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Pharmaceutical co-crystal of gefitinib and bumetanide and preparation method thereof

A gefitinib and co-crystal technology, applied in the field of medicinal chemistry, can solve the problems of excessive organic solvent residues, poor reproducibility, low solubility, etc., to alleviate the toxic and side effects of drugs, improve chemical stability, and inhibit cancer cells. Effect

Active Publication Date: 2020-07-28
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The present invention aims at the low solubility, poor stability and poor reproducibility in the preparation process of the existing gefitinib crystal form belonging to the BCS Ⅱ class of the biological pharmacy classification system and the problem of excessive organic solvent residues, and as a new type of anti-tumor drug, taking too much will have greater side effects

Method used

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  • Pharmaceutical co-crystal of gefitinib and bumetanide and preparation method thereof
  • Pharmaceutical co-crystal of gefitinib and bumetanide and preparation method thereof
  • Pharmaceutical co-crystal of gefitinib and bumetanide and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of gefitinib and bumetanide drug co-crystals: accurately weigh 89.4 mg of gefitinib and 72.3 mg of bumetanide in a 4ml centrifuge tube, mix in a vortex mixer for 10 min, and place the mixed sample Put it into a mortar, add 1mL of ethanol dropwise and grind it to a white powder, then add 10ml of ethanol, transfer the solution to a 25ml beaker, heat it in a water bath at 70°C for 10min to fully dissolve, and filter the solution through a microporous membrane with a pore size of 2.5μm Filtrate, cultivate the filtrate and let the solvent volatilize to precipitate crystals for 72 hours, filter and dry to obtain a bulk transparent crystal product that meets the requirements of single crystal diffraction, and perform single crystal diffraction experiments to determine its crystal structure.

[0038] The gefitinib and bumetanide co-crystals were tested using SuperNova, Dual, Cu athome / near, AtlasS2 diffractometer from Agilent Technologies, and the crystal testing tem...

Embodiment 2

[0052] Preparation of gefitinib and bumetanide drug co-crystals: accurately weigh 89.4 mg of gefitinib and 72.3 mg of bumetanide in a 4ml centrifuge tube, mix in a vortex mixer for 10 min, and place the mixed sample Put it into a mortar, drop 1mL of methanol and grind it to white powder, then add 10ml of methanol, transfer the solution to a 25ml beaker, heat it in a water bath at 70°C for 10min to fully dissolve, and pass the solution through a microporous filter membrane with a pore size of 2.5μm Filtrate, cultivate the filtrate and let the solvent volatilize to precipitate crystals for 72 hours, filter and dry to obtain irregular crystal products.

[0053] Such as figure 2 In the shown PXRD spectrogram, the positions of the PXRD diffraction peaks obtained in Example 2 and Example 1 are basically consistent and show that the crystal products obtained in Example 2 and Example 1 are the same eutectic, as Figure 4 The DSC spectral features shown as well as Figure 5 The show...

Embodiment 3

[0055] Preparation of gefitinib and bumetanide drug co-crystals: accurately weigh 89.4 mg of gefitinib and 72.3 mg of bumetanide in a 4ml centrifuge tube, mix in a vortex mixer for 10 min, and place the mixed sample Put it into a mortar, drop 1mL of methanol and grind it to white powder, then add 10ml of methanol, transfer the solution to a 25ml beaker, heat it in a water bath at 70°C for 10min to fully dissolve, and pass the solution through a microporous filter membrane with a pore size of 2.5μm Filtrate, cultivate the filtrate and let the solvent volatilize to precipitate crystals for 72 hours, filter and dry to obtain irregular crystal products.

[0056] Such as figure 2 In the shown PXRD spectrogram, the positions of the PXRD diffraction peaks obtained in embodiment 3 and embodiment 1 are basically consistent and show that the crystal products obtained in embodiment 3 and embodiment 1 are the same eutectic, as Figure 4 The DSC spectrogram features shown as well as Fi...

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Abstract

The invention discloses a pharmaceutical co-crystal of gefitinib and bumetanide and a preparation method thereof. A molar ratio of gefitinib to bumetanide in the pharmaceutical co-crystal is 1: 1. Inan X-ray diffraction pattern represented by 2theta, characteristic peaks occur when the value of 2theta is equal to 5.08 + / - 0.2 degrees, 8.88 + / - 0.2 degrees, 10.26 + / - 0.2 degrees, 10.56 + / - 0.2 degrees, 17.78 + / - 0.2 degrees, 19.29 + / - 0.2 degrees, 19.68 + / - 0.2 degrees, 20.04 + / - 0.2 degrees, 21.47 + / - 0.2 degrees and 22.70 + / - 0.2 degrees. Compared with gefitinib technical, the pharmaceuticalco-crystal of the invention has better storage stability, better solubility and dissolution rate. Cytotoxicity experiment results show that the pharmaceutical co-crystal has a better inhibition effect on cancer cells and obviously reduced toxic and side effects on normal cells. The preparation method of the pharmaceutical co-crystal is friendly to environment, stable in yield and easy to industrialize.

Description

technical field [0001] The invention relates to gefitinib medicine, in particular to a co-crystal of gefitinib and bumetanide medicine and a preparation method thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Gefitinib (GFB), also known as Iressa, was developed by AstraZeneca (AstraZeneca) in the United States. The classification system of biological preparations belongs to BCS Ⅱ. It has high permeability and low solubility. Its molecular formula is C 22 h 24 ClFN 4 o 3 , molecular weight 446.9, chemical structure shown in Formula 1 below. Gefitinib is a selective epidermal growth factor tyrosine kinase (EGFR-TK) inhibitor, its inhibition of EGFR-TK can hinder tumor growth, metastasis and angiogenesis, and promote tumor cell apoptosis, therefore It is commonly used in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has previously received chemotherapy or is not suitable for chemotherap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94C07C311/39C07C303/42A61K31/5377A61K31/439A61P35/00A61P7/10
CPCC07D239/94C07C303/42A61K31/5377A61K31/63A61P35/00A61P7/10C07C311/39A61K2300/00
Inventor 江燕斌蒋云鹏吴艳婷宋阳
Owner SOUTH CHINA UNIV OF TECH
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