WO2019120250A1 - Novel crystal form of pimavanserin hemi-tartrate and method for preparing crystal form - Google Patents

Abstract

The present application relates to the field of pharmaceutical chemistry, and provides a crystal form VI of pimavanserin hemi-tartrate and a method for preparing the crystal form. The XRPD pattern of the crystal form comprises the following characteristic peaks at 2θ (with an error range of ±0.2 degrees): 5.37, 7.02, 10.62, 14.07, 16.79, 18.66, 20.60, and 21.65. The crystal form has good solubility and stability, is beneficial to operations in storage, transfer, and production processes, and can be prepared into a pharmaceutical preparation.

Description

Novel crystal form of pimacillin hemi-tartrate and preparation method thereof Technical field

The present invention belongs to the field of medicinal chemistry, and in particular, the present invention relates to N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methyl) Crystal form of propoxy)-phenylmethyl)urea hemi-tartrate and preparation method thereof.

Background technique

N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl)urea, aka Pimavanserin, CAS No. 706779-91-1, is an atypical antipsychotic used to improve the psychotic symptoms of Parkinson's disease, often in the form of pimacillin hemi-tartrate. The structure of Pimavanserin hemi-tartrate is as shown in formula (1):

Patent application WO2008144326 or patent CN101035759B reports Form A, Form B, Form C, Form D, Form E, Form F and amorphous of pemasiline hemi-tartrate, and Piperazine is reported by CN107021917. Tartrate salt form II and pemasiline tartrate are amorphous, CN106916098 reports the hemihydrate of pemasiline monotartrate, and CN104961671 reports pimezerine tartrate form I.

Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and may have great differences, which may affect drug storage, application, stability, and efficacy. Different effects are produced; in order to obtain an effective crystal form suitable for production or for pharmaceutical preparations, it is necessary to conduct a comprehensive examination of the crystallization behavior of the drug to obtain a crystal form that satisfies the production requirements.

The invention obtains a new crystal form of the compound by conducting a large number of experimental studies on the pimacillin hemi-tartrate compound, and the new crystal form has high solubility, good stability, low wettability, simple preparation process and the like. Superiority, superior in industrial production; research on its crystal form provides opportunities to improve the overall performance of the pharmaceutical product (such as easy synthesis or treatment, improve dissolution or improve stability and shelf life), while expanding the formulation The variety of materials available to scientists when designing the drug is critical to drug development.

Summary of the invention

The present invention aims to solve at least one of the technical problems in the related art to some extent. To this end, it is an object of the present invention to provide a new crystalline form of pembelline hemi-tartrate and a process for the preparation thereof which have good solubility and stability.

According to one aspect of the invention, the invention provides a new crystalline form of pemasiline hemi-tartrate, referred to as Form VI.

The novel crystal form of the present invention as described above is studied, and the crystal form VI has good properties in terms of stability, wettability, and the like, and can be used for preparation of a pharmaceutical preparation.

The crystal form VI is characterized by having an X-ray powder diffractometer using Cu-Kα radiation having diffraction peaks at the following 2θ (unit: degree, error ± 0.2 degree) angle: 5.37, 7.02, 10.62, 14.07, 16.79, 18.66, 20.60, 21.65.

In some embodiments, the Form VI has diffraction peaks at the following 2θ (unit: degree, error ± 0.2 degree) angle by using an X-ray powder diffractometer of Cu-Kα radiation: 9.44, 13.14, 15.71, 17.71 , 19.61, 21.11, 23.23, 25.00, 28.19.

In some embodiments, the Form VI has a diffraction peak at the following 2θ (unit: degree, error ± 0.2 degree) angle by using an X-ray powder diffractometer of Cu-Kα radiation: 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.

In some embodiments, the X-ray powder diffraction pattern of the pimacillin hemi-tartrate salt form VI is shown in Figure 1, wherein the relative intensity of the peak at 2θ of 18.66 degrees is greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.

In some embodiments, the Form VI has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG.

In some embodiments, the differential scanning calorimetry curve (DSC) of the Form VI has an endothermic peak at 70 ° C - 100 ° C and 165 ° C - 175 ° C, wherein the sample is dried to 70 ° C - The peak at 100 °C has a slight effect.

In some embodiments, the Form VI has a differential scanning calorimetry curve (DSC pattern) as shown in FIG.

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

In some embodiments, the Form VI has a thermogravimetric analysis curve (TGA map) substantially as shown in FIG.

