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A kind of idelalisib crystal form a and preparation method thereof

A crystal form and solution technology, applied in the field of medicinal chemistry, can solve problems such as unfavorable absorption, poor solubility, poor solubility, etc., and achieve the effects of good solubility, short production cycle, and stable quality

Active Publication Date: 2021-06-15
SHANGHAI ACEBRIGHT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the WO2005113556 international patent application, Idelalisib and its preparation method were disclosed. Later studies showed that the solvate of Idelalisib with 0.4 molecules of ethanol (referred to as crystal form I in the WO2015014315 international patent application) was obtained by using the preparation method. The following defects: the weight change is about 0.95% in the range of 20-80% relative humidity, has certain hygroscopicity, and poor stability (see the background technology part in WO2015014315 for details)
And studies have shown that: Idelalisib's crystal form I, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form IX and crystal form X are all easy to transform into crystal form II; crystal form I and The other crystal forms mentioned in this invention (including crystal form VI and crystal form IX) all transform into crystal form III during the competitive reaction; while crystal form II and crystal form III are both anhydrous substances with poor solubility, which is not conducive to human body absorb
[0006] It can be seen from the above-mentioned prior art that there are various crystal forms of Idelalisib, and some crystal forms have good stability but poor solubility, while some crystal forms have good solubility but poor stability. Crystal form with good stability, suitable for industrial preparation of preparations and meeting various performance requirements of preparations

Method used

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  • A kind of idelalisib crystal form a and preparation method thereof
  • A kind of idelalisib crystal form a and preparation method thereof
  • A kind of idelalisib crystal form a and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: Preparation of Idelalisib Form A

Embodiment 11

[0061] At 30°C, dissolve 1g of Idelalisib raw material (regardless of its form) in 30mL of acetone to obtain a clear solution; at 30°C, slowly add anti-solvent water to the above solution until initial turbidity (about 100mL) ; Insulated and stirred to crystallize for 2 hours, cooled to room temperature; filtered and dried to obtain 0.85 g of crystals; the yield was 85%, and the HPLC purity was 99.58%.

[0062] figure 1 is the XRD spectrum of the obtained crystal, by figure 1 It can be seen that under powder X-ray diffraction, the crystal has Characteristic peaks with relative intensities greater than 50%; 8.5±0.2°, 10.7±0.2°, 13.6±0.2°, 14.6±0.2°, 15.0±0.2°, 15.8±0.2°, 16.8±0.2°, 17.1±0.2° in 2θ °, 19.9±0.2°, 20.2±0.2°, 22.9±0.2°, 23.6±0.2°, 23.7±0.2°, 24.3±0.2°, 26.3±0.2° have characteristic peaks with relative intensities greater than 30%.

[0063] figure 2 For the DSC spectrum of the obtained crystal, by figure 2 It can be seen that the crystal has a solvent endot...

Embodiment 12

[0067] At 65°C, dissolve 1g of Idelalisib raw material (regardless of its form) in 20mL of acetonitrile to obtain a clear solution; at 50°C, slowly add anti-solvent water to the above solution until initial turbidity (about 110mL) ; Insulated and stirred to crystallize for 2 hours, cooled to room temperature; filtered and dried to obtain 0.90 g of crystals; the yield was 90%, and the HPLC purity was 99.70%.

[0068] After determination and analysis, the obtained crystals have figure 1 Shown XRD spectrogram feature and figure 2 The DSC spectral features shown and image 3 The characteristics of the TGA spectrum shown in this example illustrate that the crystal obtained in this example is also Idelalisib crystal form A of the present invention.

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Abstract

The invention discloses an Idelalisib crystal form A and a preparation method thereof. The Idelalisib crystal form A is a molecular hydrate of Idelalisib, and under powder X-ray diffraction, the 2θ is 8.5±0.2°, 10.7±0.2°, 13.6±0.2°, 15.8±0.2°, 20.2±0.2°, 23.7±0.2°, 24.3±0.2° have characteristic peaks with relative intensities greater than 50%, and a clear solution can be obtained by dissolving the Idelalisib raw material in a suitable solvent , and then add the anti-solvent dropwise to the obtained solution until the initial turbidity, and then heat and stir to crystallize, cool down to room temperature, filter, and dry to prepare. The Idelalisib crystal form A provided by the present invention has excellent solubility, thermal stability, high humidity stability and pressure stability, and is more suitable as a pharmaceutically active component of a preparation.

Description

technical field [0001] The invention relates to an Idelalisib crystal form A and a preparation method thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Idelalisib, its chemical name is: (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, commercial Name: Zydelig, molecular formula: C 22 h 18 FN 7 O, molecular weight: 415.42, CAS number: 870281-82-6, chemical structural formula: The drug is a phosphatidylinositol 3-kinase δ inhibitor (referred to as PI3Kδ inhibitor) developed by Gilead, which is used for chronic lymphocytic leukemia, indolent non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large The treatment of B-cell lymphoma, Hodgkin's lymphoma, multiple myeloma, acute myeloid leukemia and hematological malignancies was approved by the FDA on July 23, 2014. The dosage form is tablet (100mg and 150mg). [0003] In the WO2005113556 international patent application, Idelalisib and its preparati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/34
CPCC07B2200/13C07D473/34
Inventor 安晓霞申淑匣
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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