CN108912069A - A kind of Vortioxetine and C2-C4New salt form of dicarboxylic acids and the preparation method and application thereof - Google Patents
A kind of Vortioxetine and C2-C4New salt form of dicarboxylic acids and the preparation method and application thereof Download PDFInfo
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Abstract
A kind of high solubility, the Vortioxetine with good thermodynamic stability and the new salt form of C2-C4 dicarboxylic acids and the preparation method and application thereof are intended to provide the invention discloses a kind of.The new salt form is by Vortioxetine and C2‑C4Dicarboxylic acids is connected to form two-dimension netted space structure by N+-HO hydrogen bond；The dicarboxylic acids is ethanedioic acid, malonic acid and/or succinic acid.
Description
Technical field
The present invention relates to the new salt form field of drug, especially a kind of Vortioxetine and C2-C4The new salt form of dicarboxylic acids and its preparation
Method and application.
Background technique
According to statistics, the drug candidate of about 70-80% is due to the defect of final physicochemical property, lead to research and development failure and
It cannot finally list, so the physicochemical property for improving drug has a very important significance new drug development.Drug salt form exists
It is with the obvious advantage to improve drug solubility, dissolution rate, permeability, hygroscopicity, stability and bioavilability aspect.The new salt of drug
Type is that new eutectic substance (CCF) is introduced by proton translocation, under the active force of hydrogen bond with pharmaceutical activity effective component
(API) it is self-assembly of the supramolecular complex with fixed stoichiometric ratio.The development phase before clinical drug, new drug development are public
Pharmaceutical activity effective component (API) would generally be improved solution degree, the dissolution rate, infiltration of drug by department by way of at salt
Property, hygroscopicity, stability and bioavilability and other some physicochemical properties.When selecting eutectic substance (CCF),
It selects drug to be self-assembly of new salt form as binding partner and not only saves two kinds of respective curative effects of drug, and can obviously change
Solubility, dissolution rate and the bioavilability etc. of kind drug.Compared to nanocrystalline, solid dispersion and novel pharmaceutical formulation technology,
Drug salt form advantage in terms of improvement drug solubility, dissolution rate, permeability, hygroscopicity, stability and bioavilability is bright
It is aobvious, and the new salt form of drug succeeds in developing the patent barrier that can break new drug.
Vortioxetine is adult by the treatment of Lundbeck drugmaker of Denmark and Japanese Takeda Pharmaceutical Company Limited's joint research and development exploitation
The new drug of major depressive disorder, chemical name are 1- [2- (2,4- dimethyl benzene sulfenyl) phenyl] piperazine, molecular formula C18H22N2S。
For the medicine because having water-soluble low (0.04mg/mL), the bad physicochemical drawbacks of thermodynamic stability affect it in human body
Interior assimilation effect causes it that cannot finally list in the form of pharmaceutical activity effective component (API).
Summary of the invention
An object of the present invention is to provide a kind of high solubility, the good Vortioxetine of thermodynamic stability and C2-C4Two
The new salt form of carboxylic acid.
To achieve the goals above, technical solution provided by the invention is such：A kind of Vortioxetine and C2-C4Dicarboxyl
The new salt form of acid, the new salt form is by Vortioxetine and C2-C4Dicarboxylic acids passes through N+- HO hydrogen bond is connected to form two-dimensional mesh
Shape space structure；The dicarboxylic acids is ethanedioic acid, malonic acid and/or succinic acid.
Preferably, when the dicarboxylic acids is ethanedioic acid, the crystallographic data of new salt form is：Bond distance a=5.7423
(4), (5) b=6.7539, c=26.162 (2), bond angle α=96.730 (6) °, β=91.712 (6) °, γ=105.756
(7) °, V=967.77 (12), Z=2.
