant（05）4.40kg, purity are 99.03%, yield 92.37%.
Embodiment 8：Vilazodone Hydrochloride IV is brilliant（07）Crystal formation data
Vilazodone Hydrochloride IV is brilliant（07）X diffracting spectrums refer to accompanying drawing 1, crystal formation data are as shown in the table.
The Vilazodone Hydrochloride IV of table 1 is brilliant（05）Crystal formation data
Embodiment 9：Vilazodone Hydrochloride IV is brilliant（02）Moisture, granularity and residual solvent
1st, Vilazodone Hydrochloride IV is brilliant（02）Moisture, exemplified by 160928 batches, loss on drying：0.31%.
2nd, Vilazodone Hydrochloride IV is brilliant（02）Granularity（See accompanying drawing 2）
D90=58.71μm > 50μm。
3rd, Vilazodone Hydrochloride IV is brilliant（02）Residual solvent（See accompanying drawing 4,5）
Weighing this product sample about 0.2g, in top set empty bottle, precision adds dimethyl sulfoxide (DMSO) 2ml, sealing, and shaking makes dissolving, as
Need testing solution.Separately take methanol, ethanol, 2 cbloropropane isopropyl chloride, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene, N, N- diformazans
Base formamide is appropriate, accurately weighed, is quantitatively diluted with dimethyl sulfoxide (DMSO) and reference substance solution is made.Wherein, it is every in reference substance solution
1ml μ g containing isopropanol about 500.According to residual solvent determination method（The method of four general rules of Chinese Pharmacopoeia version in 2015 0861 second）Experiment.
Take in reference substance solution head space injection gas chromatograph, peak sequence is followed successively by methanol, ethanol, 2 cbloropropane isopropyl chloride, third
Ketone, isopropanol, dichloromethane, tetrahydrofuran, toluene, DMF, dimethyl sulfoxide (DMSO), respectively into point between swarming
It all should be met the requirements from degree.Take need testing solution and reference substance solution to distinguish head space injection gas chromatograph again, record chromatogram.
It is required that 0.5% must not be crossed by external standard method with calculated by peak area, isopropanol.
Actual Vilazodone Hydrochloride IV is brilliant（02）Exemplified by 160928 batches, sample isopropanol content is about residual solvent
1.10%, be above standard limit（0.5%）, it is as shown in the table：
The Vilazodone Hydrochloride IV of table 2 is brilliant（02）Residual solvent
Embodiment 10：Vilazodone Hydrochloride IV is brilliant（07）Moisture, granularity and residual solvent
1st, Vilazodone Hydrochloride IV is brilliant（07）Moisture, by taking R160907 crowd as an example, loss on drying：0.17%.
2nd, Vilazodone Hydrochloride IV is brilliant（07）Granularity（See accompanying drawing 3）
D90=42.30μm < 50μm。
3rd, Vilazodone Hydrochloride IV is brilliant（07）Residual solvent（See accompanying drawing 6,7）
Weighing this product sample about 0.2g, in top set empty bottle, precision adds dimethyl sulfoxide (DMSO) 2ml, sealing, and shaking makes dissolving, as
Need testing solution.Separately take methanol, ethanol, 2 cbloropropane isopropyl chloride, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene, N, N- diformazans
Base formamide is appropriate, accurately weighed, is quantitatively diluted with dimethyl sulfoxide (DMSO) and reference substance solution is made.Wherein, it is every in reference substance solution
1ml μ g containing isopropanol about 500.According to residual solvent determination method（The method of four general rules of Chinese Pharmacopoeia version in 2015 0861 second）Experiment.
Take in reference substance solution head space injection gas chromatograph, peak sequence is followed successively by methanol, ethanol, 2 cbloropropane isopropyl chloride, third
Ketone, isopropanol, dichloromethane, tetrahydrofuran, toluene, DMF, dimethyl sulfoxide (DMSO), respectively into point between swarming
It all should be met the requirements from degree.Take need testing solution and reference substance solution to distinguish head space injection gas chromatograph again, record chromatogram.
It is required that 0.5% must not be crossed by external standard method with calculated by peak area, isopropanol.
Actual Vilazodone Hydrochloride IV is brilliant（07）Exemplified by R160907 batches, sample isopropanol content is residual solvent
0.44%, less than the limit that is above standard（0.5%）, it is as shown in the table：
The Vilazodone Hydrochloride IV of table 3 is brilliant（07）Residual solvent
Comparative example 11：Vilazodone Hydrochloride IV is brilliant（02）The stripping curve of the tablet of preparation
Vilazodone Hydrochloride IV is brilliant（02）, lot number 160928, homemade tablet（Make preparation by oneself）, lot number 1611108.Self-control is made
Agent 1611108 carries out In Vitro Dissolution experiment, dissolution medium：PH4.0 buffer solutions.
The Vilazodone Hydrochloride IV of table 4 is brilliant（02）Accumulation dissolution rate
Make the stripping curve of preparation and reference preparation by oneself, see accompanying drawing 8.
