Crystalline Form D of Multi-Tyrosine Kinase Inhibitor
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Solution Overview
Problem
Existing methods struggle to predict and produce stable, reproducible crystalline forms of the multi-tyrosine kinase inhibitor N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) suitable for pharmaceutical processing, as they lack desired physical properties for formulations.
Innovation Solution
The development of crystalline forms, specifically Form D, which exhibits superior physical properties and can be manufactured in large commercial scales with high quality and reproducibility, characterized by X-ray powder diffraction peaks at specific angles and suitable for pharmaceutical formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If small scale chemical synthesis of amorphous Compound 1 is performed, then the compound can be obtained, but it cannot be purified by recrystallization and is difficult to produce in large quantity with high quality
Solution Approach 1:
The invention changes the physical state parameter of Compound 1 from amorphous to crystalline form. By establishing specific crystallization conditions (solvent selection, temperature control, pH adjustment), the compound transitions to a well-defined crystalline structure that enables purification by recrystallization and scalable production while maintaining high quality standards
Solution Approach 2:
The invention utilizes phase transition from amorphous to crystalline state to resolve the contradiction. The crystalline form of Compound 1 exhibits distinct phase characteristics that enable effective purification through recrystallization and facilitate large-scale production with consistent quality, directly addressing the limitations of amorphous compound production
2Reliability
If multiple crystalline forms are obtained through systematic solid form screening, then phase uniformity can be achieved, but it is difficult to predict which form will be stable and suitable for pharmaceutical processing
Solution Approach 1:
The invention identifies and controls critical parameters (solvent type, temperature, pH, concentration) that determine which crystalline form is obtained. By establishing specific parameter ranges and conditions, the process reliably produces the desired crystalline form with phase uniformity, eliminating the need for complex prediction of stability and suitability for pharmaceutical processing
3Ease of manufacture
If crystalline forms are produced for pharmaceutical formulations, then manufacturing improvements can be achieved, but it is difficult to produce forms with desired physical properties for formulations
Solution Approach 1:
The invention optimizes crystallization parameters (solvent selection, temperature profiles, addition rates, pH control) to produce crystalline forms with specific physical properties required for pharmaceutical formulations. This approach enables manufacturing improvements while ensuring the desired physical characteristics are achieved through controlled parameter adjustments
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
Form D provides a stable and reproducible crystalline form for pharmaceutical use, enabling effective inhibition of multi-tyrosine kinase activity and treatment of cancers such as non-small cell lung cancer.
Implementation Method 1
which has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks having °2θ angle values independently selected from the group consisting of 7.8±0.2°, 14.3±0.2° and 17.2±0.2°
Implementation Method 2
X-ray powder diffraction pattern (XRPD) comprising diffraction peaks
Data Source
Figure 1A
Figure 1B
Figure 2A(1)
AI summary
The present invention relates to crystalline forms of N-(3 -fluoro-4-((2-(5-(((2- methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4- fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1), pharmaceutical compositions comprising the crystalline form, processes for preparing the crystalline form and methods of use therefore.