CN105017233A - Vilazodone hydrochloride crystal as well as preparation method, drug composition and application thereof - Google Patents
Vilazodone hydrochloride crystal as well as preparation method, drug composition and application thereof Download PDFInfo
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- CN105017233A CN105017233A CN201410166341.6A CN201410166341A CN105017233A CN 105017233 A CN105017233 A CN 105017233A CN 201410166341 A CN201410166341 A CN 201410166341A CN 105017233 A CN105017233 A CN 105017233A
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- vilazodone hydrochloride
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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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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention relates to the technical field of chemical synthesis of drugs and provides a vilazodone hydrochloride crystal. An X-ray powder diffraction pattern of the vilazodone hydrochloride crystal comprises X-ray diffraction peaks shown at the following 2theta angles: 18.76+/-0.2 degrees and 23.68+/-0.2 degrees. The vilazodone hydrochloride crystal is a new crystal without water or other solvents and has the advantages of high quality, good solubility, easiness in absorption, stability to temperature, light and humidity after storage for a long term, and the like. A preparation method of the vilazodone hydrochloride crystal has the advantages of simple process, high purity (more than or equal to 99%) and good reproducibility and is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field.Particularly, the present invention relates to a kind of new crystal, particularly a kind of new Vilazodone Hydrochloride crystal, its preparation method, medical composition and its use containing this Vilazodone Hydrochloride crystal.
Background technology
Dysthymia disorders is a kind of because of the disease caused by brain biochemical change; S&S comprises: depressed, to ordinary LOM interest, body weight or appetite noticeable change, insomnia or hypersomnia (drowsiness), be on tenterhooks/pacing (psychomotor agitation), tired increase, have sense of guilt or inferiority complex, slowness of thinking or absent minded etc., severe patient even has self inflicted injury and suicidal impulse.Dysthymia disorders seriously have impact on the happy movable ability of the work of people, sleep, study, diet and enjoyment.
Too low and the receptor hypo-function of the monoamine neurotransmitters such as central norepinephrine (NE), serotonin (5-HT), Dopamine HCL (DA) etc. is all considered to cause depressed reason.Be at first adopt electricity irritation shock therapy to the treatment of dysthymia disorders, but repeatedly use and often can lose curative effect.The current medicine for treating depression mainly contains 3 classes, and a class is tricyclic antidepressant (tricyclicantideprssant, TCA), it can improve the concentration of NE and 5-HT in brain, has become the active placebo of dysthymia disorders, but its onset is slow, with serious adverse reaction, as cardiac toxic; Another kind of thymoleptic are oxidase inhibitor (monoamine oxidase inhibitor, MAOI), and she can delay the degraded of NE and 5-HT in brain, extends the action time of these mediators.The eighties in 20th century, develop again new class thymoleptic---selectivity 5-HT reuptake inhibitor (selectiveserotoninreuptake inhibitor, SSRI), it can suppress presynaptic membrane to the re-uptake of 5-HT, increase the concentration of presynaptic membrane gap 5-HT, improve the excitability of postsynaptic membrane 5-HT1A acceptor, produce antidepressant effect, and it does not affect other neurotransmitter receptors, thus safer.But SSRI curative effect when treating severe depression, not as good as TCA, and stimulates the various hypotypes of 5-HT acceptor, so can produce some relevant untoward reactions because it is non-selection.In same year generation, researchist finds that buspirone has very high affinity to 5-HT1A acceptor, and this finds the development having promoted selectivity 5-HT1A receptor stimulant class thymoleptic.
Vilazodone Hydrochloride (Vilazodone hydrochloride), be developed by Clinical Data company, its molecular formula is C
26h
27n
5o
2.HCl, structural formula is:
Vilazodone Hydrochloride has the new antidepressant of the excitement of 5-HT1A acceptor portion and 5-HT re-uptake suppression dual function.Compare with clinical existing antidepressant drug, Vilazodone Hydrochloride has rapid-action, patient is not had to the features such as sexual dysfunction side effect.In view of the pharmacy value of Vilazodone Hydrochloride, obtain have other determine crystal formation and be applicable to suitability for industrialized production, new crystal that purity is excellent is also important.
Summary of the invention
For this reason, one object of the present invention is to provide a kind of new Vilazodone Hydrochloride crystal, and its quality is high, good stability, and has the extremely important large solubleness of medicine performance curative effect.
