TW202304862A - Pharmaceutical salt of pimavanserin, preparation method, pharmaceutical composition and use thereof - Google Patents

Abstract

The present disclosure provides a pharmaceutical salt of Pimavanserin, preparation method, pharmaceutical composition and use thereof. The pharmaceutical salt of Pimavanserin is formed from the free base of Pimavanserin and an organic acid with six carbons or more. The pharmaceutical salt of Pimavanserin prepared according to the present disclosure has good solubility and stability and is convenient to prepare, so that it is suitable for large-scale industrial production.

Description

Medicinal salt of pimaserin, preparation method, pharmaceutical composition containing it and application

The invention belongs to the technical field of medicine, and in particular relates to a medicinal salt of pimaserin and a preparation method and application thereof.

This application claims to enjoy the priority rights of the following earlier applications: the application number submitted to the State Intellectual Property Office of China on March 26, 2021 is 202110330687.5, and the invention name is "Guamaserin Medicinal Salt, Preparation Method, and Drugs Containing It" Composition and application” Chinese invention patent application. The entirety of the aforementioned prior application is incorporated into the present application by reference.

Pimavanserin is an atypical antipsychotic that is an inverse agonist and antagonist of the 5-hydroxytryptamine 5-HT2A receptor. Pimaserin is marketed in the United States as Nuplazid ^® . Nuplazid ^® , containing pimaserin hemitartrate, is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (also known as PDP) and is widely used in clinical practice.

。 The chemical name of pipemaserin is N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenyl Methyl) urea, the molecular formula is C ₂₅ H ₃₄ FN ₃ O ₂ , the molecular weight is 427.55, the CAS number is 706779-91-1, and the chemical structure is shown in the following formula,

.

Currently on the market are Pimaserin Tablets and Capsules, the raw material of which is Pimaserin Hemitartrate Crystal Form C, both of which are oral preparations that require daily administration and can only reach effective plasma levels within a limited time range. Due to the need for frequent administration, the patient's medication compliance is poor.

Patent literature CN 101031548 A discloses various salt forms of pipemaserin (including phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, clavulanate, isothiosulfate, borate , halide, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate, oxalate, Ascorbate, Niacinate, Benzoate, Methanesulfonate, Salicylate, Stearate, Tanninate, Tosylate, Valerate, Esylate, Benzenesulfonate , p-toluenesulfonate, 2-ethanedisulfonate and naphthoate) and compositions comprising these salts; and further discloses citrate, fumarate, maleate, malate, phosphoric acid Salt, succinate, sulfate, edisylate crystal form, preparation method and solubility in water.

Patent document CN 1816524A discloses pimaserin L-tartrate.

Patent document CN 101035759 A disclosed Pimaserin hemitartrate crystal form A to crystal form F, and revealed that crystal form C has high water solubility with a solubility of about 50-100 mg/mL, crystal forms A, B, D, E and F have high water solubility higher than 200 mg/mL, and Form C has higher thermodynamic and chemical stability than Form A or Form B.

Patent document CN 106916098 A discloses pimaserin monotartrate hemihydrate.

Patent document CZ 2015702 A discloses pipemaserin dibenzoyl L-tartrate, hydrochloride, p-toluenesulfonate, benzenesulfonate, 4-hydroxybenzoate, benzoate, Hydrobromide, methanesulfonate and their crystalline or amorphous forms.

Patent document WO 2018007842 A1 discloses pimaserin besylate, cyclamate, p-toluenesulfonate, benzoate and mandelate.

The reported medicinal salts of pimaserin all have high solubility and are not suitable for the application of long-acting preparations, and there are currently no relevant patents or literature reports on pimaserin long-acting injections.

In order to meet the strict requirements of pharmaceutical preparations on the form of active substances, it is still necessary to develop a pimaserin salt and its crystal form that can prolong the drug effect and be suitable for the application of long-acting preparations, so as to ensure that the drug can work for a long time in the patient's body. Reduce the frequency of medication and improve the clinical efficacy of patients.

Therefore, the development of sustained-release dosage forms of pimaserin and the pimaserin salts and crystal forms thereof suitable for the application of the sustained-release dosage forms is very useful for maintaining treatment and improving patient compliance.

I。 In order to improve the above-mentioned technical problems, the present invention provides Pimaserin medicinal salt, which is the salt formed by Pimaserin free base and organic acid with more than six carbons, wherein the structure of Pimaserin free base is as formula I Shown:

I.

The organic acid with more than six carbons in the present invention is a C ₆ -C ₃₀ organic acid, including but not limited to: hexanoic acid, heptanoic acid, caprylic acid, nonanoic acid, azelaic acid, capric acid, sebacic acid, decanoic acid, Monodecanoic Acid, Lauric Acid (Dodecanoic Acid), Tridecanoic Acid, Myristic Acid (Myristic Acid), Pentadecanoic Acid, Palmitic Acid (Hexadecanoic Acid), Margaric Acid, Stearic Acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, eicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, eicosanoid Pentasanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacosanoic acid (melisic acid), glycerin triacetic acid, ligninic acid, pamoic acid ( palmitate), 1-hydroxy-2 naphthoic acid, pamoic acid and naphthoic acid derivatives. The "naphthoic acid derivatives" include but not limited to naphthoic acid esters, such as naphthoic acid containing carboxyl and additional ester functional groups.

The pharmaceutically acceptable salt of pipemaserin in the present invention is pipemaserin hemipamoate or pipemaserin 1-hydroxyl-2-naphthoate.

In the present invention, the pharmaceutically acceptable salt of pimaserin is in crystal, polycrystalline or amorphous form.

In the present invention, the pharmaceutically acceptable salt of pimaserin includes its solvate with a solvent. The "solvate" includes the hydrate of the pharmaceutically acceptable salt of Pimaserin or the solvate formed between the pharmaceutically acceptable salt of Pimaserin and an organic solvent. The organic solvent can be one of methanol, ethanol, dimethylsulfoxide and N,N-dimethylformamide, two or more, preferably methanol and/or N,N-dimethylformamide Formamide.

In some embodiments, the pimaserin hemipamoic acid salt is a salt formed by complexing pimaserin and pamoic acid at a molar ratio of 1:0.5.

In some embodiments, the pimaserin hemipamoic acid salt can be pimaserin hemipamoic acid salt form A, pimaserin hemipamoic acid crystalline form B or an amorphous form.

In some embodiments, the X-ray powder diffraction pattern of the pimaserin hemipamolate salt form A has 2θ values of 3.3º±0.2º, 6.7º±0.2º and 7.5º±0.2º. Diffraction peak.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form A has a 2θ value of 3.3º±0.2º, 6.7º±0.2º, 7.5º±0.2º º, 12.2º±0.2º, 13.7º±0.2º and 17.0º±0.2º have diffraction peaks.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form A has a 2θ value of 3.3º±0.2º, 6.7º±0.2º, 7.5º± There are diffraction peaks at 0.2º, 12.2º±0.2º, 13.7º±0.2º, 17.0º±0.2º, 19.5º±0.2º, 20.4º±0.2º and 21.1º±0.2º.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin hemipamolate salt form A is basically as shown in FIG. 6 .

In some embodiments, the differential scanning calorimetry diagram of the pimaserin hemipamolate crystalline form A is basically as shown in Figure 4, and Figure 4 shows that its melting point is about 180°C, and its peak value is about 186°C .

In some embodiments, the thermogravimetric analysis diagram of the pimaserin hemipamolate salt form A is basically as shown in Figure 5, and Figure 5 shows that its weight loss is about 0.2% at 100°C.

In some embodiments, the X-ray powder diffraction pattern of the pimaserin hemipamolate salt form B has 2θ values of 6.1º±0.2º, 8.6º±0.2º and 19.9º±0.2º. Diffraction peak.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form B has 2θ values of 6.1º±0.2º, 8.6º±0.2º, 19.9º±0.2º º, 9.6º±0.2º, 13.0º±0.2º, 17.9º±0.2º and 19.9º±0.2º have diffraction peaks.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystalline form B has a 2θ value of 6.1º±0.2º, 8.6º±0.2º, 9.6º± 0.2º, 13.0º±0.2º, 13.3º±0.2º, 15.6º±0.2º, 17.0º±0.2º, 17.3º±0.2º, 17.9º±0.2º, 18.9º±0.2º, 19.1º±0.2º , 19.9º±0.2º, 20.2º±0.2º and 20.7º±0.2º have absorption peaks.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin hemipamolate salt form B is basically as shown in FIG. 8 .

In some embodiments, the pipemaserin 1-hydroxy-2-naphthoic acid salt is a salt formed by complexing pipemaserin and 1-hydroxy-2-naphthoic acid at a molar ratio of 1:1, which can be Pimaserin 1-hydroxy-2-naphthoate crystal form A or pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.

