CN108250064A - New salt form of Vortioxetine-dihydroxy-benzoic acid and preparation method thereof - Google Patents
New salt form of Vortioxetine-dihydroxy-benzoic acid and preparation method thereof Download PDFInfo
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- CN108250064A CN108250064A CN201810360000.0A CN201810360000A CN108250064A CN 108250064 A CN108250064 A CN 108250064A CN 201810360000 A CN201810360000 A CN 201810360000A CN 108250064 A CN108250064 A CN 108250064A
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- 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
- C07D295/08—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 bound oxygen or sulfur atoms
- C07D295/096—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention discloses the new salt form of Vortioxetine dihydroxy-benzoic acid, the new salt form is to be connected to be formed by N HO hydrogen bonds with dihydroxy-benzoic acid with Vortioxetine, including the new salt form of Vortioxetine dihydroxy-benzoic acid and the new salt form of Vortioxetine dihydroxy-benzoic acid solvate, wherein, the dihydroxy-benzoic acid includes 2,3 dihydroxy-benzoic acids, 2,4 dihydroxy-benzoic acids, 2,5 dihydroxy-benzoic acids and 2,6 dihydroxy-benzoic acids.The invention also discloses two kinds of preparation methods of the slow volatility process of room temperature solvent and solvent assisted milling method of the new salt form of Vortioxetine dihydroxy-benzoic acid.This method is easy to operate, is easy to industrialized production, and the new salt form of preparation has good thermodynamic stability for treating severe adult's depression.
Description
Technical field
The present invention relates to the new salt form of drug and preparation method more particularly to the new salt form of Vortioxetine-dihydroxy-benzoic acid and
Preparation method.
Background technology
According to statistics, the defects of drug candidate of about 70-80% is due to final physicochemical property, cause 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 active ingredient
(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 active ingredient (API) would generally be improved the solution degree, dissolution rate, infiltration of drug by department by way of into salt
Property, hygroscopicity, stability and bioavilability and some other physicochemical properties.When eutectic substance (CCF) is selected,
Drug is selected to be self-assembly of the effect of new salt form not only saves two kinds of drugs respectively as binding partner, and can significantly be changed
Solubility, dissolution rate and bioavilability of kind drug etc..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 grown up by the treatment of Lundbeck drugmaker of Denmark and the joint research and development exploitation of Japanese Takeda Pharmaceutical Company Limited
The new drug of major depressive disorder, chemical name be 1- [2- (2,4- dimethyl benzene sulfenyl) phenyl] piperazine, molecular formula C18H22N2S。
The medicine is because with water-soluble low (0.1mg/mL), the bad physicochemical drawbacks of thermodynamic stability affect it in human body
Interior assimilation effect causes it that cannot finally be listed in the form of pharmaceutical activity active ingredient (API), and listing is that a kind of irrigate is replaced
The hydrobromate of Xi Ting, trade name Brintellix.
Invention content
The first new salt of Vortioxetine-dihydroxy-benzoic acid being designed to provide with thermodynamic stability of the present invention
Type.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：The new salt form is with Vortioxetine and dihydroxy benzenes first
Acid is connected to be formed by N-HO hydrogen bonds, including the new salt form of Vortioxetine-dihydroxy-benzoic acid and Vortioxetine-dihydroxy
The new salt form of yl benzoic acid solvate.Wherein, the dihydroxy-benzoic acid includes 2,3- dihydroxy-benzoic acids, 2,4- dihydroxy benzenes
Formic acid, 2,5- dihydroxy-benzoic acids and 2,6- dihydroxy-benzoic acids.Vortioxetine structural formula as shown in Figure 1a, four kinds of dihydroxy benzenes
The molecular formula of formic acid is C7H6O4, structural formula is successively as shown in Fig. 1 b-e.
The new salt form is the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates, Vortioxetine -2,4- dihydroxies
The new salt form of half toluene solvate of yl benzoic acid, the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids and Vortioxetine -2,6-
The new salt form of dihydroxy-benzoic acid.
Vortioxetine, 2,3- dihydroxy benzenes first in the new salt form of the Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates
The molar ratio of acid and water is 1:1:0.5.It is irrigated in the half new salt form of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids
It is 1 for the molar ratio of Xi Ting, 2,4- dihydroxy-benzoic acid and toluene:1:0.5.Vortioxetine -2,5- the dihydroxy-benzoic acids
Vortioxetine and the molar ratio of 2,5- dihydroxy-benzoic acids are 1 in new salt form:1.Vortioxetine -2,6- the dihydroxy-benzoic acids
Vortioxetine and the molar ratio of 2,6- dihydroxy-benzoic acids are 1 in new salt form:1.
