CN106543105B - A kind of cariprazine hydrochloride crystal form IV and preparation method thereof - Google Patents
A kind of cariprazine hydrochloride crystal form IV and preparation method thereof Download PDFInfo
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- CN106543105B CN106543105B CN201510609586.6A CN201510609586A CN106543105B CN 106543105 B CN106543105 B CN 106543105B CN 201510609586 A CN201510609586 A CN 201510609586A CN 106543105 B CN106543105 B CN 106543105B
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- crystal form
- cariprazine hydrochloride
- acetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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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
The present invention provides a kind of cariprazine hydrochloride crystal form IV, and the X-ray powder diffraction spectrogram which is indicated with the 2 θ ± 0.2 ° angles of diffraction is 4.381,6.190,9.855,13.305 13.903,15.031,16.495,17.755 19.405,22.562, characteristic peak is shown at 24.373, the stability and dissolution rate which has had.
Description
Technical field:
The present invention relates to chemical medicines, more particularly to a kind of cariprazine hydrochloride crystal form IV and preparation method thereof.
Background technique:
Cariliprazine (Cariprazine) is drawn for treating schizophrenia, FDA in the approval Cali on the 17th of September in 2015
Piperazine capsule is for treating adult bipolar disorder.Cariprazine hydrochloride structural formula is as described below,
Notification number is that CN101679315B discloses cariprazine hydrochloride crystal form I, notification number is that CN101801381B is disclosed
Cariprazine hydrochloride crystal form III formic acid solvent closes object.
Summary of the invention:
The present invention provides a kind of crystal form IV and preparation method and application of cariprazine hydrochloride, the cariprazine hydrochloride
Crystal form can be used for preparing pharmaceutical composition.
On the one hand, the present invention provides a kind of cariprazine hydrochloride crystal form IV, the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction
Powder diffractogram is 4.38,6.19,9.86,13.31,13.90,15.03,16.49,17.76,19.41,22.56,24.37
Place's display characteristic peak.Further, the X-ray powder diffraction spectrogram that the cariprazine hydrochloride crystal form IV2 θ ± 0.2 ° angle of diffraction indicates
Also 7.92,11.09,11.91,15.72,15.95,17.13,18.16,18.63,18.99,19.94,20.14,21.03,
Characteristic peak is shown at 21.42,21.99,23.15,25.53,25.85,26.97,28.38,31.24,35.79,36.85.More into
One step, crystal form IV provided by the invention have basically as in Figure 2 shown in X-ray powder diffraction figure.
Further, cariprazine hydrochloride crystal form IV provided by the invention, infrared signature absorption peak is in 3315.18cm-1,
2928.27cm-1, 2849.76cm-1, 2663.66cm-1, 2528.81cm-1, 2437.18cm-1, 1628.54cm-1,
1533.12cm-1, 1452.40cm-1, 1261.95cm-1, 955.31cm-1, 783.95cm-1, 576.43cm-1There is characteristic absorption at place
Peak.
Further, cariprazine hydrochloride crystal form IV provided by the invention, differential scanning calorimetery (DSC) is in peak value
196.8 DEG C of temperature appearance, one exothermic peak, 263.4 DEG C of temperature appearance, one endothermic peak, as shown in Figure 3.
On the other hand, the preparation method of cariprazine hydrochloride crystal form IV provided by the invention, which is characterized in that comprising as follows
Step:
1) cariprazine hydrochloride is dissolved in glacial acetic acid and is prepared into cariprazine hydrochloride glacial acetic acid solution；
2) methyl tertiary butyl ether(MTBE) or tetrahydrofuran, analysis are added into cariprazine hydrochloride glacial acetic acid solution made from 1) step
White precipitate forms suspension out；
3) above-mentioned suspension is stood, recycling precipitating is filtered under diminished pressure, 60 DEG C of dryings obtain cariprazine hydrochloride crystal form IV.
In the preparation method of cariprazine hydrochloride crystal form IV, the dosage and cariprazine hydrochloride dosage of the glacial acetic acid
For volume and mass ratio, volume and mass values are 1.8-5.0；The dosage of the methyl tertiary butyl ether(MTBE) and glacial acetic acid dosage
Volume ratio is 20-50 times；The dosage of the tetrahydrofuran and the volume ratio of glacial acetic acid dosage are 55-100 times.It is further above-mentioned
The dosage and cariprazine hydrochloride dosage of glacial acetic acid are volume and mass ratio is preferably 1.8-2.5.
In another aspect, the present invention provides a kind of pharmaceutical composition, the above-mentioned cariprazine hydrochloride including therapeutically effective amount
Crystal form IV is as acceptable carrier on active constituent and drug effect.
Wherein " ± 0.2 " is the measurement error range allowed
Crystal form IV provided by the invention, thermogravimetric analysis (TG), figure is as indicated at 4.
