CN102372673A - Blonanserin crystallization and preparation method thereof - Google Patents
Blonanserin crystallization and preparation method thereof Download PDFInfo
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Abstract
The invention provides a 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-hexahydrocycloocta [b] pyridine (Blonanserin) crystallization and a preparation method thereof. The method includes the following steps: 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5, 6, 7, 8, 9, 10-hexahydrocycloocta [b] pyridine (Blonanserin) is heated to be dissolved in the mixture of ethanol, n-butyl alcohol, tertiary butanol, isobutyl alcohol, petroleum ether, butyl acetate, ethanol and isopropanol, and the Blonanserin crystallization is then obtained by way of recrystallization. The Blonanserin crystallization prepared by the method is safe, low in toxicity and stable for light, wet and heat, and is convenient to produce and store. Meanwhile, the invention also provides a drug combination containing the Blonanserin crystallization as an antipsychotic drug.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen cycloocta-[b] pyridine (blonanserin, Blonanserin) crystalline preparing methods.
Background technology
Blonanserin has a chemical structure of innovation fully as the anti-schizophrenia medicine of a new generation, the clinical psychosis that is used for, and tool Dopamine HCL and 5-hydroxytryptamine receptor dual antagonist are active, and the untoward reaction rate is low than other positive drug.Clinical study shows that these article all have quite or better therapeutic with respect to haloperidol that has gone on the market and risperidone, lower adverse reaction rate.
Blonanserin (Blonanserin), chemistry 2-(4-ethyl-1-piperazinyl) by name-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen cycloocta-[b] pyridines, chemical structural formula:
Summary of the invention
The object of the present invention is to provide a kind of blonanserin 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen cycloocta-[b] pyridine crystallizations, the clinical psychosis that is used for is treated.
Another object of the present invention is to provide the blonanserin crystalline preparation method that is fit to suitability for industrialized production.
A further object of the present invention is to provide and contains blonanserin crystalline pharmaceutical composition.For realizing above-mentioned purpose, the present invention provided following technical scheme:
A kind of blonanserin crystallization is characterized in that using the Cu-Ka radiation, to spend X-ray powder diffraction spectrum that 2 θ represent 7.78 ± 0.2,9.92 ± 0.2,10.70 ± 0.2,12.00 ± 0.2; 13.04 ± 0.2,15.68 ± 0.2,16.08 ± 0.2,17.52 ± 0.2,18.04 ± 0.2,18.50 ± 0.2; 18.74 ± 0.2,19.18 ± 0.2,19.72 ± 0.2,20.10 ± 0.2,20.56 ± 0.2; 21.00 ± 0.2,22.70 ± 0.2,24.68 ± 0.2,25.28 ± 0.2,25.96 ± 0.2; 27.28 ± 0.2,25.92 ± 0.2,30.74 ± 0.2,31.74 ± 0.2,36.42 ± 0.2 have characteristic peak; Infrared absorption pattern is at 2919 ± 5cm
1, 2822 ± 5cm
1, 1585 ± 5cm
1, 1507 ± 5cm
-1There is absorption peak at the place; Its DSC endothermic transition is at 124 ℃.
Blonanserin crystallization of the present invention, its X-ray powder diffraction 2 θ positions 19.18 ± 0.2 place's diffraction intensities are 100%.
The invention discloses blonanserin crystalline preparation method, it is characterized in that: with the blonanserin dissolving crude product in organic solvent, after treating to dissolve fully; Slowly be cooled to 23-27 ℃ again, be incubated 90-100 minute, reduce to-9 to-5 ℃; Be incubated 3～5 hours; Filter, heat drying obtains same blonanserin crystal to constant weight; Wherein said organic solvent comprises: (1) ethanol, propyl carbinol, the trimethyl carbinol, isopropylcarbinol, sherwood oil or butylacetate single solvent;
(2) mixed solvent of ethanol and Virahol.
Wherein the mixed solvent consumption of the single solvent of (1) or (2) is 1.5～30 times of ml/g of blonanserin bullion.Preferably the mixed solvent consumption of the single solvent of (1) or (2) be the blonanserin bullion 5～10 times of ml/g, particularly ethanol and the ratio of weight and number of isopropyl alcohol mixed solvent be 0.5: 1～2: 1.
