Gefitinib pharmaceutical co-crystal

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, relates to a gefitinib pharmaceutical co-crystal and a preparation method thereof, and particularly provides a co-crystal composed of gefitinib and malonic acid according to a molar ratio of 1:2, a co-crystal composed of gefitinib and succinic acid according to a molar ratio of 4:1, and a co-crystal composed of gefitinib, emodin and methanol according to a molar ratio of 1:2:1. The gefitinib pharmaceutical co-crystal provided by the invention has relatively high solubility and good dissolvability, is beneficial to improvement of bioavailability, and has important value for optimization and development of gefitinib preparations.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical technology, and is specifically involved in gefitinibe co-crystals and methods of preparation thereof. Background technique [0002] Gifanibi, trade name is Iressa, the chemical name is 4- (3-chloro-4-fluorophenyl amine) -7-methoxy-6- (3-morpholinopropoxy) ) Quinazoline is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by Aslikang, which is suitable for the treatment of plasmaking anti-tumor drugs and Dorset. Or is not suitable for local advanced or metastatic non-small cell lung cancer (NSCLC), which is the first small molecule protein tyrosine kinase inhibitor for solid tumor treatment to target anti-cancer drugs, 2005 approved in February 2005 Officially listed in China. [0003] There are currently many literatures reported that there is a polymorphic problem in Gefisinib. Since different crystalline profits of drugs directly affect the solubility, diss...

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Problems solved by technology

[0005] Patent CN100404032C discloses Gefitinib Form 1 (polymorph), Form 2 (methanol solvate), Form 3 (DMSO solvate), Form 5 (trihydrate) and its preparation method , the patent pointed out that after washing Form 3, Form 2 or Form 5 with a solvent or a solvent mixture, Form 1 polymorphs can be obtained by separation. The study found that Form 1 has good stability and is suitable for solid preparations of gefitinib such as tablets and Capsules, but in the actual preparation process, the acquisition of Form1 has poor reproducibility

The stability of Form 2 methanol solvate and Form 3DMSO solvate is lower than that of Form1, and the content of methanol in Form 2 crystal form is about 10 times of the pharmacopoeia limit (pharmacopoeia limit is 0.3%), and the DMSO content in Form3 crystal form The content is about 30 times of the pharmacopoeia limit (the pharmacopoeia limit is 0.5%). It can be seen that the crystal forms of Form 2 and Form 3 are relatively easy to prepare, but too much solvent residue makes it unsuitable as a pharmaceutical crystal form

The stability of Form 5 trihydrate is also not as good as Form 1. It is only very stable in water and is suitable for administration in the form of aqueous suspension, which also greatly limits the application of Form 5 crystal form.

[0006] Patent WO2006090413A1 discloses Form 6 crystal form of gefitinib and its preparation method. The preparation method is to mix anhydrous gefitinib with water, stir at ambient temperature for 18-20 hours, and filter and air-dry to obtain Form 6. The crystal form is Monohydrate crystal form, the stability is lower than Form 1, and it also has the problem of limited application similar to Form 5 crystal form

[0007] Patent CN103896863B disc

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