Baloxvir dipivoxil crystal form D and preparation method thereof

Abstract

The invention discloses a baloxvir dipivoxil crystal form D and a preparation method thereof, the baloxvir dipivoxil crystal form D is an anhydrous solvate-free crystal form of baloxvir dipivoxil, under X-ray powder diffraction, the baloxvir dipivoxil crystal form D has characteristic diffraction peaks at diffraction angles 2 theta of 4.5 degrees, 8.8 degrees, 10.8 degrees, 13.2 degrees, 14.3 degrees, 14.8 degrees and 16.2 degrees, and the test error is + / -0.2 degrees. The research result shows that the crystal form of the baloxvir dipivoxil crystal form D is a slender needle-shaped crystal, a solvent is easily removed through vacuum drying, and after drying, crystal particles of which the purity is up to 99.5%, the impurity residues and the solvent limit meet the quality standard of crude drugs and the stability, the dispersity, the flowability and the compressibility are very good can be obtained, and the baloxvir dipivoxil crystal form D is suitable for industrial production. The raw material is very suitable for tablet production; moreover, the baloxvir dipivoxil crystal form D has solubility superior to that of the existing crystal form in a simulated stomach and intestinal juice pH environment, and is very beneficial to absorption and utilization of oral preparations.

Description

technical field [0001] The invention relates to a crystal form D of baloxavir dipivoxil and a preparation method thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Baloxavir Marboxil is a new anti-influenza drug developed by Shionogi, Japan, and its trade name is Xofluza. Xofluza is an innovative Cap-dependent endonuclease inhibitor and one of the few new oral drugs that can inhibit the proliferation of influenza virus in the world. It can target the key link of influenza virus replication and inhibit it from obtaining the 5' end of host mRNA from host cells. The CAP structure, thereby inhibiting the transcription of the influenza virus's own mRNA, the drug was approved by Japan in February 2018 for the treatment of influenza A and B in adults and pediatric patients, and was approved by the FDA for the treatment of influenza in October 2018 Patients 12 years of age and older with uncomplicated acute influenza within 48 hours. ...

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Problems solved by technology

[0006] The inventor of this patent also found in experiments that both the Form II crystal form and the Form III crystal form are unstable, and they are easily converted into the Form I crystal form during the crystallization process; in addition, although the patent CN201911140898. The Form A and Form B crystal forms of virdiproxil have good stability under high temperature, high humidity and light conditions. However, through comparison, we found that the Form A crystal form is the Form I crystal form disclosed in the patent WO2018030463, while The thermogravimetric analysis of Form B shows that it has a weight loss of about 0.5%. According to the patent, it is an anhydrous substance, so this part of the weight loss shows that Form B is a mixed crystal form mixed with solvates

Since Form B is obtained by volatilization and crystallization from the acetonitrile system, and acetonitrile belongs to the second-class solvent specified by ICH, the limit is relatively low. On the other hand, mixed crystals will also affect the dissolution of the preparation, so Form B in the form of acetonitrile solvate is It is impossible to use it as a medicine, and the preparation of the Form B crystal form requires the natural volatilization of the acetonitrile solution at room temperature for 3 to 4 days, which is definitely not possible in industrial production. It is beneficial to environmental protection, and when the equivalent is large, the degree of volatilization of the surface layer and the bottom layer of the solvent is different, and it is more prone to the problem that the solvent residue caused by the mixed crystal does not meet the requirements

Due to the above-mentioned reasons, the raw material currently used for oral preparations is still the Form I crystal form (the same crystal form as the Form A crystal form), but the crystal habit of the existing Form I crystal form is flaky, and the flaky crystals, in During the drying process, it is easy to wrap the solvent and agglomerate, resulting in the hardened material after drying, and the solvent residue is easy to exceed the standard. It often takes a long time to dry to reach the solvent limit, and if the drying time is too long, it is easy to cause degradation. Impurities exceed the standard; in addition, after the material is agglomerated, the fluidity of the product is poor, and physical crushing is required to achieve the compressible particle size requirement, which has caused great trouble to the production of oral pharmaceutical preparations

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