Of the present invention being dissolved in the organic solvent refers to: 40 ℃ of heating for dissolving to the reflux temperature of solvent.
The inventor is through a large amount of experiments; Selected multiple safety, low toxicity, acceptable for pharmaceutical solvent, all can obtain blonanserin crystal formation of the present invention through recrystallization method as adopting ethanol, propyl carbinol, the trimethyl carbinol, isopropylcarbinol, sherwood oil, butylacetate single solvent.Further adopt the mixed solvent of ethanol and Virahol, its ratio is 0.5: 1～2: 1.Also can obtain blonanserin crystal formation of the present invention through recrystallization method.
The process of recrystallization comprises: with 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7; 8,9,10-six hydrogen cycloocta-[b] pyridine (blonanserins; Blonanserin) in the mixed solvent of ethanol, propyl carbinol, the trimethyl carbinol, isopropylcarbinol, sherwood oil or butylacetate single solvent or ethanol and Virahol, heat, after treating to dissolve fully, slowly be cooled to 25 ± 2 ℃ again; Be incubated 90 minutes, reduce to-7 ± 2 ℃ of insulations 3～5 hours, filter; Heat drying obtains the crystal formation with a kind of blonanserin to constant weight.
Blonanserin (Blonanserin) crystallization of the present invention's preparation has following characteristic:
1.X-ray powder diffraction:
Instrument: Japanese D/max2500 type X-ray diffractometer of science;
Target: 2 θ sweep limit: 0-50 ° of Cu-K a radiation
Step angle: 0.04 ℃
Computing time: 0.5 second
Pipe is pressed: 40KV
Pipe stream: 100mA
Sweep velocity: 8 ℃/min
Filter disc: graphite monochromator
| 2θ | Spacing (d value) | I/I 0 |
| 7.78 | 11.35 | 13 |
| 9.28 | 9.52 | 3 |
| 9.92 | 8.91 | 5 |
| 10.70 | 8.26 | 5 |
| 12.00 | 7.37 | 10 |
| 13.04 | 6.78 | 5 |
| 15.68 | 5.65 | 50 |
| 16.08 | 5.51 | 20 |
| 17.52 | 5.06 | 13 |
| 18.04 | 4.91 | 13 |
| 18.50 | 4.79 | 17 |
| 18.74 | 4.73 | 19 |
| 19.18 | 4.62 | 100 |
| 19.72 | 4.50 | 16 |
| 20.10 | 4.41 | 23 |
| 20.56 | 4.31 | 7 |
| 21.00 | 4.23 | 8 |
| 21.54 | 4.12 | 6 |
| 21.90 | 4.05 | 7 |
| 22.70 | 3.91 | 8 |
| 23.66 | 3.76 | 6 |
| 24.68 | 3.60 | 25 |
| 25.28 | 3.52 | 6 |
| 25.96 | 3.43 | 20 |
| 27.28 | 3.27 | 21 |
| 29.52 | 3.02 | 9 |
| 30.74 | 2.91 | 9 |
| 31.74 | 2.82 | 6 |
| 32.66 | 2.74 | 5 |
| 33.92 | 2.64 | 4 |
| 36.42 | 2.46 | 8 |
| 37.98 | 2.37 | 4 |
| 40.64 | 2.22 | 4 |
| 44.32 | 2.04 | 5 |
2. dsc (DSC):
Instrument: Japanese standard type TG-DTA analyser of science
TR: room temperature～400 ℃
Heat-up rate: 10 ℃/minute
Its endothermic transition of blonanserin is at about 124 ℃.
3. ir spectra (IR):
Instrument: PE-983G IR
Specimen preparation: KBr compressing tablet
The ir spectra wave number of blonanserin (pressing potassium bromide troche) is (cm
-1) be: at about 2919 ± 5cm
-1, 2822 ± 5cm
-1, 1585 ± 5cm
-1, 1507 ± 5cm
-1Characteristic spectrum belt is arranged.
4. fusing point:
Instrument: YTR-3 type fusing point appearance (Precision Instrument Factory, Tianjin Univ.)
The blonanserin crystalline melting point is 124～125 ℃.
