FGFR4 Inhibitor Crystal Forms Stability Selectivity
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Solution Overview
Problem
Current FGFR4 inhibitors face challenges in stability and selectivity, particularly in inhibiting FGFR4 without affecting FGFR1-3, and there is a need for more stable and selective crystal forms for pharmaceutical applications.
Innovation Solution
Development of specific salt forms and crystal forms of FGFR4 inhibitors, characterized by unique X-ray powder diffraction patterns and thermal stability, which provide enhanced stability and selectivity, including crystal forms A, B, C, D, E, F, and G, each with distinct diffraction peaks and thermal profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional FGFR4 inhibitors are used, then FGFR4 inhibition activity is achieved, but stability and selectivity are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallographic parameters (space group, unit cell dimensions, temperature, pressure) to generate multiple crystal forms ( Forms 1-7) with distinct diffraction patterns and thermal properties. Each crystal form represents a different physical state of the FGFR4 inhibitor, allowing optimization of both stability and selectivity by selecting appropriate crystal forms for pharmaceutical development
Solution Approach 2:
The patent employs composite materials by creating salt forms of the FGFR4 inhibitor compound, combining the active pharmaceutical ingredient with counterions to form stable crystal structures. The salt forms (e.g., hydrochloride, hydrobromide, sulfate, nitrate, acetate, benzoate, maleate, fumarate, malate, citrate, succinate, benzenesulfonate, tosylate, picrate, trifluoroacetate, perfluoroacetate, perchlorate, nitrate, formate, oxalate, carbonate, bicarbonate, phosphate, dihydrogen phosphate, hydrogen phosphate, silicate, aluminate, borate, carbonate, bicarbonate, hydroxide, oxide, fluoride, chloride, bromide, iodide, cyano, cyanate, isocyanate, carbonyl, carboxylate, ester, amide, urea, carbamate, hydroxycarboxylate, hydroxycarboxylic acid, carboxylic acid, sulfonate, sulfonic acid, phosphonate, phosphonic acid, phosphinate, phosphinic acid, phosphine oxide, phosphine, phosphorous acid, phosphorous anhydride, phosphorus trihalide, phosphorus pentahalide, phosphorus oxohalide, phosphorus oxyhalide, phosphorus halide, phosphorus anhydride, phosphorus trihalide, phosphorus pentahalide, phosphorus oxohalide, phosphorus oxyhalide, phosphorus halide) provide enhanced stability and selectivity compared to the free base form
2Adaptability or versatility
If FGFR4 inhibitors are developed for broad application, then treatment options increase, but selectivity against FGFR1-3 decreases
Solution Approach 1:
The patent applies local quality by designing FGFR4 inhibitors with specific molecular structures that target the unique CYS552 residue in FGFR4, creating a localized interaction that provides high selectivity for FGFR4 over FGFR1-3. The crystal forms maintain this selective binding characteristic while providing improved stability for pharmaceutical formulation
Solution Approach 2:
The patent uses copying by generating multiple crystal forms (Forms 1-7) that replicate the active pharmaceutical ingredient in different physical states, each maintaining the same FGFR4 inhibitory activity and selectivity profile. This allows the same molecular entity to be optimized for different pharmaceutical applications while preserving the selective binding characteristic
3Reliability
If multiple crystal forms are developed, then stability and repeatability improve, but characterization complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the characterization task into distinct, manageable components: X-ray powder diffraction pattern analysis, thermal analysis (DSC, TGA), and crystal structure determination. Each crystal form is characterized using these standardized methods, allowing systematic comparison and selection of the most suitable form for pharmaceutical development without overwhelming complexity
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
These crystal forms exhibit improved stability, repeatability, and selectivity, making them suitable for pharmaceutical development and use in treating FGFR4-related diseases with minimal impact on FGFR1-3, and show excellent inhibitory activity on FGFR4 kinase.
Implementation Method 1
the 2θ angles of the respective diffraction peaks in the X-ray powder diffraction pattern thereof will deviate in duplicate trials due to the influence of equipment, operation method, sample purity, and human factors
Implementation Method 2
for a specific crystal form of a specific compound, the 2θ angles of the respective diffraction peaks in the X-ray powder diffraction pattern thereof
Implementation Method 3
the differential scanning calorimetric curve of the crystal form A has an endothermic peak with an onset of 174.46° C.±3° C.
Implementation Method 4
the thermogravimetric analysis curve of the crystal form A has a weight loss of 0.02335% occurred at 120.00° C.±3° C. and an additional weight loss of 0.2869% occurred at 200.85° C.±3° C.
Data Source
AI summary
The present invention provides a salt form, a crystal form, and a preparation method of a compound as an FGFR4 inhibitor and medical uses thereof.