The X- powder diffractogram of the new salt form is 3.40 ± 0.2,6.86 ± 0.2,10.22 ± 0.2,13.72 in 2 θ
±0.2、 14.56±0.2、16.10±0.2、17.86±0.2、18.20±0.2、18.52±0.2、19.02±0.2、
19.64±0.2、20.40±0.2、 21.14±0.2、21.80±0.2、22.22±0.2、23.22±0.2、23.96±
0.2、24.40±0.2、26.12±0.2、26.86±0.2、 27.62±0.2、28.12±0.2、29.44±0.2、29.80
± 0.2,32.42 ± 0.2,34.50 ± 0.2,36.08 ± 0.2,36.56 ± 0.2 have characteristic peak.
The new salt form infrared spectrogram 3015,2850,2747,2508,1714,1624,1473,1381,1204,
1042、928、818、763、732、703、551、485、448cm-1There is characteristic absorption peak at place.
The fusing point of the new salt form is 208 ± 2 DEG C.
Preferably, when the dicarboxylic acids is malonic acid, the crystallographic data of new salt form is：Bond distance a=17.550
(3), (11) b=7.4423, c=18.120 (4), bond angle α=90 °, β=109.20 (2) °, γ=90 °, V=2234.0
(7) °, Z=4.
The X- powder diffractogram of the new salt form is 8.56 ± 0.2,10.66 ± 0.2,12.18 ± 0.2,12.96 in 2 θ
±0.2、 14.66±0.2、15.14±0.2、15.76±0.2、18.02±0.2、19.72±0.2、20.92±0.2、
21.42±0.2、23.30±0.2、 24.74±0.2、26.06±0.2、27.34±0.2、28.70±0.2、30.32±
0.2、30.74±0.2、31.54±0.2、32.66±0.2、 34.66±0.2、35.48±0.2、37.10±0.2、37.90
±0.2、39.14±0.2、40.32±0.2、41.34±0.2、42.56±0.2、 43.62±0.2、44.30±0.2、
45.10 ± 0.2,46.48 ± 0.2,47.76 ± 0.2,48.70 ± 0.2,50.18 ± 0.2,51.60 ± 0.2,52.36 have
Characteristic peak.
The new salt form infrared spectrogram 3474,3222,2500,1713,1436,1227,1147,1036,927,
760、544cm-1There is characteristic absorption peak at place.
The fusing point of the new salt form is 132 ± 2 DEG C.
Preferably, when the dicarboxylic acids is succinic acid, the crystallographic data of new salt form is：Bond distance a=39.091
(8), (13) b=6.5734, c=18.601 (4), bond angle α=90 °, β=112.55 (3) °, γ=90 °, V=4414.3
(15), Z=8.
The X- powder diffractogram of the new salt form 2 θ be 4.9 ± 0.2,9.8 ± 0.2,11.16 ± 0.2,13.00 ±
0.2、13.68±0.2、 14.72±0.2、15.34±0.2、16.74±0.2、17.62±0.2、18.24±0.2、19.16
±0.2、19.98±0.2、21.40±0.2、 23.22±0.2、23.84±0.2、24.64±0.2、25.56±0.2、
26.16±0.2、26.94±0.2、27.62±0.2、28.54±0.2、 30.04±0.2、31.36±0.2、32.62±
0.2、33.80±0.2、35.10±0.2、35.46±0.2、37.04±0.2、38.90±0.2、 40.08±0.2、40.96
±0.2、42.04±0.2、42.52±0.2、43.26±0.2、44.04±0.2、44.82±0.2、45.94±0.2、
46.28 ± 0.2,47.56 ± 0.2,48.72 ± 0.2,50.12 ± 0.2,51.36 ± 0.2,52.32 ± 0.2 have characteristic peak.
The new salt form infrared spectrogram 3425,3009,2716,2494,1650,1580,1413,1229,1045,
950、805、722、540cm-1There is characteristic absorption peak at place.
The fusing point of the new salt form is 116 ± 2 DEG C.
The second object of the present invention is to provide above-mentioned Vortioxetine and C2-C4The preparation method of the new salt form of dicarboxylic acids.
