ALK Inhibitor Crystal Forms for Solubility and Stability Balance
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Solution Overview
Problem
The amorphous form of the compound represented by formula I exhibits low bioavailability, poor stability, high hygroscopicity, and poor solubility, which are not effectively addressed by existing technologies.
Innovation Solution
Development of crystal forms A, B, C, D, E, F, G, and H of the compound, characterized by specific X-ray powder diffraction patterns and thermal analysis, which enhance crystallinity, stability, and solubility, thereby improving bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If amorphous form of the compound is used, then solubility is improved, but bioavailability is low and stability is poor
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of the compound from amorphous to crystalline form. This phase transition fundamentally alters the molecular arrangement and intermolecular forces, resulting in improved bioavailability and stability while maintaining or enhancing solubility characteristics. The crystalline forms exhibit defined melting points and consistent dissolution profiles that address the reliability issues of amorphous forms.
Solution Approach 2:
The core invention utilizes phase transitions by converting the amorphous compound into distinct crystalline polymorphs (Forms A through H). Each crystalline form represents a different phase with unique packing arrangements, leading to improved physical and chemical stability. The phase transition from amorphous to crystalline state provides the compound with predictable dissolution behavior and enhanced bioavailability without sacrificing solubility.
2Quantity of substance
If amorphous form of the compound is used, then solubility is improved, but hygroscopicity is high
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of the compound from amorphous to crystalline form. This phase transition fundamentally alters the molecular arrangement and intermolecular forces, resulting in improved bioavailability and stability while maintaining or enhancing solubility characteristics. The crystalline forms exhibit defined melting points and consistent dissolution profiles that address the reliability issues of amorphous forms.
Solution Approach 2:
The core invention utilizes phase transitions by converting the amorphous compound into distinct crystalline polymorphs (Forms A through H). Each crystalline form represents a different phase with unique packing arrangements, leading to improved physical and chemical stability. The phase transition from amorphous to crystalline state provides the compound with predictable dissolution behavior and enhanced bioavailability without sacrificing solubility.
3Stability of the object's composition
If crystalline forms are developed, then stability and crystallinity are improved, but solubility may be reduced
Solution Approach 1:
The patent applies segmentation by identifying and characterizing multiple distinct crystalline polymorphs (Forms A through H) of the same compound. Each polymorph represents a different segment of the crystal structure space with unique packing arrangements, intermolecular interactions, and surface properties. This segmentation allows selection of specific polymorphs that optimize both stability and solubility characteristics for different therapeutic applications.
Solution Approach 2:
The patent applies parameter changes by transforming the physical state of the compound from amorphous to crystalline form. This phase transition fundamentally alters the molecular arrangement and intermolecular forces, resulting in improved bioavailability and stability while maintaining or enhancing solubility characteristics. The crystalline forms exhibit defined melting points and consistent dissolution profiles that address the reliability issues of amorphous forms.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The crystal forms demonstrate high crystallinity, good stability, low hygroscopicity, and high solubility, addressing the deficiencies of the amorphous form and enhancing the compound's therapeutic potential.
Implementation Method 1
Development of crystal forms A, B, C, D, E, F, G, and H of the compound, characterized by specific X-ray powder diffraction patterns and thermal analysis, which enhance crystallinity, stability, and solubility
Implementation Method 2
an X-ray powder diffraction (XRPD) pattern of the crystal form has at least three, at least four, at least five, at least six, or at least seven characteristic peaks at the following 2θ angles: 5.494°±0.2°, 7.553°±0.2°, 8.711°±0.2°, 15.6°±0.2°, 17.183°±0.2°, 18.019°±0.2°, and 18.999°±0.2°
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
Provided is a crystal form of a compound represented by formula I or a salt thereof, wherein the crystal form is one equivalent of mesylate crystal form A of the compound represented by formula I, crystal form D of the compound represented by formula I, one equivalent of maleate crystal form A of the compound represented by formula I, one equivalent of tartrate crystal form C of the compound represented by formula I, one equivalent of citrate crystal form B of the compound represented by formula I, or one equivalent of succinate crystal form D of the compound represented by formula I. The crystal form has one or more of the following advantages: high crystallinity, good stability, low hygroscopicity, high solubility, and high bioavailability.