Amorphous Solid Form of BET Protein Inhibitor
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Solution Overview
Problem
There is a need for new solid forms of BET protein inhibitors with suitable properties for the manufacture of safe, effective, and high-quality drug products, as existing inhibitors lack stability and purity in their crystalline forms.
Innovation Solution
An amorphous solid form of the BET protein-inhibiting compound (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one is developed, characterized by its stability, high glass transition temperature, and purity, which is prepared through a method involving dissolution in water with a base followed by acidification to precipitate out as an amorphous powder, eliminating the need for organic solvents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline forms of BET protein inhibitors are used, then the structural order and stability are improved, but the manufacturing complexity and purity issues worsen
Solution Approach 1:
The patent changes the physical state parameter of the compound from crystalline to amorphous form. This parameter change eliminates the need for complex crystallization processes while maintaining stability, directly resolving the contradiction between structural stability and manufacturing complexity
Solution Approach 2:
The invention utilizes phase transition from crystalline to amorphous state. By controlling the phase transition during preparation (through rapid cooling or precipitation), the patent achieves a stable amorphous form that simplifies manufacturing while maintaining the desired structural properties
2Stability of the object's composition
If crystalline forms of BET protein inhibitors are used, then the structural order is improved, but the purity and residual solvent content worsen
Solution Approach 1:
By changing the physical state from crystalline to amorphous, the patent eliminates trapped solvents and impurities that commonly occur in crystalline structures. The amorphous form allows for better purity control during manufacturing while maintaining structural integrity
Solution Approach 2:
The patent employs a disposable aqueous base system during preparation that can be easily removed through acidification, leaving no persistent organic solvent residues. This approach achieves high purity by eliminating the need for extensive solvent removal steps
3Ease of operation
If conventional preparation methods with organic solvents are used, then the dissolution process is improved, but the residual solvent content and safety worsen
Solution Approach 1:
The patent introduces an aqueous base as an intermediary medium for dissolution, which temporarily facilitates the dissolving process but is subsequently removed through acidification. This intermediary approach enables easy dissolution without leaving harmful organic solvent residues in the final product
Solution Approach 2:
The patent changes the solvent system from organic to aqueous-based, fundamentally altering the dissolution mechanism. This parameter change maintains ease of dissolution while eliminating residual organic solvent content, directly addressing the contradiction between operational ease and safety
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 amorphous form exhibits improved stability, high purity, and reduced residual organic solvent content, making it suitable for large-scale production and formulation, while maintaining effectiveness as a BET protein inhibitor.
Implementation Method 1
dissolving Compound 1-(S) in water with the aid of a base
Implementation Method 2
adding an acid to the basic aqueous solution to precipitate the Compound 1-(S) as an amorphous powder
Data Source
AI summary
The present invention relates to an amorphous solid form of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one, and processes for its preparation, which is an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and is useful in the treatment of various diseases such as cancer.