CN108659037A - The polymorph and preparation method of valproic acid phospholipid derivative - Google Patents
The polymorph and preparation method of valproic acid phospholipid derivative Download PDFInfo
- Publication number
- CN108659037A CN108659037A CN201710208986.5A CN201710208986A CN108659037A CN 108659037 A CN108659037 A CN 108659037A CN 201710208986 A CN201710208986 A CN 201710208986A CN 108659037 A CN108659037 A CN 108659037A
- Authority
- CN
- China
- Prior art keywords
- vpa
- crystal form
- preparation
- ray powder
- organic solvents
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NWKKUJPMZHQVOB-UHFFFAOYSA-N C[N+](C)(C)CCI Chemical compound C[N+](C)(C)CCI NWKKUJPMZHQVOB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to 1 palmityl, 2 third valeryl sn glyceryls, 3 phosphatidyl choline (C16DP VPA) four kinds of polymorphs：Crystal form A, crystal form B, crystal form C and crystal form D, and preparation method thereof.C provided by the invention16The crystal form A and crystal form B of DP VPA is with good stability, is conducive to clinical storage and uses, disclosure satisfy that preparation needs, be suitble to drug development.
Description
Technical field
The invention belongs to field of medicaments, are related to a kind of polymorph and preparation method of valproic acid phospholipid derivative, specifically
It is related to 1- palmityls -2- the third valeryl-sn- glyceryl -3- phosphatidyl cholines (C16- DP-VPA) polymorph and its preparation side
Method.
Background technology
Epilepsy is a kind of brain chronic disease caused by Different types of etiopathogenises, with prominent caused by brain neuroblastoma member over-discharge
So, repeatedly with of short duration central nervous system function is not normal is characterized.Epileptic attack, a certain position of body or entire body are short
Temporary nonautonomy twitch (i.e. partial seizures or generalized seizures), sometimes with the loss of consciousness and urinary incontinence.Epileptic attack
Body and spiritual pain not only are brought to patient, also increases the burden of health care, it has also become important social concern.
Valproic acid (VPA) is the antiepileptic for reporting at most, but its there are the stimulation of stomach-intestines, bone marrow suppressions (especially to show as regeneration barrier
Impenetrability anaemia and thrombopenia) and the VPA inductions such as hepatosis side effect, and its drug half-life is short, i.e.,
Make to take as sustained release preparation and still needs to take medicine several times daily.
Chinese patent application 01815173.6 discloses a kind of valproic acid phospholipid derivative and preparation method thereof, which spreads out
Biological (DP-VPA) is mixture, and two components are respectively 1- palmityls -2- the third valeryl-sn- glyceryl -3- phosphatidyl cholines
(C16- DP-VPA), 1- stearoyls -2- the third valeryl-sn- glyceryl -3- phosphatidyl cholines (C18- DP-VPA), structural formula is respectively such as
Shown in lower：
Two component ratio C16-DP-VPA:C18- DP-VPA is 15 ± 5%:85 ± 5%, the medicine is by Israel D-Pharm public affairs
Department's exploitation, for treating epilepsy, is currently under clinical investigation phase.
DP-VPA is strength anticonvulsant, and essence is using lysophosphatidyl choline as carrier, by active constituent VPA (third
Valeric acid) the positions sn-2 by ester bond connect phosphatide, since phosphatide cpd essence is hydrophobic, thus can permeate biomembrane and
Barrier, to promote drug to cell or organ, such as to the intracerebral transport for needing it to act on, VPA can pass through DP-VPA chemical combination
Object is at the position sn-2 of phosphatide in phospholipase A2Any other lipase or esterase effect under cracking and release.The third penta
Acid moieties can further improve the therapeutic index of drug in the adjusting release of lesions position, because potential side effect and toxicity subtract
The effect of drug will be estimated while few to increase.The compound is much lower compared with VPA dosage used at present, and therapeutic dose
Reduction reduce toxicological risks and adjoint side effect in turn, while also reducing it and being not intended between other drugs
Interaction danger.In addition, the compound has the pharmacokinetic property significantly improved than VPA (for example, greatly prolonging
Half-life period in serum and brain tissue).The compound is expected to become a kind of excellent antiepileptic.
The polymorphic of drug is one of the factor for influencing drug quality, the different crystal forms of same drug appearance, solubility,
Fusing point, dissolution rate, biological activity etc. have differences, to influence the stability, bioavilability and clinic of drug
Curative effect etc..Therefore, further investigation, which is found, has the polymorph of good chemical stability to improve C16-DP-VPA、C18-DP-
The property of VPA various aspects is necessary.
Invention content
The purpose of the present invention is to provide 1- palmityls -2- the third valeryl-sn- glyceryl -3- phosphatidyl cholines (C16-DP-
VPA four kinds of polymorphs)：Crystal form A, crystal form B, crystal form C and crystal form D, and preparation method thereof.
The purpose of the present invention can be achieved through the following technical solutions：
C16- DP-VPA crystal forms A
The present invention provides C16The crystal form A of-DP-VPA, which is characterized in that crystal form A is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrogram is shown at 5.09,7.6,10.11,12.63,15.16,17.69,20.24,22.78,25.35
Characteristic peak.Further, the C16The X-ray powder diffraction spectrogram that the crystal form A of-DP-VPA is indicated with the 2 θ ± 0.2 ° angles of diffraction
Also characteristic peak is shown at 20.73,21.66,22.11,23.9,24.65,27.92,30.53,34.37,36.91.
The present invention provides C16The crystal form A of-DP-VPA, which is characterized in that crystal form A is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrogram 5.089,7.596,10.108,12.625,15.163,17.691,20.237,22.783,
25.351 place shows characteristic peak.Further, the C16The X-ray that the crystal form A of-DP-VPA is indicated with the 2 θ ± 0.2 ° angles of diffraction
Powder diffractogram also 20.733,21.662,22.112,23.899,24.646,27.922,30.525,34.366,
36.908 place shows characteristic peak.
