CN108659038B

CN108659038B - Polymorphic substance of 1-stearoyl-2-valoyl-sn-glycerol-3-phosphatidylcholine and preparation method thereof

Info

Publication number: CN108659038B
Application number: CN201710211850.XA
Authority: CN
Inventors: 郝超; 马彦琴; 王勇; 周英珍; 陈亮; 张桂森
Original assignee: Nhwa Pharmaceutical Corp
Current assignee: Shanghai Shujing Biotechnology Co ltd
Priority date: 2017-03-31
Filing date: 2017-03-31
Publication date: 2022-01-11
Anticipated expiration: 2037-03-31
Also published as: CN108659038A

Abstract

The invention discloses a phospholipid derivative 1-stearoyl-2-valproyl-sn-glycerol-3-phosphatidylcholine (DP-VPA-C) of valproic acid₁₈) Is/are as followsSeveral polymorphs and methods of preparation. The several polymorphic substances provided by the invention are respectively a crystal form A, a crystal form B, a crystal form C and a crystal form D.

Description

Polymorphic substance of 1-stearoyl-2-valoyl-sn-glycerol-3-phosphatidylcholine and preparation method thereof

The technical field is as follows:

the invention belongs to the field of pharmaceutical chemistry, and particularly relates to a polymorphic substance of 1-stearoyl-2-valproyl-sn-glycerol-3-phosphatidylcholine and a preparation method thereof.

Background art:

chinese patent application 01815173.6 discloses a valproic acid phospholipid derivative and its preparation method, the phospholipid derivative (DP-VPA) is a mixture, and its two components are respectively 1-palmitoyl-2-valproyl-sn-glycerol-3-phosphatidylcholine (DP-VPA-C for short)₁₆) 1-stearoyl-2-valoyl-sn-glycerol-3-phosphatidylcholine (DP-VPA-C for short)₁₈) (ii) a Chinese patent application CN104230981A also discloses a method for synthesizing these two components; the structural formula is as follows:

two component ratio DP-VPA-C₁₈:DP-VPA-C₁₆85 plus or minus 5 percent, 15 plus or minus 5 percent; the product has entered phase II clinic as a new antiepileptic drug in foreign countries.

DP-VPA molecules are disclosed in U.S. patent application 08/479, 959, International patent publication WO94/22483, Chinese patent application 01815173.6, and Chinese patent application CN104230981A also discloses a method for the synthesis of two components therein; the disclosure of which is hereby incorporated by reference.

DP-VPA-C₁₈Is a 1:1 lipid of valproic acid with 1-octadecanoyl-sn-glycero-3-phosphorylcholine, has been shown to have significant anticonvulsant activity and to be more potent than sodium valproate. Although the above patent discloses the preparation method and crystallization method, it does not mention DP-VPA-C₁₈Polycrystalline phenomenon of (2).

In Chinese patent application 01815173.6, DP-VPA-C is mentioned₁₈Formulations suitable for administration include, but are not limited to, powders, pills, emulsions, suspensions or solutions, including in aqueous or non-aqueous media, tablets, capsules, syrups or solutions.

It is well known that drug polymorphism is a common phenomenon in solid chemical drugs; different crystal forms of the same medicament are different in appearance, solubility, melting point, dissolution rate, biological activity and the like, so that the stability, bioavailability, clinical curative effect and the like of the medicament are influenced, and the phenomenon is particularly obvious in the aspect of oral solid preparations. Therefore, the polymorphism of the drug is one of the important factors influencing the quality and clinical efficacy of the drug. In the development process, a crystal form suitable for medicinal use needs to be searched, and the clinical requirement is met.

The invention content is as follows:

the object of the present invention is to provide 1-palmitoyl-2-valproyl-sn-glycero-3-phosphatidylcholine (C)₁₆-DP-VPA) in two new crystal forms, polymorph a and B of the co-crystal, and processes for preparing these polymorphs. The two crystal forms A and B have good stability, good solubility and the like, and are suitable for being prepared into oral solid preparations.

The purpose of the invention can be realized by the following technical scheme:

in one aspect, the invention provides a DP-VPA-C₁₈Form A, characterized in that form A exhibits characteristic peaks in the X-ray powder diffraction pattern at 4.67, 7.06, 9.45, 11.86, 14.28, 16.69, 19.11, 21.5523.99 as indicated by the 2 theta + -0.2 ° diffraction angle. Further, the X-ray powder diffraction spectrum of the form A expressed by the diffraction angle of 2 theta +/-0.2 degrees also shows characteristic peaks at 23.27, 26.45, 28.92, 31.40, 32.69, 35.11 and 38.96.

Preferably, the DP-VPA-C₁₈The form a of (a) has an X-ray powder diffraction pattern substantially as shown in figure 1.

