CN111201218A

CN111201218A - Novel crystal form of pimavanserin hemitartrate and preparation method thereof

Info

Publication number: CN111201218A
Application number: CN201880065490.XA
Authority: CN
Inventors: 叶辉青; 黄翠; 雷鑫; 陈勇; 黄芳芳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd; Guangdong HEC Pharmaceutical
Priority date: 2017-12-22
Filing date: 2018-12-20
Publication date: 2020-05-26
Also published as: WO2019120250A1

Abstract

The invention provides a new crystal form of pimavanserin hemitartrate and a preparation method thereof, belonging to the field of pharmaceutical chemistry. The XRPD pattern of the crystalline form contains the following characteristic peaks at 2 θ (error ± 0.2 degrees): 5.37,7.02,10.62,14.07,16.79,18.66,20.60,21.65. The crystal form has better solubility and stability, is beneficial to operation in storage, transfer and production processes, and can be used for preparing a pharmaceutical preparation.

Description

Novel crystal form of pimavanserin hemitartrate and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a crystal form of N- (4-fluorobenzyl) -N- (1-methylpiperidine-4-yl) -N' - (4- (2-methylpropyloxy) -phenylmethyl) urea hemitartrate and a preparation method thereof.

Background

N- (4-fluorobenzyl) -N- (1-methylpiperidin-4-yl) -N' - (4- (2-methylpropyloxy) -phenylmethyl) urea, also known as Pimavanserin (Pimavanserin), CAS No.: 706779-91-1, is an atypical antipsychotic drug for the amelioration of the psychotic symptoms of Parkinson's disease, often in the form of pimavanserin hemitartrate. The Pimavanserin hemitartrate (Pimavanserin hemi-tartrate) has the structure shown in formula (1):

patent application WO2008144326 or patent CN101035759B reports crystal form a, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F and amorphous form of pimavanserin hemitartrate, CN107021917 reports crystal form II and amorphous form of pimavanserin tartrate, CN106916098 reports hemihydrate of pimavanserin hemitartrate, and CN104961671 reports crystal form I of pimavanserin tartrate.

Drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same medicament may have obvious difference in physicochemical properties such as appearance, fluidity, solubility, storage stability, bioavailability and the like, may have great difference, and may have different influences on storage transfer, application, stability, curative effect and the like of the medicament; in order to obtain a crystal form that is effective for production or for pharmaceutical preparations, the crystallization behavior of the drug needs to be comprehensively examined to obtain a crystal form that meets production requirements.

According to the invention, a new crystal form of the pimavanserin hemitartrate compound is obtained through a large amount of experimental researches on the pimavanserin hemitartrate compound, and the new crystal form has the advantages of high solubility, good stability, low hygroscopicity, simple preparation process, easiness in operation and the like, and has superiority in industrial production; the research on the crystal form provides opportunities for improving the overall performance (such as easy synthesis or processing, improved dissolution rate or improved stability and shelf life) of the medicine product, and simultaneously enlarges the variety of materials available for formulation scientists to design the medicine, and is of great importance to the research and development of the medicine.

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, an object of the present invention is to provide a novel crystal form of pimavanserin hemitartrate having good solubility and stability, and a method for preparing the same.

According to one aspect of the present invention, the present invention provides a new crystalline form of pimavanserin hemitartrate, referred to as form VI.

The new crystal form is researched, and the crystal form VI has good performances in the aspects of stability, hygroscopicity and the like, and can be used for preparing pharmaceutical preparation production.

Form VI is characterized by having diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles of 5.37,7.02,10.62,14.07,16.79,18.66,20.60,21.65 by an X-ray powder diffractometer using Cu-K α radiation.

In some embodiments, the form VI has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles of 9.44,13.14,15.71,17.71,19.61,21.11,23.23,25.00,28.19 by X-ray powder diffractometry using Cu-K α radiation.