Further, the C162 θ ± 0.2 ° of X-ray powder diffraction angle of reflection of the crystal form A of-DP-VPA and its correspondence
D values, relative peak intensities it is as shown in table 1：
1 crystal form A of table
Preferably, the C16The X-ray powder diffraction figure of the crystal form A of-DP-VPA is substantially as shown in Figure 1.
The C16The absorption peak for including in the infrared spectrum of the crystal form A of-DP-VPA is：3423.66、3035.60、
2920.53、2851.68、1739.55、1663.90、1487.67、1467.34、1417.65、1382.33、1346.50、
1252.02、1231.33、1184.69、1163.74、1143.86、1100.85、1082.30、1060.12、1019.19、
970.32,951.48,929.89,875.48,809.43,782.21,745.17,722.08,594.57,512.77 ± 0.5%
cm-1。
The C16In the dsc analysis of the crystal form A of-DP-VPA, there is the first endothermic peak at 88 ± 1.5 DEG C, at 168 ± 1.5 DEG C
There is the second endothermic peak.
The C16The further thermogravimetric analysis of the crystal form A of-DP-VPA is shown：Weightless ratios of the crystal form A at 25~200 DEG C
Example is 3.15 ± 0.2%.
The C16The light microscope characteristic image of the crystal form A of-DP-VPA shows rectangular sheet, rectangular patch, does not advise
Then sheet.
The C16The scanning electron microscope characteristic image of the crystal form A of-DP-VPA shows irregular sheet.
The present invention also provides C16The preparation method of the crystal form A of-DP-VPA, including but not limited to：Stand recrystallization method.This
The C that this preparation method that invention provides is used for can be used as raw material16The existing forms of-DP-VPA are not particularly limited, can
To use arbitrary crystal form or unformed solid.
It stands recrystallization method and prepares crystal form A
Specifically, the present invention provides a kind of C16The preparation method of the crystal form A of-DP-VPA stands recrystallization method comprising
Following step：
1) by C under 40 DEG C~reflux conditions16- DP-VPA is dissolved in organic solvent；
2) cool down crystallization, is filtered, washed, dries, obtains target product.
In a preferred embodiment of the present invention, the organic solvent is selected from the mixed of ketone, ketone and inert organic solvents
The mixed solvent of bonding solvent, the mixed solvent of alcohols and inert organic solvents, alcohols and ketone, the inert organic solvents are selected from
One or more of esters, alkanes, acetonitrile, N,N-dimethylformamide, methyl tertiary butyl ether(MTBE), tetrahydrofuran.
Optional, the ketone is selected from one or more of acetone, butanone, methyl iso-butyl ketone (MIBK), the alcohols
Selected from C1-8One or more of linear chain or branched chain alkanol, in more preferable methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol
One or more, it is different that the esters are selected from Ethyl formate, butyl formate, ethyl acetate, methyl acetate, butyl acetate, acetic acid
One or more of butyl ester, the alkanes are selected from one or more of petroleum ether, n-hexane, hexamethylene, normal heptane.
In a preferred embodiment of the present invention, the C16- DP-VPA in organic solvent a concentration of 0.05~
0.25g/ml, the volume ratio of ketone and inert organic solvents is more than 1 in the combination of the ketone and inert organic solvents:10,
The volume ratio of alcohols and inert organic solvents is 1 in the combination of the alcohols and inert organic solvents:5~1:50, it is described
The volume ratio of alcohols and organic solvent of ketone is 1 in the combination of alcohols and ketone:5~1:50.
It is preferable to use vacuum drying chambers to be dried, and preferred vacuum drying temperature is 40~65 DEG C.
Another aspect provides a kind of pharmaceutical compositions, and it includes C16The crystal form A of-DP-VPA and pharmaceutically may be used
The carrier of receiving.
Another aspect of the invention provides C16The crystal form A of-DP-VPA is being prepared for treating epilepsy, migraine, the two poles of the earth
Purposes in the drug of cytopathy and pain.
C16- DP-VPA crystal forms B
The present invention also provides C16The crystal form B of-DP-VPA, which is characterized in that crystal form B is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrogram 9.18,9.92,11.92,12.42,17.51,19.65,19.97,20.56,21.48,
21.87 place shows characteristic peak.Further, the C16The X-ray powder that the crystal form B of-DP-VPA is indicated with the 2 θ ± 0.2 ° angles of diffraction
Last diffraction spectrogram is shown also at 7.41,13.40,14.98,15.93,16.39,18.30,18.73,22.62,23.7,24.50
Characteristic peak.
The present invention provides C16The crystal form B of-DP-VPA, which is characterized in that crystal form B is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrogram 9.179,9.923,11.917,12.424,17.511,19.648,19.965,20.560,
21.479, characteristic peak is shown at 21.871.Further, the C16The crystal form B of-DP-VPA is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrogram also 7.410,13.395,14.975,15.934,16.392,18.299,18.725,22.622,
23.702, characteristic peak is shown at 24.498.
Further, the C162 θ ± 0.2 ° of X-ray powder diffraction angle of reflection of the crystal form B of-DP-VPA and its correspondence
D values, relative peak intensities it is as shown in table 2.
2 crystal form B of table
Preferably, the C16The X-ray powder diffraction figure of the crystal form B of-DP-VPA is substantially as shown in Figure 7.
The C16The absorption peak for including in the infrared spectrum of the crystal form B of-DP-VPA is：3421.55、3035.60、
2920.53、2851.68、1739.55、1663.90、1487.67、1467.34、1417.65、1382.33、1346.50、
1252.02、1231.33、1184.69、1163.74、1143.86、1100.85、1082.30、1060.12、1019.19、
970.32,951.48,929.89,875.48,809.43,782.21,745.17,722.08,594.57,512.77 ± 0.5%
cm-1。
The C16In the dsc analysis of the crystal form B of-DP-VPA, there is the first endothermic peak at 87 ± 1.5 DEG C, at 167 ± 1.5 DEG C
There is the second endothermic peak.