To achieve the goals above, technical solution provided by the invention is such：A kind of Vortioxetine as described above with
C2-C4The preparation method of the new salt form of dicarboxylic acids, includes the following steps：
Step 1：By Vortioxetine and C2-C4It after dicarboxylic acids equimolar is than mixing, is dissolved in solvent, stirs 0.5-1h, obtain
Saturated solution；
Step 2：The saturated solution is placed in room temperature environment, is stood, crystallization, filtering obtains crystal；
Step 3：By step 2 gained crystal be placed in 60-70 DEG C of vacuum oven 24 hours to get.
Preferably, the solvent in the step 1 is that methanol aqueous solution, ethanol water, isopropanol water solution, acetone are water-soluble
Liquid, acetonitrile solution, methylbenzene methanol mixed solution, toluene alcohol mixed solution, toluene acetone mixed solution, toluene tetrahydrofuran
Any one or a few combination in mixed solution, toluene acetonitrile mixed solution.
The present invention also provides another kind preparation Vortioxetine and C2-C4The method of the new salt form of dicarboxylic acids, including following step
Suddenly：By Vortioxetine and C2-C4It after dicarboxylic acids equimolar is than mixing, stirs evenly, instills solvent, grind 10min, be placed in sky
2h in gas, repeat solvent, grinding is added dropwise and place step 3-5 times to get.
Preferably, the solvent is methanol, ethyl alcohol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, methylene chloride, three
Any one or a few combination in chloromethanes, acetonitrile.
Preferably, the molar ratio of the solvent and Vortioxetine is 1:1-10:1.
The third object of the present invention is to provide above-mentioned Vortioxetine and C2-C4The application of the new salt form of dicarboxylic acids.
To achieve the goals above, technical solution provided by the invention is such：A kind of Vortioxetine as described above
With C2-C4The new salt form of dicarboxylic acids is used to prepare the drug for the treatment of depression.
Beneficial effects of the present invention are：
1. Vortioxetine prepared by the present invention and C2-C4The new salt form of dicarboxylic acids has high-dissolvability and good thermodynamics steady
It is qualitative, it can be prepared into drug injection form, and Vortioxetine prepared by the present invention and C2-C4The solubility of the new salt form of dicarboxylic acids
Better than the Vortioxetine hydrobromate listed.
2. operation of the present invention is simple, favorable reproducibility, easy to industrialized production.
3. the present invention provides a kind of new Vortioxetine medicinal forms.
4. Vortioxetine and C that the present invention is prepared2-C4The new salt form of dicarboxylic acids has accurate crystal structure, there is theoretical branch
Support, crystallinity are high.
Detailed description of the invention
Fig. 1 is the crystal structure figure of the new salt form of Vortioxetine-ethanedioic acid；
Fig. 2 is Vortioxetine-malonic acid hydrate novel salt form crystal structure figure；
Fig. 3 is Vortioxetine-succinic acid semihydrate new salt form crystal structure figure；
Fig. 4 is the reality and theoretical modeling PXRD comparison diagram of the new salt form of Vortioxetine-ethanedioic acid；
Fig. 5 is Vortioxetine-malonic acid hydrate novel salt form reality and theoretical modeling PXRD comparison diagram；
Fig. 6 is Vortioxetine-succinic acid semihydrate new salt form reality and theoretical modeling PXRD comparison diagram；
Fig. 7 is the infrared spectrum of the new salt form of Vortioxetine-ethanedioic acid；
Fig. 8 is Vortioxetine-malonic acid hydrate novel salt form infrared spectrum；
Fig. 9 is Vortioxetine-succinic acid semihydrate new salt form infrared spectrum；
Figure 10 is Vortioxetine bulk pharmaceutical chemicals, the new salt form of Vortioxetine-ethanedioic acid, Vortioxetine-malonic acid hydrate novel
Salt form and Vortioxetine-succinic acid semihydrate new salt form DSC compare spectrogram；
Figure 11 is Vortioxetine bulk pharmaceutical chemicals, the new salt form of Vortioxetine-ethanedioic acid, Vortioxetine-the third under conditions of 37 DEG C
The powder dissolution rate comparison of diacid hydrate novel salt form and Vortioxetine-new salt form of succinic acid semihydrate in pure water
Figure.