Further, the DP-VPA-C₁₈The X-ray powder diffraction reflection angle 2 theta +/-0.2 degrees of the crystal form A and the corresponding d value and relative peak intensity are shown in a table 1:

TABLE 1 DP-VPA-C₁₈Form A of

The DP-VPA-C₁₈The infrared spectrum of the crystal form A contains absorption peaks: 512.78, 782.34, 809.54, 929.65, 951.53, 970.34, 998.78, 1019.59, 1060.23, 1082.23, 1100.97, 1163.82, 1183.98, 1232.59, 1253.30, 1346.02, 1382.38, 1418.14, 1467.46, 1488.00, 1662.98, 1739.45, 2851.30, 2920.18, 3422.97 ± 0.5% cm^-1。

The DP-VPA-C₁₈Form A of (a) has a first endothermic peak at 88. + -. 1.5 ℃ and a second endothermic peak at 163. + -. 1.5 ℃ in a DSC analysis.

The DP-VPA-C₁₈Further thermogravimetric analysis of form a of (a) shows: the weight loss ratio of the crystal form A at 25-200 ℃ is 2.9 +/-0.2%.

The DP-VPA-C₁₈The optical microscope characteristic image of the crystal form A shows a square sheet shape, a rectangular sheet shape and an irregular sheet shape.

The DP-VPA-C₁₈The scanning electron microscope characteristic image of form a of (a) shows irregular flakes.

In another aspect, the present invention also provides a process for preparing form a of DP-VPA by standing recrystallization, comprising the steps of:

1) DP-VPA-C is reacted at 40 ℃ to reflux temperature₁₈Dissolving in an organic solvent, wherein the organic solvent is selected from ketones, esters, aprotic solvents, or from a combination of alkanes and ketones, a mixed solvent of ketones and inert organic solvents, alcohols and inert organic solvents; the inert organic solvent is selected from one or more of ketones, esters, alkanes, ethers, acetonitrile, N-dimethylformamide, NMP, DMSO and THF;

2) cooling, crystallizing, filtering, washing and drying.

In the preparation of DP-VPA-C₁₈In the standing recrystallization method of the crystal form A, the ketone is selected from one or more of acetone, butanone and methyl isobutyl ketone, and the alcohol is selected from C_1-8Straight chain orOne or more branched chain alkanol, more preferably one or more methanol, ethanol, n-propanol, isopropanol and n-butanol; the esters are selected from one or more of ethyl formate, butyl formate, ethyl acetate, methyl acetate, butyl acetate and isobutyl acetate; the alkane is selected from one or more of petroleum ether, n-hexane, cyclohexane and n-heptane; the ether is selected from one or more of diethyl ether and methyl tert-butyl ether.

In the preparation of DP-VPA-C₁₈In a standing recrystallization method of form A of (1), the DP-VPA-C₁₈The concentration of the organic solvent is 0.05-0.25 g/ml, the volume ratio of the ketone to the inert organic solvent in the combination of the ketone and the inert organic solvent is more than 1:10, and the volume ratio of the alcohol to the inert organic solvent in the combination of the alcohol and the inert organic solvent is 1: 5-1: 50.

In another aspect, the present invention provides a DP-VPA-C₁₈Form B, which shows characteristic peaks at 4.737, 7.141, 9.207, 11.955, 12.308, 13.573, 19.210, 20.048, 20.664, 21.568 and 22.184 in an X-ray powder diffraction spectrum represented by a 2 theta +/-0.2 DEG diffraction angle. Further, the X-ray powder diffraction spectrum of the form B expressed by the diffraction angle of 2 theta +/-0.2 degrees also shows characteristic peaks at 9.558, 14.333, 15.870, 16.357, 16.803, 17.884, 18.543, 19.673, 23.984, 24.764, 25.592 and 26.492.

Preferably, the form B of DP-VPA has an X-ray powder diffraction pattern substantially as shown in FIG. 7.

Further, the DP-VPA-C₁₈The X-ray powder diffraction reflection angle 2 theta +/-0.2 degrees of the crystal form B and the corresponding d value and relative peak intensity are shown in a table 2:

TABLE 2DP-VPA-C₁₈Form B of

The DP-VPA-C₁₈The infrared spectrum of the crystal form B contains absorption peaks: 512.85, 782.47, 809.74, 929.59, 951.63, 970.31, 998.80, 1019.65, 1060.32, 1082.49, 1100.99, 1163.89, 1183.93, 1232.71, 1253.21, 1345.95, 1382.15, 1418.47, 1467.36, 1488.03, 1663.09, 1739.39, 2851.50, 2920.43, 3424.96 ± 0.5% cm^-。

The DP-VPA-C₁₈Form B of (1) has a first endothermic peak at 87 + -1.5 deg.C and a second endothermic peak at 163 + -1.5 deg.C.

The DP-VPA-C₁₈Further thermogravimetric analysis of form B of (a) shows: the weight loss ratio of the crystal form B at 25-200 ℃ is 3.05 +/-0.2%.