The C16The further thermogravimetric analysis of the crystal form B of-DP-VPA is shown：Weightless ratios of the crystal form B at 25~200 DEG C
Example is 3.10 ± 0.2%.
The C16The scanning electron microscope characteristic image of the crystal form B of-DP-VPA shows irregular stacking powder.
The present invention also provides C16The preparation method of the crystal form B of-DP-VPA, including but not limited to：Recrystallization method, grinding turn
Crystallization.
Recrystallization method prepares crystal form B
Specifically, the present invention provides a kind of C16The preparation method of the crystal form B of-DP-VPA, recrystallization method, for that can make
The C used for raw material16The existing forms of-DP-VPA are not particularly limited, and can use arbitrary crystal form or unformed solid, including
Following step：
1) by C16Suspension is made with hydrophobic inert organic solvents in-DP-VPA；
2) clear solution is obtained under 40 DEG C~reflux conditions；
3) cool down crystallization, is filtered, washed, dries to get target product.
In a preferred embodiment of the present invention, it is organic molten to be selected from esters, alkanes for the hydrophobic inert organic solvents
One or more of agent；Optional, the esters are selected from Ethyl formate, butyl formate, ethyl acetate, methyl acetate, second
One or more of acid butyl ester, isobutyl acetate, the alkanes are in petroleum ether, n-hexane, hexamethylene, normal heptane
One or more.
In a preferred embodiment of the present invention, C16- ratio of DP-VPA and hydrophobic inert organic solvents is 0.01~
0.5g/ml, each solvent can be combined with arbitrary proportion.
It is preferable to use vacuum drying chambers to be dried, and preferably drying temperature is 40~65 DEG C.
Grinding rotating crystal method prepares crystal form B
Grinding rotating crystal method of the present invention includes mechanical ball mill, underhand polish.
Specifically, the present invention provides a kind of C16The preparation method of the crystal form B of-DP-VPA, mechanical attrition method, including it is following
Step：By C of the present invention16The crystal form A of-DP-VPA is placed in the agate mortar of ball mill, with 400 revs/min of speed
It is ground, often grinds 15 minutes, rest 15 minutes, each rotation direction for recycling ball mill also alternate transition, milling time
To be more than 30 minutes to get target product.
Specifically, the present invention also provides a kind of C16The preparation method of the crystal form B of-DP-VPA, underhand polish method, including with
Lower step：By C of the present invention16The crystal form A of-DP-VPA is placed in common agate mortar, is firmly ground, milling time is not low
In 1 hour to get target product.
Another aspect provides a kind of pharmaceutical compositions, and it includes C16The crystal form B of-DP-VPA and pharmaceutically may be used
The carrier of receiving.
Another aspect of the invention provides C16The crystal form B of-DP-VPA is being prepared for treating epilepsy, migraine, the two poles of the earth
Purposes in the drug of cytopathy and pain.
C16- DP-VPA crystal forms C
The present invention also provides C16The crystal form C of-DP-VPA, which is characterized in that crystal form C is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrogram 3.518,7.425,9.944,14.429,17.528,18.084,18.690,20.080,
20.583 place shows characteristic peak.Further, the C16The X-ray that the crystal form C of-DP-VPA is indicated with the 2 θ ± 0.2 ° angles of diffraction
Powder diffractogram also 4.911,9.198,11.923,12.432,13.410,14.999,16.280,19.638,
21.514, characteristic peak is shown at 21.841,22.636,23.684,24.495.Further, the C16The crystal form of-DP-VPA
The X-ray powder diffraction figure of C is substantially as shown in figure 12.
The C16The absorption peak for including in the infrared spectrum of the crystal form C of-DP-VPA is：3423.82、3035.50、
2920.29、2851.57、1739.50、1664.31、1487.48、1467.29、1417.38、1401.25、1382.28、
1346.45、1251.91、1231.29、1184.80、1163.72、1143.90、1100.87、1082.49、1060.18、
1019.28、970.36、951.56、929.91、875.49、809.58、782.27、745.38、722.13、595.41、512.84
± 0.5%cm-1；
The C16In the dsc analysis of the crystal form C of-DP-VPA, there is the first endothermic peak at 83 ± 1.5 DEG C, at 166 ± 1.5 DEG C
There is the second endothermic peak.
The C16The further thermogravimetric analysis of the crystal form C of-DP-VPA is shown：Weightless ratios of the crystal form C at 25~200 DEG C
Example is 1.55 ± 0.2%.
The present invention also provides C16The preparation method of the crystal form C of-DP-VPA, including but not limited to：High vacuum solvent removes
Method.
High vacuum solvent removal method prepares crystal form C
The present invention also provides a kind of C16The preparation method of the crystal form C of-DP-VPA, high vacuum solvent removal method, for
It can be used as the C that raw material uses16The existing forms of-DP-VPA are not particularly limited, and can use arbitrary crystal form or unformed solid,
Include the following steps：
1) by C16- DP-VPA is dissolved in the mixture of benign organic solvent or benign organic solvent and inert organic solvents,
Clear solution is made；
2) by above-mentioned clear solution, depressurized solvent removes in high vacuum conditions；
3) Slow cooling, recycling solid is to get target product.
In a preferred embodiment of the present invention, the benign organic solvent be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol,
One or more of chloroform, dichloromethane, inert organic solvents are selected from ketone, esters, alkanes, acetonitrile, methyl tertbutyl
One or more of ether, tetrahydrofuran；It is optional, the one kind of the ketone in acetone, butanone, methyl iso-butyl ketone (MIBK)
Or it is several；The esters are selected from Ethyl formate, butyl formate, ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate
One or more of；The alkanes are selected from one or more of petroleum ether, n-hexane, hexamethylene, normal heptane.