Crystal form IV provided by the invention, FTIR spectrum (FT-IR) analysis of spectra 3315.18,2928.27,
2849.76,2663.66,2528.81,2437.18,1628.54,1533.12,1452.40,1261.95,955.31,
783.95 576.43 ± 0.5%cm-1There is characteristic absorption peak at place.As shown in figure 5, wherein " ± 0.5% " is the measurement error allowed
Range.
There is exterior appearance including but not limited to as shown in FIG. 6 in crystal form IV provided by the invention.
In the present invention, the dosage of the glacial acetic acid is meant that with the volume and mass ratio of cariprazine hydrochloride dosage,
The dosage of glacial acetic acid is measured with volume, the dosage measuring quality of cariprazine hydrochloride, and volume and mass ratio are ml/g.
Beneficial effects of the present invention:
The crystal form IV of Cariliprazine hydrochloride provided by the present invention has favorable reproducibility；Accelerated test shows that Cali is drawn
The stability that piperazine crystal form IV has had；And the water solubility having had, solubility are well positioned to meet preparation needs, are conducive to medicine
The production and storage of object preparation have good exploitation prospect.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction spectrogram of Cariliprazine hydrochloride Form I
Fig. 2 is the X-ray powder diffraction spectrogram of Cariliprazine hydrochloride Form IV of the present invention
Fig. 3 is differential scanning calorimetery (DSC) analysis chart of Cariliprazine hydrochloride Form IV of the present invention
Fig. 4 is thermogravimetric (TG) analysis chart of Cariliprazine hydrochloride Form IV of the present invention
Fig. 5 is FTIR spectrum (FT-IR) the analysis map of Cariliprazine hydrochloride Form IV of the present invention
Fig. 6 is IV scanning electron microscope of Cariliprazine hydrochloride Form (SEM) image of the present invention
Fig. 7 is IV high temperature of Cariliprazine hydrochloride Form of the present invention 5 days, the X-ray powder of 10 days factors affecting stabilities
Diffraction spectrogram
Fig. 8 is the X-ray powder of IV illumination of Cariliprazine hydrochloride Form of the present invention 5 days, 10 days factors affecting stabilities
Diffraction spectrogram
Fig. 9 is the X-ray powder diffraction figure of 6 months cariprazine hydrochloride crystal form IV
Specific embodiment:
Below will by specific embodiment, the present invention is further explained, but the protection scope being not intended to restrict the invention.
Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, these improvement also should be regarded as
Protection scope of the present invention.
In following embodiments, unless otherwise indicated, the experimental method is usually according to normal condition or manufacturer builds
The condition of view is implemented；Shown in raw material, reagent can be obtained by way of commercially available purchase.
X-ray powder diffraction figure of the present invention acquires on Bruker D8 Focus X-ray powder diffraction instrument.
The method parameter of X-ray powder diffraction of the present invention is as follows:
X-ray parameter: Cu/K α ()
Voltage: 40 volt (kV)
Electric current: 40 milliamperes (mA)
Scanning range: from 3.0 to 40 degree
Sampling step length: 0.02 degree
Sampling leg speed: 0.5 second/step
Differential scanning calorimetry (DSC) analysis chart of the present invention is by the resistance to DSC 200F3 detection of speeding of Germany, temperature range
40~280 DEG C, heating rate 10K/min；Hole is pricked in aluminium crucible, sealing, and purge gass are nitrogen (40ml/min), and protection gas is nitrogen
(20ml/min)。
Thermogravimetric analysis (TG) of the present invention is to keep balance, temperature at 25 DEG C by the resistance to TG 209F3 detection of speeding of Germany
35~300 DEG C of range, heating rate 10K/min, be open aluminium crucible, and purge gass are nitrogen (40ml/min), and protection gas is nitrogen
(20ml/min)。
FTIR spectrum (FT-IR) of the present invention is examined by NICOLET 330FT-IR infrared spectrophotometer
It surveys.180mg is weighed in advance in 120 DEG C of dry and cooling potassium bromide in agate mortar, fine powder is ground into, about 1.5mg is added
Test sample is sufficiently mixed and is ground into uniform fine powder, referring to Chinese Pharmacopoeia two VI C of annex measurements of version in 2010.
Scanning electron microscope image of the present invention is to be observed clapping by Dutch PHENOM desk type scanning electronic microscope
According to obtaining.