The DP-VPA-C₁₈The scanning electron microscope characteristic image of form B of (a) shows lamellar stacking spheres or irregular lamellar stacking.

In another aspect, the invention relates to the preparation of DP-VPA-C by a standing recrystallization process₁₈A process of form B comprising the steps of

1) DP-VPA-C₁₈Adding DMF, toluene, NMP, alkane, mixture of chloroform and acetonitrile, mixture of chloroform and alkane, mixture of chloroform and ether, mixture of dichloromethane and acetonitrile, mixture of dichloromethane and alkane, mixture of dichloromethane and ether, mixture of ether and alkane, and mixture of ester and alkane to obtain suspension;

2) heating the mixture in water bath at 40-reflux temperature to obtain clear solution;

3) and (4) cooling and crystallizing under the stirring condition, and filtering under reduced pressure to obtain the target product.

In the preparation method of the crystal form B, the alkane is preferably selected from one or a combination of more of petroleum ether, n-hexane and cyclohexane, the ether is preferably selected from one or a combination of more of diethyl ether and methyl tert-butyl ether, and the ester is preferably selected from one or a combination of more of ethyl formate, butyl formate, ethyl acetate, methyl acetate, butyl acetate and isobutyl acetate.

In another aspect, the invention provides methods for producing DP-VPA-C using lapping and recrystallization₁₈The crystal form B, wherein the grinding and crystal transformation method comprises mechanical ball milling and artificial grinding;

1. the mechanical ball milling comprises the following steps:

DP-VPA-C₁₈And (3) putting the crystal form A into an agate mortar of a ball mill, grinding at the speed of 400 r/min, and alternately changing the rotation direction of each circulating ball mill every 15 minutes after grinding and resting for 15 minutes, wherein the grinding time is more than 60 minutes, so that the target product is obtained.

2. The artificial grinding comprises the following steps:

DP-VPA-C₁₈And (3) placing the crystal form A in a common agate mortar, and forcibly grinding for not less than 3 hours to obtain the target product.

In another aspect, the present invention provides methods for preparing DP-VPA-C using solid state crystallization₁₈A process of form B comprising the steps of:

DP-VPA-C₁₈And (3) placing the crystal form C for 2 days under natural conditions, and absorbing moisture in the air to obtain a target product through crystal transformation. Wherein the DP-VPA-C₁₈Form C was prepared under high vacuum solvent removal conditions.

Description of the drawings:

FIG. 1 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form A

FIG. 2 shows DP-VPA-C₁₈FT-IR Spectroscopy of form A

FIG. 3 shows DP-VPA-C₁₈DSC thermogram of crystal form A

FIG. 4 shows DP-VPA-C₁₈TG thermogram of crystal form A

FIG. 5 shows DP-VPA-C₁₈Optical microscope photograph of Crystal form A

FIG. 6 shows DP-VPA-C₁₈Scanning electron microscope photograph of crystal form A

FIG. 7 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form B

FIG. 8 shows DP-VPA-C₁₈FT-IR Spectroscopy of form B

FIG. 9 shows DP-VPA-C₁₈DSC thermogram of crystal form BDrawing (A)

FIG. 10 shows the TG thermogram of DP-VPA-C18 form B

FIG. 11 shows DP-VPA-C₁₈Scanning electron microscope photograph of form B

FIG. 12 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form C

FIG. 13 shows DP-VPA-C₁₈FT-IR Spectroscopy of form C

FIG. 14 shows DP-VPA-C₁₈DSC thermogram of form C

FIG. 15 shows DP-VPA-C₁₈TG thermogram of crystal form C

FIG. 16 shows DP-VPA-C₁₈X-ray powder diffraction spectrogram under natural condition of crystal form C

Change with time

FIG. 17 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form D

FIG. 18 shows DP-VPA-C₁₈Change of X-ray powder diffraction spectrogram under natural condition of crystal form D along with time

FIG. 19 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form A stability influence factors after 5-day and 10-day illumination

FIG. 20 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form A high-temperature 5-day and 10-day stability influence factors

FIG. 21 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form A high-humidity 5-day and 10-day stability influence factors

FIG. 22 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form B stability influence factors after 5-day and 10-day illumination

FIG. 23 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form B high-temperature 5-day and 10-day stability influence factors

FIG. 24 shows DP-VPA-C₁₈X-ray powder diffraction spectrum of crystal form B high-temperature 5-day and 10-day stability influence factors

The specific embodiment is as follows:

the contents of the present invention will be specifically explained below with reference to the drawings and examples, but it is not intended that the present invention includes only the following contents.

The invention relates to 1-stearoyl-2-valoyl-sn-glycerol-3-phosphatidylcholine (DP-VPA-C for short)₁₈) Form a, form B, form C, form D, and processes for preparing these polymorphs are also provided.