Another object of the present invention is to provide the preparation method of described Vilazodone Hydrochloride crystal.
Another object of the present invention is to provide the medical composition and its use containing described Vilazodone Hydrochloride crystal.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
On the one hand, the invention provides a kind of Vilazodone Hydrochloride crystal, the X-ray powder diffraction of described Vilazodone Hydrochloride crystal comprises the X-ray diffraction peak shown in following 2 θ angles: 18.76 ° ± 0.2 ° and 23.68 ° ± 0.2 °.
In the present invention, the X-ray diffraction peak shown in following 2 θ angles is also comprised in the X-ray powder diffraction of described Vilazodone Hydrochloride crystal: 13.12 ° ± 0.2 °, 16.80 ± 0.2 °, 17.86 ± 0.2 °, 19.72 ± 0.2 °, 20.32 ± 0.2 °, 24.54 ± 0.2 °, 25.68 ± 0.2 ° and 27.16 ± 0.2 °.
In the present invention, the X-ray powder diffraction of described Vilazodone Hydrochloride crystal as shown in Figure 1.
On the other hand, the invention provides a kind of method preparing described Vilazodone Hydrochloride crystal, the method comprises the following steps:
(1) vilazodone free alkali is dissolved in tetrahydrofuran (THF), filters, obtain filtrate;
(2) under stirring and 40 ~ 50 DEG C of temperature, in filtrate, drip the mixed solution of dilute hydrochloric acid and tetrahydrofuran (THF), drip and finish stopping heating, be cooled to room temperature, continue stirring 0.5 ~ 1 hour, crystallize out, filter, dry at 80 ~ 100 DEG C after filtration.
In the method for the invention, described vilazodone free alkali is 1:1 ~ 1.5 with the ratio of the amount of substance of dilute hydrochloric acid; Preferably, the concentration of described dilute hydrochloric acid is 0.1 ~ 1mol/L.
In the method for the invention, in the mixed solution of described dilute hydrochloric acid and tetrahydrofuran (THF), dilute hydrochloric acid is 1:3 ~ 10 with the ratio of the weight of tetrahydrofuran (THF).
Again on the one hand, the invention provides a kind of described Vilazodone Hydrochloride crystal and preparing the purposes in anti-depression drug.Such as, can Cure of depression, Serious depression, anxiety disorder, also can be used for treating the disorder of central nervous system, as anxiety, depressed and/or psychosis, the side effect that hypertension (as with methyldopa) causes.
Another aspect, the invention provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises described Vilazodone Hydrochloride crystal; Preferably, described pharmaceutical composition also comprises one or more pharmaceutically acceptable auxiliary materials.
In the present invention, described pharmaceutical composition is tablet or capsule.
In addition, the present invention also provides a kind of described pharmaceutical composition preparing the purposes in anti-depression drug.Such as, can Cure of depression, Serious depression, anxiety disorder, also can be used for treating the disorder of central nervous system, as anxiety, depressed and/or psychosis, the side effect that hypertension (as with methyldopa) causes.
Without being limited by theory, the auxiliary material described in the present invention can be pharmaceutically acceptable any auxiliary material, such as pharmaceutically acceptable thinner, tackiness agent or antiseize paste etc.Wherein, thinner includes but not limited to starch, Microcrystalline Cellulose, PEG-6000, PEG-4000, PEG-4000, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium-chlor or N.F,USP MANNITOL etc.; Described tackiness agent includes but not limited to water, ethanol, starch slurry, syrup, gelatin, methylcellulose gum, Vltra tears, Xylo-Mucine or polyvinylpyrrolidone etc.; Described antiseize paste includes but not limited to Magnesium Stearate, stearic acid, boric acid, sodium-chlor, colloidal silica, sodium oleate etc.;
When applying Vilazodone Hydrochloride crystal of the present invention and the pharmaceutical composition containing it clinically, those skilled in the art can easily determine ideal occlusion pharmaceutical quantities, and the progress along with the concrete Vilazodone Hydrochloride crystal used and the mode of administration of pharmaceutical composition, the concentration of preparation and the disease states that contain it changes by these dosages.In addition, treat age of concrete patient, suitable adjustment that body weight, the factor such as diet and administration time also can cause dosage.
