CN106674217A - Racanisodamine crystal form and preparation method thereof - Google Patents
Racanisodamine crystal form and preparation method thereof Download PDFInfo
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- CN106674217A CN106674217A CN201611163375.5A CN201611163375A CN106674217A CN 106674217 A CN106674217 A CN 106674217A CN 201611163375 A CN201611163375 A CN 201611163375A CN 106674217 A CN106674217 A CN 106674217A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
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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
- C07B2200/07—Optical isomers
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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
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a racanisodamine crystal form and a preparation method thereof. The crystal form has the advantages of being high in degree of crystallinity, low in hygroscopicity, good in crystal form stability, high in dissolving speed and low in dissolving residue. According to the preparation method provided by the invention, low-toxicity ICH type II and type III solvents are adopted, and an operation is performed at room temperature or low temperature, so that the influence of the solvents on human and environment can be reduced to the maximum extent.
Description
Technical field
The application is related to pharmaceutical chemistry crystallization technique field.Specifically, the application is related to the crystal formation of raceanisodamine
And preparation method thereof.
Background technology
Raceanisodamine is a kind of anticholinergic agent, be mainly used in release smooth muscle spasm, stomach intestinal colic, biliary spasm with
And organophosphate poisoning etc., it can also be used to treat vertebral disc infection, sciatica, gastric and duodenal ulcers, retina
The diseases such as pigmental degeneration.Its chemical name is：The α H of (±) -6 beta-hydroxy -1；The α -ol tropates of 5 α H- tropanes -3.Molecular formula is：
C17H23NO4, molecular weight is 305.38.
Patent CN104130253A describes a kind of production method of Anisodamine, it is mentioned that after being crystallized with benzene
It is dried again, but whether do not refer to after drying is still crystalline solid.
The document of the works such as Liu Yong Taki《Alkaloid grinds in Radix Seu Herba Physochlainae Physaloidiss (Physochlaina Physaloides G.Don)
Study carefully》(Acta Pharmaceutica Sinica .1979,14 (8):497-501) report free alkali to crystallize from benzene, be colorless needles, fusing point 61~63
DEG C, it is the free alkali with a molecule benzene.
The document of the works such as Zheng Changsheng《The synthesis and separation of four optical isomers of Anisodamine》(Acta Pharmaceutica Sinica .1991,26
(2):96-102) report the synthesis of two kinds of configuration Anisodamine and separate.The crystallization of racemization product is not referred to.
The inventors discovered that, CN104130253 A patent systems use the class in ICH solvent classes for raceanisodamine
Solvent carbon tetrachloride and benzene, the ICH dissolvent residuals of two kinds of solvents require very high, respectively 4ppm and 2ppm, according to
CN104130253 A patents carry out raw material preparation and the molten residual underproof situations of ICH easily occur；No matter with reference to existing patent or text
Offer the raceanisodamine that the raceanisodamine for preparing still uses on the market and be same anhydrous crystal forms (herein
Represented with " crystal formation A " again), the present inventor has found under study for action, and crystal formation A belongs to Thermodynamically stable crystal formation, and stable state crystal formation has
The characteristics of energy is low, dissolubility is relatively small, dissolution velocity is relatively slow, and crystal formation Jing investigations have certain hygroscopicity.
Because the pharmacologic action of raceanisodamine is related to stomach intestinal colic, biliary spasm, organophosphate poisoning, vertebral disc infection, disappears
Change the acute dangerous diseases such as road ulcer, therefore improve the dissolution velocity of raceanisodamine to shorten to up to effective blood drug concentration
There is very big importance time.It is therefore desirable to develop that the crystal formation of raceanisodamine dissolution velocity can be improved, and
Solvent selected by the preparation process of the crystal formation should meet ICH dissolvent residual requirements, particularly meet a class solvent of high poison
ICH dissolvent residuals are required and hygroscopicity is low.