The new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate, crystallographic features：A=26.5624
(5), b=8.10730 (10), c=23.0375 (5), bond angle be α=90 °, β=92.162 (2), γ=90 °, V=4957.58
(16), Z=4.The X- powder diffractograms of the new salt form of the Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates are in 2 θ
6.64±0.2、7.68±0.2、10.34±0.2、11.36±0.2、12.04±0.2、13.28±0.2、13.70±0.2、
14.78±0.2、15.40±0.2、16.54±0.2、17.04±0.2、18.60±0.2、19.28±0.2、20.00±0.2、
20.82±0.2、21.18±0.2、21.72±0.2、22.30±0.2、22.84±0.2、23.14±0.2、23.20±0.2、
23.88±0.2、24.36±0.2、24.82±0.2、25.60±0.2、25.94±0.2、27.44±0.2、29.34±0.2、
29.82 ± 0.2,30.26 ± 0.2,32.04 ± 0.2 have characteristic peak.
The new salt form of half toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acid, crystallographic features：A=
12.3577 (8), b=12.9526 (6), c=17.4064 (11), bond angle be α=82.219 (5) °, β=80.757 (6), γ=
87.213 (4) °, V=2723.6 (3), Z=2.The half new salt of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids
The X- powder diffractograms of type 2 θ for 9.16 ± 0.2,10.38 ± 0.2,11.54 ± 0.2,12.14 ± 0.2,13.08 ±
0.2、13.94±0.2、14.94±0.2、15.32±0.2、15.62±0.2、16.20±0.2、17.28±0.2、18.42±
0.2、18.98±0.2、19.58±0.2、20.84±0.2、21.46±0.2、22.48±0.2、23.10±0.2、23.78±
0.2nd, 24.32 ± 0.2,25.52 ± 0.2,26.44 ± 0.2,27.48 ± 0.2,28.14 ± 0.2 have characteristic peak.
The new salt form of Vortioxetine -2,5-dihydroxybenzoic acid, crystallographic features：Bond distance a=9.9394 (8), b=
10.1982 (6), c=12.1724 (9), bond angle be α=89.628 (6) °, β=76.453 (7), γ=85.399 (6) °, V=
1195.55 (15), Z=2.The X- powder diffractograms of the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids are in 2 θ
9.16±0.2、10.38±0.2、11.54±0.2、12.14±0.2、13.08±0.2、13.94±0.2、14.94±0.2、
15.32±0.2、15.62±0.2、16.20±0.2、17.28±0.2、18.42±0.2、18.98±0.2、19.58±0.2、
20.84±0.2、21.46±0.2、22.48±0.2、23.10±0.2、23.78±0.2、24.32±0.2、25.52±0.2、
26.44 ± 0.2,27.48 ± 0.2,28.14 ± 0.2 have characteristic peak.
The new salt form of Vortioxetine -2,6-DHBA, crystallographic features：Bond distance a=17.0666 (8), b
=6.3133 (2), c=22.2716 (10), bond angle be α=90 °, β=107.112 (5), γ=90 °, V=2293.46 (17),
Z=4.The X- powder diffractograms of the new salt form of Vortioxetine -2,6- dihydroxy-benzoic acids are 6.02 ± 0.2,7.84 in 2 θ
±0.2、11.08±0.2、11.94±0.2、13.84±0.2、14.70±0.2、15.32±0.2、15.82±0.2、16.26
±0.2、17.22±0.2、18.16±0.2、19.46±0.2、20.84±0.2、21.26±0.2、21.98±0.2、22.56
± 0.2,24.06 ± 0.2,25.20 ± 0.2,26.10 ± 0.2,26.92 ± 0.2,27.70 ± 0.2,29.06 ± 0.2 have spy
Levy peak.
Second object of the present invention is to provide two kinds of sides of preparation of the above-mentioned new salt form of Vortioxetine-dihydroxy-benzoic acid
Method.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：The of the new salt form of Vortioxetine-dihydroxy-benzoic acid
A kind of preparation method, the i.e. slow volatility process of room temperature solvent, include the following steps：
(1) Vortioxetine, dihydroxy-benzoic acid are dissolved in solvent, stir 0.5h~1h, obtain Vortioxetine-dihydroxy
The saturated solution of the new salt form of yl benzoic acid；
(2) saturated solution is transferred in teat glass, ParafilmTM test tube mouth, is pricked on sealed membrane 1~3 small
Hole is stood, and room temperature volatilization, crystallization is complete after 4~30 days, obtains the new salt form of Vortioxetine-dihydroxy-benzoic acid.