Compared with prior art, the present invention at least has following beneficial effect:
1. Vilazodone Hydrochloride crystal of the present invention is a kind of crystal of not moisture and other solvent newly, and it is high that it has quality, and solubleness is good, is beneficial to absorption, and standing storage is to advantages such as temperature, light, moisture stables;
2. preparation method's technique of the present invention is simple, purity high (more than 99%), favorable reproducibility, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Below, describe embodiments of the invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 is Vilazodone Hydrochloride crystal X-ray powder diffraction;
Fig. 2 is Vilazodone Hydrochloride crystal DSC endothermic transition collection of illustrative plates;
Fig. 3 is Vilazodone Hydrochloride crystal TG-DTA collection of illustrative plates.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
Below in an example, the various process do not described in detail and method are ordinary methods as known in the art.Wherein, room temperature refers to 20 ± 5 DEG C, the preparation of vilazodone free alkali (crude product) see J.Med.Chem.2004,47,4684-4692.
embodiment 1:the preparation of Vilazodone Hydrochloride crystal
Get 1g vilazodone crude free base and 20mL tetrahydrofuran (THF) adds in 100mL four-hole bottle, heating for dissolving, filtered while hot, under stirring and 40 ~ 50 DEG C of temperature, drip the mixed solution of dilute hydrochloric acid (1N, 3.5g) and tetrahydrofuran (THF) (35g), about drip 30 minutes, drip to finish and stop heating, be slowly down to room temperature (namely naturally cooling to room temperature, lower same), continue stirring 30 minutes, crystallize out, dry at 80 ~ 100 DEG C after filtration, to obtain final product.Measure through HPLC method, purity is greater than 99%.
embodiment 2:the preparation of Vilazodone Hydrochloride crystal
Get 1g vilazodone crude free base and 10mL tetrahydrofuran (THF) adds in 100mL four-hole bottle, reflux is dissolved, filtered while hot, keep reflux temperature also under agitation, drip the mixed solution of dilute hydrochloric acid (0.1N, 23g) and tetrahydrofuran (THF) (69g), about drip 45 minutes, drip to finish and stop heating, slowly be down to room temperature, continue stirring 40 minutes, crystallize out, dry at 80 ~ 100 DEG C after filtration, to obtain final product.Measure through HPLC method, purity is greater than 99%.
embodiment 3:the preparation of Vilazodone Hydrochloride crystal
Get 1g vilazodone crude free base and 10mL tetrahydrofuran (THF) adds in 100mL four-hole bottle, reflux is dissolved, filtered while hot, keeps reflux temperature also under agitation, drip dilute hydrochloric acid (0.5N, 12g) and the mixed solution of tetrahydrofuran (THF) (60g), about drip 45 minutes, drip to finish and stop heating, slowly be down to room temperature, continue stirring 60 minutes, crystallize out, dry at 80 ~ 100 DEG C after filtration.Measure through HPLC method, purity is greater than 99%.
embodiment 4:the preparation of hydrochloric vilazodone crystal tablet
Obtained for above-described embodiment 1 to 3 Vilazodone Hydrochloride crystal 10g, Spherolac 100 40g, Microcrystalline Cellulose 12g, Magnesium Stearate 2g and colloidal silica 1g are mixed, add appropriate distilled water to granulate, dry, Conventional compression, film coating, make 1000, every sheet is containing 10mg activeconstituents.
embodiment 5:the preparation of hydrochloric vilazodone crystal capsule
Obtained for above-described embodiment 1 to 3 Vilazodone Hydrochloride crystal 20g, Microcrystalline Cellulose 30g lactose 160g, Magnesium Stearate 12g, croscarmellose sodium 40g and talcum powder 10g are mixed, add appropriate distilled water to granulate, dry, be packed into hard gelatin capsule, make 1000 capsules, every containing 20mg activeconstituents.
embodiment 9:the X-ray powder diffraction of Vilazodone Hydrochloride crystal characterizes
Use Rigaku D/Max-2500X x ray diffractometer x (CuK
αradiation) the Vilazodone Hydrochloride crystal that above embodiment 1 to 3 obtains is characterized, concrete experiment parameter arranges as follows: sweep limit 2 θ=2 ~ 40 DEG C, uses
copper radioactive source, limit of error is ± 0.2 °, pipe pressure 40KV, pipe stream 100mA, filter disc is graphite monochromatic sheet, obtain X-ray diffractogram, as shown in Figure 1; Concrete X-ray diffraction peak data is shown in Table 1.