N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl according to the invention The urea hemi-tartrate crystal form VI can be used for the preparation of an antipsychotic pharmaceutical preparation or a pharmaceutical composition, such as a pharmaceutical preparation or a pharmaceutical composition for improving psychotic symptoms of Parkinson's disease.

Another object of the present invention is to provide a therapeutically effective amount of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropane). A pharmaceutical composition of oxy)-phenylmethyl)urea hemi-tartrate salt form VI and a pharmaceutically acceptable adjuvant or excipient. Generally a therapeutically effective amount of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenyl The methylurea hemi-tartrate salt form VI is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which can be prepared in a manner well known in the pharmaceutical art. The pharmaceutical composition or formulation can be used to treat a psychiatric disorder, such as for improving psychotic symptoms of Parkinson's disease.

The beneficial effects of the invention are:

The crystal form VI provided by the invention has better stability than the crystal form A of CN101035759B. A more stable crystal form is important for improving the quality of the drug.

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

Although the crystal form C of the patent CN101035759B is a relatively stable crystal form, the preparation process is complicated and difficult to operate. It is difficult to obtain the crystal form C with high crystal purity under the conventional crystallization process, and the raw material requirement in the process production. Higher, the moisture, dissolving, and related substances in the raw materials will have a great influence on the preparation of the crystalline form C, and it is necessary to add a seed crystal, and it takes a long time to obtain a pure crystalline form C.

Compared with the crystal form C, the crystal form VI provided by the invention is simpler and easier to operate, does not require seed crystals in production, is more favorable for industrial production, and has good crystal form stability.

According to a second aspect of the invention, the invention provides a process for the preparation of the picometholin hemi-tartrate salt form VI described above.

A method for preparing the crystalline form VI of pemasiline hemi-tartrate comprises: feeding the crude pimacillin hemi-tartrate into a mixed solvent containing a good solvent and a poor solvent, heating to 25 ° C to 50 ° C, and dissolving completely The temperature was lowered to -10 ° C to 40 ° C, crystals were precipitated, crystals were collected, and the solvent was removed to obtain a crystal form VI. In some embodiments, after the dissolution is completed, the temperature is lowered to 0 ° C to 20 ° C, crystals are precipitated, crystals are collected, and the solvent is removed to obtain Form VI. The crude pemasiline hemi-tartrate may be in any form of pemasiline hemi-tartrate, including, but not limited to, Form A, Form B, Form C, Form D disclosed in Patent Application WO2008144326 or Patent CN101035759B. , Form E, Form F or amorphous. 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 is calculated in grams (g). When the volume is calculated in milliliters (mL), the mass to volume ratio of the crude product of the pimacillin hemi-tartrate to the solvent is 1:1 to 1:50, more preferably 1:1. 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 from 1:10 to 10:1. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is from 4:1 to 8:1.

In some embodiments, a method of preparing the pimacillin hemi-tartrate salt form VI comprises: piperazine color penta-tartrate crystal form A, Form B, Form C, Form D, Form E One or more of the crystalline form F or the amorphous form (disclosed in the patent application WO2008144326 or the patent CN101035759B) is put into a mixed solvent containing a good solvent and a poor solvent, and the suspension is equilibrated, the crystal is collected, and the solvent is removed to obtain a crystal form. VI. The good solvent is water. The poor solvent is methanol, ethanol or a combination thereof. The mass is calculated in grams (g). When the volume is calculated in milliliters (mL), the mass to volume ratio of the crude product of the pimacillin hemi-tartrate to the solvent is 1:1 to 1:50; more preferably 1:1. 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 from 1:10 to 10:1. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is from 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 from 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 the sample at 0.0001% to 100%, and thus, as long as the sample contains even a trace amount of, for example, more than 0.0001%, more than 0.001%, more than 0.001%, or more than 0.01%, as described in the present invention. The "crystal form" should be understood to fall within the scope of the present invention. In order to more clearly describe the various parameters of the "crystal form" of the present invention, the present invention tests various parameters and conducts the crystal form on a sample containing a substantially "some crystal form". Characterization and identification.

In the context of the present invention, all numbers disclosed herein are approximate, whether or not the words "about" or "about" are used. The value of each number may vary by 1%, 2%, or 5%.

The differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the degree of dryness of the sample, between one machine and another, and between one sample and another. The position and peak value of the thermal peak may be slightly different. The value of the experimental error or difference may be less than or equal to 10 ° C, or less than or equal to 5 ° C, or less than or equal to 4 ° C, or less than or equal to 3 ° C, or less than or equal to 2 ° C, or less than It is equal to 1 ° C, 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 a relative humidity.