In some embodiments, the form VI has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles of 5.37,7.02,9.44,10.62,13.14,14.07,15.71,16.79,17.71,18.66,19.61,20.60,21.11,21.65,23.23,25.00,28.19 by an X-ray powder diffractometer using Cu-K α radiation.

In some embodiments, the pimavanserin hemitartrate form VI has an X-ray powder diffraction pattern as shown in figure 1, wherein the relative intensity of the peak at 18.66 degrees 2 Θ is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

In some embodiments, the crystalline form VI has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in figure 1.

In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form VI has endothermic peaks at 70 ℃ -100 ℃ and 165 ℃ -175 ℃, wherein the degree of drying of the sample will have a slight effect on the peaks at 70 ℃ -100 ℃.

In some embodiments, the crystalline form VI has a differential scanning calorimetry curve (DSC profile) as shown in figure 2.

In some embodiments, the thermogravimetric analysis curve (TGA) of form VI shows a weight loss of about 2.55% between 25 ℃ and 100 ℃.

In some embodiments, the crystalline form VI has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 3.

The N- (4-fluorobenzyl) -N- (1-methylpiperidin-4-yl) -N '- (4- (2-methylpropyloxy) -phenylmethyl) urea hemitartrate crystal form VI can be used for preparing an antipsychotic pharmaceutical preparation or a pharmaceutical composition, such as a pharmaceutical preparation or a pharmaceutical composition for improving the mental symptoms of Parkinson's disease.

It is another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of N- (4-fluorobenzyl) -N- (1-methylpiperidin-4-yl) -N' - (4- (2-methylpropyloxy) -phenylmethyl) urea hemitartrate form VI and a pharmaceutically acceptable adjuvant or excipient. In general, a therapeutically effective amount of N- (4-fluorobenzyl) -N- (1-methylpiperidin-4-yl) -N' - (4- (2-methylpropyloxy) -phenylmethyl) urea hemitartrate form VI is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, which may be prepared in a manner well known in the pharmaceutical art. The pharmaceutical composition or formulation may be used for the treatment of a psychotic disorder, such as for ameliorating the psychotic symptoms of parkinson's disease.

The invention has the beneficial effects that:

compared with the crystal form A of the patent CN101035759B, the crystal form VI provided by the invention has better stability. The more stable crystal form has important significance for improving the quality of the medicine.

Compared with the crystal form A of the patent CN101035759B, the crystal form VI provided by the invention has lower hygroscopicity, is not easy to deliquesce under a high-humidity condition, and is convenient for long-term storage and placement of the medicine.

Although the crystal form C of patent CN101035759B is a relatively stable crystal form, the preparation process is complex, and is not easy to operate, it is difficult to obtain the crystal form C with high crystal form purity in the conventional crystallization process, the requirement on raw materials in the process production is high, moisture, solvent residue, related substances and the like in the raw materials all have great influence on the preparation of the crystal form C, and a seed crystal needs to be added, and a long time is needed to obtain the pure crystal form C.

Compared with the crystal form C, the crystal form VI provided by the invention has the advantages that the preparation process is simpler and easier to operate, no crystal seed is needed in production, the industrial production is more facilitated, and the crystal form stability of the product is good.

According to a second aspect of the present invention, the present invention provides a process for preparing the aforementioned pimavanserin hemitartrate form VI.

A method of preparing pimavanserin hemitartrate form VI comprising: and (2) putting the pimavanserin hemitartrate crude product into a mixed solvent containing a good solvent and a poor solvent, heating to 25-50 ℃, reducing the temperature to-10-40 ℃ after complete dissolution, separating out crystals, collecting the crystals, and removing the solvent to obtain the crystal form VI. In some embodiments, after complete dissolution, the temperature is reduced to 0 ℃ to 20 ℃, crystals are precipitated, crystals are collected, and the solvent is removed to obtain form VI. The pimavanserin hemitartrate crude product may be in any form including, but not limited to, form a, form B, form C, form D, form E, form F or amorphous form as disclosed in patent application WO2008144326 or patent CN 101035759B. The good solvent is water. The poor solvent is one or more of methanol and ethanol. In some embodiments, the poor solvent is methanol or ethanol. The mass-to-volume ratio of the pimavanserin hemitartrate crude product to the solvent is 1: 1-1: 50, more preferably 1: 1-1: 10 when the mass is calculated in grams (g) and the volume is calculated in milliliters (mL). In some embodiments, the mixed solvent is water and ethanol. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is 1:10 to 10: 1. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is 4:1 to 8: 1.