In a preferred embodiment of the present invention, the preferred vacuum pressure of condition of the depressurized solvent removal is less than
20mbar, temperature are 73~78 DEG C.
Another aspect provides a kind of pharmaceutical compositions, and it includes C16The crystal form C of-DP-VPA and pharmaceutically may be used
The carrier of receiving.
Another aspect of the invention provides C16The crystal form C of-DP-VPA is being prepared for treating epilepsy, migraine, the two poles of the earth
Purposes in the drug of cytopathy and pain.
C16- DP-VPA crystal forms D
The present invention also provides C16The crystal form D, the crystal form D of-DP-VPA is amorphous article, which is characterized in that uses Cu-
K α radiation, to spend the not sharp diffraction maximum of the X-ray powder diffraction spectrum that indicate of 2 θ.Further, the C16- DP-VPA's
The X-ray powder diffraction figure of crystal form D is substantially as shown in figure 16.
The present invention also provides a kind of C16The preparation method of the crystal form D of-DP-VPA, including but not limited to：Vacuum high-temperature is molten
Melt falling temperature method.
Vacuum high-temperature melting falling temperature method prepares crystal form D
The present invention also provides a kind of C16The preparation method of the crystal form D of-DP-VPA, vacuum high-temperature melts falling temperature method, right
In the C that can be used as raw material and use16The existing forms of-DP-VPA are not particularly limited, and can use arbitrary crystal form or unformed solid
Body includes the following steps：
1)C16- DP-VPA solids are placed in ceramic crucible in right amount, under vacuum heating melting；
2) product that above-mentioned heating melts is rapidly cooled to room temperature to get target product.
In one embodiment of the invention, the preferred vacuum degree of heating melting condition under the vacuum condition is 0.01
~0.05Mpa, temperature are 150~168 DEG C.
In one embodiment of the invention, the preferred nitrogen purging cooling of the rapid cooling.
Another aspect provides a kind of pharmaceutical compositions, and it includes C16The crystal form D of-DP-VPA and pharmaceutically may be used
The carrier of receiving.
Another aspect of the invention provides C16The crystal form D of-DP-VPA is being prepared for treating epilepsy, migraine, the two poles of the earth
Purposes in the drug of cytopathy and pain.
The advantageous effect that the present invention obtains：
C provided by the invention16The crystal form A and crystal form B of-DP-VPA has good stability, and is conducive to clinical storage and uses, can
Meet preparation needs, is suitble to drug development.
In addition, the preparation process of crystal form A and crystal form B are easy to operate, and it is stably and controllable repeatable, it is suitable for industrialized production.
Description of the drawings
Fig. 1 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal forms A
Fig. 2 C16The FT-IR spectrograms of-DP-VPA crystal forms A
Fig. 3 C16The DSC collection of illustrative plates of-DP-VPA crystal forms A
Fig. 4 C16The TG collection of illustrative plates of-DP-VPA crystal forms A
Fig. 5 C16The optical microscope photograph of-DP-VPA crystal forms A
Fig. 6 C16The electron scanning micrograph of-DP-VPA crystal forms A
Fig. 7 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal forms B
Fig. 8 C16The FT-IR spectrograms of-DP-VPA crystal forms B
Fig. 9 C16The DSC collection of illustrative plates of-DP-VPA crystal forms B
Figure 10 C16The TG collection of illustrative plates of-DP-VPA crystal forms B
Figure 11 C16The electron scanning micrograph of-DP-VPA crystal forms B
Figure 12 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal forms C
Figure 13 C16The FT-IR spectrum of-DP-VPA crystal forms C
Figure 14 C16The DSC thermograms of-DP-VPA crystal forms C
Figure 15 C16The TG thermograms of-DP-VPA crystal forms C
Figure 16 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal forms D
Figure 17 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal form A high temperature 5 days, 10 days factors affecting stabilities
Figure 18 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal form B high temperature 5 days, 10 days factors affecting stabilities
Figure 19 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal form A strong illuminations 5 days, 10 days factors affecting stabilities
Figure 20 C16The X-ray powder diffraction spectrogram of-DP-VPA crystal form B strong illuminations 5 days, 10 days factors affecting stabilities
Figure 21 C16X-ray powder diffraction spectrogram under-DP-VPA crystal form C natural conditions changes over time
Figure 22 C16X-ray powder diffraction spectrogram under-DP-VPA crystal form D natural conditions changes over time
Specific implementation mode
Below will by specific embodiment, the present invention is further explained, but the protection domain being not intended to restrict the invention.
Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, these improvement also should be regarded as
Protection scope of the present invention.
In following embodiments, unless otherwise indicated, the experimental method is usually according to normal condition or manufacturer builds
The condition of view is implemented；Shown in raw material, reagent can be obtained by way of commercially available purchase.
Experiment test equipment used
1.X- ray powder diffractions
X-ray powder diffraction figure of the present invention acquires on Bruker D8Focus X-ray powder diffraction instrument.
The method parameter of X-ray powder diffraction of the present invention is as follows：
X-ray parameter：Cu/Kα
Voltage：40 volt (kV)
Electric current：40 milliamperes (mA)
Scanning range：From 3.0 to 40 degree
Sampling step length：0.02 degree
Sample leg speed：0.5 second/step
2.DSC is composed
Differential scanning calorimetry (DSC) analysis chart of the present invention is by the resistance to DSC 200F3 detections of speeding of Germany, temperature range
35~200 DEG C, heating rate 10K/min；Hole is pricked in aluminium crucible, sealing, and purge gass are nitrogen (40ml/min), and protection gas is nitrogen
(20ml/min)。
3.TGA is composed
Thermogravimetric analysis (TG) of the present invention is to keep balance, temperature at 25 DEG C by the resistance to TG 209F3 detections of speeding of Germany
35~200 DEG C, heating rate 5K/min of range, be open aluminium crucible, and purge gass are nitrogen (40ml/min), and protection gas is nitrogen
(20ml/min)。
4. FTIR spectrum
FTIR spectrum (FT-IR) of the present invention is examined by NICOLET 330FT-IR infrared spectrophotometers
It surveys.180mg potassium bromide dry at 120 DEG C and cooling in advance is weighed in agate mortar, fine powder is ground into, about 1.5mg is added
Test sample is sufficiently mixed and is ground into uniform fine powder, with reference to Chinese Pharmacopoeia the 4th 0402 infrared spectroscopy light of general rule of version in 2015
Degree method measures.