In some embodiments, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A has 2θ values of 4.3°±0.2°, 13.2°±0.2° and 18.6° There is a diffraction peak at ±0.2º.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A has a 2θ value of 4.3°±0.2°, 8.8°±0.2° , 13.2º±0.2º, 17.7º±0.2º, 18.6º±0.2º and 20.2º±0.2º have characteristic peaks.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A has a 2θ value of 4.3°±0.2°, 7.7°±0.2° º, 8.8º±0.2º, 13.2º±0.2º, 17.0º±0.2º, 17.7º±0.2º, 18.6º±0.2º, 19.0º±0.2º and 20.2º±0.2º have absorption peaks.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A has a 2θ value of 4.3°±0.2°, 7.7°±0.2° º, 8.8º±0.2º, 11.4º±0.2º, 13.2º±0.2º, 15.1º±0.2º, 17.0º±0.2º, 17.7º±0.2º, 18.6º±0.2º, 19.0º±0.2º, There are absorption peaks at 20.2º±0.2º, 20.6º±0.2º, 21.3º±0.2º, 21.6º±0.2º, 22.7º±0.2º and 25.8º±0.2º.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A is basically as shown in FIG. 11 .

In some embodiments, the differential scanning calorimetry diagram of the pipemaserin 1-hydroxy-2-naphthoate crystal form A is basically as shown in Figure 9, and Figure 9 shows that its melting point is about 166°C, The peak is around 169 °C.

In some embodiments, the thermogravimetric analysis diagram of the pipemaserin 1-hydroxy-2-naphthoate crystal form A is basically as shown in Figure 10, and Figure 10 shows that its weight loss at 100 °C is about 0.05%.

In some embodiments, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B has a 2θ value of 3.8°±0.2°, 7.8°±0.2° And there is a diffraction peak at 14.2º±0.2º.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B has a 2θ value of 3.8°±0.2°, 7.8° There are diffraction peaks at ±0.2º, 14.2º±0.2º, 15.7º±0.2º, 17.7º±0.2º and 20.2º±0.2º.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B has a 2θ value of 3.8°±0.2°, 7.8 There are diffraction peaks at º±0.2º, 11.7º±0.2º, 14.2º±0.2º, 15.7º±0.2º, 17.7º±0.2º, 21.3º±0.2º and 22.4º±0.2º.

In some embodiments, further, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B has a 2θ value of 3.8°±0.2°, 7.8 º±0.2º, 11.7º±0.2º, 14.2º±0.2º, 15.7º±0.2º, 17.7º±0.2º, 21.3º±0.2º, 22.4º±0.2º, 23.0º±0.2º, 25.3º± There are absorption peaks at 0.2º and 26.8º±0.2º.

In some embodiments, further, the X-ray powder diffraction pattern of the crystalline form B of pipemaserin 1-hydroxy-2-naphthoate monohydrate is basically as shown in FIG. 14 .

In some embodiments, the differential scanning calorimetry diagram of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is basically as shown in Figure 12, and Figure 12 shows that it is at 100 There is an endothermic peak between ℃-150 ℃, which is caused by the removal of crystal water. Its melting point is about 168 ℃, and its peak value is about 169 ℃.

In some embodiments, the thermogravimetric analysis diagram of the pipemaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is basically as shown in Figure 13, and Figure 13 shows that it has A section of weight loss of about 2.6%, equal to about one molecule of crystal water, is the crystalline form of pimaserin 1-hydroxy-2-naphthoate monohydrate.

In some embodiments, the NMR data of the pipemaserin 1-hydroxy-2-naphthoate monohydrate crystal form B shows that the molar ratio of pipemaserin to 1-hydroxy-2-naphthoic acid is 1 :1 into salt.

The present invention also provides a preparation method of the pharmaceutically acceptable salt of pimaserin, which includes the following steps: reacting the free base of pimaserin with the organic acid having more than six carbons.

Preferably, the reaction may be referred to as "salt-forming reaction" or "neutralization reaction".

In some embodiments, the preparation method of the pharmaceutically acceptable salt of pipemaserin is carried out in a solvent, and the solvent is selected from water, methanol, ethyl acetate, tetrahydrofuran, isopropanol, dichloromethane, N,N - One, two or more of dimethylformamide, acetone, methyl tert-butyl ether and isopropyl ether solvents.

In some embodiments, in the preparation method of the pharmaceutically acceptable salt of pimaserin, the mass volume ratio of pimaserin to the organic solvent is (1:10) g/mL-(1:50) g/mL or 20-600 mg/mL, preferably (1:10) g/mL-(1:30) g/mL or 40-550 mg/mL; eg 50 mg/mL, 214 mg/mL, 42.8 mg/mL, 416.7 mg/mL, 400 mg/mL, 501 mg/mL, 90.8 mg/mL, 166.7 mg/mL, or 142.7 mg/mL.

In some embodiments, in the preparation method of the pharmaceutically acceptable salt of pimaserin, the molar ratio of pimaserin to the organic acid is preferably (1:0.5)-(1:3), more preferably (1:0.5 )-(1:1), such as (2-0.33):1, preferably (2-0.5):1; such as 1.9:1, 1.8:1, 1.55:1, 1.33:1, 1.40:1, 0.88: 1 or 0.83:1.

In some embodiments, in the preparation method of the pharmaceutically acceptable salt of pipemaserin, the reaction temperature may be 0°C-80°C, preferably 25°C-65°C, for example, 20°C-35°C.

In some embodiments, in the preparation method of the pharmaceutically acceptable salt of pimaserin, the reaction time can be monitored by conventional detection methods in the art (such as TLC, HPLC or NMR), and generally the free pimaserin The end point of the reaction is when the base disappears, and the reaction time is 0.5 hours to 10 days, preferably 1 hour to 7 days.

In some embodiments, the preparation method of the pharmaceutically acceptable salt of pimaserin comprises the following steps: Method 1: Mix the solution formed by pipemaserline and a good solvent with an organic acid, and then add a poor solvent for crystallization; or, Method 2: Add the solution formed by pipemaserline, good solvent, and organic acid into the poor solvent, and crystallize; or, Method 3: remove the solvent and crystallize the solution formed by pipemaserline, solvent and organic acid; the solvent is a good solvent or a mixed solvent of a good solvent and a poor solvent.

In some embodiments, the preparation method of the pimaserin hemipamolate crystalline form A is selected from one of the following methods: Method (a1): forming a solution of pimaserin in a good solvent, adding pamoic acid, stirring the reaction, adding a poor solvent and stirring to crystallize; or, Method (a2): taking pimaserin and pamoic acid, adding a good solvent to stir the reaction, filtering, adding a poor solvent to the filtrate, stirring and crystallizing; or, Method (a3): Take pimaserin and pamoic acid and add a good solvent to stir the reaction, filter, add the filtrate to a poor solvent, optionally, add pimaserin semi-pamoic acid salt crystal form to the poor solvent The seed crystal of A was stirred and crystallized.

In some embodiments, in methods (a1), (a2) and (a3), the good solvent is an alcohol solvent (such as methanol), a ketone solvent (such as acetone), an ester solvent (such as ethyl acetate) , acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, one of N,N-dimethylformamide and N,N-dimethylacetamide, two or more .

In some embodiments, in methods (a1), (a2) and (a3), the poor solvent is one of alkane solvent, ether solvent (such as isopropyl ether or methyl tert-butyl ether) and water , two or more.

In some embodiments, the molar ratio of pimaserin to pamoic acid described in methods (a1), (a2) and (a3) is (0.5-2):1, such as 0.88:1, 1.8:1 or 1.9:1.

In some embodiments, when the method (a2) is used, the mass volume ratio of the pimaserin to the good solvent is 40-214 mg/mL, such as 50 mg/mL or 214 mg/mL; when the method ( a3), the mass volume ratio of the pimaserin to the good solvent is 416-501 mg/mL, such as 416.7 mg/mL, 400 mg/mL or 501 mg/mL.

In some embodiments, when using method (a2), the volume ratio of poor solvent to good solvent is (5-9):1, such as 8:1 or 9:1; when using method (3), the The volume ratio of the poor solvent to the good solvent is (4-21):1, such as 20.8:1, 4:1 or 20:1.

In some embodiments, in methods (a1), (a2) and (a3), the temperature for stirring and crystallizing is room temperature.

In some embodiments, when the method (a1) is used, the stirring crystallization time is 18 hours to 7 days.

In some embodiments, when methods (a2) and (a3) are used, the time for stirring and crystallizing is 18-24 hours.

In some embodiments, the preparation method of the pimaserin hemipamolate crystalline form B comprises the following steps: Disperse pamoic acid with a solvent to obtain a suspension, dissolve pimaserin with a solvent to obtain a free base solution, add the free base solution dropwise to the suspension and stir the reaction; optionally, during the stirring reaction, add the above-mentioned Pimaserin hemipamolate crystal form A was used as the seed crystal.

In some embodiments, the solvent in the preparation method of pimaserin hemipamolate crystalline form B is selected from ester solvents, such as ethyl acetate.

In some embodiments, the preparation method of the amorphous form of pimaserin hemi-pamolate comprises the following steps: dissolving pimaserin hemi-pamoate with a solvent, and volatilizing until the solvent is dry to obtain pimaserin Hemipamoate is amorphous.