In the step (1), the molar ratio of Vortioxetine and dihydroxy-benzoic acid is 1:3~2:1, Vortioxetine and solvent
Molar ratio be 1:1~1:10.
In the step (1), the solvent for preparing the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate is acetone
Any one in aqueous solution, methanol aqueous solution, methanol, ethanol water, isopropanol and acetonitrile solution is prepared fertile for west
The solvent of the half new salt form of toluene solvate of spit of fland -2,4- dihydroxy-benzoic acids is toluene, methylbenzene methanol mixed solution and toluene second
Any one in mixed alkoxide solution, the solvent for preparing the new salt form of Vortioxetine -2,5-dihydroxybenzoic acid is aqueous acetone solution,
Any one in methanol, methanol aqueous solution and acetonitrile solution prepares the new salt form of Vortioxetine -2,6-DHBA
Solvent is any one in aqueous acetone solution, methanol, methanol aqueous solution and acetonitrile.
Second of preparation method of the new salt form of Vortioxetine-dihydroxy-benzoic acid, i.e. solvent assisted milling method, including following
Step：
(1) Vortioxetine, dihydroxy-benzoic acid are added in mortar, stirred evenly, instill solvent, ground 10min, put
It is placed in 2h in air；
(2) solvent, grinding and the operation of placement is added dropwise in the material of 2h in repeating said steps (1) in air is placed in,
It repeats 3~5 times, obtains the new salt form of Vortioxetine-dihydroxy-benzoic acid.
In the step (1), the molar ratio of Vortioxetine and dihydroxy-benzoic acid is 1:3~2:1, Vortioxetine and solvent
Molar ratio be 1:1~1:10.
In the step (1), the solvent for preparing the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate is acetone
Any one in aqueous solution, methanol aqueous solution, methanol, ethanol water, isopropanol and acetonitrile solution is prepared fertile for west
The solvent of the half new salt form of toluene solvate of spit of fland -2,4- dihydroxy-benzoic acids is toluene, methylbenzene methanol mixed solution and toluene second
Any one in mixed alkoxide solution, the solvent for preparing the new salt form of Vortioxetine -2,5-dihydroxybenzoic acid is aqueous acetone solution,
Any one in methanol, methanol aqueous solution and acetonitrile solution prepares the new salt form of Vortioxetine -2,6-DHBA
Solvent is any one in aqueous acetone solution, methanol, methanol aqueous solution and acetonitrile.
The physical state of Vortioxetine and the new salt form of dihydroxy-benzoic acid can have different shapes according to the size of preparation amount
State when amount is few, using the slow volatility process of room temperature solvent, obtains water white transparency bulk crystals, when measuring big, using solvent assisted milling
Method obtains white powder.
The present invention has the following advantages：
1. four kinds of Vortioxetines and the new salt form of dihydroxy-benzoic acid prepared by the present invention are provided with good Thermodynamically stable
Property.
2. the present invention is easy to operate, favorable reproducibility is easy to industrialized production.
3. the solvent selected is with the organic pure solvent of volatility or its aqueous solution, water is therefore fertile for western as anti-solvent
The new salt form of spit of fland-dihydroxy-benzoic acid is precipitated during organic solvent volatilizees.
Description of the drawings
Fig. 1 is the structural formula of Vortioxetine and four kinds of dihydroxy-benzoic acids；
A is Vortioxetine；B is 2,3- dihydroxy-benzoic acids；C is 2,4- dihydroxy-benzoic acids；D is 2,5- dihydroxy benzenes first
Acid；E is 2,6- dihydroxy-benzoic acids.
Fig. 2 is the crystal structure figure of the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates.
Fig. 3 is the crystal structure figure of the half new salt form of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids.
Fig. 4 is the crystal structure figure of the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids.
Fig. 5 is the crystal structure figure of the new salt form of Vortioxetine -2,6- dihydroxy-benzoic acids.
Fig. 6 is the reality of the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates and theoretical modeling PXRD comparisons
Figure.
Fig. 7 is the reality and theoretical modeling of the half new salt form of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids
PXRD comparison diagrams.
Fig. 8 is the reality of the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids and theoretical modeling PXRD comparison diagrams.
Fig. 9 is the reality of the new salt form of Vortioxetine -2,6- dihydroxy-benzoic acids and theoretical modeling PXRD comparison diagrams.
Figure 10 is the infrared spectrum of the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates.
Figure 11 is the infrared spectrum of the half new salt form of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids.
Figure 12 is the infrared spectrum of the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids.
Figure 13 is the infrared spectrum of the new salt form of Vortioxetine -2,6- dihydroxy-benzoic acids.