5. optical microphotograph crystalline substance image
Optical microphotograph crystalline substance image of the present invention is by being observed on XPN-203E polarisation Hot stage microscopes, by JVC colours
Video camera is taken pictures acquisition.
6. scanning electron microscope image
Scanning electron microscope image of the present invention is to be observed clapping by Dutch PHENOM desk type scanning electronic microscopes
According to obtaining.
7. determination of moisture
Determination of moisture of the present invention is logical in METTLER TOLEDO V20Volumetric KFTitrator
Xiu Shi methods of going to undue expense measure.
1 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g, are added in 3ml acetone, are heated to flowing back, and solution clarification continues heating stirring
Reflux；Stop stirring after 30min, stand, cooled to room temperature, there are a large amount of solids to be precipitated；Filtering, is washed with 1ml acetone, is received
Collect filter cake to be dried overnight in 60 DEG C of vacuum drying chambers, obtains white solid.The X-ray powder diffraction collection of the sample is shown in Fig. 1,
Infrared spectrum is shown in that Fig. 2, DSC collection of illustrative plates are shown in that Fig. 3, TG collection of illustrative plates are shown in Fig. 4, this crystal form are defined as crystal form A.
2 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g, are added in 2ml butanone, are heated to 40 DEG C, and solution clarification continues to stir；
Stop stirring after 30min, stand, cooled to room temperature, there are a large amount of solids to be precipitated；Filtering, is washed with appropriate butanone, collects filter
Cake is dried overnight in 60 DEG C of vacuum drying chambers, obtains white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates
With TG collection of illustrative plates through investigation and comparison, determine that product is crystal form A.
3 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 2ml acetone and 2ml ethyl acetate composition, are heated to
Reflux, solution clarification continue heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature there are a large amount of solids
It is precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, it is solid to obtain white
Body.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
4 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 2ml acetone and 2ml acetonitriles composition, are heated to back
Stream, solution clarification continue heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature, there are a large amount of solids to analyse
Go out；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, obtains white solid.
Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
5 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 2ml acetone and 2ml methyl tertiary butyl ether(MTBE)s composition, add
For heat to flowing back, solution clarification continues heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature, has a large amount of
Solid is precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, is obtained white
Color solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form through investigation and comparison
A。
6 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 2ml acetone and 2ml petroleum ethers composition, are heated to back
Stream, solution clarification continue heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature, there are a large amount of solids to analyse
Go out；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, obtains white solid.
Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
7 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 1ml butanone and 10ml hexamethylenes composition, are heated to
Reflux, solution clarification continue heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature there are a large amount of solids
It is precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, it is solid to obtain white
Body.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
8 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 0.5ml methanol and 15ml acetone composition, are heated to
Reflux, solution clarification continue heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature there are a large amount of solids
It is precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, it is solid to obtain white
Body.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
9 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 0.5ml methanol and 10ml ethyl acetate composition, add
For heat to flowing back, solution clarification continues heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature, has a large amount of
Solid is precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, is obtained white
Color solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form through investigation and comparison
A。
10 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the mixed solvent of 0.5ml methanol and 10ml methyl tertiary butyl ether(MTBE)s composition
In, it is heated to flowing back, solution clarification continues heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature,
There are a large amount of solids to be precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers,
Obtain white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine product through investigation and comparison
For crystal form A.
11 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 0.5ml methanol and 20ml n-hexanes composition, heating
To reflux, solution clarification continues heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature, has a large amount of solid
Body is precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, obtains white
Solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
12 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 1ml isopropanols and 5ml Ethyl formates composition, heating
To 40 DEG C, solution clarification continues heating stirring reflux；Stop stirring after 30min, stand, cooled to room temperature, has a large amount of solid
Body is precipitated；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, obtains white
Solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
13 C of embodiment16The preparation of-DP-VPA crystal forms A
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 0.2ml absolute ethyl alcohols and 10ml n-hexanes composition,
It is heated to flowing back, solution clarification continues to stir；Stop stirring after 30min, stand, cooled to room temperature, there are a large amount of solids to analyse
Go out；Filtering is washed with appropriate above-mentioned mixed solvent, is collected filter cake and is dried overnight in 60 DEG C of vacuum drying chambers, obtains white solid.
Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form A through investigation and comparison.
14 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16- DP-VPA sample 0.5g, are added in 3ml ethyl acetate, are heated to flowing back, and solution clarification continues to heat
It is stirred at reflux 30min；Cooled to room temperature has a large amount of solids to be precipitated；Filtering, wash with 1ml ethyl acetate, collection filter cake in
60 DEG C of vacuum drying chambers are dried overnight, and obtain white solid.The X-ray powder diffraction collection of the sample is shown in that Fig. 7, infrared spectrum are shown in
Fig. 8, DSC collection of illustrative plates are shown in that Fig. 9, TG collection of illustrative plates are shown in Figure 10, this crystal form is defined as crystal form B.