In some embodiments, the solvent in the amorphous preparation method is an alcohol solvent (such as methanol), a ketone solvent (such as acetone), an ester solvent, an ether solvent (such as tetrahydrofuran, 2-methyltetrahydrofuran), an alkane Solvent, acetonitrile, dichloromethane, chloroform, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and water, two or more.

In some embodiments, the mass volume ratio of the pimaserin hemipamolate to the solvent can be 1-500 mg/mL, preferably 10-125 mg/mL, such as 90.8 mg/mL, 20.8 mg/mL , 10 mg/mL or 125 mg/mL.

In some embodiments, the volatilization method can be normal pressure volatilization or reduced pressure volatilization.

In some embodiments, the volatilization temperature may be 0-60°C, preferably 20-40°C.

In some embodiments, the preparation method of the pimaserin 1-hydroxy-2-naphthoate crystal form A is selected from one of the following methods: Method (b1): separately form solutions of pipemaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise into the alkali solution under stirring, stir for reaction, add a poor solvent, and stir for crystallization; or, Method (b2): Pimaserin and 1-hydroxy-2-naphthoic acid are respectively formed into solutions in a good solvent, and the acid solution is added dropwise into the alkali solution under stirring, and the crystallization is carried out under stirring.

In some embodiments, in method (b1): The good solvent is selected from one, two or three of N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide, preferably N,N-dimethylformamide Amide; The mass ratio of described pimaserin and 1-hydroxyl-2-naphthoic acid is 2:1; The poor solvent is selected from alkane solvents, ether solvents and water, two or three, preferably water; The volume ratio of the poor solvent to the good solvent is (1-20):1, for example 8:1. The temperature of the stirring and crystallization can be room temperature, and the time of stirring and crystallization can be 1-12 hours.

In some embodiments, in method (b2): The good solvent is an alcohol solvent and/or an ester solvent, and the alcohol solvent is preferably isopropanol; the ester solvent is preferably ethyl acetate. The volume-to-mass ratio of the good solvent to pimaserin is 1 mL/g-25 mL/g, such as 6 mL/g, 15 mL/g or 23.4 mL/g. The molar ratio of described pipemaserin and 1-hydroxyl-2-naphthoic acid is preferably (0.5-1.5):1, such as 0.83:1; The stirring crystallization temperature is room temperature, and the stirring crystallization time is 18-24 hours.

In some embodiments, the preparation method of the pipemaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is selected from one of the following methods: or , (c2) Pimaserin 1-hydroxy-2-naphthoic acid crystal form A is dissolved in a solvent to form a solution, and evaporated until the solvent is dry; or, (c3) Dissolving pimaserin 1-hydroxy-2-naphthoic acid crystal form A in a solvent to form a suspension, stirring and crystallizing; or, (c4) Dissolving Pimaserin 1-hydroxy-2-naphthoic acid crystal form A in a good solvent to form a solution, adding an antisolvent, stirring and crystallizing; or, (c5) Dissolving Pimaserin 1-hydroxy-2-naphthoic acid crystal form A in a solvent at high temperature to form a solution, stirring and crystallizing at room temperature.

In some embodiments, in method (c1): The good solvent is a ketone solvent, preferably acetone. The molar ratio of the pimaserin to the 1-hydroxy-2-naphthoic acid is (0.5-1.5):1, for example 0.88:1. The temperature of the stirring reaction is room temperature, and the time of the stirring reaction is 1-12 hours. The poor solvent is one, two or three of alkane solvent, ether solvent and water, preferably water. The volume ratio of the poor solvent to the good solvent is (1-20):1, for example 8:1. The temperature for the stirring and crystallization is room temperature, and the time for the stirring and crystallization is 1-12 hours.

In some embodiments, in method (c2): The solvent is one, two or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, alkane solvents, dichloromethane, chloroform, dimethylsulfoxide and water. The alcoholic solvent is preferably methanol. The ester solvent is preferably ethyl acetate. The ether solvent is preferably tetrahydrofuran. The volatilization temperature is room temperature.

In some embodiments, in method (c3): Described solvent is selected from the mixed solvent that water or water and organic solvent form; Described organic solvent is selected from alcohol solvent, ester solvent, ketone solvent, ether solvent, nitrile solvent and amide solvent One, two or more; the alcohol solvent is preferably one of methanol, ethanol, n-propanol and isopropanol, two or more. The ester solvent is preferably ethyl acetate, isopropyl acetate. Described ketone solvent is preferably acetone. The preferred nitrile solvent is acetonitrile. The ether solvent is preferably tetrahydrofuran. The amide solvent is preferably N,N-dimethylformamide. The volume ratio of the water to the organic solvent is preferably (1-5):1, such as 4:1, 5:1, 3.5:1, 2.5:1 or 2:1. The solvent is further preferably a mixed solvent of ethanol and water, a mixed solvent of methanol and water, a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, a mixed solvent of n-propanol and water, a mixed solvent of acetonitrile and water, N , Mixed solvent of N-dimethylformamide and water, isopropanol or ethyl acetate. The volume-to-mass ratio of the solvent to pipemaserline is preferably 10 mg/mL-50 mg/mL, such as 30 mg/mL or 35 mg/mL. The stirring temperature is 10°C-60°C; The stirring time is 3 days to 10 days.

In some embodiments, in method (c4): The good solvent is alcohol solvent, ketone solvent, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, 1,4- One or two or more of dioxane, methylene chloride and chloroform; The poor solvent is one, two or three of alkane solvent, ether solvent and water.

In some embodiments, in method (c5): The high temperature is 60°C-80°C; Described solvent is selected from alcohol solvent, ketone solvent, ether solvent, ester solvent, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, dimethyl oxide and water One, two or more.

The present invention also provides the use of the pharmaceutically acceptable salt of pimaserin as described above in the preparation of a medicament for preventing, treating or improving the frequency and/or severity of hallucinations and delusions associated with Parkinson's psychosis.

The present invention also provides a pharmaceutical composition, which includes the pharmaceutically acceptable salt of pimaserin as described above.

In some embodiments, the pharmaceutical composition may also include pharmaceutically acceptable excipients.

In some embodiments, the purpose of the pharmaceutical composition is to facilitate the administration of the compound to a patient in need thereof, such as a human or other mammalian organism.

In some embodiments, the pharmaceutically acceptable adjuvant includes one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.

The present invention also provides a pharmaceutical preparation of pimaserin, which includes the pharmaceutically acceptable salt of pimaserin or the pharmaceutical composition of pimaserin.

In some embodiments, the dosage form of the pharmaceutical preparation of pimaserin includes but not limited to tablet, capsule, solution, suspension and semi-solid preparation.

In some embodiments, the pharmaceutical preparation of pimaserin is a pharmaceutically acceptable salt suspension of pimaserin.

In some embodiments, the suspension of the pharmaceutically acceptable salt of pimaserin can also include auxiliary materials, and the auxiliary materials can be selected from suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and surface preparations. One, two or more of the active agents.

In some embodiments, the concentration of the solid particles of pimaserin in the suspension of the pharmaceutically acceptable salt of pimaserin is 62 mg/mL-124 mg/mL.

In some embodiments, the solid particle of pipemaserin is pipemaserin, pharmaceutically acceptable salt of pipemaserin, and the pharmaceutically acceptable salt of pipemaserin includes but not limited to pipemaserin hemipamoate and Pimaserin 1-Hydroxy-2-naphthoate.

In some embodiments, the concentration range of the wetting agent is 1 mg/mL-10 mg/mL, preferably 1 mg/mL-5 mg/mL, such as 1 mg/mL, 1.5 mg/mL, 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL, or 5.0 mg/mL.

In some embodiments, the wetting agent is selected from one, two or three of Tween 20, Tween 80, and Poloxamer 188, preferably Poloxamer 188.

In some embodiments, the buffer is selected from one, two or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.

In some embodiments, the preparation method of the pimaserin medicinal salt suspension comprises the following steps: (d1) dissolving the wetting agent and the buffering agent in the solvent; (d2) adding the medicinal salt of pimaserin as described above to obtain an aqueous suspension of coarse particles; (d3) Grinding the aqueous suspension solution of the above-mentioned coarse particles using a ball mill to obtain a suspension; or, (e1) sieving the solid particles of the pharmaceutically acceptable salt of pimaserin as described above; (e2) dissolving the wetting agent and the buffering agent in the solvent; (e3) Add the solution prepared in step (e2) to the sieved pimaserin medicinal salt solid particles, fully wet and disperse; (e4) Dilute to the target volume with a solvent to obtain a suspension.

The present invention also provides a method for preventing, treating or improving the frequency and/or severity of hallucinations and delusions associated with Parkinson's psychosis, comprising the above-mentioned pharmaceutical salt of pimaserin, or a pharmaceutical composition thereof, or Pimaserin pharmaceutical preparations are administered to patients in need thereof.

Definitions and Explanations of Terms

"More kinds" in the present invention means three or more kinds.

The "crystal" mentioned in the present invention is a structure in which a large number of microscopic material units (atoms, ions, molecules, etc.) are arranged in an orderly manner according to certain rules.

The "polymorphism" mentioned in the present invention refers to different crystal forms and other solid molecular forms of the same compound, for example, two or more crystal forms and/or amorphous forms comprising the pharmaceutically acceptable salt of pimaserin form of a solid.

The "amorphous form" used in the present invention refers to the constitutional form of an amorphous solid (non-crystal).

In the present invention, the term "carrier", "diluent", "vehicle" or "excipient" refers to such a substance (or substances) that can be included together with specific agents to form a pharmaceutical composition , and can be solid or liquid. The solid carrier includes but not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. The liquid carrier includes but not limited to syrup, peanut oil, olive oil, saline solution, water and the like. The carrier or diluent may include delay or time release materials known in the art, such as glycerol monostearate alone or together with waxes, ethyl cellulose, hypromellose, methyl methacrylate, etc. ester or glyceryl distearate.

In the present invention, the "pharmaceutically acceptable excipients" refer to the following substances, which are suitable for contacting with patients' tissues within the scope of normal medical judgment without undue toxicity, irritation, allergic reaction, etc. , have a reasonable ratio of advantages and disadvantages, and can be effectively used for their intended use.

The "solvate" refers to a molecular complex containing a drug (such as pimaserin) and one or more pharmaceutically acceptable solvent molecules (such as water) in stoichiometric or non-stoichiometric amounts. When the solvent is intimately associated with the drug, the complex formed has a well-defined stoichiometry independent of humidity. However, when the solvent is weakly bound (as in channel solvates and hygroscopic compounds), the solvent content is dependent on humidity and drying conditions. In this case, the complex is usually non-stoichiometric.

The "hydrate" refers to a solvate containing a drug (such as pimaserin) and stoichiometric or non-stoichiometric water.

The "overnight" means that the time is 12-24 hours.

Reference to "patient" includes organisms such as humans or other mammals.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

In the present invention, the room temperature refers to the ambient temperature, generally 0°C-35°C.

The positive progress effect of the present invention is: The technical problem to be solved by the present invention is to provide a kind of pimaserin medicinal salt, preparation method, containing its The pharmaceutical composition and the application of the pharmaceutical composition. The pharmaceutical salt of pimaserin provided by the invention has no pH dependence, has low solubility in water (compared with the existing salt type, its solubility is significantly reduced), good stability, simple and convenient preparation method, and is suitable for industrial production .

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not indicate specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Using nuclear magnetic resonance ( ¹ H-NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), X-ray powder diffraction (XRPD), the examples and comparative examples The compounds were tested, and the test parameters were as follows: (1) The NMR test was carried out on a Bruker Advance III 500 M nuclear magnetic resonance spectrometer, the measurement frequency was 400 Mz/600 Mz, and the solvent used was deuterated DMSO. (2) DSC measurement was carried out in a TA Instruments model Q2000 sealed pan device, the sample (about 1-2 mg) was weighed in an aluminum pan, and transferred to the instrument for measurement. The test parameters are as follows: the instrument is balanced at 30 °C, the temperature is raised to 300 °C at a rate of 10 °C/min, and the experimental atmosphere is nitrogen. (3) TGA measurement was carried out in a TA Instruments model Q2000 device. The sample (about 2-5 mg) was weighed in a platinum pan and transferred to the instrument for measurement. The test parameters are as follows: the temperature of the instrument is raised to 350 °C at a rate of 10 °C/min, and the experimental atmosphere is nitrogen. (4) The XRPD measurement is carried out in a Bruker D8 Advance X-ray powder diffractometer, and a circular zero-background single-crystal silicon sample stage is used. The scanning parameters are as follows: voltage 40 kv, current 40 mA, scanning range 3°-45°, scanning step 0.02°, and scanning mode is continuous scanning.

Embodiment 1 Pimaserin free base solid-phase characterization detection

Pimaserin free base was detected by solid phase characterization, XRPD spectrum is shown in Figure 1, DSC spectrum is shown in Figure 2, TGA spectrum is shown in Figure 3, ¹ H-NMR results are as follows: 1H-NMR (400MHz, DMSO-d6): δ7 .25-7.22 (m, 2H), 7.12-7.08 (m, 4H), 6.87-6.82 (m, 3H), 4.41 (s, 2H), 4.18 (d, 2H), 3.93-3.87 (m, 1H) , 3.70 (d, 2H), 2.70 (d, 2H), 2.09 (s, 3H), 2.04-1.94 (m, 1H), 1.87 (t, 2H), 1.59-1.49 (m, 2H), 1.42 (d , 2H), 0.96 (d, 6H).

The X-ray powder diffraction pattern of Pimaserin free base is approximately 6.790º, 8.093º, 12.945º, 13.655º, 14.364º, 14.901º, 17.012º, 17.687º, 19.045º, 19.697º, 20.839º at 2θ , 21.036º, 22.219º, 24.531º, 25.219º, 25.733º, 27.133º, 27.922º, 28.971º, 30.669º and 32.935º have diffraction peaks, the error range is ±0.2º.

The differential scanning calorimetry curve (DSC) showed that the peak value of the endothermic peak of the free base of pimaserin was 122.07 °C, see Figure 2 for details. Thermogravimetric analysis (TGA) showed that the weight loss of pimaserin free base was 0.2206% at 100 °C, see Figure 3 for details.

Example 2 Preparation of pimaserin hemipamolate crystal form A

Dissolve 200 mg of pimaserin (0.88 eq) in 4 mL of methanol, add 206 mg of pamoic acid (1.0 eq) to the methanol solution containing free base, place it on a magnetic stirrer, and stir the reaction at room temperature 7 days; after the reaction, the reaction solution was centrifuged, and 8 times the volume of anti-solvent isopropyl ether was added to the supernatant to obtain a yellow viscous precipitate, which was centrifuged and vacuum-dried at 40°C for 12 hours to obtain a white to slightly yellow powder. The above samples were subjected to solid phase characterization detection ( ¹ H-NMR, DSC, TGA, PLM, XRPD).

The solid-phase DSC, TGA and XRPD characterization results of pimaserin hemipamoic acid are shown in Figure 4-Figure 6.

¹ H-NMR (400MHz, DMSO- d ₆ ): δ8.20 (t, 2H), 7.65 (d, 1H), 7.25-7.21 (m, 2H), 7.15-7.08 (m, 5H), 7.04-6.96 (m, 2H), 6.83 (d, 2H), 4.70 (s, 1H), 4.43 (s, 1H), 4.19 (d, 3H), 3.70 (d, 2H), 2.69 (s, 3H), 2.04- 1.83 (m, 3H), 1.67 (d, 2H), 0.96 (d, 6H).

NMR results showed that the acid-base molar ratio of pimaserin hemipamoic acid was 0.5:1.

The differential scanning calorimetry curve (DSC) showed that the melting point of pimaserin hemipamoic acid was about 180 °C, and the peak value was about 186 °C, see Figure 4 for details.

Thermogravimetric analysis (TGA) showed that the weight loss of pimaserin hemipamoic acid was 0.2270% at 100 °C, see Figure 5 for details.

Polarized light microscopy (PLM) showed that pimaserin hemipamoic acid had polarized light and was in crystalline form.

The X-ray powder diffraction pattern (XRPD) shows that pimaserin hemi-pamolate has diffraction peaks, and it is judged to be a crystalline form based on PLM, and it is named as pimaserin hemi-pamolate crystal form A. See Figure 6.

Example 3 Preparation of pimaserin hemipamolate crystal form A

Take 428 mg of pipemaserin (1.8 eq) and 214 mg of pamoic acid (1.0 eq), add 2 mL of methanol, stir overnight at room temperature, filter, slowly add 18 mL of isopropyl ether dropwise to the filtrate, continue stirring overnight, After filtration and vacuum drying at 35 °C for 4 hours, 569 mg of pimaserin hemipamolate salt form A sample was obtained, with a yield of about 91%.

Example 4 Preparation of Pimaserin Hemi-Pamosate Crystal Form A

Take 42.8 mg of pipemaserin (1.9 eq) and 20.4 mg of pamoic acid (1.0 eq), add 1 mL of methanol, stir overnight at room temperature, filter, add 5 mL of isopropyl ether to the filtrate, continue stirring overnight, filter, After vacuum drying at 35 °C for 3 hours, 54 mg of pimaserin hemipamolate crystal form A sample was obtained, with a yield of about 87%.

Example 5 Preparation of pimaserin hemipamolate crystal form A

Take 5 g of pimaserin (1.8 eq) and 2.5 g of pamoic acid (1.0 eq), add 12 mL of methanol, stir at room temperature overnight, filter, and add the filtrate dropwise to 50 mg of pimaserin prepared in Example 3 In 250 mL of methyl tert-butyl ether of a sample of linsemipamoic acid salt crystal form A, stir overnight, filter, wash the filter cake with 50 mL of methyl tert-butyl ether, and vacuum-dry at 60 °C for 4 hours to obtain 5.57 g of piperazine Maserin hemipamolate crystal form A sample, the yield is about 90%.

