CN113121559B

CN113121559B - High bulk density clopidogrel hydrogen sulfate spherical crystal and preparation method thereof

Info

Publication number: CN113121559B
Application number: CN201911424628.3A
Authority: CN
Inventors: 谭端明; 何晶晶; 孙宝金; 冯国建
Original assignee: Shenzhen Salubris Pharmaceuticals Co Ltd; Huizhou Salubris Pharmaceuticals Co Ltd
Current assignee: Shenzhen Salubris Pharmaceuticals Co Ltd; Huizhou Salubris Pharmaceuticals Co Ltd
Priority date: 2019-12-31
Filing date: 2019-12-31
Publication date: 2023-08-29
Anticipated expiration: 2039-12-31
Also published as: CN113121559A

Abstract

The invention provides a preparation method of a clopidogrel hydrogen sulfate crystal form II containing spheres, which comprises the steps of reacting clopidogrel hydrogen sulfate with equimolar sulfuric acid in a mixed solvent of dichloromethane and n-heptane in the presence of clopidogrel hydrogen sulfate crystal form II seed crystal to obtain spheres of clopidogrel hydrogen sulfate crystal form II with high bulk density. The powder property is favorable for realizing the powder direct compression process of the tablet, and the sticking phenomenon is avoided in the tabletting process. The invention also provides a clopidogrel bisulfate tablet directly pressed by powder and a preparation method thereof, and the tablet meets the requirements of clinical medication.

Description

High bulk density clopidogrel hydrogen sulfate spherical crystal and preparation method thereof

Technical Field

The invention belongs to the field of medicine synthesis, and in particular relates to a clopidogrel hydrogen sulfate type II spherical crystal with high bulk density and a preparation method thereof.

Background

Clopidogrel bisulfate (CAS: 135046-48-9), an antiplatelet aggregating agent, english name Clopidogrel Hydrogen Sulfate, chemical name: methyl(s) - α - (2-chlorophenyl) -6, 7-dihydrothieno [3,2-c ] pyridine-5 (4H) acetate bisulfate. It is a salt consisting of clopidogrel base (CAS: 113665-84-2) and sulfuric acid in a 1:1 molar ratio.

The main crystal forms of clopidogrel bisulfate are two types, namely a type I crystal form and a type II crystal form, wherein the type II is a thermodynamically stable crystal form, and the type I is a thermodynamically metastable crystal form.

The prior art CN201510432264.9 obtained spherical crystals of form I, but the corresponding method applied to the preparation of form II could not meet the requirements of specific tablet formulation and powder direct compression process (example 5 of this patent), and is specifically characterized by low bulk density (tap density about 0.72-0.75 g/ml), resulting in sticking and punching phenomenon during tabletting.

Other prior art for preparing the crystal form II, such as Chinese patent CN201810841998.6 and CN201811344033.2, and the like, the obtained product also has sticking and punching phenomena in the tabletting process of the specific tablet formula and process, which is not beneficial to industrialized application. Therefore, the realization of clopidogrel bisulfate crystal form II powder direct compression tablets is still an unsolved technical problem of the prior art.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a method for preparing spherical clopidogrel hydrogen sulfate II crystal forms.

The invention is realized by the following technical scheme, and the method for preparing the spherical clopidogrel bisulfate II crystal form comprises the step of reacting clopidogrel bisulfate with equimolar sulfuric acid in a mixed solvent of dichloromethane and n-heptane in the presence of clopidogrel bisulfate II crystal seeds.

As a preferable technical scheme of the invention, in the mixed solvent, the volume ratio of the n-heptane is 0.25-0.5 of the dichloromethane.

As a preferable technical scheme of the invention, the method comprises the following steps: (1) Clopidogrel base and sulfuric acid react in methylene dichloride in a molar ratio of 2:1 to form clopidogrel sulfate solution. (2) Adding a mixture of clopidogrel bisulfate powder dispersed in n-heptane, and (3) dropwise adding sulfuric acid with the same mole as clopidogrel bisulfate to precipitate crystals.

The invention further provides a spherical clopidogrel bisulfate II crystal form, which is prepared by the preparation method, and the tap density of the crystal form is not less than 0.83g/ml.

As a preferred embodiment of the present invention, the tap density is preferably between 0.83 and 0.90 g/ml.

The invention further provides a clopidogrel bisulfate direct compression tablet which is prepared by using the spherical clopidogrel bisulfate II crystal form.

As a preferred technical scheme of the invention, the clopidogrel bisulfate direct compression type tablet is characterized in that the method comprises the following steps:

1) Uniformly mixing the spherical clopidogrel hydrogen sulfate II crystal form raw material medicine with auxiliary materials such as filling agents, disintegrating agents, lubricants and the like in a prescription amount;

2) Tabletting the mixed powder obtained in the step 1) to obtain a plain tablet, wherein the hardness of the tablet in the step 2) is controlled to be 5-9 kgf.

