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A kind of preparation method of clopidogrel bisulfate I crystal form spherical crystal

A technology of clopidogrel bisulfate and clopidogrel free base, which is applied in organic chemical methods, blood diseases, extracellular fluid diseases, etc., and can solve the problems of inconvenient solvent recycling, complicated process, long time and high temperature drying To achieve the effect of solvent recovery and recycling, simple solvent removal process, and easy solvent residue

Inactive Publication Date: 2016-08-24
SHENZHEN SALUBRIS PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the solvent system used in the process is a 2-butanol-cyclohexane system, wherein cyclohexane belongs to the second class of solvents listed in relevant laws and regulations (such as "Guidelines for the Study of Residual Solvents in Chemical Drugs", etc.), and belongs to the The solvents used in the drug preparation process need to be restricted. Correspondingly, the requirements for their residues are relatively strict; and mixed solvents also bring inconvenience to the recycling of solvents.
In addition, one of the key technical factors of this process is that the sulfuric acid-cyclohexane solution needs to be slowly added to the solvent system under cooling conditions, which makes the process complicated, and cyclohexane and sulfuric acid are not miscible. If the dispersion is not uniform, it may The color of the product will become darker due to the high local sulfuric acid concentration after adding the solvent system, which will affect the product quality; in addition, the process requires a long time, and the excessively long reaction time has the risk of crystal transformation on the one hand, and also on the other hand. Will reduce product bulk density
[0009] Patent WO2011083955 discloses a method for preparing spherulites of clopidogrel hydrogen sulfate, wherein in Example 5, the solvent system is 2-butanol-water system to prepare spherulites, but the solvent used in the process method has a higher boiling point of water, It takes a long time and high temperature to dry in the follow-up; in addition, the existence of water is not conducive to the formation of the target crystal form, and the yield of this process is only 53%, and the production process level is low

Method used

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  • A kind of preparation method of clopidogrel bisulfate I crystal form spherical crystal
  • A kind of preparation method of clopidogrel bisulfate I crystal form spherical crystal
  • A kind of preparation method of clopidogrel bisulfate I crystal form spherical crystal

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Acquisition of seeds

[0058] Clopidogrel hydrogen sulfate I crystal form (purity greater than 99.0%) is pulverized with an MX50-II type airflow mill, and the air pressure is 5 to 6 atm to obtain clopidogrel hydrogen sulfate seed crystal D50=7.3 μm, and its particle size distribution is as follows: figure 1 Shown (MalvernMastersizer 2000 particle size analyzer).

[0059] Seed crystals with a specific particle size distribution can be obtained through conventional pulverization process control means in the field, such as air flow pressure, pulverization time, sieving, and the like.

Embodiment 2

[0061] Take 760g of clopidogrel bisulfate (purity greater than 99.0%) and add it into 10L of dichloromethane, add 5L of water and solid sodium bicarbonate until the pH of the aqueous phase>7. Stand still for liquid separation, take the organic phase and wash with water (1L×2), and remove water with anhydrous magnesium sulfate until the solution is clear.

[0062] The organic phase was filtered and vacuum rotary evaporated until the quality did not change, the residue was dissolved in 10.5 L of 2-butanol, and the solution was kept at 20°C. 100 mL of concentrated sulfuric acid (98%, 181 g) was dispersed in 2.5 L of 2-butanol and added to the system within 60 minutes. The temperature was raised to 25° C., and 5.8 g (about 1% wt relative to clopidogrel free base) of the crystal form I obtained in Example 1 (D50=7.3 μm) was added under rapid stirring. Keep warm at 25°C for 2.5h, then cool down to 15°C and keep warm for 4h. Suction filtration, the filter cake was washed with ethyl...

Embodiment 3

[0065] Take 1000 g of clopidogrel camphorsulfonate (purity greater than 99.0%) and add it to 10 L of dichloromethane, add 5 L of water and solid sodium bicarbonate until the pH of the aqueous phase>7. Stand still for liquid separation, take the organic phase and wash with water (1L×2), and remove water with anhydrous magnesium sulfate until the solution is clear.

[0066] The organic phase was filtered and vacuum rotary evaporated until the mass did not change, the residue was dissolved in 9L of 2-butanol, and the solution was kept at 20°C. 100 mL of concentrated sulfuric acid (98%, 181 g) was dispersed in 3 L of 2-butanol and added to the system within 60 minutes. The temperature was raised to 25° C., and 17.4 g (about 3% wt relative to clopidogrel free base) of the crystal form I obtained in Example 1 (D50 = 7.3 μm) was added under rapid stirring. Keep warm at 25°C for 3h, then cool down to 15°C and keep warm for 4.5h. Suction filtration, the filter cake was washed with et...

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Abstract

The present invention solves the technical problem of it being difficult for a single solvent to prepare spherical crystals. The present invention uses a single solvent, 2-butanol, and by controlling the amount and the particle size of added clopidogrel bisulphate crystalline form I seed crystals, enables clopidogrel bisulphate to stably precipitate out from a solution system as spherical crystals having a specific powder morphological range, the resulting clopidogrel bisulphate spherical crystals having specific powder properties, being in an optimal state in terms of aspects such as solvent residue, bulk density and fluidity, and being beneficial for the implementation of a powder direct press preparation process. Also disclosed is a pharmaceutical composition containing the clopidogrel bisulphate crystalline form I spherical crystals prepared via the process of the present invention.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of clopidogrel bisulfate I crystal form spherical crystals. Background technique [0002] Clopidogrel hydrogen sulfate (CAS: 135046-48-9), is the sulfate salt of clopidogrel, English name Clopidogrel Hydrogen Sulfate, chemical name: (s)-α-(2-chlorophenyl)-6,7 - Methyl dihydrothieno[3,2-c]pyridine-5(4H)acetate hydrogensulfate. Clopidogrel bisulfate is an antiplatelet agent. The product was developed by the French pharmaceutical company Sanofi-Aventis and was first launched in the UK and the US in 1998. Clopidogrel bisulfate entered China in 2001 and is clinically used to prevent atherosclerotic thrombosis events , is the first-line clinical oral anticoagulant drug, and its market demand is growing day by day. At present, domestic clopidogrel bisulfate preparation products mainly include Plavix of Sanofi-Aventis and Taijia of Shenzhen Xinlitai Pharmaceutical Co...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61K31/4365A61P7/02
CPCC07B2200/13C07D495/04
Inventor 谭端明郑加林叶澄海叶宇翔
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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