Cabozantinib Purification via Diastereomeric Salt Crystallization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for purifying Cabozantinib, such as preparative column chromatography, are expensive, time-consuming, and not suitable for commercial scale due to low yield and complexity.
Innovation Solution
Developing a process that converts crude Cabozantinib into its acid addition salt and then treating it with a suitable base to obtain Cabozantinib free base with enhanced purity, using specific solvents and conditions to achieve crystalline forms like form-M and form-S, which can be scaled up industrially.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If preparative column chromatography is used for purifying Cabozantinib, then purity can be achieved, but the process becomes expensive, time-consuming, and not suitable for commercial scale
Solution Approach 1:
The invention changes the purification approach from chromatographic separation to crystallization-based purification by forming diastereomeric salts with chiral acids. This parameter change from liquid-phase chromatography to solid-phase crystallization enables commercial-scale production while maintaining high purity levels
Solution Approach 2:
The invention introduces chiral acids (such as (S)-malic acid) as intermediaries to form diastereomeric salts with Cabozantinib. These intermediaries enable selective crystallization of the desired enantiomer, achieving high purity without requiring chromatographic separation
2Manufacturing precision
If complex purification processes are used, then purity can be enhanced, but the process complexity and time increase
Solution Approach 1:
The invention extracts only the essential purification step by using selective crystallization of diastereomeric salts. Instead of multiple chromatographic steps, a single crystallization step using chiral acids achieves the required purity, dramatically simplifying the process
Solution Approach 2:
The invention utilizes phase transition from solution to crystal during the crystallization process. By controlling the phase transition of diastereomeric salts, the desired enantiomer is selectively purified in a single step without complex equipment
3Manufacturing precision
If low yield processes are used, then purity can be maintained, but productivity and commercial viability decrease
Solution Approach 1:
The invention performs preliminary resolution by forming diastereomeric salts before the final product isolation. This preliminary action with chiral acids allows for high-yield recovery of the desired enantiomer through simple filtration and crystallization, avoiding low-yield chromatographic methods
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 process achieves high purity (>99.95%) and stability of Cabozantinib, with crystalline forms showing thermal and hygroscopic stability, and particle size distribution suitable for pharmaceutical applications.
Implementation Method 1
The present invention relates to novel crystalline forms of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a
Data Source
AI summary
The present invention also relates to process for the preparation of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a and its polymorphs thereof, represented by the following structural: