Crystalline C-Met Inhibitor Forms for Stability and Solubility
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Solution Overview
Problem
The amorphous form of the C-Met inhibitor compound of formula I has poor chemical stability, high thermodynamic energy, and low solubility, making it unsuitable for drug development due to instability and poor bioavailability.
Innovation Solution
Development of crystalline free bases and acid salts of the compound, including specific crystal forms with improved solubility and stability, achieved through various preparation methods such as solvent selection, cooling, and crystallization techniques, which enhance the physical and chemical properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous form of compound of formula I is used, then drug can be prepared, but chemical stability is poor and thermodynamic energy is high
Solution Approach 1:
The patent transforms the amorphous form into crystalline forms through controlled crystallization processes, changing the physical state parameters of the compound. This results in lower thermodynamic energy and improved chemical stability while maintaining manufacturability through established crystallization techniques.
Solution Approach 2:
The invention utilizes phase transition from amorphous to crystalline state to resolve the contradiction. By controlling crystallization conditions (solvent selection, temperature, cooling rate), the patent achieves stable crystalline forms that retain ease of manufacture through standardized pharmaceutical processing.
2Ease of manufacture
If amorphous form of compound of formula I is used, then drug can be prepared, but solubility is low
Solution Approach 1:
The patent employs parameter changes in crystallization conditions (solvent type, temperature, pH) to generate crystalline forms with enhanced solubility properties. Different crystal forms exhibit varying solubility characteristics, allowing optimization of both manufacturability and dissolution performance.
3Stability of the object's composition
If crystalline form is developed, then stability and solubility are improved, but purification and crystallization process complexity increases
Solution Approach 1:
The patent utilizes phase transition during crystallization as a built-in purification mechanism. The controlled crystallization process automatically separates the compound from impurities, simplifying purification steps while ensuring stable crystalline form production through standardized procedures.
4Ease of manufacture
If amorphous form of compound of formula I is used, then drug can be prepared, but bioavailability is poor
Solution Approach 1:
The patent changes the physical state from amorphous to crystalline through controlled crystallization, improving dissolution rate and bioavailability. The crystalline forms exhibit enhanced solubility and dissolution characteristics while maintaining ease of manufacture through established pharmaceutical processing techniques.
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 crystalline forms exhibit improved solubility and stability, leading to enhanced bioavailability and easier purification, making them more suitable for drug development and treatment of cancer-related diseases.
Implementation Method 1
the process of drug crystallization is an effective purification method. The resulting crystalline form also has the technological operation advantage of easy further purification
Implementation Method 2
The amorphous form of the drug has higher thermodynamic energy state than the crystalline form, which will result in the instability of thermodynamics
Data Source
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AI summary
Disclosed are crystalline free bases of 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[[4,3-a]pyridine-3-yl)thio)-4-m ethyl-2H-[1,4]oxaazido[3,2-c]quinoline-3(4H)-one as a C-Met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof. In particular, disclosed are crystal forms I, II, III and IV of the free bases; crystal form I of the hydrochloride; crystal forms I and II of the sulfate; crystal forms I, II, III and IV of the phosphate; crystal forms I, II, III, IV and V of the mesylate; crystal forms I, II and III of the p-toluenesulfonate; crystal forms I, II and III of the 1,5-naphthalenedisulfonate; and the methods for preparing the above-mentioned crystal forms and a pharmaceutical composition comprising same, and a pharmaceutical use thereof and a method for regulating the catalytic activity of a protein kinase.