In some embodiments, a method of preparing pimavanserin hemitartrate form VI comprises: putting pimavanserin hemitartrate crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or one or more amorphous (disclosed in patent application WO2008144326 or patent CN 101035759B) into a mixed solvent containing a good solvent and a poor solvent, suspending and balancing, collecting crystals, and removing the solvent to obtain crystal form VI. The good solvent is water. The poor solvent is methanol, ethanol or a combination thereof. The mass is calculated by gram (g), and when the volume is calculated by milliliter (mL), the mass-volume ratio of the pimavanserin hemitartrate crude product to the solvent is 1: 1-1: 50; more preferably 1:1 to 1: 10. In some embodiments, the mixed solvent is water and ethanol. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is 1:10 to 10: 1. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is 4:1 to 8: 1. In some embodiments, the mixed solvent is water and methanol. In some embodiments, the volume ratio of water to methanol in the mixed solvent is 1:10 to 10: 1. In some embodiments, the volume ratio of water to methanol in the mixed solvent is 4:1 or 8: 1.

The "crystal form" of the present invention may be present in a sample at 0.0001% to 100%, and therefore, as long as the sample contains even a trace amount of the "crystal form" of the present invention, for example, more than 0.0001%, more than 0.001%, or more than 0.01%, should be understood to fall within the scope of the present invention. In order to describe the parameters of the "crystal form" of the present invention more clearly, the present invention is characterized and identified by testing the parameters of a sample containing a substantially pure "crystal form".

In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may differ by 1%, 2%, or 5%.

The Differential Scanning Calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample, the position and peak value of the endothermic peak may slightly differ between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 10 ℃ or less, 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the value of the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

In the present invention, "RH" is relative humidity.

Drawings

FIG. 1: an X-ray powder diffraction (XRPD) pattern of form VI of the compound of formula (1).

FIG. 2: a Differential Scanning Calorimetry (DSC) curve of crystalline form VI of the compound of formula (1).

FIG. 3: thermogravimetric analysis (TGA) profile of crystalline form VI of the compound of formula (1).

Detailed Description

Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

In the present invention, mL or mL means mL, ul means microliter, mg means mg,

EXAMPLE 1 Process for the preparation of form VI

Adding 300mg of pimavanserin hemitartaric acid crude product into a mixed solvent of water and ethanol, wherein the ratio of ethanol to ethanol is 4:1 (volume ratio) and 1.8ml, heating to 50 ℃, stirring to obtain a clear solution, slowly cooling to 0 ℃, separating out a white solid, performing suction filtration, placing in a drying oven, and performing vacuum drying at 50 ℃ to constant weight to obtain about 250mg of white crystals, wherein the obtained crystals are confirmed to be crystal form VI through XPRD detection, and refer to fig. 1, fig. 2 and fig. 3.

Example 2 Process for the preparation of form VI

Adding 300mg of pimavanserin hemitartaric acid crude product into 1ml of water, heating to 50 ℃, stirring to obtain a clear solution, slowly cooling to 25 ℃, dropwise adding 200ul of ethanol, cooling to 0 ℃, separating out a white solid, performing suction filtration, placing in a drying oven, and performing vacuum drying at 50 ℃ to obtain about 240mg of white crystals, wherein the obtained crystals are confirmed to be crystal form VI through XPRD detection.