Example 6 Preparation of pimaserin hemipamolate crystal form A

Take 40 g of pimaserin (1.8 eq) and 20 g of pamoic acid (1.0 eq), add 100 mL of methanol, stir at room temperature overnight, filter, and add the filtrate dropwise to the solution containing 100 mg of pimaserin prepared in Example 3 In 400 mL of methyl tert-butyl ether of a sample of linsemipamoic acid salt crystal form A, stir overnight, filter, wash the filter cake with 100 mL of methyl tert-butyl ether, and dry in vacuo at 60 °C for 5 hours to obtain 52.1 g of piperazine Maserin hemipamolate crystal form A sample, the yield is about 90%.

Example 7 Preparation of pimaserin hemipamolate crystal form A

Take 3006 mg of pimaserin (1.8 eq) and 1503 mg of pamoic acid (1.0 eq), add 6 mL of methanol, stir overnight at room temperature, filter, add the filtrate dropwise to the solution containing 20 mg of pimaserin prepared in Example 3 In 120 mL of methyl tert-butyl ether of a sample of linsemipamoic acid salt crystal form A, stir overnight, filter, wash the filter cake with 100 mL of methyl tert-butyl ether, and vacuum-dry at 35 °C for 3 days to obtain 4.1 g of piperazine Maserin hemipamolate crystal form A sample, the yield is about 97%.

Its XRPD pattern is shown in Figure 7, which is the crystalline form A of pimaserin hemipamolate.

Example 8 Preparation of Pimaserin Hemi-Pamosate Crystal Form B

Take 90.8 mg of pamoic acid, add 1 mL of ethyl acetate, stir and disperse at room temperature to obtain a suspension; take 220 mg of pimaserin, add 5 mL of ethyl acetate to dissolve to obtain a free base solution; stir the free base solution Add dropwise to the suspension, stir for reaction, add 5 mg of pimaserin hemipamolate crystal form A prepared in Example 7 and 2 mL of ethyl acetate, continue stirring for 8 days, centrifuge, wash, and dry to obtain 231 mg pimaserin hemipamolate crystalline form B.

Its XRPD pattern is shown in Figure 8, which is pimaserin hemipamolate crystal form B.

Embodiment 9 Preparation of amorphous form of pimaserin semi-pamoic acid salt

Take 25 mg of the sample of Pimaserin crystal form A prepared in Example 3, add 0.2 mL of N,N-dimethylacetamide to dissolve, evaporate at 40 °C under normal pressure until the solvent is dry, and perform PLM characterization of the obtained sample. Non-polarizing solid.

Embodiment 10 Preparation of amorphous form of pimaserin semi-pamoic acid salt

Take 25 mg of the Pimaserin crystal form A sample prepared in Example 3, add 2 mL of acetone to dissolve, evaporate at room temperature and normal pressure until the solvent is dry, and perform PLM characterization on the obtained sample, which is a non-polarizing solid.

Embodiment 11 Preparation of amorphous form of pimaserin semi-pamoic acid salt

Take 25 mg of the Pimaserin crystal form A sample prepared in Example 3, add 1 mL of methanol and 0.2 mL of water to dissolve, evaporate at room temperature and pressure until the solvent is dry, and perform PLM characterization of the obtained sample, which is a non-polarized solid.

Embodiment 12 Preparation of amorphous form of pimaserin semi-pamoic acid salt

Take 100 mg of the sample of Pimaserin crystal form A prepared in Example 3, add 10 mL of tetrahydrofuran to dissolve, concentrate under reduced pressure at room temperature until the solvent is dry, and perform PLM characterization on the obtained sample, which is a non-polarizing solid.

Example 13 Preparation of Pimaserin 1-hydroxyl-2-naphthoate crystal form A

Accurately weigh 50 mg of pimaserin (0.88 eq), add an appropriate amount of N,N-dimethylformamide, and ultrasonically dissolve it completely; stir the sample on a magnetic stirrer, slowly dropwise add 25 mg of 1- Hydroxy-2-naphthoic acid (1.0 eq) N,N-dimethylformamide solution, after dripping, stirred and reacted at room temperature for 12 hours; after the reaction, no solid matter was precipitated, adding 8 times the volume of anti-solvent water, A white flocculent precipitate was obtained, which was stirred at room temperature for 12 hours; it was centrifuged, and the precipitate was vacuum-dried at 40° C. for 12 hours to obtain a white powder. The above samples were subjected to solid phase characterization detection ( ¹ H-NMR, DSC, TGA, PLM, XRPD).

The solid-phase DSC, TGA and XRPD characterization results of pipemaserin 1-hydroxy-2-naphthoate crystal form A are shown in Figures 9 to 11.

NMR results showed that the molar ratio of acid to base in pimaserin 1-hydroxy-2-naphthoate was 1:1. ¹ H-NMR (400MHz, DMSO- d ₆ ): δ8.21 (d, 1H), 7.76-7.73 (m, 2H), 7.51-7.47 (m, 1H), 7.42-7.38 (m, 1H), 7.23 -7.20 (m, 2H), 7.12-7.06 (m, 5H), 6.97 (t, 1H), 6.83 (d, 2H), 4.41 (s, 2H), 4.19-4.18 (m, 3H), 3.70 (d , 2H), 2.69 (s, 3H), 2.04-1.84 (m, 3H), 1.66 (d, 2H), 0.96 (d, 6H).

The differential scanning calorimetry curve (DSC) showed that the endothermic peak of pimaserin 1-hydroxy-2-naphthoate was 169 °C, see Figure 9 for details. Thermogravimetric analysis (TGA) showed that the weight loss of pimaserin 1-hydroxy-2-naphthoate was about 0.05074% at 100 °C, see Figure 10 for details.

Its X-ray powder diffraction pattern is shown in Figure 11, and Figure 11 shows that pimaserin 1-hydroxyl-2-naphthoate has a diffraction peak, and it is judged that pimaserin 1-hydroxyl-2-naphthoate is crystal type, and named it as pimaserin 1-hydroxy-2-naphthoate crystal form A.

Example 14 Preparation of Pimaserin 1-hydroxyl-2-naphthoate crystal form A

Take 30 g of pipemaserin (0.83 eq), add 180 mL of isopropanol, stir to dissolve, and obtain a free base solution; take 15.84 g of 1-hydroxy-2-naphthoic acid (1.0 eq), add 250 mL of isopropanol , stirred and dissolved to obtain an acid solution; under stirring, the acid solution was added dropwise to the free base solution, stirred and reacted overnight, filtered, washed with 100 mL of isopropanol, and dried under vacuum at 60°C overnight to obtain 42 g of Pimarse Lin 1-hydroxy-2-naphthoate crystal form A, the yield is about 97%.

Example 15 Preparation of Pimaserin 1-hydroxyl-2-naphthoate crystal form A

Take 42.8 mg of pipemaserin (0.83 eq) and 22.6 mg of 1-hydroxy-2-naphthoic acid (1.0 eq), add 1 mL of ethyl acetate, stir and react for 3 hours, filter to obtain about 53 mg of pipemaserin 1 -Hydroxy-2-naphthoate crystal form A, the yield is about 86%.

Example 16 Preparation of Pimaserin 1-hydroxyl-2-naphthoate crystal form A

Take 2996 mg of pipemaserin (0.83 eq), add 21 mL of isopropanol, stir to dissolve, and obtain a free base solution; take 1582 mg of 1-hydroxy-2-naphthoic acid (1.0 eq), add 45 mL of isopropanol , stirred to dissolve, and filtered to obtain an acid solution; the acid solution was added dropwise to the free alkali solution under stirring, stirred and reacted overnight, filtered, washed with 20 mL of isopropanol, and vacuum-dried at 35 °C for 3 days to obtain 3.9 g Pimaserin 1-hydroxy-2-naphthoate crystal form A, the yield is about 90.4%.

Example 17 Preparation of Pimaserin 1-Hydroxy-2-Naphthoate Form A

Take 5 g of pipemaserin (0.83 eq), add 30 mL of isopropanol, stir to dissolve, and obtain a free base solution; take 2.64 g of 1-hydroxy-2-naphthoic acid (1.0 eq), add 60 mL of isopropanol , stirred to dissolve, and filtered to obtain an acid solution; the acid solution was added dropwise to the free base solution under stirring, stirred and reacted overnight, filtered, washed with 20 mL of isopropanol, and vacuum-dried at 60 °C for 3 hours to obtain 6.7 g Pimaserin 1-hydroxy-2-naphthoate crystal form A, the yield is about 93%.

Example 18 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

Accurately weigh 50 mg of pimaserin (0.88 eq), add appropriate amount of acetone, and ultrasonically dissolve it completely; stir the sample on a magnetic stirrer, slowly add 25 mg of 1-hydroxy-2-naphthoic acid (1.0 eq ) acetone solution, dropwise, stirring at room temperature for 12 hours; after the reaction, no solid matter was separated out, adding anti-solvent water 8 times the volume of acetone to obtain a white precipitate, stirring at room temperature for 12 hours; centrifuging it, The precipitate was vacuum-dried at 40°C for 12 hours to obtain a white powder. The above samples were subjected to solid phase characterization to detect DSC, TGA, XRPD.