Specific embodiment
With reference to embodiment, claim of the invention is described in further detail, but do not constituted pair
Any restrictions of the invention, any limited times modification made in the claims in the present invention protection scope, still of the invention
In claims.
Embodiment 1
Step 1：After 20.00mg Vortioxetine is mixed with 6.00mg ethanedioic acid, the methanol for being dissolved in 5mL 80% is water-soluble
In liquid, 1h is stirred under confined conditions, two kinds of substances is made to be completely dissolved and react in a solvent, obtains Vortioxetine-ethanedioic acid saturation
Solution；
Step 2：The resulting saturated solution of step 1 is transferred in teat glass, with ParafilmTM test tube mouth, is existed with needle
1-3 aperture is pricked on sealed membrane, is stood, and room temperature volatilization starts that colorless and transparent flat crystal is precipitated after 6-18 days；
Step 3：The crystal that step 2 is precipitated is measured as Vortioxetine-ethanedioic acid by single crystal diffraction and Shelxtl software
New salt form, fusing point are 208 ± 2 DEG C, and crystal structure is detailed in Fig. 1.
See Table 1 for details for its crystallographic data, i.e.,：Bond distance a=5.7423 (4), b=6.7539 (5), c=26.162 (2), key
Angle α=96.730 (6) °, β=91.712 (6) °, γ=105.756 (7) °, V=967.77 (12), Z=2.
Its X- powder diffractogram is detailed in Fig. 4, i.e.,：It is 3.40 ± 0.2,6.86 ± 0.2,10.22 ± 0.2,13.72 in 2 θ
±0.2、 14.56±0.2、16.10±0.2、17.86±0.2、18.20±0.2、18.52±0.2、19.02±0.2、
19.64±0.2、20.40±0.2、 21.14±0.2、21.80±0.2、22.22±0.2、23.22±0.2、23.96±
0.2、24.40±0.2、26.12±0.2、26.86±0.2、 27.62±0.2、28.12±0.2、29.44±0.2、29.80
± 0.2,32.42 ± 0.2,34.50 ± 0.2,36.08 ± 0.2,36.56 ± 0.2 have characteristic peak.
Its infrared spectrogram is detailed in Fig. 7, i.e.,：3015,2850,2747,2508,1714,1624,1473,1381,
1204、1042、928、818、763、732、703、551、485、448cm-1There is characteristic absorption peak at place；Fusing point is 208 ± 2 DEG C.
Embodiment 2
Step 1：After 20.00mg Vortioxetine is mixed with 7.00mg malonic acid, it is molten to be dissolved in the mixing of 5mL toluene-methanol
In liquid, toluene:The volume ratio of methanol is 4:1；1h is stirred under confined conditions, is completely dissolved two kinds of substances in a solvent simultaneously anti-
It answers, obtains Vortioxetine-ethanedioic acid saturated solution；
Step 2：The resulting saturated solution of step 1 is transferred in teat glass, with ParafilmTM test tube mouth, is existed with needle
1-3 aperture is pricked on sealed membrane, is stood, and room temperature volatilization starts that colorless and transparent flat crystal is precipitated after 5-15 days；
Step 3：The crystal that step 2 is precipitated is measured as Vortioxetine-malonic acid by single crystal diffraction and Shelxtl software
Hydrate novel salt form, fusing point are 132 ± 2 DEG C, and crystal structure is detailed in Fig. 2.
