CN113121559A

CN113121559A - II-type clopidogrel hydrogen sulfate spherical crystal with high bulk density and preparation method thereof

Info

Publication number: CN113121559A
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: 2021-07-16
Anticipated expiration: 2039-12-31
Also published as: CN113121559B

Abstract

The invention provides a preparation method of a crystal form II containing spherical clopidogrel bisulfate, which 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 crystal seeds to obtain spherical crystals of the clopidogrel bisulfate crystal form II with high bulk density. The powder property of the tablet is beneficial to realizing the powder direct compression process of the tablet, and the sticking and punching phenomenon is not generated in the tabletting process. The invention also provides a clopidogrel hydrogen sulfate tablet directly pressed by powder and a preparation method thereof, and the tablet meets the requirement of clinical medication.

Description

II-type clopidogrel hydrogen sulfate spherical crystal with high bulk density and preparation method thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to II-type clopidogrel bisulfate spherical crystals with high bulk density and a preparation method thereof.

Background

Clopidogrel bisulfate (CAS:135046-48-9), an anti-platelet aggregation agent, is called Clopidogrel hydrogene Sulfate in English under the chemical name: (s) - α - (2-chlorophenyl) -6, 7-dihydrothieno [3,2-c ] pyridine-5 (4H) acetic acid methyl ester hydrogensulfate. It is a salt composed of clopidogrel base (CAS:113665-84-2) and sulfuric acid in a 1:1 molar ratio.

The main crystal forms of clopidogrel hydrogen sulfate include a I type and a II type, wherein the II type is a thermodynamically stable crystal form, and the I type is a thermodynamically metastable crystal form.

In the prior art, CN201510432264.9 obtains a spherical crystal of a crystal form I, but when the corresponding method is applied to the preparation of the crystal form II, the requirement of a specific tablet formula and a powder direct compression process (patent example 5) cannot be met, and the phenomenon that the bulk density is low (the tap density is about 0.72-0.75g/ml), so that the sticking phenomenon occurs during tabletting is specifically shown.

Other prior art for preparing crystal form II, such as chinese patents CN201810841998.6 and CN201811344033.2, etc., the obtained product also shows sticking phenomenon in the tabletting process of the above specific tablet formulation and process, which is not favorable for industrial application. Therefore, the direct compression tableting of the clopidogrel hydrogen sulfate crystal form II powder is still an unsolved technical problem in the prior art.

Disclosure of Invention

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

The invention is realized by the following technical scheme that the method for preparing the spherical clopidogrel hydrogen sulfate II crystal form comprises the step 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 II crystal seeds.

In a preferred embodiment of the present invention, the volume ratio of n-heptane in the mixed solvent is 0.25-0.5 of dichloromethane.

As a preferred technical scheme of the invention, the method comprises the following steps: (1) clopidogrel base and sulfuric acid react in dichloromethane at a molar ratio of 2:1 to form a clopidogrel sulfate solution. (2) Adding a mixture of II-type clopidogrel bisulfate powder dispersed in n-heptane, and (3) dropwise adding sulfuric acid with the same mole as that of clopidogrel bisulfate to separate out crystals.

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

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

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

As a preferable technical scheme, the method for directly compressing the clopidogrel hydrogen sulfate tablets is characterized by comprising the following steps of:

1) uniformly mixing the spherical clopidogrel hydrogen sulfate II crystal form raw material medicine with auxiliary materials such as a filling agent, a disintegrating agent, a lubricating agent and the like in a prescribed 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 hydrogen sulfate, the properties of the obtained powder are favorable for realizing a powder direct compression process, no sticking phenomenon exists in the tabletting process, and the obtained solid oral preparation meets the clinical medication requirements and is favorable for industrial production and preparation.

Drawings

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

FIG. 2 photomicrograph of clopidogrel hydrogen sulfate obtained in example 1;

FIG. 3 photomicrograph of clopidogrel hydrogen sulfate obtained in example 3;

FIG. 4 photomicrograph of clopidogrel hydrogen sulfate obtained in example 4.

Detailed Description

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

Example 1.