The solid-phase characterization results of pipemaserin naphthoate are shown in Figure 12 to Figure 14.

The differential scanning calorimetry curve (DSC) shows that pimaserin 1-hydroxy-2-naphthoate has an endothermic peak between 100 °C and 150 °C, which is caused by the removal of crystal water, and its melting point is about 168 °C , the peak value is about 170.15 °C, see Figure 12 for details.

Thermogravimetric analysis (TGA) shows that pimaserin 1-hydroxy-2-naphthoate has a weight loss of about 2.619% before 110 °C, which is about one molecule of crystal water. See Figure 13 for details.

The X-ray powder diffraction pattern of pimaserin 1-hydroxyl-2-naphthoate is shown in Figure 14, which has a diffraction peak different from crystalline form A of pimaserin 1-hydroxyl-2-naphthoate. It is a new crystal form, which can be judged as a monohydrate in combination with Figure 13, so it is named Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.

Example 19 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

Take 15 mg of the Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16, add 0.5 mL of methanol and 2 mL of water, ultrasonically dissolve, evaporate at room temperature until the solvent is dry, and obtain Pimaserin Form B of Lin 1-hydroxy-2-naphthoate monohydrate.

Preparation of Example 20 and Example 21 Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

By replacing the solvent in Example 19 with the following solvent, Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B can also be obtained. Example Solvent 1 Solvent 2 Example 20 Tetrahydrofuran water Example 21 Dichloromethane ethyl acetate

Example 22 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

Take 42 g of Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 14, add 400 mL of ethanol and 800 mL of water, stir at room temperature for 2 days, filter, and vacuum-dry at 60°C for 4 hours, 41.2 g of pipemaserin 1-hydroxy-2-naphthoate monohydrate crystal form B was obtained, and the yield was about 98%.

Example 23 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

Take 30 mg of Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16, add 1 mL of water, stir at room temperature for 10 days, centrifuge, and dry to obtain Pimaserin 1-hydroxy-2- 2-Naphthoate monohydrate Form B.

Preparation of Example 24 to Example 31 Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

By replacing the solvent in Example 23 with the following solvent, Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B can also be obtained. Example Solvent 1 Solvent 2 Solvent consumption (mL) stirring temperature Example 24 Isopropanol / 0.5 room temperature Example 25 Isopropyl acetate / 1.0 room temperature Example 26 water ethanol 1.0/0.2 room temperature Example 27 water acetone 1.0/0.2 room temperature Example 28 water Tetrahydrofuran 1.0/0.2 room temperature Example 29 water n-propanol 1.0/0.4 60°C Example 30 water Acetonitrile 1.0/0.4 60°C Example 31 water N,N-Dimethylformamide 1.0/0.2 60°C

Example 32 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

Take 30 mg of Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16, add 1 mL of methanol, stir at room temperature to dissolve, quickly add 4 mL of water, stir and crystallize for 24 hours, centrifuge , and dried to obtain Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.

Example 33 to Example 43 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

By replacing the solvent in Example 32 with the following solvent, Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B can also be obtained. Example Solvent 1 Solvent 2 Solvent consumption (mL) Example 33 butanone water 1.0/4.0 Example 34 ethanol water 2.0/7.0 Example 35 N,N-Dimethylformamide water 1.0/4.0 Example 36 acetone water 1.0/4.0 Example 37 Tetrahydrofuran water 1.0/4.0 Example 38 Acetonitrile water 2.0/7.0 Example 39 Dimethyridine water 1.0/4.0 Example 40 butanone isopropyl ether 0.5/4.0 Example 41 Tetrahydrofuran n-Hexane 0.5/4.0 Example 42 Tetrahydrofuran n-heptane 0.5/4.0 Example 43 butanone n-heptane 0.5/4.0

Example 44 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

Take 30 mg of Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16, add 1 mL of water and 1 mL of ethanol, stir at 60 °C to dissolve, keep warm for about 2 minutes, and then directly place in the room Warm stirring for 24 hours, centrifugation, and drying to obtain Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.

Example 45 and Example 46 Preparation of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B

Replacing the solvent in Example 44 with the following solvents can also obtain Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B. Example Solvent 1 Solvent 2 Solvent consumption (mL) Example 45 water Isopropanol 1.0/0.6 Example 46 water Methanol 1.0/ 1.2

Preparation of Comparative Example 1 Pimaserin Hemitartrate Crystal Form C

Pimaserin hemitartrate crystalline form C was prepared according to the method of Example 1 in patent document CN105924381A (also refer to Example 1 in patent document CN106008323A).

Its XRPD pattern is shown in FIG. 15 , and its DSC pattern is shown in FIG. 16 .

Embodiment 47 solubility comparison

Take respectively the pimaserin free base, the pimaserin semi-pamolate crystal form A prepared in Example 2, the pimaserin 1-hydroxyl-2-naphthoate crystalline form A prepared in Example 13, The pipemaserin 1-hydroxyl-2-naphthoate monohydrate crystal form B prepared in Example 22 and the pipemaserin hemitartrate crystal form C prepared in Comparative Example 1 were added to pure water, pH3. 0 acetate buffer solution, pH5.0 acetate buffer solution, pH7.0 phosphate buffer solution, pH9.0 phosphate buffer solution to make it a saturated solution, shake at 37 °C for 24 hours, and use a 0.45 μm micropore Membrane filtration, the filtrate was collected, and the solubility was determined by high performance liquid chromatography. The test results are shown in Table 1. Due to the high solubility of pimaserin hemitartrate crystal form C, HPLC detection was not carried out, and its solubility was calculated according to the amount of sample weighed and the amount of medium added. Table 1 Solubility Test Results medium Solubility (μg/mL) Hemipamolate Form A 1-Hydroxy-2-naphthoate Form A 1-Hydroxy-2-naphthoate Form B Hemitartrate Form C Pimaserin pH 3.0 135.60 61.05 55.15 >532000 15117.79 pH 5.0 16.83 49.38 43.54 >528000 3696.12 pH7.0 21.72 54.86 48.08 >454000 269.64 pH 9.0 23.85 19.09 13.61 >420000 10.20 water 8.28 44.07 9.19 >412000 32.20

As can be seen from Table 1, the prepared pimaserin semi-pamolate crystal form A, pimaserin 1-hydroxyl-2-naphthoate crystalline form A and pimaserin 1-hydroxyl-2 -Naphthoate monohydrate crystal form B has lower solubility than pimaserin under both acidic and neutral conditions, and the lower the pH, the greater the difference. The above results show that compared to the pipemaserin free base and the pipemaserin hemi-tartrate crystal form C, the pipemaserin hemi-pamoate crystal form A and the pipemaserin 1-hydroxyl-2-naphthyridine of the present invention Salt crystal form A and pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B are more suitable for the research and development of sustained-release preparations.

Embodiment 48 stability comparison

Take respectively the pimaserin free base, the pimaserin semi-pamolate crystal form A prepared in Example 2, the pimaserin 1-hydroxyl-2-naphthoate crystalline form A prepared in Example 13, Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B prepared in Example 22 and pipemaserin hemitartrate crystal form C prepared in Comparative Example 1 at high temperature (60°C) and high humidity (25 ℃/90% RH), conventional (ambient temperature and humidity), accelerated (40 ℃/75% RH) and long-term (20 ℃/60% RH) conditions, sampling at 0 days, 5 days and 10 days Carry out HPLC detection, the result is shown in Table 2.

As can be seen from Table 2, the pimaserin semi-pamolate crystal form A, the pimaserin 1-hydroxyl-2-naphthoate crystalline form A and the pimaserin 1-hydroxyl-2-naphthoate of the present invention Form B of formate monohydrate is relatively stable under various conditions and is suitable for the development of pharmaceutical preparations. Table 2 Stability test results sample condition time (days) Total miscellaneous (%) Pimaserin free base starting sample 0 0.06 conventional 5 0.07 10 0.05 high temperature 5 0.07 10 0.07 high humidity 5 0.05 10 0.07 accelerate 5 0.07 10 0.08 long 5 0.07 10 0.02 Hemitartrate Form C starting sample 0 0.12 conventional 5 0.09 10 0.10 high temperature 5 0.10 10 0.11 high humidity 5 0.09 10 0.08 accelerate 5 0.12 10 0.12 long 5 0.09 10 0.10 Hemipamolate Form A starting sample 0 0.88 conventional 5 1.07 10 1.18 high temperature 5 0.98 10 0.95 high humidity 5 1.22 10 1.34 accelerate 5 1.38 10 1.50 long 5 0.98 10 0.86 1-Hydroxy-2-naphthoate Form A starting sample 0 0.08 conventional 5 0.09 10 0.14 high temperature 5 0.09 10 0.08 high humidity 5 0.09 10 0.07 accelerate 5 0.08 10 0.08 long 5 0.09 10 0.10 1-Hydroxy-2-naphthoate Form B starting sample 0 not detected conventional 5 not detected 10 not detected high temperature 5 not detected 10 not detected high humidity 5 not detected 10 not detected accelerate 5 not detected 10 not detected long 5 not detected 10 not detected