DRAWINGS

Figure 1: X-ray powder diffraction (XRPD) pattern of Form VI of the compound of formula (1).

Figure 2: Differential scanning calorimetry (DSC) curve for Form VI of the compound of formula (1).

Figure 3: Thermogravimetric analysis (TGA) curve for Form VI of the compound of formula (1).

Detailed ways

The embodiments of the present invention are described in detail below, and the examples of the embodiments are illustrated in the drawings, wherein the same or similar reference numerals are used to refer to the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the drawings are intended to be illustrative of the invention and are not to be construed as limiting.

In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below by way of non-limiting embodiments.

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

In the present invention, ml or mL means milliliter, ul means microliter, and mg means milligram.

Example 1 Preparation Method of Form VI

300 mg of crude pamacillin hemi-tartaric acid was added to water: ethanol = 4:1 (volume ratio) in a mixed solvent of 1.8 ml, heated to 50 ° C to obtain a clear solution, and then slowly cooled to 0 ° C to precipitate a white solid. After suction filtration and drying in a dry box at 50 ° C to a constant weight to obtain a white crystal of about 250 mg, the obtained crystal was confirmed to be a crystal form VI by XPRD, see FIG. 1, FIG. 2, and FIG.

Example 2 Preparation Method of Form VI

300mg of crude pamacillin hemi-tartaric acid was added to 1ml of water, heated to 50 ° C to obtain a clear solution, and then slowly cooled to 25 ° C, 200ul of ethanol was added dropwise, cooled to 0 ° C to precipitate a white solid, suction filtered and placed The inside of the drying oven was vacuum dried at 50 ° C to obtain about 240 mg of white crystals, and the obtained crystal was confirmed to be a crystalline form VI by XPRD.

Example 3 Preparation Method of Form VI

300 mg of crude pamacillin hemi-tartaric acid was added to water: ethanol = 5:1 (volume ratio) in 1.8 ml of a mixed solvent, heated to 50 ° C to obtain a clear solution, and then slowly cooled to 0 ° C to precipitate a white solid, pumping The mixture was filtered and placed in a dry box at 50 ° C under vacuum to obtain about 240 mg of white crystals. The crystals obtained were confirmed to be crystal form VI by XPRD.

Example 4 Preparation Method of Form VI

500 mg of crude pamacillin hemi-tartaric acid was added to water: methanol = 4:1 (volume ratio) in 3.0 ml of a mixed solvent, heated to 50 ° C to obtain a clear solution, and then slowly cooled to 0 ° C to precipitate a white solid, pumping The mixture was filtered and placed in a dry box at 50 ° C under vacuum to obtain about 350 mg of white crystals. The crystals obtained were confirmed to be crystal form VI by XPRD.

Example 5 Preparation Method of Form VI

500mg of crude pamacillin hemi-tartaric acid was added to 1ml of water, heated to 50 ° C to obtain a clear solution, and then slowly cooled to 25 ° C, 200ul of methanol was added dropwise, a white solid was precipitated, filtered and placed in a dry box at 50 ° C It was dried under vacuum to obtain about 350 mg of white crystals, and the obtained crystals were confirmed to be crystal form VI by XPRD.

Example 6 Preparation Method of Form VI

500 mg of the crude product B of pamazerin hemi-tartaric acid was added to water: ethanol = 4:1 (volume ratio) in 5.0 ml of a mixed solvent, and the mixture was cooled to 10 ° C and stirred for 10 hours to obtain a white solid, which was filtered and placed. The inside of the drying oven was vacuum dried at 50 ° C to obtain about 450 mg of white crystals, and the obtained crystal was confirmed to be a crystalline form VI by XPRD and DSC.

Example 7 stability experiment

In the following experiments, with respect to the method of the patent application WO2008144326 or the patent CN101035759B, the pamazeline hemi-tartrate crystal form A, the crystal form B, the crystal form C, the crystal form D, the crystal form E, the form F and the amorphous form were obtained.

1) Humidity study: comparative study on the wettability of crystal form VI and crystal form A

Two samples of the pimacillin hemi-tartrate crystal form VI were placed at 80% relative humidity and 95% relative humidity for 24 h to test the wettability. The results are shown in Table 1 below.

Table 1: Comparison of the wettability between Form VI and Form A

According to the description of the patent application CN104961671A, the weight gain of the crystal form A at 80% relative humidity and the weight gain of 95% relative humidity are 10.73% and 28.47%, respectively, thereby showing that the form VI has a lower index than the form A. Wet.

