FGFR Inhibitor Crystal Forms for Reliable Solid-State Manufacture
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional methods struggle to obtain solid forms of the FGFR inhibitor compound WX001A or WX001B, hindering its manufacture, purification, storage, and use.
Innovation Solution
A method involving the use of specific solvents and conditions to produce crystal forms A and B of the compound WX001A or WX001B, characterized by distinct X-ray diffraction peaks and thermal properties, including stirring the compound in nitrile or ester solvents for crystal form A and alcohol or alcohol-water mixtures for crystal form B, followed by centrifugation and drying.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional methods (methanol, ethanol, tetrahydrofuran) are used to obtain solid form of compound WX001, then the compound remains in solution form, but solid form product is failed to obtain
Solution Approach 1:
The patent changes the solvent parameters from conventional alcohols and ethers to specific nitrile solvents (acetonitrile, propionitrile, butyronitrile) and ester solvents (ethyl acetate, methyl acetate, isopropyl acetate, ethyl formate), which fundamentally alters the crystallization outcome and enables reliable solid form product obtainability
Solution Approach 2:
The patent introduces specific solvent intermediaries (nitrile and ester solvents) that mediate the transformation from solution to solid crystal form, facilitating the formation of crystal forms A and B that were not achievable with conventional solvents
2Ease of manufacture
If conventional solvents are used under conventional processing conditions, then the compound stays in solution, but solid form and crystal form are difficult to obtain
Solution Approach 1:
The patent systematically changes solvent parameters by selecting specific nitrile and ester solvents with appropriate polarity and solubility characteristics, enabling solid and crystal form formation without requiring complex processing equipment or multi-step procedures
Solution Approach 2:
The patent obtains crystal forms A and B as distinct solid forms of the same compound, providing multiple solid form copies that can be used for different therapeutic purposes, with crystal form A showing preferential crystallization under certain conditions
3Ease of operation
If the compound is obtained in solid form, then convenient for manufacture, purification, storage and use, but requires new solvent system and processing conditions
Solution Approach 1:
The patent changes the solvent system parameters to nitrile and ester classes, which provide optimal conditions for solid form formation while maintaining relatively simple processing conditions that can be adapted to existing manufacturing infrastructure
Solution Approach 2:
The patent segments the solvent options into distinct categories (nitrile solvents and ester solvents) with different crystallization characteristics, allowing selective application based on specific product requirements and facilitating streamlined process development
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 resulting crystal forms exhibit good inhibitory activity against both wild-type and mutant-type FGFR, show minimal hygroscopicity, and have favorable pharmacokinetic indices, facilitating the development of medicaments for FGFR-related diseases.
Implementation Method 1
stirring the compound in nitrile or ester solvents for crystal form A
Implementation Method 2
stirring the compound in nitrile or ester solvents
Implementation Method 3
stirring the compound in alcohol or alcohol-water mixtures for crystal form B
Implementation Method 4
stirring the compound in alcohol or alcohol-water mixtures
Implementation Method 5
followed by centrifugation and drying
Implementation Method 6
characterized by distinct X-ray diffraction peaks
Implementation Method 7
X-ray powder diffraction pattern
Implementation Method 8
has an endothermic peak at 141.05° C.±5° C. in a differential scanning calorimetry curve
Data Source
AI summary
Disclosed are the solid form, crystalline form, crystal form A of a compound of formula (I), and a preparation method therefor, crystal form B and a preparation method therefor. Also disclosed are use of the solid form, crystalline form, crystal form A, and crystal form B in the preparation of drugs for the treatment of diseases related to FGFR.