Crystalline Dual RAF/MEK Inhibitor Forms for Stable Oral Processing
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Solution Overview
Problem
There is a need for effective therapeutic means to treat abnormal cell growth, particularly cancer, targeting the RAS/RAF/MEK/ERK signal transduction pathway with selective inhibitors.
Innovation Solution
Development of solid forms of dual RAF/MEK inhibitors, specifically crystalline Forms 1, 8, and 10, characterized by unique X-ray powder diffraction patterns, and their pharmaceutical compositions for oral dosage forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If selective inhibitors of RAS/RAF/MEK/ERK pathway are used to treat abnormal cell growth, then therapeutic efficacy is improved, but processing properties and stability of the compounds deteriorate
Solution Approach 1:
The patent applies parameter changes by converting the compound from an amorphous state to specific crystalline forms (Form 1, Form 8, Form 10). This phase transition fundamentally alters the physical properties including processing characteristics, stability, and solubility while preserving the therapeutic efficacy of the dual RAF/MEK inhibitor against abnormal cell growth.
Solution Approach 2:
The invention utilizes phase transitions by establishing specific crystalline structures with defined X-ray diffraction patterns. The transition from amorphous to crystalline state provides improved processing properties and stability, enabling better manufacturing handling and storage while maintaining the compound's biological activity in treating cancer.
2Reliability
If selective inhibitors of RAS/RAF/MEK/ERK pathway are used to treat abnormal cell growth, then therapeutic efficacy is improved, but stability of the compounds deteriorates
Solution Approach 1:
The patent applies parameter changes by converting the compound from an amorphous state to specific crystalline forms (Form 1, Form 8, Form 10). This phase transition fundamentally alters the physical properties including processing characteristics, stability, and solubility while preserving the therapeutic efficacy of the dual RAF/MEK inhibitor against abnormal cell growth.
Solution Approach 2:
The invention utilizes phase transitions by establishing specific crystalline structures with defined X-ray diffraction patterns. The transition from amorphous to crystalline state provides improved processing properties and stability, enabling better manufacturing handling and storage while maintaining the compound's biological activity in treating cancer.
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 solid forms of dual RAF/MEK inhibitors provide improved processing properties, stability, and therapeutic efficacy in treating cancer by targeting the RAS/RAF/MEK/ERK pathway.
Implementation Method 1
exhibits an X-ray power diffraction pattern comprising a characteristic XRPD peak at the following diffraction angle (2θ (degrees))=9.0±0.2
Implementation Method 2
exhibits an X-ray power diffraction pattern comprising a characteristic XRPD peak at the following diffraction angle (2θ (degrees))=9.0±0.2
Implementation Method 3
heating the mixture prepared according to step (i) to about 40° C. to about 60° C.
Implementation Method 4
cooling the heated mixture of step (ii) to about −10° C. to about 5° C. to form a precipitate
Implementation Method 5
cooling the heated mixture of step (ii) to about −10° C. to about 5° C. to form a precipitate
Implementation Method 6
drying the solid from step (iv), to give Form 1. In some embodiments, the drying comprises drying the solid under reduced pressure at elevated temperature
Data Source
AI summary
Solid forms of a dual RAF/MEK inhibitor, pharmaceutical compositions thereof, oral dosage forms thereof, and methods of treating cancer are described herein. Also provided herein are processes for preparing solid forms of a dual RAF/MEK inhibitor and pharmaceutical compositions and oral dosage forms thereof.