Blonanserin physico-chemical property and pharmacodynamic study thereof
One, the stability of blonanserin crystal habit
(1) gets the blonanserin crystallization in weighing bottle, respectively at 60 ℃, 4500 ± 500LX illumination and 92.5% relative humidity held, in sampling in 5 days, 10 days, high effective liquid chromatography for measuring related substance, result such as table 1
Table 1 blonanserin influence factor is measured the result
Conclusion: blonanserin was 60 ℃, 4500 ± 500LX illumination and 92.5% relative humidity held 5,10 days, and related substance is not all seen obvious change, and powdery diffractometry is not seen variation.
(2) slope of repose determination test
For confirming the flowability of this crystal formation compressing tablet powder, measured the slope of repose of three lot sample article powder.Use the 20g powder, in the triangular funne of packing into, powder is fallen naturally, form a conical pile, with its base diameter of vernier caliper measurement, it is high to measure heap with vernier height gauge, calculates its slope of repose, and the result sees the following form 2:
The result is measured at table 2 blonanserin slope of repose
Spend good fluidity by visible these article tablet powder slope of repose of result in the table less than 40.
(3) blonanserin dissolution of crystals degree
Table 3 blonanserin dissolution of crystals degree is measured the result
The part omitted of these article 0.1M hydrochloric acid soln is dissolved, and slightly soluble in methyl alcohol, ethanol is insoluble in water.
Two, the pharmacokinetics behind the oral blonanserin crystal formation of the rat raw material
The invention provides psychotolytic treat-ment, this method be to the patient give with pharmacology on the blonanserin of crystal habit of significant quantity.Pharmacokinetic behind the oral blonanserin crystal formation of the rat raw material shows that blonanserin absorbs at the all-digestive tract except that stomach, and its specific absorption is 80～98%.Behind the blonanserin to rat single oral 10mg/kg, 52% by being drained in bile, about 40% (dosage about 1/5) is absorbed again, is the liver sausage circulation.Visible from medicine for parameter, the Stability Analysis of Structures of crystal formation, absorption in animal body, elimination basically identical.Pharmaceutical composition provided by the invention contains the blonanserin and the pharmaceutically acceptable carrier of crystal habit.
The blonanserin of crystal habit of the present invention is suitable for oral Preparation, comprises fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coated tablet etc. like tablet; Capsule comprises hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.; Granule comprises mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.; Oral solution; Oral suspensions; Syrup or the like.Preparation is during oral solid formulation, can blonanserin crystallization and suitable pharmaceutical excipient processed the particle pack or pack gelatine capsule or compacting in flakes.
Acceptable carrier comprises one or more pharmaceutical excipients on the pharmacology, and for example tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant and lubricant or the like are the auxiliary material commonly used in the preparation.The peroral administration optimised form of this compsn is a tablet.
The positively effect that the blonanserin of crystal habit of the present invention is compared with prior art had is:
(1) 2-provided by the invention (4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7; 8,9,10-six hydrogen cycloocta-[b] pyridine (blonanserins; Blonanserin) preparation of crystal formation, the solvent toxicity of employing is little, the production safe preparation process; Resulting quality product is high, can residual more toxic substance, meet the required standard of SFDA.
(2) the prepared blonanserin crystal of the present invention because intramolecule is ordered arrangement, thereby has increased stability effectively; Also increase simultaneously the solvability of medicine, promoted the absorption of medicine, improved bioavailability.
(3) the prepared blonanserin crystal of the present invention also has good mobile and good preparation performance.To light, wet, thermally-stabilised, be fit to long storage, be more suitable for industrialized production.
Description of drawings
Fig. 1 a, Fig. 1 b are blonanserin (Blonanserin) crystalline X-ray powder diffraction collection of illustrative plates.
Fig. 2 is blonanserin (Blonanserin) crystalline infared spectrum.
Fig. 3 is blonanserin (Blonanserin) crystalline DSC endothermic transition collection of illustrative plates.
Fig. 4 is the mass spectrum (Ms) of blonanserin (Blonanserin).
Fig. 5 be blonanserin (Blonanserin) proton nmr spectra (
1H-NMR).
Specific embodiment
Below in conjunction with embodiment the present invention is done further explanation, make this area professional and technical personnel better understand the present invention.It is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.
