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Gefitinib and 3-hydroxybenzoic acid eutectic

A technology of hydroxybenzoic acid and gefitinib, which is applied in the field of gefitinib and 3-hydroxybenzoic acid co-crystal and its preparation, can solve the problems of excessive organic solvent residue, low solubility, poor reproducibility, etc., and achieve Inhibition of the formation and crystallization phenomenon, good reproducibility, and easy operation

Inactive Publication Date: 2019-08-16
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Aiming at the problems of low solubility, poor stability, poor reproducibility in the preparation process and excessive residual organic solvents in the existing gefitinib crystal form, the present invention aims to provide a gefitinib crystal form that can replace the existing gefitinib crystal form. Ni-3-hydroxybenzoic acid co-crystal, the co-crystal has good chemical stability, has a higher solubility than the existing crystal form, and has excellent bioavailability, and effectively avoids the existing crystal form through the formation of the co-crystal. Type of crystallization phenomenon and the problem of solvent residue

Method used

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  • Gefitinib and 3-hydroxybenzoic acid eutectic
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  • Gefitinib and 3-hydroxybenzoic acid eutectic

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Add 45.0mg of gefitinib and 11.6mg of 3-hydroxybenzoic acid into the mortar, and dropwise add 0.5mL of methanol, fully grind for 35min, then add 1mL of methanol and continue grinding for 15min to obtain a transparent solution. Stand at 5-10°C for crystallization for 48 hours, filter, and vacuum-dry at 55°C for 8 hours to obtain gefitinib-3-hydroxybenzoic acid co-crystal with a yield of 91.12%, HPLC: 99.94%.

Embodiment 2

[0054] Add 35.0mg of gefitinib and 11.0mg of 3-hydroxybenzoic acid into the mortar, and dropwise add 0.5mL of ethanol to it, thoroughly grind for 30min, then add 1mL of ethanol and continue grinding for 10min to obtain a transparent solution, control the temperature Stand at 5-10°C for crystallization for 48 hours, filter, and vacuum-dry at 55°C for 10 hours to obtain gefitinib-3-hydroxybenzoic acid co-crystal with a yield of 90.52%, HPLC: 99.92%.

Embodiment 3

[0056] Add 45.0mg of gefitinib and 11.6mg of 3-hydroxybenzoic acid into the mortar, and dropwise add 0.5mL of methanol, fully grind for 50min, then add 1mL of methanol and continue grinding for 20min to obtain a transparent solution. Stand at 5-10°C for crystallization for 48 hours, filter, and vacuum-dry at 55°C for 8 hours to obtain gefitinib-3-hydroxybenzoic acid co-crystal with a yield of 90.76%, HPLC: 99.93%.

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Abstract

The invention provides a gefitinib and 3-hydroxybenzoic acid eutectic, and concretely relates to the gefitinib and 3-hydroxybenzoic acid eutectic, and a preparation method and an application thereof.The X-ray diffraction spectrum of the gefitinib and 3-hydroxybenzoic acid eutectic has characteristic peaks at 2theta of 7.06 + / - 0.2 DEG, 14.08 + / - 0.2 DEG, 15.92 + / - 0.2 DEG, 24.66 + / - 0.2 DEG, 25.06 + / - 0.2 DEG and 28.33 + / - 0.2 DEG. The eutectic has a good chemical stability, has a higher solubility than a gefitinib crystal or its solvate, and has an excellent bioavailability; and the preparation method allows the eutectic to be obtained by a simple grinding process, and has the advantages of simplicity in operation, and stable yield.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a co-crystal of gefitinib and 3-hydroxybenzoic acid, a preparation method and application thereof. Background technique [0002] Gefitinib, the trade name is Iressa, the chemical name is 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy ) quinazoline, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by AstraZeneca, is suitable for the treatment of patients who have previously received platinum-based antineoplastic drugs and docetaxel chemotherapy. Or locally advanced or metastatic non-small cell lung cancer (NSCLC) not suitable for chemotherapy, it is the first small molecule protein tyrosine kinase inhibitor targeted anticancer drug for the treatment of solid tumors, approved in February 2005 Officially launched in China. [0003] At present, many literatures have reported that gefitinib has polymor...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07C65/03C07C51/42A61K31/5377A61P35/00
CPCC07D239/94C07C51/42A61K31/5377A61P35/00C07B2200/13C07C65/03
Inventor 张贵民郭立红翟立海张明明
Owner LUNAN PHARMA GROUP CORPORATION
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