The content of the invention
It is an object of the invention to provide a kind of raceanisodamine crystal formation and preparation method thereof.The crystal formation is solid for crystalline state
Body, has fast dissolution velocity, the good advantage of stability of crystal form in medium such as water, stomach simulated solution, intestinal simulated solution and does not inhale
It is wet.Moreover, it relates to the preparation method of the crystal formation, the method is from two classes such as acetonitrile or three class solvents as crystallization
Medium, it is to avoid the use of a class solvent of high poison, and finished product fully meets the molten residual requirements of ICH.
According to the object of the invention, present disclosure is to provide raceanisodamine crystal formation I of solid-state and preparation method thereof.
Radiated using Cu-K α, the raceanisodamine crystal formation I (being represented with " crystal formation I " again herein) is with 2 θ angles
The X-ray powder diffraction figure of expression has following characteristics peak：7.3±0.2°、14.7±0.2°、15.7±0.2°、16.5±
0.2 °, 17.6 ± 0.2 ° and 22.2 ± 0.2 °.
In a currently preferred embodiment, the raceanisodamine crystal formation I is penetrated with the X- that 2 θ angles are represented
Line powder diagram has following characteristics peak：7.3±0.2°、10.5±0.2°、11.0±0.2°、14.7±0.2°、15.7±
0.2 °, 16.5 ± 0.2 °, 17.2 ± 0.2 °, 17.6 ± 0.2 °, 18.7 ± 0.2 °, 19.0 ± 0.2 °, 22.2 ± 0.2 ° and 23.2
±0.2°。
In a further preferred embodiment of the present invention, the raceanisodamine crystal formation I is represented with 2 θ angles
X-ray powder diffraction figure there is following characteristics peak and its relative intensity：
Without limitation, a representative instance of the raceanisodamine crystal formation I has XRPD figures as shown in Figure 2
Spectrum.
Without limitation, the TGA collection of illustrative plates of the raceanisodamine crystal formation I is as shown in Figure 3.
Without limitation, the DSC collection of illustrative plates of the raceanisodamine crystal formation I is as shown in Figure 4.
Compared with known raceanisodamine crystal formation A, the crystal formation I of the present invention has following beneficial property：
1) from adsorption isothermal curve in comparative example 1, the moisture absorption of raceanisodamine crystal formation A and crystal formation I is respectively
1.8% and 0.10%, the crystal formation I of the present invention has lower hygroscopicity；
2) from the dissolution velocity test result of comparative example 2, raceanisodamine crystal formation I is in water, stomach simulated solution, full abdomen
Dissolution velocity is faster than crystal formation A in intestinal simulated solution, empty stomach intestinal simulated solution；
3) from comparative example 3, raceanisodamine crystal formation I and crystal formation A is in room temperature, high temperature, high humidity, acceleration environment decentralization
Put 14 days crystal formations not changing, stability of crystal form is preferable；
4) from comparative example 4, the raceanisodamine crystal formation I that various preparation methoies are obtained in the present invention can meet
ICH dissolvent residuals are required.
Above-mentioned beneficial property shows：Compared with the raceanisodamine crystal formation A of prior art, the racemization Radix Anisodi Tangutici of the present invention
Alkali crystal formation I has various advantage performances, is suitable as the active component of pharmaceutical preparation.Raceanisodamine crystal formation I is crystalline state
Solid, degree of crystallinity is high, stability of crystal form is good, hygroscopicity is low, molten residual low, can avoid or reduce medicine manufacture and/or storage etc.
During quality, safety and stability problem, such as active component content is uneven, impurity etc., it is to avoid special and costliness
Packaging；Raceanisodamine crystal formation I dissolution velocities are fast, can arrive more quickly at effective blood drug concentration, quickly play drug effect,
It is particularly critical to rescue poisoning in time or shock patient；Raceanisodamine crystal formation I prepares solvent for use and is two, three class solvents
And can meet ICH dissolvent residual requirements, toxic and side effects are little, safe.