15 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16- DP-VPA sample 0.5g, are added in 3ml methyl acetates, are heated to 40 DEG C, and solution clarification continues to stir
30min；Cooled to room temperature has a large amount of solids to be precipitated；Filtering, is washed with appropriate methyl acetate, and it is true in 60 DEG C to collect filter cake
Empty drying box is dried overnight, and obtains white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates are through grinding
Study carefully comparison, determines that product is crystal form B.
16 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16- DP-VPA sample 0.5g, are added in 1ml Ethyl formates, are heated to flowing back, and solution clarification continues to heat
It is stirred at reflux 30min；Cooled to room temperature has a large amount of solids to be precipitated；Filtering, is washed with appropriate Ethyl formate, collects filter cake
It is dried overnight in 60 DEG C of vacuum drying chambers, obtains white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG
Collection of illustrative plates determines that product is crystal form B through investigation and comparison.
17 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16- DP-VPA sample 0.5g, are added in 5ml petroleum ethers, are heated to flowing back, and solution clarification continues heating and stirs
Mix reflux 30min；Cooled to room temperature has a large amount of solids to be precipitated；Filtering collects filter cake in 60 with appropriate petroleum ether
DEG C vacuum drying chamber is dried overnight, and obtains white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates
Through investigation and comparison, determine that product is crystal form B.
18 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16- DP-VPA sample 0.5g, are added in 50ml n-hexanes, are heated to flowing back, and solution clarification continues heating and stirs
Mix reflux 30min；Cooled to room temperature has a large amount of solids to be precipitated；Filtering, is washed with appropriate n-hexane, collects filter cake in 60
DEG C vacuum drying chamber is dried overnight, and obtains white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates
Through investigation and comparison, determine that product is crystal form B.
19 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16- DP-VPA sample 0.5g are added to the in the mixed solvent of 2ml ethyl acetate and 2ml petroleum ethers composition, heating
To reflux, solution clarification continues heating stirring reflux 30min；Cooled to room temperature has a large amount of solids to be precipitated；Filtering, with suitable
Petroleum ether is measured, filter cake is collected and is dried overnight in 60 DEG C of vacuum drying chambers, obtain white solid.Its X-ray powder diffraction figure
Spectrum, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form B through investigation and comparison.
20 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16The crystal form A of-DP-VPA is total to about 4g and is placed in two agate mortars of ball mill, and each mortar sample is about
2.0g is ground with 400 revs/min of speed, is often ground 15 minutes, is rested 15 minutes, each rotation for recycling ball mill
Direction also alternate transition, grinding 30 minutes is to get white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates
With TG collection of illustrative plates through investigation and comparison, determine that product is crystal form B.
21 C of embodiment16The preparation of-DP-VPA crystal forms B
By C16The crystal form A about 2.0g of-DP-VPA are placed in common agate mortar, are firmly ground, and often grinding is changed a for 15 minutes
Direction continues to grind, and grinds 60 minutes to get white solid.Its X-ray powder diffraction collection, infared spectrum, DSC collection of illustrative plates and
TG collection of illustrative plates determines that product is crystal form B through investigation and comparison.
22 C of embodiment16The preparation of-DP-VPA crystal forms C
By C16- DP-VPA sample 0.5g, are added in 10ml methanol and clear solution are made, and are evaporated under reduced pressure and remove methanol, pressure
Power is 20mbar, and temperature is 75 DEG C；It is cooled to room temperature to get C16- DP-VPA crystal form C, X-ray powder diffraction collection are shown in figure
12, infrared spectrum is shown in that Figure 13, DSC collection of illustrative plates are shown in that Figure 14, TG collection of illustrative plates are shown in Figure 15.
23 C of embodiment16The preparation of-DP-VPA crystal forms C
By C16- DP-VPA sample 0.5g, are added in the mixture of 5ml methanol and 5ml acetone and clear solution are made, decompression
Evaporation of solvent, pressure 20mbar, temperature are 73 DEG C；It is cooled to room temperature, obtains white solid.Its X-ray powder diffraction figure
Spectrum, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form C through investigation and comparison.
24 C of embodiment16The preparation of-DP-VPA crystal forms C
By C16- DP-VPA sample 0.5g, are added in the mixture of 5ml chloroforms and 5ml acetonitriles and clear solution are made, decompression
Evaporation of solvent, pressure 20mbar, temperature are 78 DEG C；It is cooled to room temperature, obtains white solid.Its X-ray powder diffraction figure
Spectrum, infared spectrum, DSC collection of illustrative plates and TG collection of illustrative plates determine that product is crystal form C through investigation and comparison.
25 C of embodiment16The preparation of-DP-VPA crystal forms D
C16- DP-VPA solids 2.0g is placed in ceramic crucible, under vacuum heating melting；Vacuum degree 0.01Mpa, temperature
Degree is 155 DEG C.Make its rapid near room temperature using nitrogen purging, obtains C16- DP-VPA crystal forms D.
1 determination of moisture of test example is tested
It is measured according to 2015 editions 0832 aquametry mono- Fa Feixiushi methods of the 4th general rule of Chinese Pharmacopoeia.
Assay method：Precision weighs C16Crystal form A, the crystal form B of-DP-VPA is appropriate, sets in dry tool plug vial, adds nothing
Water methanol, be titrated to solution from expense not test solution under stiring becomes rufous from light yellow, blank test is separately done, by the expense consumed
Not test solution calculates the content of moisture.
3 C of table16- DP-VPA crystal forms A, crystal form B determination of moisture results
Learnt by the data of table 3, crystal form A, crystal form B moisture be all 2.95%.
The stability experiment of test example 2 crystal form A and crystal form B
(1) hot test
By the C of 1 gained of embodiment16The crystal form A samples of-DP-VPA, the C of 14 gained of embodiment16The crystal form B samples of-DP-VPA
Product opening divides placement, is placed 10 days under the conditions of 60 ± 2 DEG C, is sampled in the 5th day and the 10th day, and XPRD detections are carried out after sampling,
And compareed with 0 day result, 4 are the results are shown in Table, as shown in figs. 17-18.