Example 3 Process for the preparation of form VI

Adding 300mg of pimavanserin hemitartaric acid crude product into 1.8ml of mixed solvent of water and ethanol, wherein the volume ratio of ethanol to ethanol is 5:1, heating to 50 ℃, stirring to obtain a clear solution, slowly cooling to 0 ℃, separating out a white solid, carrying out suction filtration, placing in a drying oven, and carrying out vacuum drying at 50 ℃ to obtain about 240mg of white crystals, wherein the obtained crystals are confirmed to be crystal form VI through XPRD detection.

EXAMPLE 4 Process for preparing form VI

Adding 500mg of pimavanserin hemitartaric acid crude product into 3.0ml of mixed solvent of water and methanol, wherein the volume ratio of methanol to methanol is 4:1, heating to 50 ℃, stirring to obtain a clear solution, slowly cooling to 0 ℃, separating out a white solid, performing suction filtration, placing in a drying oven, and performing vacuum drying at 50 ℃ to obtain about 350mg of white crystals, wherein the obtained crystals are confirmed to be crystal form VI through XPRD detection.

EXAMPLE 5 Process for preparing form VI

Adding 500mg of pimavanserin hemitartaric acid crude product into 1ml of water, heating to 50 ℃, stirring to obtain a clear solution, slowly cooling to 25 ℃, dropwise adding 200ul of methanol, separating out a white solid, performing suction filtration, placing in a drying oven, and performing vacuum drying at 50 ℃ to obtain about 350mg of white crystals, wherein the obtained crystals are confirmed to be crystal form VI through XPRD detection.

Example 6 Process for the preparation of form VI

Adding 500mg of pimavanserin hemitartaric acid crude crystal form B into 5.0ml of mixed solvent of water and ethanol, wherein the volume ratio of ethanol to ethanol is 4:1, cooling to 10 ℃, suspending and stirring for 10h to obtain white solid, performing suction filtration, placing in a drying oven, and performing vacuum drying at 50 ℃ to obtain white crystals of about 450mg, wherein the obtained crystals are confirmed to be crystal form VI through XPRD and DSC detection.

Example 7 stability experiment

In the following experiments, pimavanserin hemitartrate form a, form B, form C, form D, form E, form F and amorphous form were obtained with reference to the methods of patent application WO2008144326 or patent CN 101035759B.

1) Hygroscopicity study: comparison research on hygroscopicity of crystal form VI and crystal form A

Two pimavanserin hemitartrate crystal forms VI are respectively placed under 80% relative humidity and 95% relative humidity for 24 hours, and the hygroscopicity is tested, and the results are shown in the following table 1.

Table 1: comparison of hygroscopicity of form VI with that of form A

According to the description of patent application CN104961671A, the weight gain of form a at 80% relative humidity and the weight gain at 95% relative humidity are 10.73% and 28.47%, respectively, and thus it can be seen that form VI has lower hygroscopicity than form a.

The above results show that: form VI has lower hygroscopicity than form A

2) Comparative study on stability of crystal forms VI and A

Two samples of the crystal form VI and the crystal form A of the invention are respectively placed in a refrigerator in an open state at 4 ℃ (temperature deviation +/-2 ℃), and after 7 days, the samples are taken for XRPD measurement, and the experimental results are shown in the following table 2.

Table 2: comparison of stability of Crystal form VI and Crystal form A

Starting crystal form	Stable standing condition	Time of standing	Crystal form
Crystal form VI (as in figure 1)	4℃	7 days	Form VI unchanged

Crystal form A

4℃

7 days

Crystal modification

The above results show that: the crystal form VI is placed in a refrigerator at 4 ℃ for 7 days in an open way, and the crystal form is unchanged; and the crystal form A is changed; thus, the crystal form VI has better stability than the crystal form A

3) Stability comparison research under high-humidity conditions of crystal form VI and crystal form A or crystal form C

The crystal form VI and the crystal form a or the crystal form C samples of the present invention were respectively placed under high humidity (98% RH) conditions for 3 days with the experimental results as shown in table 3 below.