The present invention provides the preparation method of raceanisodamine crystal formation I, comprises the following steps：
Raceanisodamine is formed into suspension, stirring and crystallizing in acetonitrile or the mixed solvent containing acetonitrile, and then is separated
Crystal, is dried, and obtains raceanisodamine crystal formation I；
Preferably, the mixed solvent is formed selected from acetonitrile with water, alcohols, ketone, esters, ethers, cyclic ethers class, aromatics
Solvent；
Preferably, in the mixed solvent acetonitrile percent by volume be 50%~100%, more preferably 80%~
100%；
Preferably, the raceanisodamine and the mass volume ratio of solvent are 65~200mg:1mL, more preferably 65~
100mg:1mL；
Preferably, the mixing time is 5~10 days；
Preferably, the whipping process is carried out at -10~20 DEG C, more preferably -10~5 DEG C；
Preferably, the drying mode is vacuum drying；
Preferably, the baking temperature is 10~30 DEG C, more preferably 25~30 DEG C；
Preferably, the drying time is 10~48 hours, more preferably 24~48 hours.
The present invention also provides raceanisodamine crystal formation II of solid-state and preparation method thereof.
Radiated using Cu-K α, the raceanisodamine crystal formation II has with the X-ray powder diffraction figure that 2 θ angles are represented
There is following characteristics peak：4.5±0.2°、9.1±0.2°、11.8±0.2°、14.1±0.2°、14.3±0.2°、14.8±0.2°、
15.9 ± 0.2 °, 16.6 ± 0.2 °, 17.4 ± 0.2 °, 17.7 ± 0.2 °, 21.1 ± 0.2 ° and 22.0 ± 0.2 °.
Without limitation, a representative instance of the raceanisodamine crystal formation II has XRPD figures as shown in Figure 9
Spectrum.
The present invention provides the preparation method of raceanisodamine crystal formation II, comprises the following steps：Raceanisodamine is existed
Suspension, stirring and crystallizing are formed in acetonitrile, and then separates crystal, obtain raceanisodamine crystal formation II；
Preferably, the raceanisodamine and the mass volume ratio of solvent are 65~100mg:1mL；
Preferably, the whipping temp is 5 DEG C, and mixing time is 5~7 days；
Preferably, the separate mode is centrifugation.
Term used in the present invention has：
The cyclic ether solvents refer to tetrahydrofuran, 1,4- dioxane；The aromatic solvents refer to toluene.
" room temperature ", refers to 10~30 DEG C.
" stirring " can adopt the conventional method of this area, such as alr mode to include magnetic agitation, mechanical agitation,
Mixing speed is 50~1800 revs/min, preferably 300~900 revs/min.
" separation " can adopt the conventional method of this area, for example, be centrifuged or filter.It is preferred that filtration under diminished pressure, usually
At room temperature sucking filtration is carried out with the pressure less than atmospheric pressure, preferred pressure is less than 0.09MPa.
" drying ", can be completed using the ordinary skill in the art, and such as normal temperature drying, forced air drying or decompression are dry
It is dry；Can reduce pressure or normal pressure, preferred pressure is less than 0.09MPa.It is dried instrument and method is unrestricted, can is fume hood, drum
Wind baking oven, spray dryer, fluid bed drying or vacuum drying oven；Can carry out in decompression or under not reducing pressure, preferably pressure is little
In 0.09Mpa.
