CN107344934B - The solid form of pharmaceutically active substance - Google Patents
The solid form of pharmaceutically active substance Download PDFInfo
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- CN107344934B CN107344934B CN201610291115.XA CN201610291115A CN107344934B CN 107344934 B CN107344934 B CN 107344934B CN 201610291115 A CN201610291115 A CN 201610291115A CN 107344934 B CN107344934 B CN 107344934B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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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 invention discloses compound N-(the 5- ((4- (5 that a kind of Formulas I indicates, 6- dihydro -4H- pyrrolo- [3,2,1-ij] quinoline -1- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) methylamino) -4- methoxyphenyl) acrylamide solid form and preparation method thereof, the solid form stability is high, pharmaceutically it is EGFR (surface growth factor receptors) modulator, can be used for the prevention and treatment for the disease that the surface growth factor receptors of certain variation patterns are mediated.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to compound N-(5- ((4- (5, the 6- dihydro -4H- pyrroles that Formulas I indicates
And [3,2,1-ij] quinoline -1- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) methylamino) -4- methoxy
Base phenyl) acrylamide solid form and preparation method thereof.
Background technique
(((4- (5,6- dihydro -4H- pyrrolo- [3,2,1-ij] quinoline -1- base) is phonetic by 5- for the compound N-indicated by Formulas I
Pyridine -2- base) amino) -2- ((2- (dimethylamino) ethyl) methylamino) -4- methoxyphenyl) acrylamide, structural formula
Are as follows:
The compound is described in patent WO2015175632 for the first time, it was recently reported that its synthetic method, but its different salt is not mentioned
Crystal form in terms of problem.
Active pharmaceutical ingredient is prepared with a variety of different forms such as pharmaceutically acceptable salt of compound of formula I, is used for
The prevention and treatment for the disease that the surface growth factor receptors of certain variation patterns are mediated can be their one or more
Crystalline forms, different crystalline forms can change its physicochemical properties, such as lead to different solubility, Thermodynamically stable
Property, various forms of density or fusing point.Therefore, the effect of such physicochemical properties can be to active constituent or bioavilability
With important influence.
Summary of the invention
The present invention provides the solid form and preparation method thereof of compound of formula I, specifically:
A kind of solid form of compound of formula I,
Wherein the solid form is selected from mesylate, sulfate or the hydrochloride of compound of formula I.
Further, the solid form is crystal.
Further, the solid form is the mesylate of the compound of formula I of crystal form.
Further, the mesylate of the compound of formula I be crystal form A, in X-ray powder diffraction figure, especially with
There is characteristic diffraction: 25.0 ± 0.2 °, 20.6 ± 0.2 °, 17.9 ± 0.2 °, X-ray diffracting spectrum at lower 2 θ of the angle of diffraction
Substantially such as Fig. 1；The differential calorimetry curve of maximum value is shown with about 246.60 DEG C；With the red of following characteristics absorption peak
External spectrum: 3249cm-1、3034cm-1、1942cm-1、1916cm-1、1675cm-1、1576cm-1、1552cm-1、1533cm-1、
1358cm-1、1159cm-1、727cm-1。
Further, the preparation method of the Mesylate Form A of the compound of formula I is that compound of formula I solvent is molten
Methane sulfonic acid is added dropwise in solution, and low temperature stirring and crystallizing to obtain the final product.
Further, the solid form of the mesylate of the compound of formula I is crystal form B, in X-ray powder diffraction figure
In, have characteristic diffraction especially at following 2 θ of the angle of diffraction: 14.9 ± 0.2 °, 22.7 ± 0.2 °, 26.2 ± 0.2 °, X- is penetrated
Ray diffraction diagram spectrum is substantially such as Fig. 5；The differential calorimetry curve of maximum value is shown with about 247.68 DEG C；With following characteristics
The infrared spectroscopy of absorption peak: 3249cm-1、3034cm-1、1906cm-1、1708cm-1、1675cm-1、1618cm-1、1575cm-1、
1533cm-1、1234cm-1、1160cm-1、807cm-1。
Further, the preparation method of the Mesylate Form B of the compound of formula I is to add compound of formula I solvent
Methane sulfonic acid is added dropwise to reflux dissolution in heat, cooling stirring and crystallizing to obtain the final product, wherein the solvent is methylene chloride, acetone or it is mixed
It closes, dosage is 5~40 times of compound of formula I, and preferably 10~15 times, in terms of ml/g unit, the crystallization temperature is 10~20
℃。
Further, the solid form is the sulfate of the compound of formula I of crystal form, in X-ray powder diffraction
In figure, there is characteristic diffraction: 15.3 ± 0.2 °, 20.5 ± 0.2 °, 25.2 ± 0.2 °, X- especially at following 2 θ of the angle of diffraction
X ray diffraction map is substantially such as Fig. 9；The differential calorimetry curve of maximum value is shown with about 260.05 DEG C；With following spy
Levy the infrared spectroscopy of absorption peak: 3220cm-1、2653cm-1、1672cm-1、1582cm-1、1530cm-1、1385cm-1、1213cm-1、
1169cm-1、1110cm-1、833cm-1、753cm-1。
Further, the preparation method of the sulfate of the compound of formula I of the crystal form is by compound of formula I solvent
Dissolution is added dropwise the concentrated sulfuric acid, is stirred for crystallization to obtain the final product, wherein the solvent is methylene chloride, acetone or its mixing, dosage is formula
5~40 times of Compound I, preferably 10~15 times, in terms of ml/g unit, the crystallization temperature is 10~20 DEG C.