Its crystallographic features is referring to table 1, i.e.,：Bond distance a=17.550 (3), b=7.4423 (11), c=18.120 (4), key
Angle α=90 °, β=109.20 (2) °, γ=90 °, V=2234.0 (7) °, Z=4.
Its X- powder diffractogram is detailed in Fig. 5, i.e.,：2 θ be 8.56 ± 0.2,10.66 ± 0.2,12.18 ± 0.2,
12.96±0.2、 14.66±0.2、15.14±0.2、15.76±0.2、18.02±0.2、19.72±0.2、20.92±
0.2、21.42±0.2、23.30±0.2、24.74±0.2、26.06±0.2、27.34±0.2、28.70±0.2、30.32±
0.2、30.74±0.2、31.54±0.2、32.66±0.2、 34.66±0.2、35.48±0.2、37.10±0.2、37.90
±0.2、39.14±0.2、40.32±0.2、41.34±0.2、42.56±0.2、 43.62±0.2、44.30±0.2、
45.10 ± 0.2,46.48 ± 0.2,47.76 ± 0.2,48.70 ± 0.2,50.18 ± 0.2,51.60 ± 0.2,52.36 have
Characteristic peak.
Its infrared spectrogram is detailed in Fig. 8, i.e.,：3474,3222,2500,1713,1436,1227,1147,1036,
927、760、544cm-1There is characteristic absorption peak at place.
Embodiment 3
Step 1：After 20.00mg Vortioxetine is mixed with 8.00mg succinic acid, it is dissolved in the aqueous acetonitrile of 5mL 80%
In liquid, 1h is stirred under confined conditions, two kinds of substances is made to be completely dissolved and react, and obtains Vortioxetine-succinic acid semihydrate saturation
Solution；
Step 2：The resulting saturated solution of step 1 is transferred in teat glass, with ParafilmTM test tube mouth, is existed with needle
1-3 aperture is pricked on sealed membrane, is stood, and room temperature volatilization starts that colorless and transparent acicular crystal is precipitated after 5-20 days；
Step 3：The crystal of precipitation is measured as half water of Vortioxetine-succinic acid by single crystal diffraction and Shelxtl software
The new salt form of object is closed, fusing point is 116 ± 2 DEG C, and crystal structure is detailed in Fig. 3.
Its crystallographic features is referring to table 1, i.e.,：Bond distance a=39.091 (8), b=6.5734 (13), c=18.601 (4), key
Angle α=90 °, β=112.55 (3) °, γ=90 °, V=4414.3 (15), Z=8.
Its X- powder diffractogram is detailed in Fig. 6, i.e.,：2 θ be 4.9 ± 0.2,9.8 ± 0.2,11.16 ± 0.2,13.00 ±
0.2、13.68±0.2、 14.72±0.2、15.34±0.2、16.74±0.2、17.62±0.2、18.24±0.2、19.16
±0.2、19.98±0.2、21.40±0.2、 23.22±0.2、23.84±0.2、24.64±0.2、25.56±0.2、
26.16±0.2、26.94±0.2、27.62±0.2、28.54±0.2、 30.04±0.2、31.36±0.2、32.62±
0.2、33.80±0.2、35.10±0.2、35.46±0.2、37.04±0.2、38.90±0.2、 40.08±0.2、40.96
±0.2、42.04±0.2、42.52±0.2、43.26±0.2、44.04±0.2、44.82±0.2、45.94±0.2、
46.28 ± 0.2,47.56 ± 0.2,48.72 ± 0.2,50.12 ± 0.2,51.36 ± 0.2,52.32 ± 0.2 have characteristic peak.
Its infrared spectrogram is detailed in Fig. 9, i.e.,：3425,3009,2716,2494,1650,1580,1413,1229,
1045、950、805、722、540cm-1There is characteristic absorption peak at place.