Figure 14 is the DSC spectrograms of the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates.
Figure 15 is the DSC spectrograms of the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids.
Figure 16 is the DSC spectrograms of the new salt form of Vortioxetine -2,6- dihydroxy-benzoic acids.
Specific embodiment
Technical scheme of the present invention is further described by the following examples, but does not form any limit to the present invention
System.
Embodiment 1
(1) by 20.00mg Vortioxetines and 10.00mg 2,3- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of objects
The volume ratio that matter is dissolved in 5mL first alcohol and waters is 4:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances molten
It is completely dissolved and reacts in agent, obtain Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solution.
(2) Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solutions in reaction vessel are transferred to glass
In test tube, with ParafilmTM test tube mouth, 3 apertures are pricked on sealed membrane with needle, are stood, room temperature volatilization starts to be precipitated after 7 days
Water white transparency flat crystal.
(3) crystal of precipitation is determined as Vortioxetine -2,3- dihydroxy benzenes first by single crystal diffraction and Shelxtl softwares
The sour new salt form of semihydrate, crystallographic features are referring to table 1, and crystal structure is referring to Fig. 2.
Embodiment 2
(1) by 20.00mg Vortioxetines and 10.00mg 2,3- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of objects
It is 1 that matter, which is dissolved in 5mL acetonitriles and the volume ratio of water,:In 1 mixed solution.0.5h is stirred under confined conditions, and two kinds of substances is made to exist
It is completely dissolved and reacts in solvent, obtain Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solution.
(2) Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solutions in reaction vessel are transferred to glass
In test tube, with ParafilmTM test tube mouth, 3 apertures are pricked on sealed membrane with needle, are stood, room temperature volatilization starts to analyse after 15 days
Go out water white transparency acicular crystal.
(3) that the crystal of precipitation is determined as Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates by single crystal diffraction is new
Salt form, crystallographic features are referring to table 1.
Embodiment 3
(1) by 20.00mg Vortioxetines and 10.00mg 2,3- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of objects
It is 1 that matter, which is dissolved in 5mL acetone and the volume ratio of water,:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances molten
It is completely dissolved and reacts in agent, obtain Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solution.
(2) Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solutions in reaction vessel are transferred to glass
In test tube, with ParafilmTM test tube mouth, 3 apertures are pricked on sealed membrane with needle, are stood, room temperature volatilization starts to be precipitated after 4 days
Water white transparency acicular crystal.
(3) that the crystal of precipitation is determined as Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates by single crystal diffraction is new
Salt form, crystallographic features are referring to table 1.
Embodiment 4
(1) by 20.00mg Vortioxetines and 10.00mg 2,3- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of objects
The volume ratio that matter is dissolved in 5mL second alcohol and waters is 4:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances molten
It is completely dissolved and reacts in agent, obtain Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solution.
(2) Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solutions in reaction vessel are transferred to glass
In test tube, with ParafilmTM test tube mouth, 3 apertures are pricked on sealed membrane with needle, are stood, room temperature volatilization starts to analyse after 15 days
Go out water white transparency bulk crystals.
(3) that the crystal of precipitation is determined as Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates by single crystal diffraction is new
Salt form, crystallographic features are referring to table 1.
Embodiment 5
(1) by 20.00mg Vortioxetines and 10.00mg 2,3- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of objects
Matter is dissolved in 10mL isopropanols.1h is stirred under confined conditions, and two kinds of substances is made to be completely dissolved and react in a solvent, are irrigated
For Xi Ting -2,3- dihydroxy-benzoic acid semihydrate saturated solutions.
(2) Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate saturated solutions in reaction vessel are transferred to glass
In test tube, with ParafilmTM test tube mouth, 3 apertures are pricked on sealed membrane with needle, are stood, room temperature volatilization starts to analyse after 30 days
Go out water white transparency bulk crystals.
(3) that the crystal of precipitation is determined as Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates by single crystal diffraction is new
Salt form, crystallographic features are referring to table 1.
Embodiment 6
(1) by 20.00mg Vortioxetines and 10.00mg 2,4- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of objects
It is 4 that matter, which is dissolved in 5mL toluene and the volume ratio of methanol,:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances
It is completely dissolved and reacts in a solvent, obtain half toluene solvate saturated solution of Vortioxetine -2,4- dihydroxy-benzoic acid.
(2) the half toluene solvate saturated solution of Vortioxetine -2,4- dihydroxy-benzoic acids in reaction vessel is shifted
Into teat glass, with ParafilmTM test tube mouth, 3 apertures are pricked on sealed membrane with needle, are stood, room temperature volatilization, after 14 days
Start that water white transparency bulk crystals are precipitated.
