Alectinib Solid Forms and Salts for Solubility and Stability
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Solution Overview
Problem
Existing Alectinib salts and solid forms exhibit inadequate solubility, crystallinity, and stability, which hampers their effectiveness in treating ALK-positive non-small cell lung cancer.
Innovation Solution
Development of novel solid forms of Alectinib salts, including acetate, tartrate, maleate, fumarate, and ethane/ methane sulfonate salts, characterized by specific XRPD, DSC, and TGA patterns, prepared through controlled mixing and drying processes with solvents like 2-butanone, acetic acid, and water, optimizing molar and volume ratios.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If existing Alectinib salts and solid forms are used, then the basic therapeutic function is maintained, but solubility is inadequate
Solution Approach 1:
The patent applies parameter changes by developing multiple solid forms (Forms I-VI) with different crystalline structures, each having distinct XRPD patterns and solubility characteristics. By changing the physical and chemical parameters of the solid state through controlled crystallization processes using different solvents and conditions, the invention achieves improved solubility while maintaining therapeutic efficacy
Solution Approach 2:
The patent creates composite solid forms through salt formation with various counterions (acetate, tartrate, maleate, fumarate, ethane sulfonate, methane sulfonate). These composite salt forms combine Alectinib with different anions to produce materials with enhanced solubility properties compared to the parent compound, directly addressing the solubility-efficacy contradiction
2Stability of the object's composition
If existing Alectinib salts and solid forms are used, then the basic structural integrity is maintained, but crystallinity is inadequate
Solution Approach 1:
The patent segments the crystallization process into six distinct solid forms, each with unique XRPD patterns characterized by specific diffraction peaks at different 2θ angles. This segmentation allows selection of the most appropriate crystalline form for specific applications requiring particular crystallinity and stability profiles
Solution Approach 2:
The patent employs preliminary action through controlled crystallization procedures where specific solvents, temperatures, and drying conditions are predetermined and applied before final product formation. This preliminary control over crystallization conditions ensures consistent production of solid forms with desired crystallinity and stability characteristics
3Reliability
If existing Alectinib salts and solid forms are used, then the basic chemical structure is preserved, but stability is inadequate
Solution Approach 1:
The patent utilizes parameter changes by forming salts with different counterions that have varying hygroscopicity, acidity, and molecular sizes. These parameter changes in the salt structure directly influence the stability and shelf life of Alectinib, with certain salt forms demonstrating superior resistance to degradation and moisture uptake over time
Data Source
AI summary
The invention relates to Alectinib, compound of formula (1), solid forms thereof, salts thereof, solid forms of the salts and processes for preparation thereof,.