Clopidogrel base 483 g (1.5mol) was dissolved in 3L of dichloromethane, cooled to 5-10 deg.C, and 73.5 g (0.75mol) of sulfuric acid was added with stirring to form a clopidogrel sulfate solution. The temperature is raised to 25 to 28 ℃, 10 g of clopidogrel hydrogen sulfate type II powder suspended and dispersed in 1.5L of n-heptane is firstly added, and then 73.5 g (0.75mol) of sulfuric acid is slowly dropped for 1 to 2 hours. Stirring is continued for 1 hour, and then the temperature is reduced to about 0 ℃. After 4 hours, the filter cake is filtered off with suction and washed with a suitable amount of dichloromethane-n-heptane mixture (1:1, v/v). Vacuum drying at 40 ℃ gave about 550 g of white spherulites in 87% yield. XRD powder diffraction test results show clopidogrel hydrogen sulfate form II, as shown in figure 1; the microscope photograph of clopidogrel hydrogen sulfate is shown in fig. 2.

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

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

Example 6. Clopidogrel base 483 g (1.5mol) was dissolved in 3L of dichloromethane, the temperature was controlled at 25-28 ℃ and 10 g of clopidogrel hydrogen sulfate form II powder suspended in 1.5L of n-heptane was added first, then 147 g (1.5mol) of sulfuric acid was slowly added dropwise over about 2 hours. Stirring is continued for 1 hour, and then the temperature is reduced to about 0 ℃. After 4 hours, the filter cake is filtered off with suction and washed with a suitable amount of dichloromethane-n-heptane mixture (1:1, v/v). Vacuum drying at 40 ℃ gave about 540 g of white spherulites in 86% yield. Obtaining the clopidogrel hydrogen sulfate II.

Comparative example 1

Refer to example 1 of the Chinese invention patent (application No. 201810841998.6) for preparing clopidogrel hydrogen sulfate II type spherulites.

Comparative example 2

Refer to example 3 of the Chinese invention patent (application No. 201811344033.2) for preparing clopidogrel hydrogen sulfate II type spherulites.

Example 7. The samples prepared by the above-mentioned methods of examples were subjected to direct powder tableting by referring to the solid formulation and process in example 5 of the chinese patent application No. 201510432264.9, and the severity of the sticking phenomenon was judged according to the smoothness of the tablet surface.

Table 1.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. A spherical clopidogrel hydrogen sulfate II crystal form is characterized in that the tap density is not less than 0.83 g/ml.

2. The spherical clopidogrel hydrogen sulfate crystalline form II as claimed in claim 1, characterized by a tap density between 0.83 and 0.90 g/ml.

3. A method for preparing spherical clopidogrel hydrogen sulfate II crystal form is characterized in that clopidogrel hydrogen sulfate reacts with equimolar sulfuric acid in a mixed solvent of dichloromethane and n-heptane in the presence of clopidogrel hydrogen sulfate II crystal seeds.

4. The process according to claim 3, wherein the volume ratio of n-heptane in said mixed solvent is 0.25 to 0.5 of methylene chloride.

5. A method according to claim 3, characterized by comprising the steps of: (1) clopidogrel base and sulfuric acid react in dichloromethane at a molar ratio of 2:1 to form a clopidogrel sulfate solution. (2) Adding a mixture of II-type clopidogrel bisulfate powder dispersed in n-heptane, and (3) dropwise adding sulfuric acid with the same mole as that of clopidogrel bisulfate to separate out crystals.

6. A spherical clopidogrel hydrogen sulfate crystal form II, which is prepared by the preparation method of any one of claims 3 to 5 and has a tap density of not less than 0.83 g/ml.

7. The crystalline form II spherical clopidogrel bisulfate of claim 6 characterized by a tap density between 0.83 and 0.90 g/ml.

8. A clopidogrel bisulfate tablet of a direct compression type, which is prepared by using the spherical clopidogrel bisulfate crystal form II as claimed in any one of claims 1, 2, 6 or 7.

9. A process for the preparation of clopidogrel hydrogen sulfate straight compression tablets of claim 8, comprising the steps of:

1) uniformly mixing the spherical clopidogrel hydrogen sulfate II crystal form raw material medicine as claimed in any one of claims 1, 2, 6 or 7 with auxiliary materials such as a filling agent, a disintegrating agent, a lubricant and the like in a prescribed amount;