(3) crystal of precipitation is determined as Vortioxetine -2,4- dihydroxy benzenes first by single crystal diffraction and Shelxtl softwares
The new salt form of sour half toluene solvate, crystallographic features are referring to table 1, and crystal structure is referring to Fig. 3.
Embodiment 7
(1) by 20.00mg Vortioxetines and 10.00mg 2,4- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of objects
It is 4 that matter, which is dissolved in 10mL toluene and the volume ratio of ethyl alcohol,:In 1 mixed solution.1h is stirred under confined conditions, and two kinds of substances is made to exist
It is completely dissolved and reacts in solvent, obtain half toluene solvate saturated solution of Vortioxetine -2,4- dihydroxy-benzoic acid.
(2) the half toluene solvate saturated solution of Vortioxetine -2,4- dihydroxy-benzoic acids in reaction vessel is shifted
Into teat glass, with ParafilmTM test tube mouth, 3 apertures are pricked on sealed membrane with needle, are stood, room temperature volatilization, after 30 days
Start that water white transparency bulk crystals are precipitated.
(3) crystal of precipitation is determined as half toluene solvant of Vortioxetine -2,4- dihydroxy-benzoic acids by single crystal diffraction
The new salt form of object is closed, crystallographic features are referring to table 1.
Embodiment 8
(1) by 20.00mg Vortioxetines and 10.00mg 2,5-dihydroxybenzoic acid, i.e. molar ratio is 4:5 two kinds of objects
The volume ratio that matter is dissolved in 6mL first alcohol and waters is 2:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances complete
It dissolves and reacts, obtain Vortioxetine -2,5-dihydroxybenzoic acid saturated solution.
(2) Vortioxetine in reaction vessel -2,5-dihydroxybenzoic acid saturated solution is transferred in teat glass, used
ParafilmTM test tube mouth pricks 3 apertures with needle on sealed membrane, stands, and room temperature volatilization starts that water white transparency is precipitated after 10 days
Bulk crystals.
(3) crystal of precipitation is determined as Vortioxetine -2,5- dihydroxy benzenes first by single crystal diffraction and Shelxtl softwares
The new salt form of acid, crystallographic features are referring to table 1, and crystal structure is referring to Fig. 4.
Embodiment 9
(1) by 20.00mg Vortioxetines and 10.00mg 2,5-dihydroxybenzoic acid, i.e. molar ratio is 4:5 two kinds of objects
Matter solution is 1 in the volume ratio of 5mL acetone and water:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances completely molten
It solves and reacts, obtain Vortioxetine -2,5-dihydroxybenzoic acid saturated solution.
(2) Vortioxetine in reaction vessel -2,5-dihydroxybenzoic acid saturated solution is transferred in teat glass, used
ParafilmTM test tube mouth pricks 3 apertures with needle on sealed membrane, stands, and room temperature volatilization starts that water white transparency is precipitated after 7 days
Bulk crystals.
(3) crystal of precipitation is determined as the new salt form of Vortioxetine -2,5-dihydroxybenzoic acid by single crystal diffraction, it is brilliant
Body feature is referring to table 1.
Embodiment 10
(1) by 20.00mg Vortioxetines and 10.00mg 2,5-dihydroxybenzoic acid, i.e. molar ratio is 4:5 two kinds of objects
It is 2 that matter, which is dissolved in 5mL acetonitriles and the volume ratio of water,:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances complete
It dissolves and reacts, obtain Vortioxetine -2,5-dihydroxybenzoic acid saturated solution.
(2) Vortioxetine in reaction vessel -2,5-dihydroxybenzoic acid saturated solution is transferred in teat glass, used
ParafilmTM test tube mouth pricks 3 apertures with needle on sealed membrane, stands, and room temperature volatilization starts that water white transparency is precipitated after 15 days
Bulk crystals.
(3) crystal of precipitation is determined as the new salt form of Vortioxetine -2,5-dihydroxybenzoic acid by single crystal diffraction, it is brilliant
Body feature is referring to table 1.
Embodiment 11
(1) by 20.00mg Vortioxetines and 10.00mg 2,6-DHBAs, i.e. molar ratio is 4:5 two kinds of objects
The volume ratio that matter is dissolved in 5mL first alcohol and waters is 1:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances complete
It dissolves and reacts, obtain Vortioxetine -2,6-DHBA saturated solution.
(2) Vortioxetine in reaction vessel -2,6-DHBA saturated solution is transferred in teat glass, used
ParafilmTM test tube mouth pricks 3 apertures with needle on sealed membrane, stands, and room temperature volatilization starts that water white transparency is precipitated after 7 days
Bulk crystals.