The main X-ray diffraction peak of table 1 Vilazodone Hydrochloride crystal
| Peak number | 2 θ angles | Peak relative intensity (%) | Peak number | 2 θ angles | Peak relative intensity (%) |
| 1 | 13.12 | 29 | 6 | 20.32 | 50 |
| 2 | 16.80 | 29 | 7 | 23.68 | 100 |
| 3 | 17.86 | 34 | 8 | 24.54 | 32 |
| 4 | 18.76 | 62 | 9 | 25.68 | 21 |
| 5 | 19.72 | 30 | 10 | 27.16 | 52 |
embodiment 10:the DSC of Vilazodone Hydrochloride crystal characterizes
The Vilazodone Hydrochloride crystal using the DCC822e/500 differential scanning calorimeter of Switzerland METTLER-TOLEDO obtained to above embodiment 1 to 3 characterizes, concrete experiment parameter arranges as follows: sample 5.54mg, temperature range 200-350 DEG C, temperature rise rate 10 DEG C/min.Characterization result as shown in Figure 2.
embodiment 11:the TG-DTA of Vilazodone Hydrochloride crystal characterizes
The Vilazodone Hydrochloride crystal using the TGA/DSC1LF/1277 analyser of Switzerland METTLER-TOLEDO obtained to above embodiment 1 to 3 characterizes, and concrete experiment parameter arranges as follows: sample size: 7.3mg; Temperature range: 60-310 DEG C; Temperature rise rate: 10 DEG C/min; Characterization result as shown in Figure 3.
embodiment 12:the study on the stability of Vilazodone Hydrochloride crystal
1, high temperature experiment
Experimental technique: Vilazodone Hydrochloride crystal obtained for embodiment 1 to 3 is placed in uncovered crystallizing dish, is placed in 80 DEG C of thermostat containers, respectively at sampling in 5,10 days, observes outward appearance, and measures related substance and the change of Vilazodone Hydrochloride crystalline content.Experimental result is in table 2.
Table 2 Vilazodone Hydrochloride crystal 80 DEG C of thermal-stable experimental results
| Storage period | Outward appearance | Content (%) | Related substance (%) |
| 0 day | Off-white color crystalline powder | 99.43 | 0.040 |
| 5 days | Off-white color crystalline powder | 99.66 | 0.042 |
| 10 days | Off-white color crystalline powder | 100.17 | 0.041 |
2, illumination experiment
Experimental technique: crystal obtained for embodiment 1 to 3 is placed in uncovered crystallizing dish, under 4500 ± 500 lux illumination, observes outward appearance respectively at sampling in 5,10 days, and measures the change of related substance (total impurities) and Vilazodone Hydrochloride crystalline content.Wherein measure and adopt high performance liquid chromatography, actual conditions comprises: chromatographic column: enlightening horse C18 post, long 250 millimeters, column temperature 25 DEG C; Determined wavelength 280 nanometer, moving phase: 0.1% trifluoroacetic acid aqueous solution: methyl alcohol=35:65, flow velocity 1.0 ml/min.Experimental result is in table 3.
Table 3 Vilazodone Hydrochloride crystal is to the stability test result of light
| Storage period | Outward appearance | Content (%) | Related substance (%) |
| 0 day | Off-white color crystalline powder | 99.43 | 0.040 |
| 5 days | Off-white color crystalline powder | 99.52 | 0.039 |
| 10 days | Off-white color crystalline powder | 99.70 | 0.042 |
3, high humidity experiment
Experimental technique: the Vilazodone Hydrochloride crystal that embodiment 1 to 3 is obtained is placed in RH92.5% ± 5%(containing the saturated KNO3 aqueous solution) moisture eliminator in, under putting 25 DEG C of conditions, respectively at sampling in 5,10 days, observe outward appearance, measure related substance and Vilazodone Hydrochloride crystalline content.Experimental result is in table 4.