(2) strong illumination is tested
By the C of 1 gained of embodiment16The crystal form A samples of-DP-VPA, the C of 14 gained of embodiment16The crystal form B samples of-DP-VPA
Product opening divides placement, is placed 10 days under the conditions of 4500lx ± 500lx, sampled in the 5th day and the 10th day, is carried out after sampling
XPRD is detected, and is compareed with 0 day result, 5 is the results are shown in Table, as shown in Figure 19-20.
(3) accelerated test
By each 3 crowdes of crystal form A and crystal form B, after suitable packaging material packaging, in 40 ± 2 DEG C of temperature, relative humidity 75%
It is placed 6 months under conditions of ± 5%.1st month during experiment, 2 months, 3 months, 6 the end of month separately sampled carry out HPLC
Assay the results are shown in Table 6, table 7.
4 crystal form A of table, crystal form B high-temperature stability data
5 crystal form A of table, crystal form B strong illumination test datas
The accelerated test data of 6 crystal form A of table
The accelerated test data of 7 crystal form B of table
It can be seen from the above result that C provided by the invention16Crystal form A, the crystal form B of-DP-VPA is in high temperature (60 ± 2 DEG C), Qiang Guang
It irradiates and places 5 days, the XPRD spectrograms of 10 days XPRD spectrograms and placement 0 day in the environment of (exposure intensity 4500lx ± 500lx)
It is almost the same, crystal phenomenon does not occur, shows that crystal form A, crystal form B have good crystal stability with this condition.In addition, 6
In a month accelerated test, the 1st month, 2 months, 3 months, the XPRD spectrograms of 6 the end of month separately sampled gained crystal form A and crystal form B
XPRD spectrograms with 0 month are almost the same, also that crystal phenomenon does not occur, show that crystal stability provided by the invention is good, profit
In clinic storage and use.
The stability experiment of 3 crystal form C of test example
By C16- DP-VPA crystal forms C is placed in surface plate, at ambient conditions (relative humidity 45%, 25 DEG C of temperature) exposure
In air, XPRD tests are carried out respectively at 2 hours, 6 hours, 24 hours, sampling in 48 hours, and carry out with 0 hour result
Control, the results are shown in Table 8, as shown in figure 21.
8 C of table16- DP-VPA crystal form C stability datas
From the above results, crystal form C is placed easily absorbs the moisture in air and is transformed into crystal form B at ambient conditions,
It is a kind of extremely unstable crystal form.
The stability experiment of 4 crystal form D of test example
By C16- DP-VPA crystal forms D is placed in surface plate, at ambient conditions (relative humidity 45%, 25 DEG C of temperature) exposure
In air, XPRD tests are carried out, and are compareed with 0 day result respectively at 1 day, 2 days, sampling in 5 days, 9 is the results are shown in Table, such as schemes
Shown in 22.
The stability experiment of 9 crystal form D of table
From the above results, crystal form D is placed at ambient conditions, is easily absorbed the moisture in air and is transformed into crystal form A,
It is a kind of extremely unstable crystal form.
Claims (10)
1. a kind of C16The crystal form A of-DP-VPA, which is characterized in that the X-ray powder that crystal form A is indicated with the 2 θ ± 0.2 ° angles of diffraction
Diffraction spectrogram shows characteristic peak at 5.09,7.6,10.11,12.63,15.16,17.69,20.24,22.78,25.35.
2. C according to claim 116The crystal form A of-DP-VPA, which is characterized in that crystal form A is with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction spectrogram of expression also 20.73,21.66,22.11,23.9,24.65,27.92,30.53,34.37,
36.91 place shows characteristic peak.
3. a kind of C according to claim 1 or 216The preparation method of the crystal form A of-DP-VPA comprising following step：
1) by C under 40 DEG C~reflux conditions16- DP-VPA is dissolved in organic solvent, wherein the organic solvent is selected from
Ketone, the mixed solvent of ketone and inert organic solvents, the mixed solvent of alcohols and inert organic solvents, alcohols and ketone it is mixed
Bonding solvent, the inert organic solvents are selected from esters, alkanes, acetonitrile, n,N-Dimethylformamide, methyl tertiary butyl ether(MTBE), four
One or more of hydrogen furans；
2) cool down crystallization, is filtered, washed, dries.
4. the preparation method of crystal form A according to claim 3, which is characterized in that the ketone be selected from acetone, butanone,
One or more of methyl iso-butyl ketone (MIBK), the alcohols are selected from C1-8One or more of linear chain or branched chain alkanol, it is more excellent
One or more of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the esters is selected to be selected from Ethyl formate, formic acid fourth
One or more of ester, ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate, the alkanes are selected from oil
One or more of ether, n-hexane, hexamethylene, normal heptane.
5. the preparation method of crystal form A according to claim 3, which is characterized in that the C16- DP-VPA is in organic solvent
A concentration of 0.05~0.25g/ml, the body of ketone and inert organic solvents in the combination of the ketone and inert organic solvents
Product is than being more than 1:10, the volume ratio of alcohols and inert organic solvents is 1 in the combination of the alcohols and inert organic solvents:5
~1:50.
6. a kind of C16The crystal form B of-DP-VPA, which is characterized in that the X-ray powder that crystal form B is indicated with the 2 θ ± 0.2 ° angles of diffraction
Diffraction spectrogram shows feature at 9.18,9.92,11.92,12.42,17.51,19.65,19.97,20.56,21.48,21.87
Peak.
7. C according to claim 616The crystal form B of-DP-VPA, which is characterized in that crystal form B is with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction spectrogram of expression also 7.41,13.40,14.98,15.93,16.39,18.30,18.73,22.62,
23.7, characteristic peak is shown at 24.50.