The different configuration and orientation of molecules in the unit cell defining a particular polymorphic form of a substance leads to different physical properties that allow solid state analytical characterization of these phases. Different crystal structures have characteristic reflections with more or less characteristic relative intensities in the X-ray powder diffraction pattern, which generally allows for unambiguous identification of polymorphic forms. This variation may cause different thermal performance than other passes. Thermal properties are measured in the laboratory by techniques such as capillary melting point, specific analysis (TG) and Differential Scanning Calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular solid phase may also give rise to different spectral properties, which can be detected by solid state nuclear magnetic resonance (nmr) spectrometry, raman spectrometry and fourier infrared (FT-IR) spectroscopy. A particular solid phase has different packing patterns of molecules, and the appearance form of the solid phase, namely the appearance form of the solid phase, can show different appearances, and the appearance forms can be observed by an optical microscope and a scanning electron microscope. These analytical techniques are therefore suitable for characterizing polymorphic forms.

DP-VPA-C₁₈Crystal form A

According to the present invention, it has been found that DP-VPA-C is prepared from an organic solvent by a standing recrystallization method, a dissolution precipitation method₁₈Form A; DP-VPA-C₁₈Solid state characterization of form a (XPRD, IR, DSC, TG, optical microscope, scanning electron microscope) are given in figures 1-6, respectively. Form a is characterized by one or more of the following solid state characteristics:

an X-ray powder diffraction pattern substantially in accordance with figure 1;

(i) a FT-IR spectrum substantially in accordance with figure 2;

(ii) a DSC thermogram substantially in accordance with figure 3;

(iii) a TG thermogram substantially in accordance with fig. 4;

(iv) an optical microscope image substantially in accordance with figure 5;

(v) a scanning electron microscope image substantially in accordance with figure 6;

DP-VPA-C₁₈hygroscopicity of form a

Measured according to the guiding principle of XI XJ in the second part appendix of the 2010 version of the Chinese pharmacopoeia;

the determination method comprises the following steps: taking a certain amount of a test sample, placing the test sample into a precisely weighed weighing bottle (the outer diameter is 50mm, and the height is 15mm), and precisely weighing; placing the open port of the weighing bottle in a constant-temperature dryer with the proper temperature of 25 +/-1 ℃ and the relative humidity of 80 +/-2%, placing for 24 hours, covering the cover of the weighing bottle, and precisely weighing;

DP-VPA-C₁₈the moisture absorption weight of the crystal form A is increased by 0.40 percent, and the crystal form A has slight hygroscopicity.

DP-VPA-C₁₈Water content titration of form a

The first method Fischer method is determined according to the guidance principle of the item VIII M in the appendix of the 2010 edition second part of the Chinese pharmacopoeia;

the determination method comprises the following steps: precisely weighing about 0.3g of the crystal form A, placing the crystal form A into a dry glass bottle with a plug, adding 40ml of anhydrous methanol, titrating the solution from the Fischer test solution to light yellow to reddish brown under stirring, performing a blank test, and calculating the water content from the consumed Fischer test solution;

and (3) measuring results: the water content is 2.86 +/-0.05%

DP-VPA-C₁₈Stability of form A

DP-VPA-C₁₈And respectively carrying out high-humidity, high-temperature and illumination experiments on the crystal form A. Samples were taken for XPRD testing on days 5 and 10, respectively, and compared to day 0 results, which are shown in Table 3.

TABLE 3DP-VPA-C₁₈Test of Crystal form influencing factor of Crystal form A

Table 3 shows that the crystal form A can keep stable under the conditions of 75 +/-5% of high humidity, 60 ℃ of high temperature and 4500lx +/-500 lx of illumination without crystal transformation.

DP-VPA-C₁₈Crystal form B

According to the present invention, it has been found that DP-VPA-C can be prepared from organic solvents by recrystallization, solvent removal, polish transformation, solid state transformation₁₈A crystal form B; DP-VPA-C₁₈Solid state characterization of form B (XPRD, IR, DSC, TG, scanning electron microscope) are given in figures 7-11, respectively. Form B is characterized by one or more of the following solid state characteristics:

an X-ray powder diffraction pattern substantially in accordance with figure 7;

(i) a FT-IR spectrum substantially in accordance with figure 8;

(ii) a DSC thermogram substantially in accordance with figure 9;

(iii) a TG thermogram substantially in accordance with fig. 10;

(iv) a scanning electron microscope image substantially in accordance with figure 11;

DP-VPA-C₁₈hygroscopicity of form B

DP-VPA-C₁₈the moisture absorption weight of the crystal form B is increased by 0.45 percent, and the crystal form B has slight hygroscopicity.