Table 3: comparison of stability of form VI with form A or form C under high humidity conditions

Starting crystal form	Stable standing condition	Time of standing	Crystal form
Crystal form A	25 ℃ and 98% relative humidity	3 days	Deliquescence
Crystal form C	25 ℃ and 98% relative humidity	3 days	Deliquescence
Crystal form VI (as in figure 1)	25 ℃ and 98% relative humidity	3 days	Form VI unchanged

The above results show that: form VI is less susceptible to deliquescence under high humidity conditions than form a or form C.

4) Comparative study of crystal form VI with crystal form a, crystal form B, crystal form C, crystal form D and amorphous stability:

the crystal form A, the crystal form B, the crystal form C, the crystal form D and the amorphous form are respectively mixed with a solvent system of the crystal form VI at the temperature of 10 ℃ and the ratio of water to ethanol is 5:1 (volume ratio) for suspension and stirring for about 24 hours, the stability of the crystal forms is inspected, the crystal forms are all converted into the crystal form VI, the crystal form VI has better stability, and the specific experimental conditions and results are shown in the following table 4.

Table 4: stability comparisons of form VI with forms A, B, C, D and amorphous forms

The above results show that: after the crystal form VI is respectively mixed with the crystal form A, the crystal form B, the crystal form C, the crystal form D and the amorphous form in a water-ethanol (volume ratio) system for about 24 hours in a suspension manner, all crystals are transformed into the crystal form VI, and the crystal form VI has better stability than the crystal form A, the crystal form B, the crystal form C, the crystal form D and the amorphous form.

5) Stability study of form VI under influential conditions:

form VI was separately placed open at 60 ℃ elevated temperature without humidity control, 90% RH ± 2% RH and uv light 4500lux1.7w × h/m2, at about 25 ℃ under light, XRPD was detected for 5 days, 10 days, 15 days, respectively, with the results as in table 5 below.

Table 5: stability of form VI under influential conditions

Condition of influence factor	5 days	10 days	15 days
60 ℃ high temperature without controlling humidity	Crystal form VI	Crystal form VI	Crystal form VI
90％±2％RH	Crystal form VI	Crystal form VI	Crystal form VI
UV (ultraviolet) light illumination	Crystal form VI	Crystal form VI	Crystal form VI

The above results show that: the crystal form VI is kept for 15 days under the condition of influencing factors, and the crystal form is not changed, namely the crystal form VI is more stable.

6) Stability study of form VI at 40 ℃ and 75% RH accelerated conditions:

XRPD of form VI was measured after 3 months in PE (polyethylene bag) plus aluminum foil packaging under accelerated conditions of 40 ℃ and 75% RH, and the results are given in table 6 below.

Table 6: stability of form VI at 40 ℃ and 75% RH acceleration

Time of day	Accelerated for 0 day	Accelerated for 3 months
Crystal form	Crystal form VI	Crystal form VI
HPLC purity	99.74％	99.70％

The above results show that: the crystal form VI is packaged by PE and aluminum foil, and is placed for 3 months under the acceleration condition of 40 ℃ and 75% RH, the crystal form is not changed, the HPLC purity shows no obvious change, namely the crystal form VI is more stable under the acceleration condition.

Test instrument and method

(1) Powder X-ray diffraction (XRPD) study

X-ray powder diffraction (XRPD) patterns were collected on a PANALYtic Empyrean X-ray diffractometer equipped with a transmissive reflective sample stage with an automated 3X 15 zero background sample holder using a radiation source of (Cu, K α, K α 1)

1.540598；Kα2

1.544426, K α 2/K α 1 intensity ratio: 0.50), where the voltage is set at 45KV and the current is set at 40 mA.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 10mm. the effective 2 theta range of 3-40 deg. is obtained using a theta-theta continuous scanning mode.A suitable amount of sample is taken at the circular groove of a zero background sample holder under ambient conditions (about 18-32 deg.C), lightly pressed with a clean glass slide to obtain a flat plane and the zero background sample holder is fixed.A conventional XRPD pattern is generated by scanning the sample at 0.0168 deg. in the range of 3-40 deg. 2 theta.C.