HPLC content measuring in the present invention:
Instrument: 1200 liquid chromatograph of Agilent
Foundation: two annex V D of Chinese Pharmacopoeia version in 2010
Test condition: 5 μ BDS C18 of chromatographic column Phenomenex Hyperclone
4.6 × 250mm, 5 μm
Mobile phase A: 0.01M ammonium dihydrogen phosphate (containing 0.2% triethylamine, phosphoric acid adjusts pH3.0)-acetonitrile (80:20)
Mobile phase B: 0.01M ammonium dihydrogen phosphate (containing 0.2% triethylamine, phosphoric acid adjusts pH3.0)-acetonitrile (20:80)
Diluent: methanol
Detection wavelength: 220nm
Column temperature: 35 DEG C
Flow velocity: 1.0ml/min
Gradient condition:
Comparative example 1
Described Cariliprazine hydrochloride Form I is prepared according to Hungarian patent application the P0700339th.Product is penetrated through X-
The crystal form I of line powder diffraction proof Cariliprazine hydrochloride.As shown in Figure 1.
Embodiment 1
Cariliprazine hydrochloride sample 0.77g addition glacial acetic acid 1.5ml is allowed to be completely dissolved；Rapidly into above-mentioned solution
It is poured into 30ml methyl tertiary butyl ether(MTBE), a large amount of white solids are precipitated to form suspension；Suspension is stood, decompression filters, methyl- tert fourth
The washing of base ether.60 DEG C of drying.Obtain product 0.71g.The product proves Cariliprazine hydrochloride through X-ray powder diffraction
Crystal form IV.X-ray powder diffraction figure is as shown in Fig. 2, data are as shown in table 1.Embodiment 2
Cariliprazine hydrochloride sample 0.05g addition glacial acetic acid 0.1ml is allowed to be completely dissolved；Rapidly into above-mentioned solution
It is poured into 6ml tetrahydrofuran, white solid is precipitated to form suspension；Suspension is stood, decompression filters, acetone washing.60 DEG C of drying.
Obtain product 0.04g.The product proves the crystal form IV of Cariliprazine hydrochloride through X-ray powder diffraction.
Embodiment 3
Cariliprazine hydrochloride sample 0.77g addition glacial acetic acid 1.4ml is allowed to be completely dissolved；Rapidly into above-mentioned solution
It is poured into 69ml methyl tertiary butyl ether(MTBE), a large amount of white solids are precipitated to form suspension；Suspension is stood, decompression filters, methyl- tert fourth
The washing of base ether.60 DEG C of drying.Obtain product 0.72g.The product proves Cariliprazine hydrochloride through X-ray powder diffraction
Crystal form IV.
Embodiment 4
Cariliprazine hydrochloride sample 0.77g addition glacial acetic acid 3.8ml is allowed to be completely dissolved；Rapidly into above-mentioned solution
It is poured into 76ml methyl tertiary butyl ether(MTBE), a large amount of white solids are precipitated to form suspension；Suspension is stood, decompression filters, methyl- tert fourth
The washing of base ether.60 DEG C of drying.Obtain product 0.70g.The product proves Cariliprazine hydrochloride through X-ray powder diffraction
Crystal form IV.
Embodiment 5
Cariliprazine hydrochloride sample 5g addition glacial acetic acid 12.5ml is allowed to be completely dissolved；Incline rapidly into above-mentioned solution
Enter 687ml tetrahydrofuran, white solid is precipitated to form suspension；Suspension is stood, decompression filters, acetone washing.60 DEG C of drying.
Obtain product 4.1g.The product proves the crystal form IV of Cariliprazine hydrochloride through X-ray powder diffraction.
Embodiment 6
Cariliprazine hydrochloride sample 5g addition glacial acetic acid 10ml is allowed to be completely dissolved；It is poured into rapidly into above-mentioned solution
800ml tetrahydrofuran, white solid are precipitated to form suspension；Suspension is stood, decompression filters, acetone washing.60 DEG C of drying.?
To product 4g.The product proves the crystal form IV of Cariliprazine hydrochloride through X-ray powder diffraction.
The data of the X-ray figure of the cariprazine hydrochloride crystal form IV are shown in table 1
Table 1:
Test example 1: cariprazine hydrochloride IV stability of crystal form test
Cariprazine hydrochloride crystal form IV is carried out respectively constant humidity (RH 65%), high temperature (60 DEG C), illumination (4500 ±
Factors affecting stability experiment under the conditions of 500lx).PXRD detection, and the result with 0 day are carried out respectively at 5 days, sampling in 10 days
It is compareed, the results are shown in Table 1.And carry out HPLC assay.
The test of 2. cariprazine hydrochloride crystal form of table, IV stability of crystal form influence factor
It is learnt from the data of table 2, the crystal form IV under the conditions of high temperature 10 days, illumination 10 days, constant humidity 10 days of crystal form IV does not occur
Crystal phenomenon, the crystal stability having had (see attached drawing 7,8), and chemical property are stablized, and content did not change with 0 day, contains
Amount can reach 99.60 or more.Other 6 months Acceleration studies, the x-ray diffraction pattern of cariprazine hydrochloride I crystal and initial
Data consistent (see attached drawing 9) show that crystal stability provided by the invention is good also there is no crystal phenomenon, are conducive to preparation
Storage.