(3) crystal of precipitation is determined as Vortioxetine -2,6- dihydroxy benzenes first by single crystal diffraction and Shelxtl softwares
The new salt form of acid, crystallographic features are referring to table 1, and crystal structure is referring to Fig. 5.
Embodiment 12
(1) by 20.00mg Vortioxetines and 10.00mg 2,6-DHBAs, i.e. molar ratio is 4:5 two kinds of objects
Matter is dissolved in 5mL acetonitriles.1h is stirred under confined conditions, two kinds of substances is made to be completely dissolved and react, and obtains Vortioxetine -2,6-
Dihydroxy-benzoic acid saturated solution.
(2) Vortioxetine in reaction vessel -2,6-DHBA saturated solution is transferred in teat glass, used
ParafilmTM test tube mouth pricks 3 apertures with needle on sealed membrane, stands, and room temperature volatilization starts that water white transparency is precipitated after 20 days
Bulk crystals.
(3) crystal of precipitation is determined as the new salt form of Vortioxetine -2,6-DHBA by single crystal diffraction, it is brilliant
Body feature is referring to table 1.
Embodiment 13
(1) by 20.00mg Vortioxetines and 10.00mg 2,6-DHBAs, i.e. molar ratio is 4:5 two kinds of objects
It is 2 that matter, which is dissolved in 5mL acetone and the volume ratio of water,:In 1 mixed solution.1h is stirred under confined conditions, makes two kinds of substances complete
It dissolves and reacts, obtain Vortioxetine -2,6-DHBA saturated solution.
(2) Vortioxetine in reaction vessel -2,6-DHBA saturated solution is transferred in teat glass, used
ParafilmTM test tube mouth pricks 3 apertures with needle on sealed membrane, stands, and room temperature volatilization starts that water white transparency is precipitated after 7 days
Bulk crystals.
(3) crystal of precipitation is determined as the new salt form of Vortioxetine -2,6-DHBA by single crystal diffraction, it is brilliant
Body feature is referring to table 1.
Embodiment 14
(1) by 1g and 0.516g 2,3- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of substances are added in mortar,
It stirs evenly, instills 2mL methanol, grind 10min, be positioned over 2h in air.
(2) it repeats that 2mL methanol, grinding and the operation of placement is added dropwise in the material of 2h in air is placed in, is repeated 5 times, obtains
To white powder sample.
(3) crystal of precipitation is determined that it is into the new salt of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate by testing
Type, fusing point are 200 DEG C (Figure 14), have good thermodynamic stability.Infrared spectrum is referring to Figure 10, the reality and reason of new salt form
By simulation PXRD comparison diagrams referring to Fig. 6.
Embodiment 15
(1) by 1g and 0.516g 2,4- dihydroxy-benzoic acids, i.e. molar ratio are 4:5 two kinds of substances are added in mortar,
It stirs evenly, instills 2mL toluene, grind 10min, be positioned over 2h in air.
(2) it repeats that 2mL toluene, grinding and the operation of placement is added dropwise in the material of 2h in air is placed in, is repeated 5 times, obtains
To white powder sample.
(2) crystal of precipitation is determined that it is into half toluene solvant of Vortioxetine -2,4 dihydroxy-benzoic acid by testing
The new salt form of object, the reality and theoretical modeling PXRD comparison diagrams of new salt form are referring to Fig. 7, and infared spectrum is referring to Figure 11.
Embodiment 16
(1) by 1g and 0.516g 2,5-dihydroxybenzoic acid, i.e. molar ratio is 4:5 two kinds of substances are added in mortar,
It stirs evenly, instills 2mL methanol, grind 10min, be positioned over 2h in air.
(2) it repeats that 2mL methanol, grinding and the operation of placement is added dropwise in the material of 2h in air is placed in, is repeated 5 times, obtains
To white powder sample.
(2) crystal of precipitation is determined that it is into the new salt form of Vortioxetine -2,5 dihydroxy-benzoic acid, fusing point is by testing
275 DEG C (Figure 15), have good thermodynamic stability.The reality and theoretical modeling PXRD comparison diagrams of new salt form are red referring to Fig. 8
Outer collection of illustrative plates is referring to Figure 12.
Embodiment 17
(1) by 1g and 0.516g 2,6-DHBAs, i.e. molar ratio is 4:5 two kinds of substances are added in mortar,
It stirs evenly, instills 2mL methanol, grind 10min, be positioned over 2h in air.