DP-VPA-C₁₈Water content titration of form B

the determination method comprises the following steps: precisely weighing about 0.3g of the crystal form B, placing the crystal form B into a dry glass bottle with a plug, adding 40ml of anhydrous methanol, titrating the solution from the Fischer-Tropsch test solution to change the light yellow into reddish brown under stirring, carrying out a blank test, and calculating the water content from the consumed Fischer-Tropsch test solution;

and (3) measuring results: the water content is 2.90 +/-0.05%

DP-VPA-C₁₈Stability of form B

DP-VPA-C₁₈And respectively carrying out high-humidity, high-temperature and illumination experiments on the crystal form B. Samples were taken for XPRD testing on days 5 and 10, respectively, and compared to day 0 results, which are shown in Table 2.

TABLE 4DP-VPA-C₁₈Test of Crystal form influencing factor of Crystal form B

Table 4 shows that the crystal form B can keep stable under the conditions of 75 +/-5% of high humidity, 60 ℃ of high temperature and 4500 +/-500 lx of illumination.

DP-VPA-C₁₈Crystal form C

According to the present invention it has been found that DP-VPA-C is prepared from organic solvents by high vacuum solvent removal₁₈Form C; DP-VPA-C₁₈Solid state characterization of form C (XPRD, IR, DSC, TG) are given in fig. 12-15, respectively. DP-VPA-C₁₈Form C is characterized by one or more of the following solid state characteristics:

an X-ray powder diffraction pattern substantially in accordance with figure 12;

(i) a FT-IR spectrum substantially in accordance with figure 13;

(ii) a DSC thermogram substantially in accordance with figure 14;

(iii) a TG thermogram substantially in accordance with fig. 15;

DP-VPA-C₁₈characteristic solid state characterization data for form C are as follows:

1.DP-VPA-C₁₈the characteristic XPRD reflection 2 θ ± 0.2 ° for form C is as follows:

3.382，4.722，6.859，7.116，11.911，17.222，19.165，19.755，20.073，20.674，21.565，23.736；

DP-VPA-C as described above₁₈An XPRD spectrum of the crystal form C expressed by a 2 theta +/-0.2 DEG diffraction angle shows special characteristics at 3.382, 4.722, 6.859, 7.116, 9.222, 9.517, 10.245, 11.911, 12.317, 13.748, 14.332, 15.768, 16.324, 16.743, 17.222, 19.165, 19.755, 20.073, 20.674, 21.565, 21.953, 23.736 and 26.468And (5) characterizing an absorption peak.

2.DP-VPA-C₁₈The characteristic FT-IR absorption bands for form C are as follows:

512.82，782.51，809.73，929.35，951.58，970.22，1019.48，1060.29，1082.30，1100.89，1163.99，1232.97，1253.40，1345.89，1382.10，1417.70，1467.38，1487.49，1662.00，1739.11，2851.37，2920.38，3426.40±0.5％cm^-1；

3.DP-VPA-C₁₈the DSC thermogram characteristic endothermic peaks for form C are as follows:

the peak value of the first endothermic peak is 83 +/-1.5 ℃, and the peak value of the second endothermic peak is 163 +/-1.5 ℃;

4.DP-VPA-C₁₈the TG thermogram characteristic weight loss for form C is as follows:

the weight loss ratio of 25-200 ℃ is 1.80 +/-0.2%;

DP-VPA-C₁₈stability of form C

DP-VPA-C₁₈Form C was placed in a watch glass, exposed to air at ambient conditions, sampled at 6 hours, 20 hours, 48 hours respectively for XPRD testing and compared to 0 hours, with the results shown in table 5;

TABLE 5 DP-VPA-C₁₈Stability of form C under ambient conditions

DP-VPA-C₁₈The X-ray powder diffraction pattern of form C as a function of time when placed under ambient conditions is shown in fig. 16. The crystal form C is very unstable and is easy to absorb moisture in the air to be converted into the crystal form B.

The invention also provides DP-VPA-C₁₈A process for preparing form C, comprising the steps of:

1) DP-VPA-C₁₈Dissolving in benign organic solvent or mixture of benign organic solvent and inert organic solvent to obtain clear solution; wherein the clear solution is consistent with the clear solution in the second preparation method of the crystal form B and the step 1).

2) Removing the solvent of the clear solution obtained in the step 1) under the condition of high vacuum;

the conditions for removing the reduced-pressure solvent in the step 2) are as follows: the vacuum pressure should be less than 20mbar and the temperature should be 75-80 ℃.

3) Slowly cooling, and recovering the solid to obtain the target product.

DP-VPA-C₁₈Crystal form D

According to the present invention it has been found that DP-VPA-C is prepared by a vacuum high temperature melting temperature reduction process₁₈Form D; DP-VPA-C₁₈Solid state characterization (XPRD) of form D is given in fig. 17;

DP-VPA-C₁₆the crystal form D is close to an amorphous substance, and the X-ray powder diffraction pattern of the crystal form D is characterized in that the X-ray powder diffraction spectrogram expressed by the diffraction angle of 2 theta +/-0.2 degrees is shown in figure 17.