Experimental example 2: the dissolubility test of cariprazine hydrochloride IV crystal form:
Test condition: point taking appropriate hydrochloric acid Cariliprazine IV crystal form and the sample of I crystal to be dissolved in water, in 0.01M HCl,
It is made after continuously shaking 30min at 25 DEG C of supersaturated solution, after filtering dilution certain multiple, ultraviolet spectrophotometer method tests it
The solubility of specific concentration, test display crystal form IV is better than I crystal.Specific test result is shown in Table 3:
Table 3: the solubility data table of cariprazine hydrochloride
Claims (9)
1. a kind of cariprazine hydrochloride crystal form IV, which is characterized in that the X- that the crystal form IV is indicated with the 2 θ ± 0.2 ° angles of diffraction
Ray powder diffractogram 4.38,6.19,9.86,13.31,13.90,15.03,16.49,17.76,19.41,22.56,
24.37 place's display characteristic peak.
2. cariprazine hydrochloride crystal form IV according to claim 1, which is characterized in that the crystal form IV is with 2 θ ± 0.2 °
The X-ray powder diffraction spectrogram that the angle of diffraction indicates 7.92,11.09,11.91,15.72,15.95,17.13,18.16,
18.63、18.99、19.94、20.14、21.03、21.42、21.99、23.15、25.53、25.85、26.97、28.38、
31.24, characteristic peak is shown at 35.79,36.85.
3. cariprazine hydrochloride crystal form IV according to claim 1, which is characterized in that the crystal form IV has substantially
X-ray powder diffraction figure as shown in Figure 2.
4. cariprazine hydrochloride crystal form IV according to any one of claims 1 to 3, which is characterized in that the crystal form IV's
Infrared spectroscopy is included in 3315.18cm-1, 2928.27cm-1, 2849.76cm-1, 2663.66cm-1, 2528.81cm-1,
2437.18cm-1, 1628.54cm-1, 1261.95cm-1, 955.31cm-1, 783.95cm-1, 576.43cm-1There is characteristic absorption at place
Peak.
5. a kind of preparation method of the cariprazine hydrochloride crystal form IV as described in claim 1-4 is any, which is characterized in that include
Following steps:
1) cariprazine hydrochloride is dissolved in glacial acetic acid and is prepared into cariprazine hydrochloride glacial acetic acid solution；
2) methyl tertiary butyl ether(MTBE) or tetrahydrofuran are added into cariprazine hydrochloride glacial acetic acid solution made from 1) step, is precipitated white
Color precipitates to form suspension；
3) above-mentioned suspension is stood, recycling precipitating is filtered under diminished pressure, 60 DEG C of dryings obtain cariprazine hydrochloride crystal form IV.
6. preparation method according to claim 5, which is characterized in that the dosage and cariprazine hydrochloride of the glacial acetic acid
The volume and mass ratio of dosage are 1.8-5.0.
7. preparation method according to claim 6, which is characterized in that the dosage and cariprazine hydrochloride of the glacial acetic acid are used
The volume and mass ratio of amount are preferably 1.8-2.5.
8. preparation method according to claim 5, which is characterized in that the dosage and glacial acetic acid of the methyl tertiary butyl ether(MTBE)
The volume ratio of dosage is 20-50 times；The dosage of the tetrahydrofuran and the volume ratio of glacial acetic acid dosage are 55-100 times.
9. a kind of pharmaceutical composition, which is characterized in that the hydrochloric acid as described in Claims 1-4 is any including therapeutically effective amount
Cariliprazine crystal form IV is as acceptable carrier on active constituent and drug effect.
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| WO2020056929A1 (en) | 2018-09-21 | 2020-03-26 | 上海诚妙医药科技有限公司 | New cariprazine hydrochloride crystal form and preparation method and application of new cariprazine hydrochloride crystal form |
| US20230355612A1 (en) * | 2020-08-26 | 2023-11-09 | Shanghai Bocimed Pharmaceutical Co., Ltd. | Pharmaceutically acceptable salt of cariprazine and crystal form thereof, and preparation method therefor and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801381A (en) * | 2007-05-11 | 2010-08-11 | 里克特格德翁公司 | Novel solvate and crystalline forms of carbamoyl-cyclohexane derivatives |
| US7943621B2 (en) * | 2007-05-11 | 2011-05-17 | Richter Gedeon Nyrt. | Salts of piperazine compounds as D3/D2 antagonists |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801381A (en) * | 2007-05-11 | 2010-08-11 | 里克特格德翁公司 | Novel solvate and crystalline forms of carbamoyl-cyclohexane derivatives |
| US7943621B2 (en) * | 2007-05-11 | 2011-05-17 | Richter Gedeon Nyrt. | Salts of piperazine compounds as D3/D2 antagonists |
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