It can be seen that from upper table and accompanying drawing 8, it is brilliant by Vilazodone Hydrochloride IV（02）, lot number 160928, homemade tablet
（Make preparation by oneself）, lot number 1611108, the cumulative in vitro dissolution rate in pH4.0 buffer solutions is compared with original grinds reference preparation, each
There is larger gap at time point, visible by accompanying drawing, and both stripping curves can not be fitted, and imply that both internal Dissolution behaviours
There to be very big difference, and then produce the difference of bioavilability and curative effect.
Embodiment 12：Vilazodone Hydrochloride IV is brilliant（07）The stripping curve of the tablet of preparation
Vilazodone Hydrochloride IV is brilliant（07）, lot number R160907, homemade tablet（Make preparation by oneself）, lot number 171026.Self-control is made
Agent 171026 carries out In Vitro Dissolution experiment, dissolution medium：PH4.0 buffer solutions.
The Vilazodone Hydrochloride IV of table 5 is brilliant（07）Accumulation dissolution rate
Make the stripping curve of preparation and reference preparation by oneself, see accompanying drawing 9.
It can be seen that from upper table and accompanying drawing 9, it is brilliant by Vilazodone Hydrochloride IV（07）, lot number R160907, homemade tablet
（Make preparation by oneself）, lot number 171026, the cumulative in vitro dissolution rate in pH4.0 buffer solutions is compared with original grinds reference preparation, when each
Between put equal difference very little, can be fitted by both visible stripping curves of accompanying drawing, imply that both Dissolution behaviours in vivo can
Can there is no difference, the bioavilability and curative effect and original of this self-control preparation are ground more close.
It should be noted that foregoing invention content and embodiment are intended to prove technical scheme provided by the present invention
Practical application, it should not be construed as limiting the scope of the present invention.Those skilled in the art are in spirit and principles of the present invention
It is interior, when can various modifications may be made, equivalent substitution or improve.Protection scope of the present invention is defined by appended claims.
Claims (8)
1. preparation method brilliant a kind of Vilazodone Hydrochloride IV, it is characterised in that the preparation method comprises the following steps：
（1）1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine is added into isopropyl
In alcohol, filtered after being heated to reflux；
（2）The aqueous isopropanol containing 5% ~ 35% hydrogen chloride is added dropwise into filtrate；
（3）Flow back, filter after being added dropwise, drying obtains IV crystalline substances.
2. preparation method according to claim 1, it is characterised in that in the step 1）In, the isopropanol with it is described
The volume/mass ratio of 1- [4- (5- cyanoindole -3- bases) butyl] -4- (2- carbamyls-benzofuran -5- bases)-piperazine（ml/
g）For 50 ~ 150；Preferably 70 ~ 100.
3. according to the preparation method described in any one of claim 1 or 2 claim, it is characterised in that in the step 1）In,
It is described to be heated to reflux the time as 0.5 ~ 2 hour, it is preferably described to be heated to reflux the time as 0.5 ~ 1 hour, after filtering, by the filter
Liquid is heated to 50 ~ 75 DEG C, and the filtrate preferably is heated into 65 ~ 75 DEG C.
4. preparation method according to claim 1, it is characterised in that in the step 2）In, the containing hydrogen chloride it is different
Propanol solution, concentration are 10% ~ 15%.
5. the preparation method according to claim 1 or 4, it is characterised in that in the step 2）In, the dropwise addition process is protected
Temperature is held at 50 ~ 75 DEG C, preferably 65 ~ 75 DEG C.
6. preparation method according to claim 5, it is characterised in that in the step 2）In, the dropwise addition process continues
0.2 ~ 2 hour, preferably 0.5 ~ 1 hour.
7. preparation method according to claim 1, it is characterised in that in the step 3）In, flow back 1.5 after being added dropwise
~ 6 hours, preferably flow back 2 ~ 4 hours, after filtering under 80-100 DEG C, vacuum -0.09~-0.1Mpa, dry 10 ~ 25 hours,
It is preferred that dry 12 ~ 18 hours.
8. preparation method according to claim 1, it is characterised in that IV that the preparation method obtains is brilliant, granularity 10 ~
200 μm, preferably D90<50 μm, isopropanol solvent residual<0.5%.
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| CN201711163592.9A CN107827878A (en) | 2017-11-21 | 2017-11-21 | A kind of preparation method brilliant Vilazodone Hydrochloride IV |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772368A (en) * | 2012-10-24 | 2014-05-07 | 杭州和泽医药科技有限公司 | Preparation method and application of vilazodone hydrochloride IV crystal |
| WO2015037010A1 (en) * | 2013-09-13 | 2015-03-19 | Symed Labs Limited | Preparation of vilazodone hydrochloride crystalline form iv |
-
2017
- 2017-11-21 CN CN201711163592.9A patent/CN107827878A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772368A (en) * | 2012-10-24 | 2014-05-07 | 杭州和泽医药科技有限公司 | Preparation method and application of vilazodone hydrochloride IV crystal |
| WO2015037010A1 (en) * | 2013-09-13 | 2015-03-19 | Symed Labs Limited | Preparation of vilazodone hydrochloride crystalline form iv |
Non-Patent Citations (1)
| Title |
|---|
| 程青芳等: "盐酸维拉唑酮的合成方法改进", 《中国新药杂志》 * |
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Application publication date: 20180323 |