Ripretinib Cocrystals and Polymorphs for Stable Oral Formulation
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Solution Overview
Problem
There is a need for a solid state form of ripretinib suitable for use in the pharmaceutical industry, as existing forms may lack desirable properties such as chemical stability, solubility, and bioavailability, which are crucial for effective treatment of gastrointestinal stromal tumors (GIST), advanced systemic mastocytosis (ASM), gliomas, and other solid tumors driven by tyrosine-protein kinase KIT or platelet derived growth factor alpha (PDGFRα) kinase.
Innovation Solution
The development of various solid state forms of ripretinib, including crystalline and amorphous forms, characterized by specific PXRD and 13C NMR patterns, which offer improved chemical stability, solubility, and bioavailability, facilitating the preparation of pharmaceutical compositions and formulations for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing solid state forms of ripretinib are used, then the compound can be administered orally, but the chemical stability, solubility, and bioavailability are insufficient for effective treatment
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple polymorphic forms (Forms 1-7) of ripretinib, each with distinct crystal structures and physical properties. By changing the solid state form parameter, the invention achieves improved chemical stability while maintaining or enhancing solubility characteristics. Each polymorph represents a different parameter state of the same compound, allowing optimization of both stability and solubility through selective form selection.
Solution Approach 2:
The patent employs composite material principles by creating cocrystals of ripretinib with various coformers (e.g., nicotinamide, succinic acid, tartaric acid). These cocrystals combine ripretinib with complementary molecules to achieve enhanced chemical stability and improved solubility simultaneously. The composite structure allows each component to contribute its favorable properties to the overall formulation.
2Reliability
If existing solid state forms of ripretinib are used, then the compound can be processed, but the bioavailability and treatment efficacy are limited
Solution Approach 1:
By changing the solid state form parameter to optimized polymorphs and cocrystals, the invention achieves enhanced bioavailability. The distinct crystal structures of different polymorphs (Forms 1-7) and cocrystal compositions create different dissolution rates and absorption characteristics, allowing selection of the form that maximizes bioavailability and consequently treatment efficacy for GIST and other KIT/PDGFRα-driven tumors.
3Ease of operation
If multiple solid state forms are developed, then processing and handling characteristics improve, but the complexity of selection and characterization increases
Solution Approach 1:
The patent applies segmentation by dividing the ripretinib solid state landscape into distinct, well-characterized polymorphic forms (Forms 1-7) and cocrystal types. Each form is characterized by specific PXRD patterns, DSC profiles, and stability profiles, creating segmented categories that simplify selection and processing. This segmentation approach reduces the complexity of handling by providing clear distinctions between forms.
Solution Approach 2:
The patent uses characteristic PXRD patterns and DSC profiles as 'fingerprints' to identify and differentiate between polymorphic forms. These distinctive analytical signatures serve as identification markers, allowing rapid characterization and selection of the desired form without complex analysis. Each polymorph has unique diffraction patterns and thermal behavior that facilitate easy identification.
Data Source
AI summary
The present disclosure relates to solid state forms of ripretinib, processes for preparation thereof, as well as a pharmaceutical composition including the same.