Used blonanserin (Blonanserin) among the present invention, i.e. 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen cycloocta-[b] pyridines are that the method that provides according to document EP 385273 is synthetic.The synthetic blonanserin is through mass spectrum (Ms), proton nmr spectra (
1H-NMR) etc. conclusive evidence proves that chemical structure is correct, sees Fig. 4, Fig. 5.
Preparation embodiment
Blonanserin bullion 1g is added ethanol 10ml, be heated to backflow, after treating to dissolve fully, slowly be cooled to 25 ± 2 ℃ again; Be incubated 90 minutes, reduce to-7 ± 2 ℃ of insulations 5 hours, filter; Heat drying obtains blonanserin crystal form samples 0.85g of the present invention to constant weight, and HPLC measures 99.8%.
Blonanserin bullion 1g is added propyl carbinol 15ml, be heated to backflow, after treating to dissolve fully; Slowly be cooled to 25 ± 2 ℃ again, be incubated 90 minutes, reduce to-7 ± 2 ℃ of insulations 3 hours; Filter; Heat drying obtains blonanserin crystal form samples 0.8g of the present invention to constant weight, and HPLC measures 99.6%.
Blonanserin bullion 1g is added trimethyl carbinol 20ml, be heated to backflow, after treating to dissolve fully; Slowly be cooled to 25 ± 2 ℃ again, be incubated 90 minutes, reduce to-7 ± 2 ℃ of insulations 3 hours; Filter; Heat drying obtains blonanserin crystal form samples 0.75g of the present invention to constant weight, and HPLC measures 99.7%.
Blonanserin bullion 1g is added isopropylcarbinol 8ml, be heated to backflow, after treating to dissolve fully, slowly be cooled to 25 ± 2 ℃ again; Be incubated 90 minutes, reduce to-7 ± 2 ℃ of insulations 5 hours, filter; Heat drying obtains blonanserin crystal form samples 0.8g of the present invention to constant weight, and HPLC measures 99.8%.
Blonanserin bullion 1g is added sherwood oil 5ml, be heated to backflow, after treating to dissolve fully; Slowly be cooled to 25 ± 2 ℃ again, be incubated 90 minutes, reduce to-7 ± 2 ℃ of insulations 3 hours; Filter; Heat drying obtains blonanserin crystal form samples 0.86g of the present invention to constant weight, and HPLC measures 99.5%.
Blonanserin bullion 1g is added butylacetate 25ml, be heated to 40 ℃ of dissolvings after, slowly be cooled to 25 ± 2 ℃ again; Be incubated 90 minutes, reduce to-7 ± 2 ℃ of insulations 5 hours, filter; Heat drying obtains blonanserin crystal form samples 0.7g of the present invention to constant weight, and HPLC measures 99.7%.
Blonanserin bullion 1g is added ethanol 5ml and Virahol 5ml; After being heated to dissolving fully, slowly be cooled to 25 ± 2 ℃ again, reduce to-7 ± 2 ℃ again and leave standstill insulation 5 hours; Filter; Heat drying is loss of weight extremely no longer, obtains blonanserin crystal form samples 0.85g of the present invention, and HPLC measures 99.7%.
Blonanserin bullion 1g is added ethanol 5ml and Virahol 10ml; After being heated to dissolving fully, slowly be cooled to 25 ± 2 ℃ again, reduce to-7 ± 2 ℃ again and leave standstill insulation 5 hours; Filter; Heat drying is loss of weight extremely no longer, obtains blonanserin crystal form samples 0.81g of the present invention, and HPLC measures 99.7%.
FORMULATION EXAMPLE
Blonanserin crystallization 4g, Microcrystalline Cellulose 80g, lactose 150g, sodium starch glycolate 5g, Magnesium Stearate 2g, PVPP 5g, micropowder silica gel 2g processes 1000.
Blonanserin crystallization bulk drug is ground, cross 200 mesh sieves, filter, drain, 60 ℃ of dryings, the inspection related substance promptly gets.Get Microcrystalline Cellulose, sodium starch glycolate, lactose, Magnesium Stearate, PVPP, the differential silica gel of recipe quantity and cross 100 mesh sieves; With blonanserin and the mixing of auxiliary material grinding uniformly, cross 60 mesh sieves three times with the stepwise dilution method.It is an amount of to add 60% ethanolic soln, granulates with 20 mesh sieves.Put 60 ℃ of dryings, with the whole grain of 30 mesh sieves, sampling and measuring content and related substance, stator is heavy, and compressing tablet is processed 1000.