1 Vortioxetine of table and its C2-C4The crystallographic parameter table of the new salt form series of dicarboxylic acids
Embodiment 4
It after 20.00mg Vortioxetine is mixed with 6.00mg ethanedioic acid, stirs evenly, instills 5mL methanol, grind 10min,
It is placed in 2h in air, repeat that solvent, grinding is added dropwise and places step 3-5 times to get the new salt form of Vortioxetine-ethanedioic acid.
Embodiment 5
It after 20.00mg Vortioxetine is mixed with 7.00mg malonic acid, stirs evenly, instills 5mL ethyl acetate, grinding
10min is placed in 2h in air, repeats that solvent, grinding is added dropwise and places step 3-5 times to get one water of Vortioxetine-malonic acid
Close the new salt form of object.
Embodiment 6
It after 20.00mg Vortioxetine is mixed with 8.00mg succinic acid, stirs evenly, instills 5mL tetrahydrofuran, grinding
10min is placed in 2h in air, repeats that solvent, grinding is added dropwise and places step 3-5 times to get half water of Vortioxetine-succinic acid
Close the new salt form of object.
Embodiment 7
Embodiment 1-3 is distinguished into the new salt form of resulting Vortioxetine-ethanedioic acid, Vortioxetine-malonic acid hydrate novel
Salt form, Vortioxetine-new salt form of succinic acid semihydrate and Vortioxetine bulk pharmaceutical chemicals carry out DSC comparison, are as a result detailed in Figure 10,
In figure：VOT represents Vortioxetine bulk pharmaceutical chemicals, VOT-OA represents the new salt form of Vortioxetine-ethanedioic acid, VOT-PA-H2O represents fertile
For Xi Ting-malonic acid hydrate novel salt form, VOT-SUA-H2O represents Vortioxetine-new salt form of succinic acid semihydrate.
Embodiment 8
Embodiment 1-3 is distinguished into the new salt form of resulting Vortioxetine-ethanedioic acid, Vortioxetine-malonic acid hydrate novel
Salt form, Vortioxetine-new salt form of succinic acid semihydrate and Vortioxetine bulk pharmaceutical chemicals carry out solubility test in water：
100mg sample is weighed, sieving filters out sample of the particle size range between 140-250 μm, is placed on 37 DEG C of pure water
Middle stirring, with the solubility for 24 hours and powder dissolution rate of liquid chromatograph Agilent1290 test sample.
The result shows that three kinds of salt form improve its solubility, as shown in table 2 compared with Vortioxetine raw material.Three kinds
Salt form has also been all shown quickly dissolves out phenomenon very much, belongs to the drug scope of very Fast Stripping, can be used for preparing patent medicine
Composition injection, as shown in figure 11, in figure：VOT represents Vortioxetine bulk pharmaceutical chemicals, VOT-OA represents the new salt of Vortioxetine-ethanedioic acid
Type, VOT-PA-H2O represents Vortioxetine-malonic acid hydrate novel salt form, VOT-SUA-H2O represents Vortioxetine-succinic acid
The new salt form of semihydrate.
2 solubility contrast table of table
Used test instrument of the present invention is with reference to as follows：Crystal structure is by Bruker ApexII CCD single crystal diffractometer molybdenum
Target It includes；Powder diffraction is measured by German Bruker company D8Advance diffractometer, and test scope is
3-60°( V=40kV and I=40mA)；Infrared spectroscopy is using German Brooker company Vertex33FT-IR
The measurement of infrared spectroscopy instrument, test scope 4000-400cm-1；DSC is included using Mettler-Toledo, and Convergence-free spaces are normal
Temperature is to 300 DEG C, nitrogen protection, heating rate 10K/min.Condition selected by liquid chromatogram is：Mobile phase：0.01mol/L phosphoric acid
Potassium dihydrogen:Acetonitrile=60:40, flow velocity 0.4ml/min, column temperature 40, wavelength：226nm, chromatographic column： Thermo Accucore aQ
100*2.1mm liquid phase model：Agilent 1290.
Above-described is only presently preferred embodiments of the present invention, all timess done within the scope of the spirit and principles in the present invention
What modifications, equivalent substitutions and improvements etc., should be included within the scope of the present invention.