(2) it repeats that 2mL methanol, grinding and the operation of placement is added dropwise in the material of 2h in air is placed in, is repeated 5 times, obtains
To white powder sample.
(2) crystal of precipitation is determined that it is into the new salt form of Vortioxetine -2,6 dihydroxy-benzoic acid, fusing point is by testing
195 DEG C (Figure 16), have good thermodynamic stability.The reality and theoretical modeling PXRD comparison diagrams of new salt form are red referring to Fig. 9
Outer collection of illustrative plates is referring to Figure 13.
The crystallographic parameter of 1 Vortioxetine of table and new salt form
Claims (10)
1. the new salt form of Vortioxetine-dihydroxy-benzoic acid, which is characterized in that the new salt form is with Vortioxetine and dihydroxy benzenes first
Acid is connected to be formed by N-HO hydrogen bonds, including the new salt form of Vortioxetine-dihydroxy-benzoic acid and Vortioxetine-dihydroxy
The new salt form of yl benzoic acid solvate, wherein, the dihydroxy-benzoic acid includes 2,3- dihydroxy-benzoic acids, 2,4- dihydroxy
Benzoic acid, 2,5- dihydroxy-benzoic acids and 2,6- dihydroxy-benzoic acids.
2. the new salt form of Vortioxetine-dihydroxy-benzoic acid according to claim 1, which is characterized in that the new salt form is
The new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrates, half toluene solvant of Vortioxetine -2,4- dihydroxy-benzoic acids
The new salt form of object, the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids and the new salt form of Vortioxetine -2,6- dihydroxy-benzoic acids.
3. the new salt form of Vortioxetine-dihydroxy-benzoic acid according to claim 2, which is characterized in that the Vortioxetine-
The molar ratio of Vortioxetine, 2,3- dihydroxy-benzoic acids and water is 1 in the new salt form of 2,3- dihydroxy-benzoic acid semihydrates:1:
0.5；Vortioxetine, 2,4- dihydroxy benzenes in the half new salt form of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids
The molar ratio of formic acid and toluene is 1:1:0.5；Vortioxetine and 2 in the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids,
The molar ratio of 5- dihydroxy-benzoic acids is 1:1；Vortioxetine and 2 in the new salt form of Vortioxetine -2,6- dihydroxy-benzoic acids,
The molar ratio of 6- dihydroxy-benzoic acids is 1:1.
4. the new salt form of Vortioxetine-dihydroxy-benzoic acid according to Claims 2 or 3, which is characterized in that described fertile for west
The crystallographic features of the new salt form of spit of fland -2,3- dihydroxy-benzoic acid semihydrates：A=26.5624 (5), b=8.10730 (10), c
=23.0375 (5), bond angle be α=90 °, β=92.162 (2), γ=90 °, V=4957.58 (16), Z=4；It is described fertile for west
The X- powder diffractograms of the new salt form of spit of fland -2,3- dihydroxy-benzoic acid semihydrates 2 θ for 6.64 ± 0.2,7.68 ± 0.2,
10.34±0.2、11.36±0.2、12.04±0.2、13.28±0.2、13.70±0.2、14.78±0.2、15.40±0.2、
16.54±0.2、17.04±0.2、18.60±0.2、19.28±0.2、20.00±0.2、20.82±0.2、21.18±0.2、
21.72±0.2、22.30±0.2、22.84±0.2、23.14±0.2、23.20±0.2、23.88±0.2、24.36±0.2、
24.82±0.2、25.60±0.2、25.94±0.2、27.44±0.2、29.34±0.2、29.82±0.2、30.26±0.2、
32.04 ± 0.2 have characteristic peak.
5. the new salt form of Vortioxetine-dihydroxy-benzoic acid according to Claims 2 or 3, which is characterized in that described fertile for west
The crystallographic features of the half new salt form of toluene solvate of spit of fland -2,4- dihydroxy-benzoic acids：A=12.3577 (8), b=12.9526
(6), c=17.4064 (11), bond angle be α=82.219 (5) °, β=80.757 (6), γ=87.213 (4) °, V=2723.6
(3), Z=2；The X- powder diffractograms of the half new salt form of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids are 2
θ for 9.16 ± 0.2,10.38 ± 0.2,11.54 ± 0.2,12.14 ± 0.2,13.08 ± 0.2,13.94 ± 0.2,14.94 ±
0.2、15.32±0.2、15.62±0.2、16.20±0.2、17.28±0.2、18.42±0.2、18.98±0.2、19.58±
0.2、20.84±0.2、21.46±0.2、22.48±0.2、23.10±0.2、23.78±0.2、24.32±0.2、25.52±
0.2nd, 26.44 ± 0.2,27.48 ± 0.2,28.14 ± 0.2 have characteristic peak.