Further, the solid form is the hydrochloride of the compound of formula I of crystal form, in X-ray powder diffraction
In figure, there is characteristic diffraction: 19.8 ± 0.2 °, 20.6 ± 0.2 °, 20.9 ± 0.2 °, X- especially at following 2 θ of the angle of diffraction
X ray diffraction map is substantially such as Figure 13；The differential calorimetry curve of maximum value is shown with about 265.99 DEG C；With following
The infrared spectroscopy of characteristic absorption peak: 3208cm-1、3079cm-1、1907cm-1、1757cm-1、1665cm-1、1533cm-1、
1376cm-1、1227cm-1、1157cm-1、760cm-1、609cm-1。
Further, the preparation method of the hydrochloride of the compound of formula I of the crystal form is by compound of formula I solvent
Dissolution is added dropwise concentrated hydrochloric acid, is stirred for crystallization to obtain the final product, wherein the solvent is methylene chloride, acetone or its mixing, dosage is formula
5~40 times of Compound I, preferably 10~15 times, in terms of ml/g unit, the crystallization temperature is 10~20 DEG C.
In addition, the purposes the invention further relates to the solid form of compound of formula I in preparation pharmaceutical composition, the medicine group
Close prevention and treatment of the object for the disease that the surface growth factor receptors of certain variation patterns are mediated.
The crystal form of compound of formula I difference salt of the present invention has to pharmaceutical processing and applies strong physical property,
Including preferable solubility, stability height and non-hygroscopic.Firstly, being compared with salt-independent shape, have in water and simulation hydrochloric acid
There is preferable dissolubility, is suitble to prepare stable pharmaceutical preparation；Compound of formula I difference salt crystal according to the present invention simultaneously
DSC peak value is single, it was demonstrated that it has stable heat exchange range, and crystal itself is relatively stable；And setting-out is being accelerated to test (temperature
Be 40 DEG C, relative humidity 75%) and long-term setting-out experiment (temperature is 25 DEG C, relative humidity 60%) in, purity and have
Impurity is closed without large change, illustrating it, stability is preferable with this condition；But under the conditions of 80 DEG C are dried under reduced pressure for 24 hours, Formulas I chemical combination
Object methyl sulfonate crystal form A is converted into crystal form B, illustrates that in high temperature crystal phenomenon, storage process easily occur for methyl sulfonate crystal form A
In it should be noted that and crystal form B better heat stability.
The solvent toxicity used in the crystal form preparation process of Compound I difference salt provided by invention is small, system
Standby process safety, products obtained therefrom purity are higher.
The pharmaceutically acceptable salt of compound of formula I disclosed herein can be further processed into those skilled in the art institute
Well known any kind of solid drugs formulated or dosage form, Solid form compositions include powder agent, tablet, glue
Capsule, pill, powder, suspension etc.；Liquid form preparation includes solution, suspension and emulsion etc..Its pharmaceutical composition can be by Formulas I
Compound difference salt and its crystal form and one or more non-toxic pharmaceutically acceptable carriers and filler, lubricant, dilution
The excipient such as agent, solubilizer, corrigent, stabilizer, thickener, colorant, sweetener, adhesive or disintegrating agent, and it is necessary
When other active components form together, the carrier and excipient are known to this technical field.
The solid form so obtained is pharmaceutically EGFR (surface growth factor receptors) modulator, can be used for certain changes
The prevention and treatment for the disease that the surface growth factor receptors of special-shaped state are mediated.
