Amorphous Thiocolchicine Derivative IDN 5404 Solubility
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Solution Overview
Problem
The existing methods for preparing thiocolchicine derivative IDN 5404 result in crystalline forms contaminated with toxic solvents and having low solubility, which are not ideal for pharmaceutical applications.
Innovation Solution
An amorphous form of IDN 5404 is obtained by dissolving the crude compound in DMSO, removing residual solvents under vacuum, and precipitating it into water, resulting in a form with improved solubility and stability, free from toxic solvents like dichloromethane and hexane.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If column chromatography purification is used, then purity is improved, but toxic solvent residues remain in the crystalline product
Solution Approach 1:
The patent changes the physical state parameter of the product from crystalline to amorphous form. This parameter change allows the product to be obtained as an amorphous precipitate rather than crystals, which eliminates the incorporation of toxic solvents into the crystal lattice while maintaining high purity through the precipitation process
Solution Approach 2:
The patent utilizes phase transition by controlling the precipitation process to form an amorphous solid rather than a crystalline solid. This phase transition approach prevents toxic solvents from being trapped in the product structure, as amorphous materials do not have the ordered lattice structure that can incorporate solvent molecules
2Stability of the object's composition
If crystalline form is obtained, then stability is improved, but solubility decreases
Solution Approach 1:
The patent changes the physical state parameter from crystalline to amorphous form. Amorphous materials generally exhibit higher solubility and faster dissolution rates compared to their crystalline counterparts due to the lack of ordered molecular arrangement, while maintaining adequate stability through proper formulation and storage conditions
3Device complexity
If simple solvent evaporation is used, then manufacturing complexity is reduced, but product form becomes amorphous with low solubility
Solution Approach 1:
The patent changes the recovery method from simple evaporation to controlled precipitation. By adding a non-solvent (water) to the DMSO solution, the product precipitates as an amorphous solid with improved solubility characteristics. This method remains relatively simple while achieving the desired solubility improvement
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 form exhibits increased solubility, chemical and physical stability, and is devoid of toxic solvent residues, facilitating the preparation of pharmaceutical compositions with enhanced bioavailability and ease of formulation.
Implementation Method 1
dissolving the crude compound of formula (I) in DMSO
Implementation Method 2
removing the possible residual solvents coming from the synthetic process by heating the solution at 65°C under vacuum
Implementation Method 3
precipitating the amorphous compound of formula (I) by adding drop wise the solution obtained in step b) to water at 20-25°C under stirring
Data Source
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AI summary
The present invention refers to an amorphous form of a thiocolchicine derivative, IDN 5404, to a process for producing it and to pharmaceutical compositions thereof. The amorphous form is characterised by the XRPD pattern, DSC profile and/or TG/DTA profile.