Amorphous Salt Quinolinecarboxamide Stability Usability
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Solution Overview
Problem
There is a need for angiogenesis inhibitors and c-Kit kinase inhibitors with improved physical properties and pharmacokinetics compared to the existing free-form product 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, which is effective but lacks usability and stability as a medicament.
Innovation Solution
The development of amorphous forms of salts such as methanesulfonate and ethanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, prepared by dissolving crystalline forms in alcohol and water, followed by lyophilization, to enhance usability and stability as medicaments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the free-form product 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is used as a medicament, then it exhibits angiogenesis inhibition and c-Kit kinase inhibition activity, but it has poor usability and instability due to its physical properties
Solution Approach 1:
The patent changes the physical state parameter of the compound from crystalline to amorphous form. This parameter change improves both stability and usability by eliminating the crystalline structure that causes poor solubility and handling issues, while maintaining the pharmacological activity of the free-form product.
Solution Approach 2:
The patent creates composite materials by forming salts of the quinolinecarboxamide compound with various acids (e.g., methanesulfonic acid, ethanesulfonic acid). These salt forms combine the active pharmaceutical ingredient with counterions to improve physical properties such as solubility, stability, and manufacturability while retaining biological activity.
2Stability of the object's composition
If the crystalline form of the salt is used, then it has better stability, but it exhibits poor dissolution rate and bioavailability
Solution Approach 1:
The patent changes the physical state parameter from crystalline to amorphous form. This eliminates the ordered crystal lattice structure that limits dissolution rate, while the amorphous state provides high energy and randomness that enhances solubility and bioavailability. The amorphous salt forms maintain chemical stability while improving dissolution kinetics.
3Ease of operation
If the amorphous form of salt is prepared by dissolving crystalline form in alcohol and water followed by lyophilization, then improved dissolution rate and bioavailability are achieved, but the process complexity increases
Solution Approach 1:
The patent uses alcohol and water as intermediary solvents to transform the crystalline salt into amorphous form. The lyophilization process uses these solvents as intermediaries to remove the structured crystal lattice, creating an amorphous solid dispersion that improves bioavailability. The intermediaries facilitate the phase transition without requiring complex equipment.
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 amorphous forms exhibit improved dissolution rates and stability, making them more effective as angiogenesis inhibitors and c-Kit kinase inhibitors for treating various cancers and inflammatory diseases, with increased bioavailability and therapeutic efficacy.
Implementation Method 1
dissolving a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate in an alcohol and water
Implementation Method 2
The amorphous form of a salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
Implementation Method 3
The amorphous forms exhibit improved dissolution rates
Data Source
AI summary
An amorphous form of a salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.