Detailed description of the invention
Attached drawing 1: the X-ray powder diffraction collection of 1 compound of formula I methyl sulfonate crystal form A of embodiment；
Attached drawing 2: the infared spectrum of 1 compound of formula I methyl sulfonate crystal form A of embodiment；
Attached drawing 3: the thermogravimetric analysis map (TG) of 1 compound of formula I methyl sulfonate crystal form A of embodiment；
Attached drawing 4: the differential calorimetry curve map (DSC) of 1 compound of formula I methyl sulfonate crystal form A of embodiment；
Attached drawing 5: the X-ray powder diffraction collection of 3 compound of formula I methyl sulfonate crystal form B of embodiment；
Attached drawing 6: the infrared spectrogram of 3 compound of formula I methyl sulfonate crystal form B of embodiment；
Attached drawing 7: the thermogravimetric analysis map (TG) of 3 compound of formula I methyl sulfonate crystal form B of embodiment；
Attached drawing 8: the differential calorimetry curve map (DSC) of 3 compound of formula I methyl sulfonate crystal form B of embodiment；
Attached drawing 9: the X-ray powder diffraction collection of 5 compound of formula I vitriol of embodiment；
Attached drawing 10: the infrared spectrogram of 5 compound of formula I vitriol of embodiment；
Attached drawing 11: the thermogravimetric analysis map (TG) of 5 compound of formula I vitriol of embodiment；
Attached drawing 12: the differential calorimetry curve map (DSC) of 5 compound of formula I vitriol of embodiment；
Attached drawing 13: the X-ray powder diffraction collection of 7 compound of formula I hydrochloric acid salt crystal of embodiment
Attached drawing 14: the infrared spectrogram of 7 compound of formula I hydrochloric acid salt crystal of embodiment；
Attached drawing 15: the thermogravimetric analysis map (TG) of 7 compound of formula I hydrochloric acid salt crystal of embodiment；
Attached drawing 16: the differential calorimetry curve map (DSC) of 7 compound of formula I hydrochloric acid salt crystal of embodiment；
Specific embodiment
Following detailed embodiment describe how to prepare various compounds and/or implement various methods of the invention and
It is interpreted as only illustrative, is not the limitation to above disclosure.Those skilled in the art will be rapidly and accurately
Identify the variation of reactant and reaction condition and technical aspect.
Embodiment 1: the preparation of compound of formula I Mesylate Form A
300mg compound of formula I is added in 3ml methylene chloride, is stirred to dissolved clarification, 10~20 DEG C of dropwise additions of temperature control are prepared
Methane sulfonic acid (methane sulfonic acid 55mg is dissolved in 1ml methylene chloride), filtering, 50 DEG C of vacuum drying obtain product 287mg, yield
95.7%, X- powder diffraction spectrum with and infrared spectroscopy respectively such as Fig. 1 and Fig. 2.
Embodiment 2: the preparation of compound of formula I Mesylate Form A
300mg compound of formula I is added in 4.5ml methylene chloride, is stirred to dissolved clarification, 10~20 DEG C of dropwise additions of temperature control prepare
Methane sulfonic acid (methane sulfonic acid 55mg is dissolved in 1ml methylene chloride), filtering, 50 DEG C vacuum drying, obtain product 262mg, yield
87.3%, X- powder diffraction spectrum and infrared spectroscopy are compared with Example 1 in error range.
Embodiment 3: the preparation of compound of formula I Mesylate Form B
300mg compound of formula I is added in 3ml acetone, reflux dissolution is heated to, configured methane sulfonic acid (first is added dropwise
Base sulfonic acid 57mg is dissolved in 1ml acetone), 10~20 DEG C, temperature control stirring crystallization 4h are cooled to, filtering, 50 DEG C of vacuum drying are produced
Object 250mg, yield 80.1%.X- powder diffraction spectrum with and infrared spectroscopy respectively such as Fig. 5 and Fig. 6.
Embodiment 4: the preparation of compound of formula I Mesylate Form B
300mg compound of formula I is added in 4.5ml acetone, reflux dissolution is heated to, configured methane sulfonic acid is added dropwise
(methane sulfonic acid 57mg is dissolved in 1ml acetone) is cooled to 10~20 DEG C, temperature control stirring crystallization 4h, and filtering, 50 DEG C of vacuum drying obtain
To product 250mg, yield 83.3%, X- powder diffraction spectrum and infrared spectroscopy are compared with Example 3 in error range.
