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Crystal form of larotretinib bisulfate and its preparation and application

A bisulfate and crystal form technology, which is applied in the field of larotretinib bisulfate crystal form and its preparation and application, can solve the problems of low solubility of anhydrous crystal form, affecting therapeutic effect, and low bioavailability

Active Publication Date: 2021-02-05
ANLITE SHANGHAI PHARMA TECH CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Patent WO2016077841 discloses an anhydrous I-HS of compound bisulfate of formula (I), but the anhydrous form has low solubility, which leads to low bioavailability and affects the therapeutic effect

Method used

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  • Crystal form of larotretinib bisulfate and its preparation and application
  • Crystal form of larotretinib bisulfate and its preparation and application
  • Crystal form of larotretinib bisulfate and its preparation and application

Examples

Experimental program
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Effect test

preparation example Construction

[0135] (3) The preparation method of the crystal form has the characteristics of simple operation, low cost, and is suitable for application in drug research and development and industrial production;

[0136] (4) The pharmaceutical composition prepared with the crystal form has better dissolution rate, and has excellent absorption performance and bioavailability after being administered to patients.

Embodiment 1

[0148] Embodiment 1: Preparation of crystal form AZT-I

[0149] Weigh 47.1 mg of the bisulfate salt of the compound of formula (I), dissolve it in 0.5 mL of N-methylpyrrolidone, and filter. At 25°C, 0.2 mL of the filtrate was slowly dropped into 2.0 mL of chloroform, and stirred until solids were precipitated. The obtained solid is the hydrogen sulfate salt crystal form AZT-I of the compound of formula (I).

[0150] Carry out XRPD test to the obtained solid, its X-ray powder diffraction pattern is as follows figure 1 Shown; Carry out TGA test to gained solid, its spectrogram is as figure 2 shown.

[0151] From figure 1 It can be seen that the main diffraction peaks and relative intensities of crystal form AZT-I are shown in Table 1.

[0152] Table 1

[0153]

[0154]

[0155] From figure 2 It can be seen that the weight loss of crystal form AZT-I is about 18% at 25-190°C.

Embodiment 2

[0156] Embodiment 2: Preparation of crystal form AZT-I

[0157] Weigh 30.0mg of hydrogen sulfate compound of formula (I), dissolve in 0.2mL N,N-dimethylacetamide, and filter. At 25°C, the filtrate was placed in a closed atmosphere of chloroform until solids were precipitated.

[0158] Carry out XRPD test to the obtained solid, its X-ray powder diffraction pattern is basically as figure 1 As shown, the obtained solid is the hydrogen sulfate salt crystal form AZT-I of the compound of formula (I).

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Abstract

The present invention relates to a crystalline form of Larotrectinib hydrogen sulfate salt and a preparation method therefor and a use thereof. In particular, the crystalline form of Larotrectinib hydrogen sulfate salt disclosed in the present invention has excellent solubility, stable mechanical properties and stability under high humidity conditions.

Description

technical field [0001] The invention relates to the field of medicine, in particular to larottinib bisulfate crystal form and its preparation and application. Background technique [0002] Larotrectinib (trade name: LOXO-101) is a tropomyosin receptor inhibitor developed by ARRAY BIOPHARMA in the United States, and is used to treat adults or children with solid tumors carrying Trk fusion genes. The pharmaceutical form of larotrectinib is bisulfate. The drug has been granted breakthrough therapy designation and orphan drug qualification issued by the US FDA, and has shown good curative effect on cancer patients carrying Trk fusion gene in multiple clinical trials. The chemical name of larotrectinib is (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a ] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, its molecular structure is as shown in formula (I): [0003] [0004] Different crystal forms can cause differences in the solubility and stability of d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCA61P35/00C07B2200/13C07D487/04
Inventor 彭欢黄继霆张良陈少雄
Owner ANLITE SHANGHAI PHARMA TECH CO LTD
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