Compared with the prior art, the invention has the following advantages and beneficial effects:

the invention provides a preparation method of a crystal form II containing spherical clopidogrel bisulfate, the property of the obtained powder is favorable for realizing a powder direct compression process, the phenomenon of sticking and punching is avoided in the tabletting process, and the obtained solid oral preparation meets the clinical medication requirement and is favorable for industrialized production and preparation.

Drawings

FIG. 1 shows a PXRD spectrum of clopidogrel bisulfate obtained in example 1;

FIG. 2 is a photomicrograph of clopidogrel bisulfate obtained in example 1;

FIG. 3 is a photomicrograph of clopidogrel bisulfate obtained in example 3;

FIG. 4 is a photomicrograph of clopidogrel bisulfate obtained in example 4.

Detailed Description

The present invention will be described in further detail with reference to examples and drawings, but embodiments of the invention are not limited thereto.

Example 1.

Clopidogrel base 483 g (1.5 mol) was dissolved in 3L of dichloromethane, cooled to 5-10 ℃, and 73.5 g (0.75 mol) of sulfuric acid was added with stirring to form a clopidogrel sulfate solution. Heating to 25-28 ℃, adding 10 g of clopidogrel hydrogen sulfate powder II into 1.5L of mixture suspended and dispersed in n-heptane, and slowly dripping 73.5 g (0.75 mol) of sulfuric acid for 1-2 hours. Stirring was continued for 1 hour, and then cooled to about 0 ℃. After 4 hours, suction filtration was carried out and the filter cake was washed with an appropriate amount of methylene chloride-n-heptane mixture (1:1, v/v). Vacuum drying at 40 ℃ gives about 550 g of white spherulites with a yield of 87%. XRD powder diffraction test results showed clopidogrel bisulfate form II as shown in fig. 1; a microscopic photograph of clopidogrel bisulfate is shown in fig. 2.

Examples 2 to 4. Referring to example 1, the amount of n-heptane was changed to obtain clopidogrel bisulfate of form II, the specific results are shown in table 1, and the microscopic photographs of clopidogrel bisulfate of form II obtained in examples 3 and 4 are shown in fig. 3 and 4, respectively.

Example 5. Reference example 1, n-heptane was changed to cyclohexane. Clopidogrel bisulfate form II was obtained, and specific results are shown in table 1.

Example 6. Clopidogrel base 483 g (1.5 mol) was dissolved in 3L of methylene chloride, the temperature was controlled at 25-28 ℃, 10 g of clopidogrel hydrogen sulfate powder II was added to a mixture suspended and dispersed in 1.5L of n-heptane, and 147 g (1.5 mol) of sulfuric acid was slowly added dropwise over a period of about 2 hours. Stirring was continued for 1 hour, and then cooled to about 0 ℃. After 4 hours, suction filtration was carried out and the filter cake was washed with an appropriate amount of methylene chloride-n-heptane mixture (1:1, v/v). Vacuum drying at 40 ℃ gives about 540 g of white spherulites with 86% yield. And obtaining clopidogrel bisulfate of the II type.

Comparative example 1

Clopidogrel bisulfate type II spherulites were prepared with reference to example 1 of the chinese patent application No. 201810841998.6.

Comparative example 2

Clopidogrel bisulfate type II spherulites were prepared with reference to example 3 of the chinese patent application No. 201811344033.2.

Example 7. The samples prepared by the above example methods were used respectively, and powder direct compression tablets were prepared by referring to the solid preparation formulation and process in example 5 of the chinese patent application No. 201510432264.9, and the severity of sticking phenomenon was judged according to the smoothness of the tablet surface.

Table 1.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. Use of spherical clopidogrel hydrogen sulfate form II for a direct compression tablet, characterized in that the method for preparing the direct compression tablet comprises the steps of:

1) Uniformly mixing spherical clopidogrel hydrogen sulfate II crystal form bulk drug with auxiliary materials selected from filling agents, disintegrating agents and lubricating agents in prescription amount;

2) Tabletting the mixed powder obtained in the step 1) to obtain a plain tablet, wherein the hardness of the tablet in the step 2) is controlled to be 5-9 kgf;

the preparation method of the spherical clopidogrel bisulfate II crystal form comprises the following steps: (1) Clopidogrel base reacts with sulfuric acid in methylene dichloride according to a molar ratio of 2:1 to form clopidogrel sulfate solution; (2) Adding a mixture of clopidogrel bisulfate powder II dispersed in n-heptane, (3) dropwise adding sulfuric acid with the same mole as clopidogrel bisulfate to precipitate crystals;

the volume ratio of the n-heptane is 0.25-0.5 of the dichloromethane;

the tap density of the spherical clopidogrel bisulfate II crystal form is between 0.83 and 0.90 g/ml.