DP-VPA-C₁₈Stability of Crystal form D

DP-VPA-C₁₈Form D was placed in a watch glass, exposed to air at ambient conditions, sampled for XPRD testing at 20min, 2hour, 5hour, 1Day, 3Day, respectively, and compared to Day 0, with the results shown in table 6;

TABLE 6 DP-VPA-C₁₈Stability of form D under ambient conditions

DP-VPA-C₁₈The X-ray powder diffraction pattern of form D over time when placed under ambient conditions is shown in figure 18. The crystal form D is very unstable and is easy to absorb moisture in the air to be converted into the crystal form A.

The invention also provides DP-VPA-C₁₈A process for preparing form D, comprising the steps of:

1)DP-VPA-C₁₈putting a proper amount of solid in a ceramic crucible, and heating and melting under a vacuum condition; the heating and melting conditions under the vacuum condition are that the vacuum degree is 0.01-0.05 Mpa, and the temperature is 150-168 ℃.

2) Rapidly cooling the product obtained by heating and melting to room temperature, wherein rapid cooling is preferably nitrogen purging cooling; and obtaining the target product.

The specific implementation mode is as follows:

the invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the protection scope of the present invention.

In the examples that follow, unless otherwise indicated, the experimental procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown in the figure can be obtained by a commercially available mode.

The X-ray powder diffractogram according to the invention was collected on a Bruker D8 Focus X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:

x-ray parameters:

voltage: 40 KV (kV)

Current: 40 milliampere (mA)

Scanning range: from 3.0 to 40 DEG

Sampling step length: 0.02 degree

Sampling pace speed: 0.5 sec/step

The Differential Scanning Calorimetry (DSC) analysis chart is detected by a German relaxation-resistant DSC 200F3, the temperature range is 35-200 ℃, and the temperature rise rate is 10K/min; sealing the pricking hole in an aluminum crucible, wherein the purging gas is nitrogen (40ml/min), and the protective gas is nitrogen (20 ml/min).

The thermogravimetric analysis (TG) is detected by German relaxation-resistant TG 209F3, the balance is kept at 25 ℃, the temperature range is 35-200 ℃, the heating rate is 5K/min, an aluminum crucible is opened, the purging gas is nitrogen (40ml/min), and the protective gas is nitrogen (20 ml/min).

The infrared spectrum (FT-IR) of the invention is detected by a NICOLET 330FT-IR infrared spectrophotometer. Weighing 180mg of potassium bromide which is dried and cooled at 120 ℃ in advance, putting the potassium bromide into an agate mortar, grinding the potassium bromide into fine powder, adding about 1.5mg of a test sample, fully mixing the test sample and grinding the test sample into uniform fine powder, and determining the test sample according to appendix VI C of the second part of the 2010 edition of Chinese pharmacopoeia.

The optical microcrystal image is observed on an XPN-203E polarizing hot stage microscope and is obtained by taking a picture by a JVC color camera.

The scanning electron microscope image is obtained by observing and photographing a desk type scanning electron microscope of a PHENOM in the Netherlands.

The moisture content measurement described herein is by the Fischer method in the METTLER TOLEDO V20 Volumetric KF Titrator.

Example 1 DP-VPA-C₁₈Preparation of form A

Example 1.1

DP-VPA-C₁₈Adding 0.5g of sample into 3ml of acetone, heating until reflux, clarifying the solution, and continuously heating, stirring and refluxing; stopping stirring after 30min, standing, naturally cooling to room temperature, and separating out a large amount of solids; filtering, washing with 1ml acetone, collecting filter cake, and vacuum drying at 60 deg.C overnight to obtain DP-VPA-C₁₈Form A.

Example 1.2

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by 3ml of ethyl acetate.

Example 1.3

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by 3ml of acetonitrile.

Example 1.4

The same test procedure as in example 1.1 was used, but 3ml of acetone as the solvent used was replaced by 3ml of tetrahydrofuran.

Example 1.5

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by 3ml of methyl tert-butyl ether.

Example 1.6

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 2ml of acetone and 2ml of ethyl acetate.

Example 1.7

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 2ml of acetone and 2ml of acetonitrile.

Example 1.8

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 2ml of acetone and 2ml of methyl tert-butyl ether.

Example 1.9

Example 1.10

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 2ml of acetone and 2ml of petroleum ether.

Example 1.11

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 0.5ml of methanol and 15ml of acetone.

Example 1.12

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 0.5ml of methanol and 10ml of ethyl acetate.

Example 1.13

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 0.5ml of methanol and 10ml of methyl tert-butyl ether.

Example 1.14

The same test procedure as in example 1.1 was used, but 3ml of the solvent acetone used was replaced by a mixture of 0.5ml of methanol and 20ml of n-hexane.