The above results show that Form VI has lower moisture absorption than Form A.

2) Comparative study on the stability of crystal form VI and crystal form A

Two samples of Form VI and Form A of the present invention were respectively placed in a refrigerator at 4 ° C (temperature deviation ± 2 ° C), and XRPD was sampled after 7 days. The experimental results are shown in Table 2 below.

Table 2: Comparison of the stability of crystal form VI and crystal form A

Initial crystal form	Stability placement condition	Placement time	Crystal form
Crystal VI (Figure 1)	4 ° C	7 days	Form VI, unchanged

Crystal form A

4 ° C

7 days

Crystal form change

The above results show that the crystalline form VI is placed in the refrigerator at 4 ° C for 7 days, and its crystal form is unchanged; while the crystalline form A is changed; it can be seen that the crystalline form VI has better stability than the crystalline form A.

3) Comparative study on the stability of crystal form VI and crystal form A or crystal form C under high humidity conditions

The crystal form VI and the crystal form A or the crystal form C sample of the present invention were respectively placed under high humidity (98% RH) conditions for 3 days, and the experimental results are shown in Table 3 below.

Table 3: Stability comparison between Form VI and Form A or Form C under high humidity conditions

Initial crystal form	Stability placement condition	Placement time	Crystal form
Crystal form A	25 ° C, 98% relative humidity	3 days	deliquescence
Crystal form C	25 ° C, 98% relative humidity	3 days	deliquescence
Crystal VI (Figure 1)	25 ° C, 98% relative humidity	3 days	Form VI, unchanged

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

4) Comparative study on the stability of crystal form VI and crystal form A, crystal form B, crystal form C, crystal form D and amorphous form:

The crystal form A, the crystal form B, the crystal form C, the crystal form D and the amorphous form are respectively suspended and stirred in a solvent system of the form VI at 10 ° C in water: ethanol = 5:1 (volume ratio) for about 24 hours. When the stability was investigated, it was found that all of them were converted to crystal form VI, and the form VI had good stability. The specific experimental conditions and results are shown in Table 4 below.

Table 4: Comparison of stability between Form VI and Form A, Form B, Form C, Form D and Amorphous

The above results show that: Form VI is mixed with Form A, Form B, Form C, Form D and amorphous in a water:ethanol = 5:1 (volume ratio) system for about 24 hours, all after When the crystal is converted into the crystal form VI, it can be seen that 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) Study on the stability of crystal form VI under influencing factors:

The crystal form VI was separately placed at a high temperature of 60 ° C and the humidity condition was not controlled, 90% RH ± 2% RH condition and ultraviolet light 4500 Lux 1.7 w * h / m 2 , under illumination conditions of about 25 ° C, respectively, in 5 days, XRPD was detected for 10 days and 15 days, and the results are shown in Table 5 below.

Table 5: Stability of Form VI under influencing factors

Influential factors	5 days	10 days	15 days
60 ° C high temperature, no humidity control	Crystal VI	Crystal VI	Crystal VI
90%±2% RH	Crystal VI	Crystal VI	Crystal VI
UV (ultraviolet) illumination	Crystal VI	Crystal VI	Crystal VI

The above results show that the crystal form VI is placed under the influence factor for 15 days, and the crystal form is unchanged, that is, the crystal form VI is relatively stable.

6) Study on the stability of crystal form VI at 40 ° C and 75% RH acceleration:

The crystal form VI was placed in a PE (polyethylene bag) and an aluminum foil package, and allowed to stand under an accelerated condition of 40 ° C and 75% RH for 3 months, and the XRPD was examined. The results are shown in Table 6 below.

Table 6: Stability of Form VI at 40 ° C and 75% RH Acceleration

time	Accelerate 0 days	Accelerate for 3 months
Crystal form	Crystal VI	Crystal VI
HPLC purity	99.74%	99.70%

The above results show that the crystal form VI is placed under the condition of 40 ° C + 75% RH for 3 months under the condition of PE plus aluminum foil, the crystal form is unchanged, and the HPLC purity shows no significant change, that is, the crystal form VI is also under accelerated conditions. More stable.