The crystalline forms prepared in examples 1-8 were each subjected to XRPD detection using the conditions described above.

(2) Differential Scanning Calorimetry (DSC) analysis

DSC measurements in TA Instruments^TMModel Q2000 was performed using a sealed disk apparatus. Samples (approximately 1-3 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The apparatus was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis.

(3) Thermogravimetric analysis (TGA) analysis

TGA measurements in TA Instruments^TMIn model Q500. The operation steps are that the empty crucible is peeled, about 10mg of solid sample is taken and put in the peeled empty crucible, and the solid sample is spread evenly. After the instrument runs stably, data are collected at a heating rate of 10 ℃/min between room temperature and 300 ℃ under nitrogen purging, and a spectrum is recorded.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

A crystalline form of pimavanserin hemitartrate, said crystalline form being form VI, characterized by an X-ray powder diffraction spectrum expressed in terms of 2 Θ (error ± 0.2 degrees) using radiation from Cu-K α, wherein the X-ray powder diffraction pattern of form VI has diffraction peaks at positions having a 2 Θ of 5.4,7.0,10.6,14.1,16.79,18.7,20.6,21.6 degrees.
The crystalline form of claim 1, wherein form VI has an X-ray powder diffraction pattern having diffraction peaks at 9.4,13.1,15.7,17.7,19.6,21.1,23.2,25.0,28.2 degrees 2 Θ; or form VI has a diffraction peak at a position where 2 θ is 5.4,7.0,9.4,10.6,13.1,14.1,15.7,16.8,17.7,18.7,19.6,20.6,21.1,21.6,23.2,25.0,28.2 degrees in an X-ray powder diffraction pattern; or form VI, as shown in figure 1, wherein the relative intensity of the diffraction peak at 18.7 degrees 2 Θ is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
The crystalline form of pimavanserin hemitartrate of claim 1, wherein the purity of form VI is at least 90% or at least 95% or at least 98%.
A process for preparing the crystalline form of pimavanserin hemitartrate of any one of claims 1 to 3, comprising: and (3) putting the pimavanserin hemitartrate crude product into a mixed solvent containing a good solvent and a poor solvent, heating until the pimavanserin hemitartrate crude product is completely dissolved, cooling to 10-40 ℃, separating out crystals, collecting the crystals, and removing the solvent to obtain the crystal form VI.
The method according to claim 4, wherein the good solvent is water.
The method of claim 4, wherein the poor solvent is methanol, ethanol, or a combination thereof.
The method according to claim 4, wherein the mixed solvent is water and ethanol, and the volume ratio of the water to the ethanol is 1:10 to 10: 1.
The method of claim 4, wherein heating to 25-50 ℃ completes dissolution.
A process for preparing the crystalline form of pimavanserin hemitartrate of any one of claims 1 to 3, comprising: adding one or more of pimavanserin hemitartrate crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or amorphous form into a mixed solvent containing a good solvent and a poor solvent, suspending and balancing, collecting crystals, and removing the solvent to obtain crystal form VI.
The method of claim 9, wherein the good solvent is water.
The method of claim 9, wherein the poor solvent is methanol, ethanol or a combination thereof.
The method according to claim 9, wherein the mixed solvent is water and ethanol, and the volume ratio of the water to the ethanol is 1:10 to 10: 1.
A pharmaceutical composition comprising an effective amount of the crystalline form VI of any one of claims 1-3 and a pharmaceutically acceptable excipient.
Use of a pharmaceutical composition according to claim 13 for the preparation of an antipsychotic pharmaceutical formulation. .