Example 2DP-VPA-C₁₈Preparation of form B

Example 2.1

DP-VPA-C₁₈Adding 0.5g of sample into 5ml of petroleum ether, heating until refluxing, clarifying the solution, and continuously heating, stirring and refluxing for 30 min; naturally cooling to room temperature, and separating out a large amount of solids; filtering, washing with 2ml petroleum ether, collecting filter cake, and vacuum drying at 60 deg.C overnight to obtainDP-VPA-C₁₈Form B.

Example 2.2

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by DMF5 ml.

Example 2.3

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 3ml of ethyl acetate and 3ml of petroleum ether.

Example 2.4

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 3ml of methyl tert-butyl ether and 3ml of petroleum ether.

Example 2.5

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 1ml of chloroform and 30ml of acetonitrile.

Example 2.6

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 1ml of dichloromethane and 30ml of acetonitrile.

Example 2.7

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 1ml of chloroform and 30ml of petroleum ether.

Example 2.8

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 1ml of dichloromethane and 30ml of petroleum ether.

Example 2.9

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 1ml of chloroform and 30ml of methyl tert-butyl ether.

Example 2.10

The same test procedure as in example 2.1 was used, but 5ml of the solvent petroleum ether used was replaced by a mixture of 1ml of dichloromethane and 30ml of methyl tert-butyl ether.

Example 2.11

DP-VPA-C₁₈0.5g of sample was added to 10ml of methanol to prepare a clear solution, and the methanol was removed by evaporation under reduced pressure using a rotary evaporator at 45 ℃ under 0.05MPa until no more droplets fell. Collecting solid, and vacuum drying at 60 deg.C overnight to obtain DP-VPA-C₁₈Form B.

Example 2.12

The same test procedure as in example 2.16 was used, but 10ml of methanol as the solvent used was replaced by 10ml of ethanol.

Example 2.13

Example 2.14

The same test procedure as in example 2.16 was used, but 10ml of the solvent methanol used was replaced by a mixture of 5ml of ethanol and 5ml of acetone.

Example 2.15

DP-VPA-C₁₆0.5g of sample was added to 10ml of chloroform to prepare a clear solution, and the chloroform was removed by evaporation under reduced pressure using a rotary evaporator at 35 ℃ under 0.09MPa until no more droplets were dropped. Collecting solid, and vacuum drying at 60 deg.C overnight to obtain DP-VPA-C₁₈Form B.

Example 2.16

The same test procedure as in example 2.20 was used, but 10ml of chloroform as the solvent used was replaced by 10ml of dichloromethane.

Example 2.17

The same test procedure as in example 2.20 was used, but 10ml of chloroform was used as the solvent instead of a mixture of 5ml of chloroform and 5ml of acetone.

Example 2.18

The same test procedure as in example 2.20 was used, but 10ml of chloroform, the solvent used, was replaced by a mixture of 5ml of dichloromethane and 5ml of acetone.

Example 2.19

DP-VPA-C₁₈About 4g of the crystal form A in total is placed in two agate mortars of a ball mill, about 2.0g of each mortar sample, so as toGrinding at 400 rpm for 15 min, and grinding for 60 min to obtain DP-VPA-C₁₆Form B.

Example 2.20

DP-VPA-C₁₈Placing about 2.0g of the crystal form A in a common agate mortar, grinding with force, continuously grinding in the direction of changing the direction every 15 minutes, and grinding for 180 minutes to obtain DP-VPA-C₁₆Form B.

Example 2.21

DP-VPA-C₁₈Crystal form C of about 2.0g is placed in a watch glass, the watch glass is placed under the environmental condition, the relative humidity is about 45 percent, the temperature is about 25 ℃, and after being placed for 2 days, the DP-VPA-C is obtained₁₈Form B.

Example 3DP-VPA-C₁₈Preparation of form C

Example 3.1

DP-VPA-C₁₈Sample 0.5g, added to 10ml methanol to make clear solution, and the methanol was removed by evaporation under reduced pressure at 20mbar and 78 ℃; cooling to room temperature to obtain DP-VPA-C₁₈Form C.

Example 3.2

The same test procedure as in example 3.1 was used, but 10ml of the solvent methanol used was replaced by a mixture of 5ml of methanol and 5ml of acetone.

Example 3.3

The same test procedure as in example 3.1 was used, but 10ml of the solvent methanol used was replaced by a mixture of 5ml of chloroform and 5ml of acetonitrile.

Example 4DP-VPA-C₁₈Preparation of form D

Example 4.1

DP-VPA-C₁₈2.0g of solid is placed in a ceramic crucible and heated and melted under the vacuum condition; the vacuum degree is 0.01Mpa, and the temperature is 167 ℃. Purging with nitrogen to quickly reach room temperature to obtain DP-VPA-C₁₈Form D.

Test example 1 hygroscopicity test

The determination method comprises the following steps: taking a certain amount of DP-VPA-C₁₈Crystal form A and crystal form B, respectively adding purified extractPrecisely weighing in a weighing bottle (the outer diameter is 50mm, and the height is 15mm) in a dense weighing way; placing the open weighing bottle in a suitable constant temperature dryer (with ammonium chloride saturated solution placed at the lower part) at 25 + -1 deg.C, standing for 24 hr at relative humidity of 80 + -2%, covering the bottle, and precisely weighing.

