Solid preparation containing BIBW 2992MA2 and preparation method thereof

Abstract

The invention relates to a powder intermediate containing BIBW 2992MA2. The powder intermediate comprises 5-30% of BIBW 2992MA2 and 70-95% of medical auxiliary materials. The powder intermediate is prepared through the following steps: after being smashed and screened, the BIBW 2992MA2 is uniformly mixed with a flow agent accounting for 3-30% percent by weight of BIBW 2992MA2, and then the mixture is uniformly mixed with residual medical auxiliary materials, so that the total mixed powder preparation is obtained; or after being smashed and screened, the smashed and screened BIBW 2992MA2 is uniformly mixed with a flow agent accounting for 3-30% by weight of BIBW 2992MA2 and a lubricating agent accounting for 2-15% by weight of BIBW 2992MA2, and then the mixture is uniformly mixed with residual medical auxiliary materials, so that the total mixed powder preparation is obtained. The powder intermediate has good liquidity, compressibility and lubricating property, and is suitable for being prepared into tablets, coated tablets or solid preparations such as capsules.

Description

technical field [0001] The invention relates to a pharmaceutical preparation of quinazoline anticancer drugs and a preparation method thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Afatinib dimaleate (BIBW2992MA2), the chemical name is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)- 1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline, (2Z)-2-butenedioic acid (1 :2), its structural formula is as follows: [0003] [0004] Afatinib dimaleate, an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor tyrosine kinase (HER2), is the first treatment for lung cancer after failure of EGFR inhibitor therapy The therapeutic drug can be used for the treatment of advanced non-small cell lung cancer, advanced breast cancer and intestinal cancer. [0005] Patent Document No. WO2005 / 037824A discloses an anhydrous stable polymorphic form of afatinib dimaleate. WO2...

AI Technical Summary

Problems solved by technology

WO2009 / 147238A1 discloses that the polymorphic form described in WO2005 / 037824A is a fine needle form, which in the process of preparing solid oral dosage forms has the following challenging physicochemical properties related to processability: moisture sensitivity, moisture will Affects the chemical stability of the API and leads to a decrease in the active ingredient and increased contamination by hydrolytic degradation products; needle-like precipitated active ingredient, which leads to large variations in its low bulk density due to the random arrangement and length of the needles, Poor flow due to increased resistance to needles aligned in the direction of flow, capping or lamination of tablets during the direct compression process due to too much air entrapment inside the final blend ( laminating); low compressibility, the active ingredient is also combined with other excipients such as binders or fillers, which leads to mechanically weaker granules during dry granulation and subsequently during tablet compression The tendency of the API to segregate due to the fragmentation of these particles, and the adhesion of the API to the surface due to the increase in electrostatic charge, leads to a decrease in the selectivity of BIBW2992MA2 in the powder mixture during processing, and thus in the manufactured Lack of API in tablet which would show inappropriate assay values

In view of the poor fluidity and workability caused by BIBW2992MA2-like crystals, large differences between different batches, and easy sticking and punching, direct compression is not possible, so the prior art WO2009 / 147238A1 (Chinese patent application number CN200980121080.3) BIBW2992MA2 in the form of needle crystals is ground, mixed with a lubricant in an amount of 0 to 1.0% by weight of BIBW2992MA2, subjected to a compaction step (roller compaction, briquetting or pre-compacting) to compact the material, and applying one or Multiple subsequent sieving steps to break up the ribbons and further reduce particle size and disperse the API to obtain a powdery granular intermediate with controlled particle size distribution in the range of 1μm<x50<300μm, which is then blended with all excipients Obtain the intermediate blend, and then further direct compression to obtain tablets of required specifications

[0006] The above method belongs to the dry granulation and tabletting method, and the problem of difficulty in processing due to the needle-like shape of the API can be improved by crushing and granulating after rolling, but this method increases the unit operation of rolling and crushing, which leads to complicated procedures , long production cycle, high labor intensity and high production cost

In addition, BIBW2992MA2 is a polymorphic drug, which may have the problem of crystal transformation after double compression after grinding, and the crystal transformation rate begins to increase with the increase in the number of repetitions of tablet compression

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