BTK Inhibitor Salt Forms for Scalable Purification and Stability
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Solution Overview
Problem
Existing synthesis methods for the BTK inhibitor compound (I) are not suitable for large-scale manufacturing and result in high residual solvent content and thermal instability, posing challenges for effective formulation and increased costs.
Innovation Solution
Development of specific salts and solid forms of compound (I), particularly sulfonic acid and carboxylic acid salts, in amorphous form, with high purity (E) or (Z) isomers, to enhance stability and reduce residual solvent levels, enabling efficient large-scale synthesis and formulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If column chromatography purification is used to obtain compound (I), then purity is improved, but manufacturing complexity and cost increase significantly
Solution Approach 1:
The patent extracts and eliminates the problematic foam formation and column chromatography step by developing alternative purification methods using salt formation and crystallization techniques, thereby simplifying the manufacturing process while maintaining purity
Solution Approach 2:
The patent changes the physical and chemical parameters of compound (I) by forming salts with different counterions (e.g., hydrochloride, sulfate, methanesulfonate) to alter solubility and crystallization behavior, enabling simplified purification without column chromatography
2Ease of manufacture
If the compound is isolated as foam and dried under vacuum at ambient temperature, then processing simplicity is improved, but residual solvent content increases beyond ICH limits
Solution Approach 1:
The patent employs phase transition from foam to crystalline solid form through controlled crystallization and drying processes, transforming the physical state to eliminate residual solvents while maintaining processing efficiency
Solution Approach 2:
The patent creates composite salt forms of compound (I) with pharmaceutically acceptable counterions, which exhibit improved physical properties including reduced solvent retention and enhanced stability during processing
3Adaptability or versatility
If the compound is stored and handled as the free base form, then formulation flexibility is improved, but thermal stability deteriorates
Solution Approach 1:
The patent changes the chemical form of compound (I) from free base to salt forms, fundamentally altering thermal stability parameters while maintaining or enhancing formulation flexibility through diverse salt options
4Productivity
If large-scale synthesis is attempted using existing methods, then production volume is improved, but product quality and stability deteriorate
Solution Approach 1:
The patent extracts and removes the problematic steps (column chromatography, foam isolation) from the synthesis protocol, replacing them with scalable crystallization and filtration operations that maintain quality at large scale
Solution Approach 2:
The patent implements parameter changes in the synthesis and isolation process, including controlled crystallization conditions and salt formation, to enable large-scale production while maintaining high product quality and stability
Data Source
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AI summary
Disclosed herein are processes for preparing 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile free base (compound (I)), salts of compound (I) and solid state form of said salts. Also disclosed herein are pharmaceutical compositions comprising such salts and solid state form thereof and methods of treating cancer, autoimmune, and inflammatory diseases using compound (I) or a pharmaceutically acceptable salt thereof.