TABLE 7 DP-VPA-C₁₈Moisture absorption detection results of crystal form A and crystal form B

The results in Table 7 show that DP-VPA-C₁₈The moisture absorption weight gain of the crystal form A and the moisture absorption weight gain of the crystal form B are respectively 0.40 percent and 0.45 percent, and the crystal form A and the crystal form B have slight moisture absorption.

Test example 2 Water content titration

Test example 2.1

Precisely weighing about 0.3184g of the crystal form A, placing the crystal form A into a dry glass bottle with a plug, adding 40ml of anhydrous methanol, titrating the crystal form A from a Fischer-Tropsch test solution to a state that the solution is changed from light yellow to reddish brown under stirring, and performing a blank test to calculate the water content from the consumed Fischer-Tropsch test solution;

and (3) measuring results: the water content is 2.86 percent

Test example 2.2

Precisely weighing about 0.2998g of the crystal form B, placing the crystal form B in a dry glass bottle with a plug, adding 40ml of anhydrous methanol, titrating the solution from the Fischer test solution to light yellow to reddish brown under stirring, performing a blank test, and calculating the water content from the consumed Fischer test solution;

and (3) measuring results: the water content is 2.92 percent

Test example 3 stability test

Test example 3.1

DP-VPA-C₁₈And respectively placing the crystal form A and the crystal form B in an illumination, high-temperature and high-humidity environment for 5 days and 10 days for PXRD detection.

The test conditions were:

the illumination condition is as follows: irradiation intensity of 4500 lx. + -. 500lx

High temperature conditions: 60 deg.C

High humidity conditions: relative humidity 75% (saturated solution of sodium chloride), temperature 25 ℃.

The results show that:

DP-VPA-C₁₈the XPRD spectrogram of the crystal form A after being placed in an environment with illumination (the irradiation intensity is 4500lx +/-500 lx), high temperature (60 ℃) and high humidity (the relative humidity is 75%, the temperature is 25 ℃) for 5 days and 10 days does not change, and the crystal form A is proved to be stable under the conditions as shown in figures 19-21.

DP-VPA-C₁₈The XPRD spectrogram of the crystal form B is placed in an environment with illumination (the irradiation intensity is 4500lx +/-500 lx), high temperature (60 ℃) and high humidity (the relative humidity is 75%, the temperature is 25 ℃) for 5 days and 10 days, as shown in figures 22-24, and the crystal form is stable under the conditions.

Test example 3.2

DP-VPA-C₁₈Form C was placed in a petri dish and exposed to air at ambient conditions (45% relative humidity, 25 ℃ temperature) and sampled for XPRD testing at 6 hours, 20 hours, and 48 hours, respectively.

The results show that:

DP-VPA-C₁₈the crystal form C is easy to absorb the moisture in the air and is transformed into the crystal form B when being placed under the environmental condition. As shown in table 5, fig. 16; indicating that form C is a very unstable form.

Test example 3.3

DP-VPA-C₁₈Form D was placed in a petri dish and exposed to air at ambient conditions (45% relative humidity, 25 ℃ C.) and sampled for XPRD testing at 20min, 2hour, 5hour, 1Day, and 3Day, respectively.

The results show that:

DP-VPA-C₁₈the crystal form D is easy to absorb moisture in the air and is transformed into the crystal form A when being placed under the environmental condition. As shown in table 6, fig. 18; indicating that form D is a very unstable form.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be made by those skilled in the art without inventive work within the technical scope of the present invention are included in the scope of the present invention.

Claims

1. DP-VPA-C₁₈Form A, characterized in that the form A shows characteristic peaks at 4.67, 7.06, 9.45, 11.86, 14.28, 16.69, 19.11, 21.55, 23.99 of X-ray powder diffraction pattern expressed by 2 theta +/-0.2 DEG diffraction angle; DP-VPA-C₁₈Has the structural formula

2. The DP-VPA-C of claim 1₁₈Form A, characterized in that form A further exhibits characteristic peaks at 23.27, 26.45, 28.92, 31.40, 32.69, 35.11, 38.96 in its X-ray powder diffraction pattern expressed in terms of 2 θ ± 0.2 ° diffraction angles.

3. DP-VPA-C according to any one of claims 1 to 2₁₈The crystal form A is characterized in that an X-ray powder diffraction spectrum of the crystal form A is shown in figure 1.

4. A process for preparing DP-VPA-C according to any one of claims 1 to 3₁₈The preparation method of the crystal form A is characterized by comprising the following steps:

1) under the condition of reflux temperature, DP-VPA-C₁₈Dissolving in acetone;

2) cooling, crystallizing, filtering, washing and drying.