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Novel crystal form of gefitinib and preparation method thereof based on supercritical anti-solvent technology

A technology of gefitinib and its crystal form, which is applied in organic chemical methods, bulk chemical production, organic chemistry, etc., can solve the problems of insufficient stability, large dosage, poor water solubility, etc., and achieve easy industrial production and preparation The method is simple and the effect of little environmental pollution

Active Publication Date: 2016-11-09
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Among the above-mentioned crystal forms, the crystal form Form 1 is the most stable, and it is also the most commonly used crystal form in clinical applications at present, but the reproducibility of its preparation is poor, and its solubility is low. The solubility in high-purity water with pH=7 is only 2.55 μg / ml
The drug is marketed in the form of tablets. Due to its poor water solubility, it is difficult to reach the effective blood concentration in the body after oral administration, and the dosage is large, causing severe gastrointestinal reactions and other toxic side effects.
The other crystal forms are all obtained by recrystallization method, the stability is not as good as the Form1 crystal form, and its water solubility has not been significantly improved

Method used

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  • Novel crystal form of gefitinib and preparation method thereof based on supercritical anti-solvent technology
  • Novel crystal form of gefitinib and preparation method thereof based on supercritical anti-solvent technology
  • Novel crystal form of gefitinib and preparation method thereof based on supercritical anti-solvent technology

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] A preparation of gefitinib crystal form β: accurately measure 40mL of DCM and 160mL of EtOH and configure it into a mixed solvent, accurately weigh 100mg of gefitinib powder (the bulk drug crystal form is Form 1), and dissolve it in the above 100 mL of mixed solvent was prepared into a gefitinib solution with a concentration of 1 mg / mL, and the remaining mixed solvent was used for later use. Before starting, set the temperature of the autoclave to 40°C and the pressure to 90bar. Open the steel cylinder, use a high pressure pump to introduce carbon dioxide from the top of the settling kettle at a flow rate of 20 g / min, when the temperature and pressure in the kettle reach the above set values, use another high pressure pump to transfer the remaining mixed solvent of DCM and EtOH to The rate of 1.0mL / min was passed into the sedimentation kettle. After 15min, the system in the reaction kettle reached an equilibrium state, and the introduction of the mixed solvent was stopp...

Embodiment 2

[0053] A preparation of gefitinib crystal form β: accurately measure 200 mL of EtOH as a solvent, accurately weigh 200 mg of gefitinib powder, and dissolve it in 100 mL of solvent to prepare a 2 mg / mL solution, and the remaining solvent is to be prepared. Use; set the temperature of the settling kettle to be 40°C, the pressure to be 90bar, and the flow rate of carbon dioxide injected into the settling kettle is 20g / min. Open the steel cylinder, and use a high-pressure pump to pass carbon dioxide into the settling kettle. When the temperature and pressure in the kettle reach the above set values, use another high-pressure pump to pass the solvent into the settling kettle at a rate of 0.5 mL / min. After 15 minutes, stop the flow of the solvent. into the solvent, and the gefitinib solution was injected at the same rate. After the sample injection was completed, carbon dioxide was continued to be introduced for 40 min, the carbon dioxide pump was stopped, the pressure of the sedime...

Embodiment 3

[0056] A preparation of gefitinib crystal form β: accurately measure 40 mL of DMSO and 160 mL of EtOH to prepare a mixed solvent, accurately weigh 200 mg of gefitinib powder, and dissolve it in 100 mL of the above mixed solvent to configure a concentration of 2 mg / mL of gefitinib solution, and the remaining mixed solvent for use. Before starting, set the temperature of the settling kettle to be 40° C., the pressure to be 90 bar, and the flow rate of carbon dioxide injected into the settling kettle to be 20 g / min. Open the steel cylinder, and use a high-pressure pump to pass carbon dioxide into the settling kettle. When the temperature and pressure in the kettle reach the above set values, use another high-pressure pump to pass the mixed solvent into the settling kettle at a rate of 0.5 mL / min. After 15 minutes, stop The mixed solvent was passed through, and the gefitinib solution was injected at the same rate. After the sample injection was completed, carbon dioxide was cont...

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Abstract

The invention discloses a novel crystal form of gefitinib and a preparation method thereof based on supercritical anti-solvent technology. The novel crystal form of gefitinib is a crystal form beta. The crystal form beta has a strongest characteristic peak in an XRPD pattern at a position where 2theta is equal to 6.7. The crystal form beta has main characteristic peaks in the XRPD pattern at positions where 2theta is about 6.7 and 13.0, and the relative intensity of the main characteristic peaks is greater than 20%. Characteristic peaks occur in the XRPD pattern when 2theta is 14.0, 19.7, 26.1, 32.8, 38.8, 40.5 and 46.5, and the relative intensity of the characteristic peaks is no more than 5%. The preparation method based on the supercritical anti-solvent technology is simple in process, mild in conditions and good in reproducibility; and the obtained crystal form beta of gefitinib is small in particle size, narrow in particle size distribution and high in solubility.

Description

technical field [0001] The invention relates to gefitinib, in particular to a new crystal form beta of gefitinib, and a preparation method of the crystal form; the preparation method is supercritical anti-solvent granulation technology. Background technique [0002] Gefitinib (Gefitinib) is a semi-synthetic derivative of camptothecin, developed by British Astra Zenica Limited, the trade name is Iressa, and the chemical name is N-(3-chloro-4 -Fluorophenyl)-7-methoxy-6-(3-morpholine-4-propoxy)quinazolin-4-amine, the molecular formula is C 22 H 24 ClFN 4 O 3 , the molecular weight is 446.9, the Chemical Abstracts Registration Number (CAS number) is 184475-35-2, and its chemical structure is as follows: [0003] [0004] Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, which is normally expressed in solid tumors of epithelial origin, and is indicated for the treatment of locally advanced chemotherapy previously treated or not ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
CPCC07D239/94C07B2200/13Y02P20/54
Inventor 江燕斌黄银霞刘贵金汪红娣
Owner SOUTH CHINA UNIV OF TECH
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