8. the C described in a kind of according to claim 6 or 716The preparation method of the crystal form B of-DP-VPA comprising following step：
1) by C16Suspension is made with hydrophobic inert organic solvents in-DP-VPA；
2) clear solution is obtained under 40 DEG C~reflux conditions；
3) cool down crystallization, is filtered, washed, dries.
9. the preparation method of crystal form B according to claim 8, which is characterized in that the hydrophobic inert organic solvents choosing
From one or more of esters, alkanes organic solvent；Optional, the esters are selected from Ethyl formate, butyl formate, second
One or more of acetoacetic ester, methyl acetate, butyl acetate, isobutyl acetate, the alkanes are selected from petroleum ether, just oneself
One or more of alkane, hexamethylene, normal heptane.
10. the preparation method of crystal form B according to claim 8, which is characterized in that the C16- DP-VPA is hydrophobic lazy
A concentration of 0.01~0.5g/ml in property organic solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710208986.5A CN108659037B (en) | 2017-03-31 | 2017-03-31 | Polymorphic substance of valproic acid phospholipid derivative and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710208986.5A CN108659037B (en) | 2017-03-31 | 2017-03-31 | Polymorphic substance of valproic acid phospholipid derivative and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108659037A true CN108659037A (en) | 2018-10-16 |
| CN108659037B CN108659037B (en) | 2022-01-11 |
Family
ID=63783987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710208986.5A Active CN108659037B (en) | 2017-03-31 | 2017-03-31 | Polymorphic substance of valproic acid phospholipid derivative and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108659037B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019206266A1 (en) * | 2018-04-28 | 2019-10-31 | 江苏恩华药业股份有限公司 | Crystal form of phospholipid derivative of valproic acid and preparation method therefor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6077837A (en) * | 1995-06-07 | 2000-06-20 | D-Pharm Ltd. | Prodrugs with enhanced penetration into cells |
| CN1774252A (en) * | 2000-07-12 | 2006-05-17 | 迪-药品有限公司 | Phospholipid derivatives of valproic acid and mixtures thereof |
| CN104230981A (en) * | 2013-06-20 | 2014-12-24 | 江苏恩华药业股份有限公司 | Preparation method of valproic acid phospholipid derivative |
-
2017
- 2017-03-31 CN CN201710208986.5A patent/CN108659037B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6077837A (en) * | 1995-06-07 | 2000-06-20 | D-Pharm Ltd. | Prodrugs with enhanced penetration into cells |
| CN1774252A (en) * | 2000-07-12 | 2006-05-17 | 迪-药品有限公司 | Phospholipid derivatives of valproic acid and mixtures thereof |
| CN104230981A (en) * | 2013-06-20 | 2014-12-24 | 江苏恩华药业股份有限公司 | Preparation method of valproic acid phospholipid derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019206266A1 (en) * | 2018-04-28 | 2019-10-31 | 江苏恩华药业股份有限公司 | Crystal form of phospholipid derivative of valproic acid and preparation method therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108659037B (en) | 2022-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6925318B2 (en) | Method for producing dicycloplatin | |
| Láng et al. | Polymorph screening of an active material | |
| EP3377498A1 (en) | Process for the preparation of the amorphous form of ibrutinib and novel crystalline form | |
| TW201402563A (en) | Form I crystal of dimaleate salt of tyrosine kinase inhibitor and preparation method thereof | |
| WO2016206534A1 (en) | New crystal form of apremilast and preparation method therefor | |
| WO2011163430A1 (en) | Polymorphs of osi-906 | |
| WO2016023905A1 (en) | New and efficient process for the preparation of crystalline form 6 of sofosbuvir | |
| WO2021000687A1 (en) | Preparation method for crystal form of pac-1 | |
| JP2021518403A (en) | Crystal form of compound and method of producing crystal form of compound | |
| CN102875531B (en) | A kind of (R)-lansoprazole anhydrous crystal forms and preparation method thereof | |
| JP2022530812A (en) | Crystal form of Wee1 inhibitor compound and its applications | |
| CN118994125A (en) | Crystal form, preparation method and application of pyrazolyl-amino-pyrimidinyl derivative | |
| CN108659037A (en) | The polymorph and preparation method of valproic acid phospholipid derivative | |
| EP2528913A1 (en) | Crystalline forms of l-malic acid salt of sunitinib | |
| JP7068411B2 (en) | Hexadecyltreprostinyl crystal and its manufacturing method | |
| CN114478512A (en) | Crystal form of acid and preparation method thereof | |
| WO2020186962A1 (en) | Crystal form e of bulleyaconitine a, preparation method therefor and application thereof | |
| HUP0303055A2 (en) | Polymorphs of zaleplon and methods for the preparation thereof and pharmaceutical compositions containing them | |
| WO2020186960A1 (en) | Bulleyaconitine a crystalline form c, preparation method therefor and application thereof | |
| CN108794383B (en) | Co-crystal of nifedipine and isonicotinamide | |
| US20090012111A1 (en) | Crystalline polymorph of 7-ethyl-10-hydroxycamptothecin | |
| JP2014514274A (en) | Polymorphs of maxacalcitol and methods for preparing maxacalcitol | |
| TW200825092A (en) | A method for reducing the level of AED in atorvastatin calcium sample | |
| Chinta et al. | Synthesis, photophysical properties, bioimaging potential and in vitro toxicity studies of naphthalimide imidazole boron complexes | |
| CN103059013B (en) | Crystal formation of Dasatinib monohydrate and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220831 Address after: 201208 building 12, No. 356, ZHENGBO Road, Lingang xinpian District, pilot Free Trade Zone, Pudong New Area, Shanghai Patentee after: Shanghai Shujing Biotechnology Co.,Ltd. Address before: 221009 No.18, Yangshan Road, Xuzhou Economic Development Zone, Jiangsu Province Patentee before: NHWA PHARMA. Corp. |
|
| TR01 | Transfer of patent right |