Heretofore described " crystal formation " refers to that compound characterizes what is confirmed by shown X-ray powder diffraction collection,
There is unique orderly molecules align or configuration in lattice.As well known to those skilled in the art, experimental error therein depends on instrument
Device condition, preparation of samples and sample purity.The 2 θ angles at the peak in XRD spectrum would generally slightly have as instrument is different with sample
It is different.The difference of peak angle degree may differ by 1 ° according to different instruments, different samples etc., 0.8 °, 0.5 °, 0.3 °, 0.1 ° etc., generally
Allowable error ± 0.2 °, so the difference of peak angle degree cannot function as sole criterion.The relative intensity at peak may be with sample, sample system
Standby and other experiment conditions and change, so the order of peak intensity cannot function as unique or deciding factor.Height of specimen etc. is real
Testing the impact of factor can cause peak angle degree overall offset, allow generally for certain skew.Thus, those skilled in the art can manage
Solution, it is any to belong to the present invention's with the crystal formation of the same or similar characteristic peak of X-ray powder diffraction pattern of the present invention
Category." single crystal form " refers to that Jing X-ray powder diffractions are detected as single crystal form.
Raceanisodamine crystal formation of the present invention is substantially pure, single, any other is not mixed substantially brilliant
Type or amorphous state." substantially pure " refers to that this novel crystal forms accounts for existing compound when novel crystal forms are used to refer in the present invention
At least 80% (weight), more refers at least 90% (weight), especially at least 95% (weight), particularly relates at least 99% (weight
Amount).
The initiation material raceanisodamine for preparing raceanisodamine crystal formation I of the present invention can refer to patent documentation
Method in CN104130253 A described by embodiment 1 is prepared, and also can be commercially available by commercially available, and the document is by quoting
The mode of its full text is incorporated in the application.
Description of the drawings
Raceanisodamine crystal formation A that Fig. 1 is prepared with reference to the production method in patent CN104130253 A (on) and
Commercially available raceanisodamine crystal formation A (under) XRPD collection of illustrative plates
The XRPD collection of illustrative plates of the raceanisodamine crystal formation I that Fig. 2 embodiment of the present invention 2 is prepared
The TGA collection of illustrative plates of the raceanisodamine crystal formation I that Fig. 3 embodiment of the present invention 2 is prepared
The DSC collection of illustrative plates of the raceanisodamine crystal formation I that Fig. 4 embodiment of the present invention 2 is prepared
The XRPD collection of illustrative plates of raceanisodamine crystal formation A is obtained in Fig. 5 comparative examples 1
The PLM collection of illustrative plates of raceanisodamine crystal formation A is obtained in Fig. 6 comparative examples 1
The adsorption isothermal curve of raceanisodamine crystal formation A is obtained in Fig. 7 comparative examples 1
The XRPD collection of illustrative plates of raceanisodamine crystal formation I is obtained in Fig. 8 comparative examples 1
The PLM collection of illustrative plates of raceanisodamine crystal formation I is obtained in Fig. 9 comparative examples 1
The adsorption isothermal curve of raceanisodamine crystal formation I is obtained in Figure 10 comparative examples 1
The XRPD collection of illustrative plates of the raceanisodamine crystal formation II that Figure 11 embodiment of the present invention 1 is prepared
Specific embodiment
Will be helpful to further understand the present invention by following embodiments, but be not used in restriction present disclosure.
Detecting instrument and method：
X-ray powder diffraction (XRPD)：Instrument is Bruker D8 Advance diffractometer.Sample is in room
The lower test of temperature.Testing conditions are as follows, angular range：3~40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 second/step.
Differential thermal analyses data are picked up from TA Instruments Q200 DSC.Detection method is：Take the sample of 1~10mg
It is positioned in aperture aluminum crucible, N is dried in 40mL/min with the programming rate of 10 DEG C/min2Protection under by sample from room temperature liter
To 200 DEG C.
Thermogravimetric analysis data is picked up from TA Instruments Q500 TGA.Detection method is：Take the sample of 5~15mg
It is positioned in platinum crucible, by the way of segmentation high resolution detection, is dried in 40mL/min with the programming rate of 10 DEG C/min
N2Protection under sample is risen to into 350 DEG C from room temperature.
Dynamic moisture content adsorption analyses data and isothermal adsorption analytical data are picked up from TA Instruments Q5000 TGA.
