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Crystal forms A, H and I of barrack gefitinib phosphate and preparation methods thereof

A technology of phosphate and crystal form of tinib, which is applied in the field of polymorphic forms of baricitinib derivatives, and can solve the problems of increasing solubility of phosphate and affecting bioavailability of baricitinib.

Active Publication Date: 2016-05-25
SHANGHAI SUNTRONG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The problem to be solved by the present invention is the problem that the solubility of existing baricitinib phosphate needs to be improved to affect the bioavailability. At the same time, it is hoped that a new crystal form of baricitinib phosphate can be sought to provide a solid drug for the curative effect research. More qualitative and quantitative information

Method used

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  • Crystal forms A, H and I of barrack gefitinib phosphate and preparation methods thereof
  • Crystal forms A, H and I of barrack gefitinib phosphate and preparation methods thereof
  • Crystal forms A, H and I of barrack gefitinib phosphate and preparation methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 to 5

[0093] Examples 1 to 5 Preparation of Baricitinib Phosphate A Crystal Form

[0094] Weigh 1.0 g of baricitinib phosphate into a sample bottle, add 5 mL of N,N dimethylformamide to completely dissolve it, and then slowly add the solvents in Table 1 to the dissolved product. After a solid precipitated from the mixture of the dissolved substance and the organic solvent, an additional 5 mL of the organic solvent was added dropwise. The resulting mixture was allowed to stand overnight at room temperature, and then the precipitate obtained after standing overnight was filtered and vacuum-dried to obtain an off-white solid, which was weighed to calculate its yield, and the results are shown in Table 1. The reagents used in the process were all analytically pure.

[0095] Table 1 Preparation of baricitinib A crystal form

[0096] Example

Embodiment 6

[0097] Example 6 Characterization of baricitinib phosphate A crystal form by XRPD pattern

[0098] The measurement of the X-ray powder diffraction (XRPD) pattern is carried out using the RigakuUltimaIV model combined multifunctional X-ray diffractometer, and the specific collection information is as follows: Cu anode (40kV, 40mA), scanning speed 20° / min, scanning range (2θ range) 3~45°, scan step size 0.02, slit width 0.01. Samples were processed using glass slides pressed directly onto the test plate. Subsequent XRPD patterns all adopt similar measurement methods.

[0099] Determination of the XRPD pattern of the baricitinib phosphate A crystal form prepared according to the method described in Example 1, at 2θ=8.38, 8.88, 10.48, 13.00, 15.06, 16.22, 16.82, 17.76, 19.18, 19.70, 21.04, 22.22 , There are diffraction peaks at 22.68, 24.40, 24.94, 26.48, and 27.40, such as figure 1 shown. The error range of 2θ value is ±0.2. After testing, the error range of 2θ value can als...

Embodiment 7

[0101] Example 7 Investigation of the High Temperature Stability of Baricitinib Phosphate A Crystal Form

[0102] Take an appropriate amount of baricitinib phosphate A crystal form and place it in a 60°C oven, take out the sample after 5 days and 10 days for XRPD testing (such as figure 2 Shown), to investigate the crystal form stability of baricitinib phosphate A crystal form to temperature. The results showed that the crystalline form of baricitinib phosphate A was stable under high temperature conditions.

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Abstract

The invention provides crystal forms A, H and I of barrack gefitinib phosphate as shown in a formula (I). The formula (I) is as shown in the specification, wherein the XRPD atlas of the crystal form A has diffraction peaks at angles 2theta of 8.38, 8.88, 10.48, 13.00, 15.06, 16.22, 16.82, 17.76, 19.18, 19.70, 21.04, 22.22, 22.68, 24.40, 24.94, 26.48 and 27.40, and the 2theta value error range is + / -0.2. The crystal forms A, H and I of barrack gefitinib phosphate have stability approximate to that of an existing crystal form X of barrack gefitinib phosphate, have solubility higher than that of the crystal form X, are enhanced in bioavailability, and are beneficial to use in pharmaceutical processing and pharmaceutical compositions.

Description

technical field [0001] The present invention relates to polymorphic forms of baricitinib derivatives as JAK inhibitors, in particular, to the A crystal form, H crystal form and I crystal form of baricitinib phosphate and a preparation method thereof. Background technique [0002] JAK is Janus Kinase, which is a non-receptor tyrosine protein kinase and a non-transmembrane tyrosine kinase. This is because JAK can not only phosphorylate the cytokine receptors associated with it, but also phosphorylate multiple signaling molecules containing specific SH2 domains. The JAK protein family includes 4 members: JAK1, JAK2, JAK3 and TYK2, which have 7 JAK homology domains (JAKhomology domain, JH) in their structure, of which the JH1 domain is the kinase domain and the JH2 domain is the "false" The kinase domain, JH6 and JH7 are receptor binding domains. [0003] TYK2 is a potential target for immunoinflammatory diseases, which has been confirmed by human genetics and mouse knockout s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07B2200/13C07D487/04
Inventor 任国宾弋东旭陈金姚
Owner SHANGHAI SUNTRONG BIOTECH
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