Embodiment 5: the preparation of compound of formula I vitriol
280mg compound is added in 2.8ml methylene chloride, 10~20 DEG C of temperature control are added dropwise the configured concentrated sulfuric acid (dense sulphur
Sour 52mg is dissolved in 1ml methylene chloride), 10~20 DEG C of temperature control, stirring and crystallizing 12~for 24 hours, filtering, 50 DEG C of vacuum drying obtain product
150mg, yield 53.6%.X- powder diffraction spectrum with and infrared spectroscopy respectively such as Fig. 9 and Figure 10.
Embodiment 6: the preparation of compound of formula I vitriol
280mg compound is added in 4.2ml methylene chloride, 10~20 DEG C of temperature control are added dropwise the configured concentrated sulfuric acid (dense sulphur
Sour 52mg is dissolved in 1ml methylene chloride), 10~20 DEG C of temperature control, stirring and crystallizing 12~for 24 hours, filtering, 50 DEG C of vacuum drying obtain product
142mg, yield 50.7%, X- powder diffraction spectrum and infrared spectroscopy are compared with Example 5 in error range.
Embodiment 7: the preparation of compound of formula I hydrochloric acid salt crystal
350mg compound is added in 3.5ml methylene chloride, (concentrated hydrochloric acid 64mg is molten for 10~20 DEG C of dropwise addition concentrated hydrochloric acids of temperature control
In 1ml methylene chloride), 10~20 DEG C of stirring and crystallizings 12 of temperature control~for 24 hours, filtering, 50 DEG C of vacuum drying obtain product 213mg, receive
Rate 60.9%.X- powder diffraction spectrum with and infrared spectroscopy respectively such as Figure 13 and Figure 14.
Embodiment 8: the preparation of compound of formula I hydrochloric acid salt crystal
350mg compound is added in 5.3ml methylene chloride, (concentrated hydrochloric acid 64mg is molten for 10~20 DEG C of dropwise addition concentrated hydrochloric acids of temperature control
In 1ml methylene chloride), 10~20 DEG C of stirring and crystallizings 12 of temperature control~for 24 hours, filtering, 50 DEG C of vacuum drying obtain product 205mg, receive
Rate 58.6%, X- powder diffraction spectrum and infrared spectroscopy are compared with Example 7 in error range.
Effect example: the property of compound of formula I solid form
One, dissolubility
Precision weighs dissolution of the crystal of suitable compound of formula I difference salt in water and simulation hydrochloric acid (pH=1~2)
Degree, concrete outcome are shown in Table 1, table 2.
Solubility in 1 compound of formula I of table and its different salt crystal different solvents
The above test proves, compound of formula I at after salt with can be dissolved in water, before at salt compared with solubility greatly improve.
Two, stability
1. differential scanning calorimetry (DSC) is tested
Instrument: 204 type differential thermal analyzer of NETZSCH DSC
Heating rate: 10.00 DEG C/min
DSC peak temperature:
The DSC peak temperature of 2 compound of formula I difference salt crystal of table
The above test proves that compound of formula I difference salt crystal DSC peak value is single, it was demonstrated that it has stable heat exchange amount
Journey, crystal itself are relatively stable.
2. crystal stability is tested
Compound of formula I difference salt crystal sample is dried under reduced pressure for 24 hours in 80 DEG C, measures its X-ray diffracting spectrum.As a result
It has been shown that, methyl sulfonate crystal form A can be transformed into methyl sulfonate crystal form B；Its methyl sulfonate crystal form B, vitriol, salt
Same Fig. 4,7 and 10 of X-ray powder diffraction (XRD) result of hydrochlorate crystal.
3. accelerating setting-out test
Compound of formula I difference salt crystal sample is placed in culture dish, being placed in temperature is 40 DEG C, relative humidity 75%
Under the conditions of, respectively at 0, January, 2 months, March, June sample detection, the results are shown in Table 3:
3 compound of formula I difference salt crystal of table accelerates setting-out test
Above it is demonstrated experimentally that compound of formula I difference salt crystal accelerates in setting-out test, each project of investigating becomes without obvious
Change, illustrates that three kinds of corresponding crystal forms of salt form are more stable under the conditions of Acceleration study.
4. long-term setting-out experiment
Compound of formula I difference salt crystal sample is placed in culture dish, being placed in temperature is 25 DEG C, relative humidity 60%
Under the conditions of, respectively at 0, March, June sample detection, the results are shown in Table 4:
The long-term setting-out test of 4 compound of formula I difference salt crystal of table
Above it is demonstrated experimentally that in the long-term setting-out test of compound of formula I difference salt crystal, each project of investigating becomes without obvious
Change, illustrates that three kinds of corresponding crystal forms of salt form are more stable under the conditions of long-term experiment.