Detection method is：The sample for taking 1~10mg is positioned in platinum crucible, and detection relative humidity changed from 0% to 80% to 0%
Weight change in journey.
Comminution by gas stream：Instrument is GJ-150 × 200 jet mill, and charging air pressure is 0.1~0.2MPa, crushes air pressure big
In 0.3MPa.
Data from gas chromatography picks up from Agilent 7890B type gas chromatographs, and detection method is accurately weighed appropriate amount of sample
It is dissolved in as need testing solution in DMF, accurately weighed coordinative solvent is molten with DMF
Solution, dilution are detected after sample introduction as reference substance solution by fid detector.
Single punch tablet machine：Tableting pressure is 5MPa, and tablet diameters are 10mm, and the tabletting time is 1 minute.
Various reagents used are if no special instructions commercially available purchase in embodiment.
It is ambient operation in embodiment if no special instructions.
Preparation example 1
Raceanisodamine is prepared with reference to the method for embodiment 1 in patent CN104130253 A.
Commercially available raceanisodamine is selected from Henan Puri.
Its XRPD collection of illustrative plates with reference to embodiment 1 in patent CN104130253 A as shown in figure 1, prepare and commercially available acquisition
Raceanisodamine raw produce be crystal formation A.
Embodiment 1
Take the commercially available raceanisodamine of 65mg, add 1.0mL acetonitriles to form suspension, 5 DEG C of stirring and crystallizings, after 7 days, from
The heart, obtains raceanisodamine crystal formation II.
Its XRPD collection of illustrative plates is as shown in figure 11.
Embodiment 2
The commercially available raceanisodamine of 325g is taken, adds 5.0L acetonitriles to form suspension, 5 DEG C of stirring and crystallizings, mistake after 10 days
Filter, room temperature in vacuo is dried 48 hours, obtains 230g raceanisodamine crystal formation I, and yield is 71%.
Its XRPD collection of illustrative plates is as shown in Figure 2.
Its TGA collection of illustrative plates is as shown in Figure 3.
Its DSC collection of illustrative plates is as shown in Figure 4.
Embodiment 3
The commercially available raceanisodamine of 50mg is taken, adds 0.75mL acetonitriles to form suspension, 5 DEG C of stirring and crystallizings, after 10 days
Filter, room temperature in vacuo is dried 48 hours, obtains 32mg raceanisodamine crystal formation I, and yield is 64%.
Embodiment 4
The commercially available raceanisodamine of 50mg is taken, adds 0.75mL acetonitriles to form suspension, 10 DEG C of stirring and crystallizings, after 5 days
Filter, room temperature in vacuo is dried 24 hours, obtains 28mg raceanisodamine crystal formation I, and yield is 56%.
Embodiment 5
The commercially available raceanisodamine of 100mg is taken, adds aqueous solutions of the 1mL containing 80% acetonitrile to form suspension, -10 DEG C are stirred
Crystallize is mixed, is filtered after 5 days, room temperature in vacuo is dried 24 hours, obtains 75mg raceanisodamine crystal formation I, and yield is 75%.
Embodiment 6
The commercially available raceanisodamine of 1g is taken, adds aqueous solutions of the 8mL containing 50% acetonitrile to form suspension, 0 DEG C of stirring analysis
Crystalline substance, filters after 7 days, and room temperature in vacuo is dried 30 hours, obtains 630mg raceanisodamine crystal formation I, and yield is 63%.
Embodiment 7
Take the commercially available raceanisodamine of 100mg, add aqueous solutions of the 1.2mL containing 70% acetonitrile to form suspension, 20 DEG C
Stirring and crystallizing, filters after 10 days, and room temperature in vacuo is dried 36 hours, obtains 49mg raceanisodamine crystal formation I, and yield is 49%.