Test instrument and method

(1) Powder X-ray Diffraction (XRPD) Study

X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with a transflective sample stage equipped with an automated 3*15 zero background sample holder. The radiation source used is (Cu, kα, Kα1

1.540598; Kα2

1.544426; Kα2/Kα1 intensity ratio: 0.50), wherein the voltage is set at 45KV, the current is set at 40 mA. X-ray beam divergence, ie the effective size of the X-ray constraint on the sample, is 10 mm. Using θ-θ In the continuous scan mode, an effective 2θ range of 3° to 40° is obtained. Take an appropriate amount of sample under ambient conditions (about 18 ° C ~ 32 ° C) in the circular groove of the zero background sample holder, gently press with a clean glass slide to obtain a flat plane, and fix the zero background sample holder. The sample was subjected to a conventional XRPD pattern in the range of 3 to 40 ° 2θ with a scan step of 0.0168°. The software used for data collection is Data Collector, and the data is analyzed and presented using Data Viewer and HighScore Plus.

The crystal forms prepared in Examples 1-8 were subjected to XRPD detection using the above conditions.

(2) Differential Scanning Calorimetry (DSC) Analysis

DSC measurements were performed using TA Instruments ^TM Model Q2000 sealing disk apparatus. The sample (about 1-3 mg) was weighed in an aluminum pan, capped with a Tzero, accurately recorded to one hundredth of a milligram, and the sample was transferred to an instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected at room temperature to 300 ° C at a heating rate of 10 ° C/min. The endothermic peak was drawn down and the data was analyzed and displayed using TA Universal Analysis.

(3) Thermogravimetric analysis (TGA) analysis

TGA measurements were performed in a TA Instruments ^TM model Q500. The operation steps are empty and peeled, take about 10 mg of the solid sample, and peel it in the peeled open space. After the instrument was operated stably, data was collected at room temperature to 300 ° C at a heating rate of 10 ° C / min under a nitrogen purge, and the spectra were recorded.

In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" and the like means a specific feature described in connection with the embodiment or example. A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.

Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims (14)

1. a crystalline form of pimacillin hemi-tartrate, said crystal form being crystalline form VI, characterized by an X-ray powder diffraction spectrum expressed by 2θ (error ± 0.2 degrees) using Cu-Kα radiation, wherein the crystal form The X-ray powder diffraction pattern of VI has diffraction peaks at positions of θ, 5.4, 7.0, 10.6, 14.1, 16.79, 18.7, 20.6, and 21.6 degrees.
2. The crystal form according to claim 1, wherein the X-ray powder diffraction pattern of Form VI has a diffraction peak at a position of θ, 9.4, 13.1, 15.7, 17.7, 19.6, 21.1, 23.2, 25.0, 28.2 degrees; The X-ray powder diffraction pattern of Form VI is at positions of 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. There is a diffraction peak; or the X-ray powder diffraction pattern of Form VI is shown in Figure 1, wherein the relative intensity of the diffraction peak at 18.1 degrees of 2θ is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
3. The crystalline form of the pemasiline hemi-tartrate of claim 1 wherein the purity of Form VI is at least 90% or at least 95% or at least 98%.
4. A process for the preparation of a crystalline form of the pamacillin hemi-tartrate according to any one of claims 1 to 3, which comprises: feeding a crude pemasiline hemi-tartrate into a mixed solvent containing a good solvent and a poor solvent, After heating until the dissolution is completed, the temperature is lowered to 10 to 40 ° C, crystals are precipitated, crystals are collected, and the solvent is removed to obtain a crystal form VI.
5. The method of claim 4 wherein said good solvent is water.
6. The method of claim 4 wherein said poor solvent is methanol, ethanol, or a combination thereof.
7. The method according to claim 4, wherein said mixed solvent is water and ethanol, and the volume ratio of water to ethanol is from 1:10 to 10:1.
8. The method according to claim 4, wherein the heating is completed to a temperature of from 25 ° C to 50 ° C.
9. A process for the preparation of a crystalline form of the pamacillin hemi-tartrate according to any one of claims 1 to 3, comprising: pemasilin penta-tartrate crystal form A, crystal form B, form C, crystal form One or more of D, Form E, Form F or amorphous is introduced into a mixed solvent containing a good solvent and a poor solvent, and after suspension suspension, crystals are collected, and the solvent is removed to obtain Form VI.
10. The method of claim 9 wherein said good solvent is water.
11. The method of claim 9 wherein said poor solvent is methanol, ethanol or a combination thereof.
12. The method according to claim 9, wherein said mixed solvent is water and ethanol, and the volume ratio of water to ethanol is from 1:10 to 10:1.
13. A pharmaceutical composition comprising an effective amount of Form VI of any of claims 1-3 and a pharmaceutically acceptable excipient.
14. Use of the pharmaceutical composition of claim 13 for the preparation of an antipsychotic pharmaceutical formulation. .

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