6. the new salt form of Vortioxetine-dihydroxy-benzoic acid according to Claims 2 or 3, which is characterized in that described fertile for west
The crystallographic features of the new salt form of spit of fland -2,5- dihydroxy-benzoic acids：Bond distance a=9.9394 (8), b=10.1982 (6), c=
12.1724 (9), bond angle be α=89.628 (6) °, β=76.453 (7), γ=85.399 (6) °, V=1195.55 (15), Z=
2；The X- powder diffractograms of the new salt form of Vortioxetine -2,5- dihydroxy-benzoic acids 2 θ for 9.16 ± 0.2,10.38 ±
0.2、11.54±0.2、12.14±0.2、13.08±0.2、13.94±0.2、14.94±0.2、15.32±0.2、15.62±
0.2、16.20±0.2、17.28±0.2、18.42±0.2、18.98±0.2、19.58±0.2、20.84±0.2、21.46±
0.2、22.48±0.2、23.10±0.2、23.78±0.2、24.32±0.2、25.52±0.2、26.44±0.2、27.48±
0.2nd, 28.14 ± 0.2 have characteristic peak.
7. the new salt form of Vortioxetine-dihydroxy-benzoic acid according to Claims 2 or 3, which is characterized in that described fertile for west
The crystallographic features of the new salt form of spit of fland -2,6- dihydroxy-benzoic acids：Bond distance a=17.0666 (8), b=6.3133 (2), c=
22.2716 (10), bond angle be α=90 °, β=107.112 (5), γ=90 °, V=2293.46 (17), Z=4；It is described fertile for west
The X- powder diffractograms of the new salt form of spit of fland -2,6- dihydroxy-benzoic acids 2 θ for 6.02 ± 0.2,7.84 ± 0.2,11.08 ±
0.2、11.94±0.2、13.84±0.2、14.70±0.2、15.32±0.2、15.82±0.2、16.26±0.2、17.22±
0.2、18.16±0.2、19.46±0.2、20.84±0.2、21.26±0.2、21.98±0.2、22.56±0.2、24.06±
0.2nd, 25.20 ± 0.2,26.10 ± 0.2,26.92 ± 0.2,27.70 ± 0.2,29.06 ± 0.2 have characteristic peak.
8. the preparation method of claim 1-7 any one of them Vortioxetine-new salt form of dihydroxy-benzoic acid, feature exist
In including the following steps：
(1) Vortioxetine, dihydroxy-benzoic acid are dissolved in solvent, stir 0.5h~1h, obtain Vortioxetine-dihydroxy benzenes
The saturated solution of the new salt form of formic acid；
(2) saturated solution is transferred in teat glass, and ParafilmTM test tube mouth pricks hole on sealed membrane, is stood, room temperature
Volatilization, crystallization is complete after 4~30 days, obtains the new salt form of Vortioxetine-dihydroxy-benzoic acid.
9. the preparation method of claim 1-7 any one of them Vortioxetine-new salt form of dihydroxy-benzoic acid, feature exist
In including the following steps：
(1) Vortioxetine, dihydroxy-benzoic acid are added in mortar, stirred evenly, instill solvent, ground 10min, be positioned over
2h in air；
(2) solvent, grinding and the operation of placement is added dropwise in the material of 2h in repeating said steps (1) in air is placed in, repeats 3
~5 times, obtain the new salt form of Vortioxetine-dihydroxy-benzoic acid.
10. the preparation method of the new salt form of Vortioxetine-dihydroxy-benzoic acid according to claim 8 or claim 9, feature exist
In Vortioxetine and the molar ratio of dihydroxy-benzoic acid are 1 in the step (1):3~2:1, mole of Vortioxetine and solvent
Than being 1:1~1:10；In the step (1), the solvent of the new salt form of Vortioxetine -2,3- dihydroxy-benzoic acid semihydrate is prepared
For any one in aqueous acetone solution, methanol aqueous solution, methanol, ethanol water, isopropanol and acetonitrile solution, prepare
The solvent of the half new salt form of toluene solvate of Vortioxetine -2,4- dihydroxy-benzoic acids for toluene, methylbenzene methanol mixed solution and
Any one in toluene alcohol mixed solution, the solvent for preparing the new salt form of Vortioxetine -2,5-dihydroxybenzoic acid are acetone
Any one in aqueous solution, methanol, methanol aqueous solution and acetonitrile solution prepares Vortioxetine -2,6-DHBA
The solvent of new salt form is any one in aqueous acetone solution, methanol, methanol aqueous solution and acetonitrile.
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