The stability test result of table 4 Vilazodone Hydrochloride crystal relative humidity 92.5%
| Storage period | Outward appearance | Content (%) | Related substance (%) |
| 0 day | Off-white color crystalline powder | 99.43 | 0.040 |
| 5 days | Off-white color crystalline powder | 99.39 | 0.037 |
| 10 days | Off-white color crystalline powder | 99.05 | 0.046 |
Above-mentioned experimental result shows, Vilazodone Hydrochloride crystal of the present invention has outstanding stability under high temperature, illumination and super-humid conditions, storage that can be steady in a long-term.
embodiment 13:antidepressant activity and solubleness test
At behavior despair animal depression model Tail suspension test: get mouse random packet, often organize 10, be divided into Vilazodone Hydrochloride crystal group (8mg/kg, ip) that saline control group and embodiment 1 to 3 obtain, 60min administration before experiment.Experiment starts that mouse tail is about 2cm place clip apart from end and fixes, and make it hang upside down in the case of 20cm × 25cm × 25cm, head is about 5cm apart from case bottom surface.Hang 6min altogether to observe, the dead time after accumulative in 4min.Test result sees the following form:
| Group | The outstanding tail dead time |
| Saline control group | 98.7 ± 35.9 seconds |
| Crystal formation of the present invention | 29.5 ± 20.6 seconds |
The dead time of mouse shortens as seen from the above table.This shows, Vilazodone Hydrochloride crystal of the present invention has the medicine that antidepressant activity can be used for manufacturing Cure of depression.
Measure the solubleness (representing with μ g/mL) of the obtained Vilazodone Hydrochloride crystal of the embodiment of the present invention 1 to 3 according to the solubility test method of the Chinese Pharmacopoeia note on the use, measurement result is 0.36.
Although present invention has been detailed description; but should be appreciated that foregoing description and be not used to limit the present invention, without departing from the spirit and scope of the present invention; any amendment of doing, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. a Vilazodone Hydrochloride crystal, is characterized in that, the X-ray powder diffraction of described Vilazodone Hydrochloride crystal comprises the X-ray diffraction peak shown in following 2 θ angles: 18.76 ° ± 0.2 ° and 23.68 ° ± 0.2 °.
2. Vilazodone Hydrochloride crystal according to claim 1, it is characterized in that, also comprise the X-ray diffraction peak shown in following 2 θ angles in the X-ray powder diffraction of described Vilazodone Hydrochloride crystal: 13.12 ° ± 0.2 °, 16.80 ± 0.2 °, 17.86 ± 0.2 °, 19.72 ± 0.2 °, 20.32 ± 0.2 °, 24.54 ± 0.2 °, 25.68 ± 0.2 ° and 27.16 ± 0.2 °.
3. Vilazodone Hydrochloride crystal according to claim 1 and 2, is characterized in that, the X-ray powder diffraction of described Vilazodone Hydrochloride crystal as shown in Figure 1.
4. prepare a method for the Vilazodone Hydrochloride crystal according to any one of claims 1 to 3, the method comprises the following steps:
(1) vilazodone free alkali is dissolved in tetrahydrofuran (THF), filters, obtain filtrate;
(2) under stirring and 40 ~ 50 DEG C of temperature, in filtrate, drip the mixed solution of dilute hydrochloric acid and tetrahydrofuran (THF), drip and finish stopping heating, be cooled to room temperature, continue stirring 0.5 ~ 1 hour, crystallize out, dry at 80 ~ 100 DEG C after filtration.
5. method according to claim 4, is characterized in that, described vilazodone free alkali is 1:1 ~ 1.5 with the ratio of the amount of substance of dilute hydrochloric acid; Preferably, the concentration of described dilute hydrochloric acid is 0.1 ~ 1mol/L.
6. the method according to claim 4 or 5, is characterized in that, in the mixed solution of described dilute hydrochloric acid and tetrahydrofuran (THF), dilute hydrochloric acid is 1:3 ~ 10 with the ratio of the weight of tetrahydrofuran (THF).
7. the Vilazodone Hydrochloride crystal according to any one of a claims 1 to 3 is preparing the purposes in anti-depression drug.
8. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises the Vilazodone Hydrochloride crystal according to any one of claims 1 to 3; Preferably, described pharmaceutical composition also comprises one or more pharmaceutically acceptable auxiliary materials.
9. pharmaceutical composition according to claim 8, is characterized in that, described pharmaceutical composition is tablet.
10. the pharmaceutical composition described in a claim 8 or 9 is preparing the purposes in anti-depression drug.
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Application publication date: 20151104 |