Example 49 to Example 51 Preparation of pimaserin hemipamolate crystal form A components Dosage (mg) Example 49 Example 50 Example 51 Hemipamolate Form A 1236.7 618.3 1236.7 Tween 20 100 25 10 Disodium phosphate 45 45 45 Sodium dihydrogen phosphate 9 9 9 Water for Injection qs10.0 mL

Preparation process: (1) Weigh the prescription amount of Tween 20, disodium hydrogen phosphate, sodium dihydrogen phosphate and about 60% (volume fraction) of the total preparation water for injection, stir to dissolve and disperse; (2) Add the prescription amount pimaserin hemipamolate crystal form A to obtain an aqueous suspension of coarse particles; (3) use a ball mill to grind and disperse the aqueous suspension of coarse particles obtained above; (4) dilute to 10 mL with water for injection, The pimaserin hemi-pamolate crystal form A suspension was obtained; (5) The micronity distribution of the samples of the examples after grinding was measured with an OMEC LS-909 micronity tester, and the results are shown in the following table: Example Dv10 (µm) Dv50 (µm) Dv90 (µm) Example 49 1.357 6.219 14.334 Example 50 0.898 3.294 8.917 Example 51 0.848 3.292 8.945 (6) Take the prescription samples obtained in Examples 49 to 51 , conduct needle penetration and sedimentation ratio investigation, and find that the needle penetration and sedimentation ratio of the above samples are good.

Example 52 and Example 53 Preparation of pimaserin hemipamolate crystal form A components Dosage (mg) Example 52 Example 53 Hemipamolate Form A 2443 2444 Tween 20 40 0 Poloxamer 188 0 20 Disodium phosphate 90 90 Sodium dihydrogen phosphate 18 18 Water for Injection Qs20.0 mL

Preparation Process: (1) Weigh the prescription amount of Tween 20, poloxamer, 188 disodium hydrogen phosphate, sodium dihydrogen phosphate and about 60% (volume fraction) of the total amount of water for injection prepared, stir to dissolve and disperse; (2) Add the pimaserin hemi-pamolate crystal form A passing through a 300-mesh sieve in the prescribed amount, fully wet and disperse; (3) Dilute to 10 mL with water for injection, and shake well to obtain the pimaserin hemipamolate crystal form A suspension; (4) Take the prescription samples obtained in Examples 52 and 53, conduct needle penetration and sedimentation ratio investigation, and find that the needle penetration and sedimentation ratio of the above samples are good.

Example 54 and Example 55 Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B preparation components Dosage (mg) Example 54 Example 55 1-Hydroxy-2-naphthoate Form B 2490 2490 Tween 20 40 0 Poloxamer 188 0 20 Disodium phosphate 90 90 Sodium dihydrogen phosphate 18 18 Water for Injection Qs20.0 mL

Preparation Process: (1) Weigh the prescription amount of Tween 20, Poloxamer 188, disodium hydrogen phosphate, sodium dihydrogen phosphate and about 60% (volume fraction) of the total amount of water for injection prepared, stir to dissolve and disperse; (2) Add the Pimaserin 1-hydroxyl-2-naphthoate monohydrate crystal form B passing through a 300-mesh sieve in the prescribed amount, fully wet and disperse; (3) Dilute the volume to 10 mL with water for injection, shake well, and obtain the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B suspension; (4) The prescription samples obtained in Examples 54 and 55 were taken, and the needle penetration and sedimentation ratio were investigated, and it was found that the needle penetration and sedimentation ratio of the above samples were good.

Embodiment 56 Prescription Stability Investigation

Get the pimaserin hemipamoate prescription prepared in Example 53 and the 1-hydroxyl-2-naphthoate prescription sample prepared in Example 55 and place them in high temperature (60°C) respectively, accelerate (40°C/75% RH), light (25 ℃/5000 Lux) and long-term (20 ℃/60% RH) conditions, samples were taken at 0 days, 5 days and 10 days for HPLC detection.

The results are shown in the table below. The results show that the prescription sample of pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is relatively stable under various conditions, and the pimaserin hemipamolate crystal form A The prescription samples are stable under long-term light conditions except for a slight degradation. Prescription Stability Test Results prescription sample condition time (days) Total miscellaneous (%) Hemipamoate Form A Prescription starting sample 0 0.45 high temperature 5 0.40 10 0.39 illumination 5 0.81 10 1.46 accelerate 5 0.38 10 0.36 long 5 0.42 10 0.39 1-Hydroxy-2-naphthoate Form B Prescription starting sample 0 not detected high temperature 5 not detected 10 not detected illumination 5 not detected 10 not detected accelerate 5 not detected 10 not detected long 5 not detected 10 not detected

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

none

[Fig. 1] is the XRPD pattern of the free base of pimaserin. [ Fig. 2 ] is the DSC spectrum of the free base of pimaserin. [ Fig. 3 ] is the TGA spectrum of the free base of pimaserin. [ FIG. 4 ] is the DSC spectrum of pimaserin hemipamolate salt crystal form A obtained in Example 2. [ FIG. 5 ] is the TGA spectrum of pimaserin hemipamolate salt crystal form A obtained in Example 2. [ Fig. 6 ] is the XRPD spectrum of the pimaserin hemipamolate salt crystal form A obtained in Example 2. [ FIG. 7 ] is the XRPD pattern of pimaserin hemipamolate salt crystal form A obtained in Example 7. [ FIG. 8 ] is the XRPD pattern of pimaserin hemipamolate salt crystal form B obtained in Example 8. [ FIG. 9 ] is the DSC spectrum of Pimaserin 1-hydroxy-2 naphthoate crystal form A obtained in Example 13. [ FIG. 10 ] is the TGA spectrum of Pimaserin 1-hydroxy-2-naphthoate crystal form A obtained in Example 13. [ FIG. 11 ] is the XRPD pattern of Pimaserin 1-hydroxy-2-naphthoate crystal form A obtained in Example 13. [ FIG. 12 ] is the DSC spectrum of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B obtained in Example 18. [ FIG. 13 ] is the TGA spectrum of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B obtained in Example 18. [ FIG. 14 ] is the XRPD spectrum of Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B obtained in Example 18. [ FIG. 15 ] is the XRPD pattern of Pimaserin hemitartrate crystal form C obtained in Comparative Example 1. [ FIG. 16 ] is the DSC spectrum of Pimaserin hemitartrate crystal form C obtained in Comparative Example 1.

Claims (10)

A kind of Pimaserin medicinal salt, it is the salt that Pimaserin free base and organic acid more than six carbons form; The structure of Pimaserin free base is as shown in formula I:

I Preferably, the "organic acid with more than six carbons" is a C ₆ -C ₃₀ organic acid; the "C ₆ -C ₃₀ organic acid" is preferably hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid , capric acid, sebacic acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosane Acid, oleic acid, behenic acid, behenic acid, tricosanoic acid, lignoceric acid, pentadecanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid One or more of alkanoic acid, nonacosanoic acid, triacosanoic acid, glycerol triacetic acid, ligninic acid, pamoic acid, 1-hydroxy-2 naphthoic acid, pamoic acid and naphthoic acid derivatives; also preferably Preferably, the pharmaceutically acceptable salt of pipemaserin is pipemaserin hemipamoate or pipemaserin 1-hydroxy-2-naphthoate. The medicinal salt of pimaserin as described in claim 1, wherein the pimaserin hemi-pamoic acid salt is a salt formed by compounding pimaserin and pamoic acid at a molar ratio of 1:0.5; Preferably, the pimaserin hemi-pamoic acid salt is pimaserin hemi-pamoic acid salt crystal form A, pimaserin hemi-pamoic acid crystalline form B or an amorphous form; Preferably, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form A has diffraction peaks at 2θ values of 3.3º±0.2º, 6.7º±0.2º and 7.5º±0.2º; Preferably, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form A has a 2θ value of 3.3º±0.2º, 6.7º±0.2º, 7.5º±0.2º, 12.2º±0.2º , 13.7º±0.2º, 17.0º±0.2º, 19.5º±0.2º, 20.4º±0.2º and 21.1º±0.2º have diffraction peaks; Also preferably, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form A is basically as shown in Figure 6; Preferably, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form B has diffraction peaks at 2θ values of 6.1º±0.2º, 8.6º±0.2º and 19.9º±0.2º; Preferably, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystal form B has a 2θ value of 6.1º±0.2º, 8.6º±0.2º, 9.6º±0.2º, 13.0º±0.2º , 13.3º±0.2º, 15.6º±0.2º, 17.0º±0.2º, 17.3º±0.2º, 17.9º±0.2º, 18.9º±0.2º, 19.1º±0.2º, 19.9º±0.2º, 20.2º There are absorption peaks at º±0.2º and 20.7º±0.2º; Also preferably, the X-ray powder diffraction pattern of the pimaserin hemipamolate crystalline form B is basically as shown in FIG. 8 . The medicinal salt of pipemaserin as described in claim 1, wherein the pipemaserin 1-hydroxy-2-naphthoic acid salt is pipemaserin and 1-hydroxy-2-naphthoic acid in a molar ratio of 1 : 1 compounded salt, which can be Pimaserin 1-hydroxyl-2-naphthoate crystal form A or Pimaserin 1-hydroxyl-2-naphthoate monohydrate crystal form B; Preferably, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A is at 2θ values of 4.3º±0.2º, 13.2º±0.2º and 18.6º±0.2º There are diffraction peaks; Preferably, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A has a 2θ value of 4.3º±0.2º, 7.7º±0.2º, 8.8º±0.2º, 11.4º±0.2º, 13.2º±0.2º, 15.1º±0.2º, 17.0º±0.2º, 17.7º±0.2º, 18.6º±0.2º, 19.0º±0.2º, 20.2º±0.2º, 20.6º There are absorption peaks at ±0.2º, 21.3º±0.2º, 21.6º±0.2º, 22.7º±0.2º and 25.8º±0.2º; More preferably, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate crystal form A is basically as shown in Figure 11; Preferably, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B has 2θ values of 3.8º±0.2º, 7.8º±0.2º and 14.2º± There is a diffraction peak at 0.2º; Preferably, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B has 2θ values of 3.8º±0.2º, 7.8º±0.2º, 11.7º± 0.2º, 14.2º±0.2º, 15.7º±0.2º, 17.7º±0.2º, 21.3º±0.2º, 22.4º±0.2º, 23.0º±0.2º, 25.3º±0.2º and 26.8º±0.2º There is an absorption peak; More preferably, the X-ray powder diffraction pattern of the pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is basically as shown in FIG. 14 . A method for preparing the pharmaceutically acceptable salt of pipemaserin as described in any one of claims 1 to 3, comprising the following steps: reacting the free base of pipemaserin with the organic acid having more than six carbons; Preferably, the preparation method of the pharmaceutically acceptable salt of pimaserin is carried out in a solvent selected from water, methanol, ethyl acetate, tetrahydrofuran, isopropanol, dichloromethane, N,N-dimethylformyl One, two or more of amine, acetone, methyl tert-butyl ether and isopropyl ether solvents. The preparation method as described in claim 4, wherein: The preparation method of the pimaserin semi-pamolate crystal form A is selected from one of the following methods: Method (a1): forming a solution of pimaserin in a good solvent, adding pamoic acid, stirring the reaction, adding a poor solvent and stirring to crystallize; or, Method (a2): taking pimaserin and pamoic acid, adding a good solvent to stir the reaction, filtering, adding a poor solvent to the filtrate, stirring and crystallizing; or, Method (a3): Take pimaserin and pamoic acid and add a good solvent to stir the reaction, filter, add the filtrate to a poor solvent, optionally, add pimaserin semi-pamoic acid salt crystal form to the poor solvent The seed crystal of A, stirred and crystallized; Wherein, in methods (a1), (a2) and (a3), the good solvent is alcohol solvent (such as methanol), ketone solvent (such as acetone), ester solvent (such as ethyl acetate), acetonitrile, dichloro One or two or more of methane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide and N,N-dimethylacetamide; the poor solvent is One, two or more of alkane solvents, ether solvents (such as isopropyl ether or methyl tert-butyl ether) and water; The preparation method of the pimaserin semi-pamoic acid salt crystal form B comprises the following steps: dispersing the pamoic acid with a solvent to obtain a suspension, dissolving the pimaserin with a solvent to obtain a free base solution, and adding the free base solution dropwise Stir the reaction into the suspension; optionally, add the pimaserin hemipamolate crystal form A as a crystal seed during the stirring reaction; The preparation method of the amorphous pimaserin hemi-pamolate comprises the following steps: dissolving the pimaserin hemi-pamolate in a solvent, volatilizing until the solvent is dry, and obtaining the amorphous pimaserin hemi-pamolate ; Preferably, in the amorphous preparation method, the solvent is an alcohol solvent (such as methanol), a ketone solvent (such as acetone), an ester solvent, an ether solvent (such as tetrahydrofuran, 2-methyltetrahydrofuran), an alkane Solvent, acetonitrile, dichloromethane, chloroform, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and water, two or more. The preparation method as described in claim 4, wherein: The preparation method of the pimaserin 1-hydroxyl-2-naphthoate crystal form A is selected from one of the following methods: Method (b1): separately form solutions of pipemaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise into the alkali solution under stirring, stir for reaction, add a poor solvent, and stir for crystallization; Wherein, the good solvent is selected from one, two or three of N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfide, preferably N,N-dimethyl Formamide; The poor solvent is selected from one, two or three of alkane solvents, ether solvents and water; or, Method (b2): Pimaserin and 1-hydroxy-2-naphthoic acid are respectively formed into a solution in a good solvent, and the acid solution is added dropwise to the alkali solution under stirring, and the crystallization is carried out while stirring; Wherein, the good solvent is an alcohol solvent and/or an ester solvent, the alcohol solvent is preferably isopropanol; the ester solvent is preferably ethyl acetate; The preparation method of the pimaserin 1-hydroxyl-2-naphthoate monohydrate crystal form B is selected from one of the following methods: (c1) respectively dissolving pipemaserin and 1-hydroxy-2-naphthoic acid in a good solvent to form a solution, adding the acid solution dropwise to the alkali solution under stirring, stirring for reaction, adding a poor solvent, and stirring for crystallization; Wherein, the good solvent is a ketone solvent, preferably acetone; the poor solvent is one of alkane solvent, ether solvent and water, two or three, preferably water; or, (c2) dissolving pimaserin 1-hydroxy-2-naphthoic acid crystal form A in a solvent to form a solution, and volatilizing until the solvent is dry; Wherein, the solvent is one, two or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, alkane solvents, dichloromethane, chloroform, dimethylsulfoxide and water; the alcohols The solvent is preferably methanol; the ester solvent is preferably ethyl acetate; the ether solvent is preferably tetrahydrofuran; or, (c3) dissolving pimaserin 1-hydroxy-2-naphthoic acid crystal form A in a solvent to form a suspension, stirring and crystallizing; Wherein, the solvent is selected from water or a mixed solvent composed of water and an organic solvent; the organic solvent is selected from one of alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents and amide solvents, Two or more; the alcohol solvent is preferably one of methanol, ethanol, n-propanol and Virahol, two or more; the ester solvent is preferably ethyl acetate, isopropyl acetate; the ketones The solvent is preferably acetone; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran; the amide solvent is preferably N,N-dimethylformamide; or, (c4) Dissolving pimaserin 1-hydroxy-2-naphthoic acid crystal form A in a good solvent to form a solution, adding an antisolvent, stirring and crystallizing; Wherein, the good solvent is alcohol solvent, ketone solvent, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, 1,4 - one, two or more of dioxane, dichloromethane and chloroform; the poor solvent is one, two or three of alkane solvents, ether solvents and water; or, (c5) Dissolving Pimaserin 1-hydroxy-2-naphthoic acid crystal form A in a solvent at high temperature to form a solution, stirring and crystallizing at room temperature; Wherein, the solvent is selected from the group consisting of alcohol solvents, ketone solvents, ether solvents, ester solvents, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, dimethylsulfoxide and water One, two or more. Application of a pharmaceutically acceptable salt of pimaserin as described in any one of Claims 1 to 3 in the preparation of a drug for preventing, treating or improving the frequency and/or severity of hallucinations and delusions associated with Parkinson's psychosis . A pharmaceutical composition comprising the pharmaceutically acceptable salt of pimaserin as described in any one of claims 1 to 3; Preferably, the pharmaceutical composition also includes pharmaceutically acceptable excipients; Preferably, the pharmaceutically acceptable adjuvant includes one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients. A pharmaceutical preparation of pimaserin, comprising the pharmaceutically acceptable salt of pimaserin as described in any one of claims 1 to 3 or the pharmaceutical composition as described in claim 8; Preferably, the dosage form of the pimaserin pharmaceutical preparation is selected from tablets, capsules, solutions, suspensions and semi-solid preparations; Preferably, the suspension also includes auxiliary materials, which can be selected from one, two or more of suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and surfactants. A preparation method of the suspension as claimed in item 9, wherein said preparation method comprises the following steps: (d1) dissolving the wetting agent and the buffering agent in the solvent; (d2) adding the pharmaceutically acceptable salt of pimaserin to obtain an aqueous suspension of coarse particles; (d3) Grinding the aqueous suspension solution of the above-mentioned coarse particles using a ball mill to obtain a suspension; or, The preparation method comprises the following steps: (e1) sieving the solid particles of the pimaserin medicinal salt; (e2) dissolving the wetting agent and the buffering agent in the solvent; (e3) Add the solution prepared in step (e2) to the sieved solid particles of pimaserin medicinal salt, fully wet and disperse; (e4) Dilute to the target volume with a solvent to obtain a suspension.

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