The above results can obtain, and compound of formula I difference salt crystal according to the present invention is accelerating setting-out test (temperature 40
DEG C, relative humidity 75%) and long-term setting-out experiment (temperature be 25 DEG C, relative humidity 60%) in, purity with it is related miscellaneous
Matter illustrates that its stability is preferable without large change.
Claims (18)
1. a kind of Mesylate Form A of compound of formula I,
Its X-ray diffracting spectrum such as Fig. 1.
2. Mesylate Form A according to claim 1, it is characterised in that have 246.60 DEG C of display maximum values shows difference
Scanning calorimetric curve.
3. Mesylate Form A according to claim 1, it is characterised in that its infrared light with following characteristics absorption peak
Spectrum: 3249cm-1、3034cm-1、1942cm-1、1916cm-1、1675cm-1、1576cm-1、1552cm-1、1533cm-1、1358cm-1、1159cm-1、727cm-1。
4. the preparation method of Mesylate Form A described in a kind of claim 1, it is characterised in that compound of formula I solvent is molten
Methane sulfonic acid is added dropwise in solution, and low temperature stirring and crystallizing to obtain the final product；The solvent is methylene chloride, acetone or its mixing, and dosage is Formulas I
5~40 times of compound, in terms of ml/g unit；The crystallization temperature is 10~20 DEG C.
5. a kind of Mesylate Form B of compound of formula I,
Its X-ray diffracting spectrum such as Fig. 5.
6. Mesylate Form B according to claim 5, it is characterised in that have 247.68 DEG C of display maximum values shows difference
Scanning calorimetric curve.
7. Mesylate Form B according to claim 5, it is characterised in that its infrared light with following characteristics absorption peak
Spectrum: 3249cm-1、3034cm-1、1906cm-1、1708cm-1、1675cm-1、1618cm-1、1575cm-1、1533cm-1、1234cm-1、1160cm-1、807cm-1。
8. the preparation method of Mesylate Form B described in a kind of claim 5, it is characterised in that add compound of formula I solvent
To reflux dissolution methane sulfonic acid is added dropwise, cooling stirring and crystallizing in heat to obtain the final product；The solvent be methylene chloride, acetone or its mixing,
Dosage is 5~40 times of compound of formula I, in terms of ml/g unit；Crystallization temperature is 10~20 DEG C.
9. a kind of sulfate crystal form of compound of formula I,
Its X-ray diffracting spectrum such as Fig. 9.
10. sulfate crystal form according to claim 9, it is characterised in that have 260.05 DEG C of display maximum values shows that difference is swept
Retouch calorimetric curve.
11. sulfate crystal form according to claim 9, it is characterised in that its infrared light with following characteristics absorption peak
Spectrum: 3220cm-1、2653cm-1、1672cm-1、1582cm-1、1530cm-1、1385cm-1、1213cm-1、1169cm-1、1110cm-1、833cm-1、753cm-1。
12. the preparation method of sulfate crystal form described in a kind of claim 9, it is characterised in that compound of formula I is dissolved with solvent,
The concentrated sulfuric acid is added dropwise, is stirred for crystallization to obtain the final product；The solvent is methylene chloride, acetone or its mixing, and dosage is compound of formula I
5~40 times, in terms of ml/g unit；Crystallization temperature is 10~20 DEG C.
13. a kind of hydrochloride Form of compound of formula I,
Its X-ray diffracting spectrum such as Figure 13.
14. hydrochloride Form according to claim 13, it is characterised in that have 265.99 DEG C of display maximum values shows difference
Scanning calorimetric curve.
15. hydrochloride Form according to claim 13, it is characterised in that its infrared light with following characteristics absorption peak
Spectrum: 3208cm-1、3079cm-1、1907cm-1、1757cm-1、1665cm-1、1533cm-1、1376cm-1、1227cm-1、1157cm-1、760cm-1、609cm-1。
16. a kind of preparation method of hydrochloride Form described in claim 13, it is characterised in that compound of formula I solvent is molten
Solution is added dropwise concentrated hydrochloric acid, is stirred for crystallization to obtain the final product；The solvent is methylene chloride, acetone or its mixing, and dosage is Formulas I chemical combination
5~40 times of object, in terms of ml/g unit；Crystallization temperature is 10~20 DEG C.
17. according to the described in any item preparation methods of claim 4,8,12,16, it is characterised in that the solvent usage is Formulas I
10~15 times of compound, in terms of ml/g unit.
18. purposes of the crystal form described in claim 1,5,9,13 in preparation pharmaceutical composition, the pharmaceutical composition is for becoming
The prevention and treatment for the disease that the surface growth factor receptors of special-shaped state are mediated.
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