Sunitinib Polymorphic Form III Free Base Solubility
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Solution Overview
Problem
Sunitinib, a receptor tyrosine kinase inhibitor used to treat renal cell carcinoma and gastrointestinal stromal tumors, faces challenges with poor solubility, stickiness during processing, and manufacturing issues due to its crystalline malate salt form, affecting its oral bioavailability and production scalability.
Innovation Solution
The use of Sunitinib in its crystalline free base form, specifically polymorphic form III, which offers improved solubility, homogeneity, and flowability, overcoming the limitations of its salt forms and amorphous counterparts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Sunitinib is used in its crystalline malate salt form, then stability and processability are improved, but solubility deteriorates
Solution Approach 1:
The patent changes the physical form parameter from salt form to free base form, and specifically identifies polymorphic form III of the free base as the optimal configuration that achieves both improved solubility and acceptable stability, resolving the contradiction between these two properties
2Ease of manufacture
If Sunitinib is used in its crystalline malate salt form, then processability is improved, but oral bioavailability deteriorates
Solution Approach 1:
The patent changes the physical form parameter from salt form to free base form, specifically polymorphic form III, which exhibits improved solubility characteristics that directly enhance oral bioavailability while maintaining adequate processability for manufacturing
3Quantity of substance
If Sunitinib is used in higher concentrations over 40 wt.%, then therapeutic effect is improved, but manufacturing problems such as stickiness occur
Solution Approach 1:
The patent changes the physical form to polymorphic form III of the free base, which exhibits improved flowability and reduced stickiness, enabling the formulation to be processed at higher concentrations (over 40 wt.%) without manufacturing difficulties
4Object-affected harmful factors
If amorphous form of Sunitinib is used, then solubility is improved, but stability deteriorates
Solution Approach 1:
The patent identifies and utilizes polymorphic form III of the free base, which provides a crystalline structure with improved solubility characteristics compared to salt forms, while maintaining the stability advantages of crystalline over amorphous forms
Solution Approach 2:
Contrary to the general expectation that salt forms provide better stability and processability, the patent inverts this approach by using the free base form, specifically polymorphic form III, which unexpectedly delivers superior solubility and bioavailability while maintaining adequate stability and processability
Data Source
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AI summary
The present invention relates to a pharmaceutical composition comprising N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide as active pharmaceutical ingredient.