Claims (10)
1. a kind of Vortioxetine and C2-C4The new salt form of dicarboxylic acids, which is characterized in that the new salt form is by Vortioxetine and C2-C4Two
Carboxylic acid passes through N+- HO hydrogen bond is connected to form two-dimension netted space structure；The dicarboxylic acids is ethanedioic acid, malonic acid
And/or succinic acid.
2. Vortioxetine according to claim 1 and C2-C4The new salt form of dicarboxylic acids, which is characterized in that when the dicarboxylic acids
When for ethanedioic acid, the crystallographic data of new salt form is：Bond distance a=5.7423 (4), b=6.7539 (5), c=26.162 (2), key
Angle α=96.730 (6) °, β=91.712 (6) °, γ=105.756 (7) °, V=967.77 (12), Z=2；
The X- powder diffractogram of the new salt form 2 θ be 3.40 ± 0.2,6.86 ± 0.2,10.22 ± 0.2,13.72 ±
0.2、14.56±0.2、16.10±0.2、17.86±0.2、18.20±0.2、18.52±0.2、19.02±0.2、19.64±
0.2、20.40±0.2、21.14±0.2、21.80±0.2、22.22±0.2、23.22±0.2、23.96±0.2、24.40±
0.2、26.12±0.2、26.86±0.2、27.62±0.2、28.12±0.2、29.44±0.2、29.80±0.2、32.42±
0.2,34.50 ± 0.2,36.08 ± 0.2,36.56 ± 0.2 have characteristic peak；
The new salt form infrared spectrogram 3015,2850,2747,2508,1714,1624,1473,1381,1204,
1042、928、818、763、732、703、551、485、448cm-1There is characteristic absorption peak at place.
3. Vortioxetine according to claim 1 and C2-C4The new salt form of dicarboxylic acids, which is characterized in that when the dicarboxylic acids
When for malonic acid, the crystallographic data of new salt form is：Bond distance a=17.550 (3), b=7.4423 (11), c=18.120 (4),
Bond angle α=90 °, β=109.20 (2) °, γ=90 °, V=2234.0 (7) °, Z=4；
The X- powder diffractogram of the new salt form 2 θ be 8.56 ± 0.2,10.66 ± 0.2,12.18 ± 0.2,12.96 ±
0.2、14.66±0.2、15.14±0.2、15.76±0.2、18.02±0.2、19.72±0.2、20.92±0.2、21.42±
0.2、23.30±0.2、24.74±0.2、26.06±0.2、27.34±0.2、28.70±0.2、30.32±0.2、30.74±
0.2、31.54±0.2、32.66±0.2、34.66±0.2、35.48±0.2、37.10±0.2、37.90±0.2、39.14±
0.2、40.32±0.2、41.34±0.2、42.56±0.2、43.62±0.2、44.30±0.2、45.10±0.2、46.48±
0.2,47.76 ± 0.2,48.70 ± 0.2,50.18 ± 0.2,51.60 ± 0.2,52.36 have characteristic peak；
The new salt form infrared spectrogram 3474,3222,2500,1713,1436,1227,1147,1036,927,760,
544cm-1There is characteristic absorption peak at place.
4. Vortioxetine according to claim 1 and C2-C4The new salt form of dicarboxylic acids, which is characterized in that when the dicarboxylic acids
When for succinic acid, the crystallographic data of new salt form is：Bond distance a=39.091 (8), b=6.5734 (13), c=18.601 (4),
Bond angle α=90 °, β=112.55 (3) °, γ=90 °, V=4414.3 (15), Z=8；
The X- powder diffractogram of the new salt form 2 θ be 4.9 ± 0.2,9.8 ± 0.2,11.16 ± 0.2,13.00 ± 0.2,
13.68±0.2、14.72±0.2、15.34±0.2、16.74±0.2、17.62±0.2、18.24±0.2、19.16±0.2、
19.98±0.2、21.40±0.2、23.22±0.2、23.84±0.2、24.64±0.2、25.56±0.2、26.16±0.2、
26.94±0.2、27.62±0.2、28.54±0.2、30.04±0.2、31.36±0.2、32.62±0.2、33.80±0.2、
35.10±0.2、35.46±0.2、37.04±0.2、38.90±0.2、40.08±0.2、40.96±0.2、42.04±0.2、
42.52±0.2、43.26±0.2、44.04±0.2、44.82±0.2、45.94±0.2、46.28±0.2、47.56±0.2、
48.72 ± 0.2,50.12 ± 0.2,51.36 ± 0.2,52.32 ± 0.2 have characteristic peak；
The new salt form infrared spectrogram 3425,3009,2716,2494,1650,1580,1413,1229,1045,950,
805、722、540cm-1There is characteristic absorption peak at place.
5. one kind Vortioxetine and C as described in claim 1-4 is any2-C4The preparation method of the new salt form of dicarboxylic acids, feature exist
In including the following steps：
Step 1：By Vortioxetine and C2-C4It after dicarboxylic acids equimolar is than mixing, is dissolved in solvent, stirs 0.5-1h, must be saturated
Solution；
Step 2：The saturated solution is placed in room temperature environment, is stood, crystallization, filtering obtains crystal；
Step 3：By step 2 gained crystal be placed in 60-70 DEG C of vacuum oven 24 hours to get.
6. Vortioxetine and C according to claim 52-C4The preparation method of the new salt form of dicarboxylic acids, which is characterized in that the step
Solvent in rapid 1 is methanol aqueous solution, ethanol water, isopropanol water solution, aqueous acetone solution, acetonitrile solution, toluene first
Mixed alkoxide solution, toluene alcohol mixed solution, toluene acetone mixed solution, toluene tetrahydrofuran mixed solution, toluene acetonitrile are mixed
Close any one or a few combination in solution.
7. one kind Vortioxetine and C as described in claim 1-4 is any2-C4The preparation method of the new salt form of dicarboxylic acids, feature exist
In including the following steps：By Vortioxetine and C2-C4It after dicarboxylic acids equimolar is than mixing, stirs evenly, instills solvent, grinding
10min, is placed in 2h in air, repeat solvent, grinding is added dropwise and place step 3-5 times to get.
8. Vortioxetine and C according to claim 72-C4The preparation method of the new salt form of dicarboxylic acids, which is characterized in that described molten
Agent is methanol, ethyl alcohol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, methylene chloride, chloroform, any one in acetonitrile
Kind or several combinations.
9. according to any Vortioxetine of claim 5-8 and C2-C4The preparation method of the new salt form of dicarboxylic acids, which is characterized in that
The molar ratio of the solvent and Vortioxetine is 1:1-10:1.
10. a kind of Vortioxetine and C as described in claim 1-9 is any2-C4The new salt form of dicarboxylic acids is used to prepare treatment depression
The drug of disease.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015035802A1 (en) * | 2013-09-12 | 2015-03-19 | 杭州普晒医药科技有限公司 | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
| CA2940097A1 (en) * | 2014-04-28 | 2015-11-05 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts |
| CN106103418A (en) * | 2014-01-31 | 2016-11-09 | 埃吉斯药物私人有限公司 | The fertile preparation method for western spit of fland salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015035802A1 (en) * | 2013-09-12 | 2015-03-19 | 杭州普晒医药科技有限公司 | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
| CN106103418A (en) * | 2014-01-31 | 2016-11-09 | 埃吉斯药物私人有限公司 | The fertile preparation method for western spit of fland salt |
| CA2940097A1 (en) * | 2014-04-28 | 2015-11-05 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts |
Non-Patent Citations (1)
| Title |
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| 何赛飞: "沃替西汀新盐：设计、制备、表征及性质研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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