Embodiment 8
The commercially available raceanisodamine of 1g is taken, adds methanol solutions of the 5.0mL containing 90% acetonitrile to form suspension, 8 DEG C are stirred
Crystallize is mixed, is filtered after 7 days, room temperature in vacuo is dried 40 hours, obtains 500mg raceanisodamine crystal formation I, and yield is 50%.
Embodiment 9-22
Solvent in embodiment 8 is replaced by below table and can obtain raceanisodamine crystal formation I.
The sample that embodiment 3~22 is prepared with the sample of embodiment 2 there is same or analogous XRPD collection of illustrative plates (not show
Go out), DSC collection of illustrative plates (not shown), TGA collection of illustrative plates (not shown), illustrate that the sample of embodiment 3~22 is identical with the sample of embodiment 2
Crystal formation.
Comparative example 1
Step 1：Taking the commercially available raceanisodamine crystal formation A of 100g preparation examples 1 carries out micronization processes, obtains 82g micro-
The crystal formation A granules of efflorescence.
Its XRPD collection of illustrative plates is as shown in figure 5, consistent with crystal formation A in preparation example 1.
Its PLM collection of illustrative plates is as shown in fig. 6, grain diameter is approximately less than 25 microns.
Its adsorption isothermal curve is as shown in fig. 7, weight change is 1.8% in the range of 20-80%RH.
Step 2：Taking the raceanisodamine crystal formation I of 100g embodiments 2 carries out micronization processes, obtains 78g micronized
Crystal formation I granules.
Its XRPD collection of illustrative plates is as shown in figure 8, consistent with crystal formation I in embodiment 2.
Its PLM collection of illustrative plates is as shown in figure 9, grain diameter is approximately less than 25 microns.
As shown in Figure 10, weight change is 0.10% to its adsorption isothermal curve in the range of 20-80%RH.
From crystal formation A and the adsorption isothermal curve of crystal formation I, the crystal formation I hygroscopicity of the present invention is significantly lower than crystal formation A.
Comparative example 2
Step 1
With reference to Qiu Yihong, Chen Yisheng. the research and development-pharmaceutical theory of solid orally ingestible with put into practice [M]. Beijing：Chemical industry
Also publishing house, 2013:The full abdomen intestinal simulated solution of method configuration in 330-349, empty stomach intestinal simulated solution stomach function regulating simulated solution.
Step 2
Sample：Micronized crystal formation A and crystal formation I in comparative example 1.
Experimental temperature：25℃±2℃；Mixing speed：100 revs/min.
Experimental implementation：Corresponding crystal form samples 100mg are added in 5mL vials, corresponding dissolving is slowly added while stirring
Medium, to completely molten clear, records dissolving medium consumption, obtains the apparent solubility data of crystal formation A and crystal formation I.
It is tabletted that each crystal formation takes sample 200mg.Calculate with reference to apparent dissolubility data and reach sink conditions (i.e. mesh
Mark concentration is far below dissolubility) quantity of solvent, respectively water 20mL, stomach simulated solution 14mL, full abdomen intestinal simulated solution 13mL, empty stomach intestinal
Simulated solution 24mL.Above-mentioned solvent is added in corresponding vial, stirring is opened, to be added and start timing after tablet, recorded
The CL time.As a result see the table below 1.
The dissolution time of table 1 raceanisodamine crystal formation A and I in different medium
As a result show：In each dissolving medium, in the situation for meeting sink conditions and identical compound concentration, racemization mountain Liang
The dissolution velocity of henbane alkali crystal formation I than crystal formation A faster, can arrive more quickly at effective blood drug concentration.
Comparative example 3
Raceanisodamine crystal formation A that appropriate preparation example 1 obtains is taken respectively and the raceanisodamine crystal formation I of embodiment 2 enters
Row stability of crystal form is tested, and experimental condition is:Room temperature is open, high temperature open (50 DEG C), high humidity open (75%RH), accelerate it is open
(40 DEG C of -75%RH), result of the test see the table below 2：
The raceanisodamine crystal formation A of table 2 and I crystal stability experiment
As a result show：Raceanisodamine crystal formation A and raceanisodamine crystal formation I is in room temperature, high temperature, high humidity, acceleration bar
Place 14 days crystal formations under part not changing, stability of crystal form is good.
