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Crystallization method for preparing high-purity monodisperse I crystal form atorvastatin calcium in single kettle

A high-purity technology of atorvastatin calcium, applied in the field of crystallization of atorvastatin calcium raw materials, can solve the problems of fine crystals, coalescence of crystal powders, etc. Effect

Active Publication Date: 2020-01-10
TIANJIN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0029] The above documents have described the purification process of atorvastatin calcium raw material and the preparation process of I crystal form, and have explained the removal methods of related impurities with higher content, and these methods can ensure the purity of atorvastatin calcium after refining. Purity and crystal form requirements, but the existing problem is that these documents have not studied and optimized the refining process of atorvastatin calcium from the perspective of crystallization and crystallization process
This process is almost instantaneous, so the precipitated crystals are fine, and the problem of agglomeration of the final crystalline powder is very serious

Method used

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  • Crystallization method for preparing high-purity monodisperse I crystal form atorvastatin calcium in single kettle
  • Crystallization method for preparing high-purity monodisperse I crystal form atorvastatin calcium in single kettle
  • Crystallization method for preparing high-purity monodisperse I crystal form atorvastatin calcium in single kettle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment example 1

[0087] Get 40g of methanol-water solution with methanol content of 15wt%, drop into 0.04g of I crystal form atorvastatin calcium, keep the solution temperature at 20°C, and ultrasonicate for 30min under the condition of ultrasonic power of 300W until the crystal particles are completely dispersed. The suspension is fed to a crystallizer as a solution for eluting crystallization.

[0088] Take 3.5 g of atorvastatin calcium raw material powder, add 20 g of anhydrous methanol, stir and dissolve in a water bath ultrasonically, then centrifuge and press filter to make methanol feed liquid.

[0089] Adopt the way of double-strand feeding of each material, drop methanol feed liquid and anti-solvent pure water into the above solution at the same time; keep the methanol concentration of the solvent in the solution in the co-current elution process basically unchanged, then 113.3g of water is required; Set the dissolution time to 2h, then the flow rate of water is 0.944g / min. The tempe...

Embodiment example 2

[0096] Get 40g of methanol-water solution with methanol content of 25wt%, drop 0.085g of I crystal form atorvastatin calcium, keep the solution temperature at 20°C, and ultrasonicate for 100min under the ultrasonic power condition of 360W until the crystal particles are completely dispersed. The suspension is fed to a crystallizer as a solution for eluting crystallization.

[0097] Take 3.5 g of atorvastatin calcium raw material powder, add 20 g of anhydrous methanol, stir and dissolve in a water bath ultrasonically, then centrifuge and press filter to make methanol feed liquid.

[0098] Adopt the mode of double-strand feeding of every kind of material, drop methanol feed liquid and anti-solvent pure water in the above-mentioned solution simultaneously; Keep the methanol concentration of the solvent in the solution in the co-current elution process to be basically constant, then need water 60g; If the dissolution time is 4h, the flow rate of water is 0.25g / min. The temperatur...

Embodiment example 3

[0105] Get 40g of methanol-water solution with a methanol content of 30wt%, add 0.15g of I crystal form atorvastatin calcium, keep the solution temperature at 20°C, and ultrasonicate for 1h under the condition of ultrasonic power of 360W until the crystal particles are completely dispersed. The suspension is fed to a crystallizer as a solution for eluting crystallization.

[0106] Take 2.98g of atorvastatin calcium raw material powder, add 17g of anhydrous methanol, stir and dissolve in a water-bath ultrasonic, then centrifuge and press filter to make methanol feed liquid.

[0107] Adopt the method of double-strand feeding of each material, drop methanol feed liquid and anti-solvent pure water into the above solution at the same time; keep the methanol concentration of the solvent in the solution in the co-current elution process basically unchanged, then 39.67g of water is required; Set the dissolution time to 204.5min, then the flow rate of water is 0.194g / min. The temperat...

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Abstract

The invention relates to a crystallization method for preparing high-purity monodisperse I crystal form atorvastatin calcium in a single kettle. The method is as follows: adding a mixed solvent consisting of a good solvent and an antisolvent of atorvastatin calcium into a crystallizer, adding crystalline powder of crystal form I atorvastatin calcium into the crystallizer, keeping the temperature of the solution at normal temperature, dispersing crystal particles by using ultrasound, and then raising the temperature to the temperature of the dissolution process; adding two solutions of the anti-solvent and the good solvent for dissolving the atorvastatin calcium into seed crystal suspension at the same time, and keeping the solvent composition in the seed crystal suspension in the process basically unchanged; adding the antisolvent into the crystallizer continuously, and then keeping temperature and suspending; reducing the temperature of the solution to normal temperature, and then filtering the solution, washing by pure water and drying to obtain crystal the form I crystalline atorvastatin calcium powder. The crystal particles of the powder are long rod-shaped, and the longitudinal dimension of the powder is not more than 30mu m, and the cross-sectional dimension is not more than 5mu m. The production cycle is short, the cost of the solvent is low, the operation is simple, andthe method is suitable for industrial production.

Description

technical field [0001] This application relates to a crystallization method of atorvastatin calcium bulk drug, in particular to the purification of the bulk drug, the preparation of I crystal form and the particle size control method of crystal particles; specifically, a single-pot preparation of high-purity monodisperse I crystal Crystallization method of type atorvastatin calcium. Background technique [0002] Atorvastatin calcium, the full chemical name is [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- Calcium 3-phenyl-4-[(anilino)carbonyl]-1H-pyrrole-1-heptanoate. Molecular formula is C 66 h 68 o 10 N 4 f 2 Ca, molecular weight 1155.42, structural formula as follows [0003] Atorvastatin Calcium is a white or off-white crystalline powder, odorless and bitter in taste. It is a blood lipid-lowering drug that can effectively regulate the blood lipid content in the blood. The substance is easily soluble in methanol, slightly soluble in ethanol or ace...

Claims

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Application Information

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IPC IPC(8): C07D207/34
CPCC07D207/34C07B2200/13
Inventor 龚俊波秦春雷侯晓清吴送姑侯宝红
Owner TIANJIN UNIV