Claims (9)
1. a blonanserin crystallization is characterized in that using the Cu-Ka radiation,
To spend X-ray powder diffraction spectrum that 2 θ represent 7.78 ± 0.2,9.92 ± 0.2,10.70 ± 0.2,12.00 ± 0.2,13.04 ± 0.2; 15.68 ± 0.2,16.08 ± 0.2,17.52 ± 0.2,18.04 ± 0.2,18.50 ± 0.2; 18.74 ± 0.2,19.18 ± 0.2,19.72 ± 0.2,20.10 ± 0.2,20.56 ± 0.2; 21.00 ± 0.2,22.70 ± 0.2,24.68 ± 0.2,25.28 ± 0.2,25.96 ± 0.2; 27.28 ± 0.2,25.92 ± 0.2,30.74 ± 0.2,31.74 ± 0.2,36.42 ± 0.2 have characteristic peak; Infrared absorption pattern is at 2919 ± 5cm
-1, 2822 ± 5cm
-1, 1585 ± 5cm
-1, 1507 ± 5cm
-1There is absorption peak at the place; Its DSC endothermic transition is at 124 ℃.
2. the described blonanserin crystallization of claim 1, its described X-ray powder diffraction 2 θ positions 19.18 ± 0.2 place's diffraction intensities are 100%.
3. one kind prepares the said blonanserin crystalline of claim 1 method, it is characterized in that: with the blonanserin dissolving crude product in organic solvent, after treating to dissolve fully; Slowly be cooled to 23-27 ℃ again, be incubated 90-100 minute, reduce to-9 to-5 ℃; Be incubated 3～5 hours; Filter, heat drying obtains same blonanserin crystal to constant weight; Wherein said organic solvent comprises: (1) ethanol, propyl carbinol, the trimethyl carbinol, isopropylcarbinol, sherwood oil or butylacetate single solvent; (2) mixed solvent of ethanol and Virahol.
4. the described preparation method of claim 3, wherein the mixed solvent consumption of the single solvent of (1) or (2) is 1.5～30 times of ml/g of blonanserin bullion.
5. the described preparation method of claim 4, wherein the mixed solvent consumption of the single solvent of (1) or (2) be the blonanserin bullion 5～10 times of ml/g.
6. each described preparation method of claim 3-6, wherein the ratio of weight and number of ethanol and isopropyl alcohol mixed solvent is 0.5: 1～2: 1.
7. the described preparation method of claim 3, wherein said being dissolved in the organic solvent refers to: 40 ℃ of heating for dissolving to the reflux temperature of solvent.
8. pharmaceutical composition, said composition contains right and requires 1 described blonanserin crystallization and pharmaceutically acceptable carrier thereof.
9. the described compsn of claim 8 is characterized in that tablet or capsule are processed in combinations such as blonanserin and Microcrystalline Cellulose, lactose, micropowder silica gel, Magnesium Stearate, PVPP, polyvidone, HPMC, sodium starch glycolate, Sodium Croscarmellose, low-substituted hydroxypropyl cellulose.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831578A (en) * | 2017-02-14 | 2017-06-13 | 北京万全德众医药生物技术有限公司 | The method of purification of antipsychotic drug blonanserin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5021421A (en) * | 1989-03-03 | 1991-06-04 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
| CN101747274A (en) * | 2008-12-02 | 2010-06-23 | 浙江华海药业股份有限公司 | Method for preparing crystal form A of blonanserin |
-
2010
- 2010-08-27 CN CN201010264341.1A patent/CN102372673B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5021421A (en) * | 1989-03-03 | 1991-06-04 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
| CN101747274A (en) * | 2008-12-02 | 2010-06-23 | 浙江华海药业股份有限公司 | Method for preparing crystal form A of blonanserin |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831578A (en) * | 2017-02-14 | 2017-06-13 | 北京万全德众医药生物技术有限公司 | The method of purification of antipsychotic drug blonanserin |
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