Comparative example 4
Choose embodiment 2, embodiment 6, embodiment 8 and embodiment 9, embodiment 14, embodiment 16, embodiment 19, enforcement
Example 20, embodiment 21, the sample of embodiment 22 carry out gas chromatographic detection, determine whether solvent residual amount meets the requirements, as a result
3 are see the table below, data are the ICH bound requirements of the solvent in table bracket.As a result the equal energy of crystal formation I samples of present invention preparation is shown
Meet ICH dissolvent residual requirements.
The molten residual testing result of the raceanisodamine crystal formation I prepared in the different embodiments of table 3
Claims (4)
1. a kind of raceanisodamine crystal formation I, it is characterised in that radiated using Cu-K α, the crystal formation I is represented with 2 θ angles
X-ray powder diffraction figure has following characteristics peak：7.3±0.2°、14.7±0.2°、15.7±0.2°、16.5±0.2°、
17.6 ± 0.2 ° and 22.2 ± 0.2 °.
2. raceanisodamine crystal formation I according to claim 1, it is characterised in that the crystal formation I is represented with 2 θ angles
X-ray powder diffraction figure has following characteristics peak：7.3±0.2°、10.5±0.2°、11.0±0.2°、14.7±0.2°、
15.7±0.2°、16.5±0.2°、17.2±0.2°、17.6±0.2°、18.7±0.2°、19.0±0.2°、22.2±0.2°
With 23.2 ± 0.2 °.
3. raceanisodamine crystal formation I according to claim 2, it is characterised in that the crystal formation I is represented with 2 θ angles
X-ray powder diffraction figure has following characteristics peak and its relative intensity：
4. the preparation method of raceanisodamine crystal formation I any one of claim 1-3, the preparation method includes following
Step：
Raceanisodamine is formed into suspension, stirring and crystallizing in acetonitrile or the mixed solvent containing acetonitrile, and then separates crystal,
It is dried, obtains raceanisodamine crystal formation I；
Preferably, the mixed solvent is molten with what water, alcohols, ketone, esters, ethers, cyclic ethers class, aromatics were formed selected from acetonitrile
Agent；
Preferably, the percent by volume of acetonitrile is 50%~100%, more preferably 80%~100% in the mixed solvent；
Preferably, the raceanisodamine and the mass volume ratio of solvent are 65~200mg:1mL, more preferably 65~
100mg:1mL；
Preferably, the mixing time is 1~10 day；More preferably 5~10 days；
Preferably, the whipping process is carried out at -10~20 DEG C, more preferably -10~5 DEG C；
Preferably, the drying mode is vacuum drying；
Preferably, the baking temperature is 10~30 DEG C, more preferably 25~30 DEG C；
Preferably, the drying time is 10~48 hours, more preferably 24~48 hours.
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| CN201611163375.5A Active CN106674217B (en) | 2016-12-15 | 2016-12-15 | Racanisodamine crystal form and preparation method thereof |
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| CN (1) | CN106674217B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130253A (en) * | 2014-06-30 | 2014-11-05 | 施佩蓓 | Anisodamine production method |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130253A (en) * | 2014-06-30 | 2014-11-05 | 施佩蓓 | Anisodamine production method |
Non-Patent Citations (3)
| Title |
|---|
| HUAIXIA CHEN等: "Liquid chromatography–tandem mass spectrometry analysis of anisodamine and its phase I and II metabolites in rat urine", 《JOURNAL OF CHROMATOGRAPHY B》 * |
| 谢晶曦等: "山莨菪碱的全合成", 《药学学报》 * |
| 郑长胜等: "消旋山莨菪碱的新合成法", 《中国医药工业杂志》 * |
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