Crystalline Form 1 Standardization for ABT-869 Ethanolate
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Solution Overview
Problem
There is a need for the identification and reproducible synthesis of crystalline forms of N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, as the crystallinity affects its physical and mechanical properties such as stability, solubility, and dissolution rate, which are crucial for ease of manufacture and therapeutic applications.
Innovation Solution
The development of N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea•¼ Ethanolate Crystalline Form 1, characterized by specific lattice parameters and powder diffraction patterns, and methods for its production involving solvents like ethanol and ethyl acetate, along with crystallization processes, to stabilize and standardize the compound for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If crystalline forms of ABT-869 are identified and standardized, then manufacturing precision and therapeutic reliability are improved, but the complexity of characterization and quality control increases
Solution Approach 1:
The patent applies parameter changes by establishing specific crystallographic parameters (lattice constants a=8.971Å, b=11.646Å, c=19.26Å and angles α=87.67°, β=90.21°, γ=76.82°) and PXRD pattern parameters (peak positions at 2θ=4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7°, 18.4°) to define Crystalline Form 1. These standardized parameters enable precise identification and reproduction of the desired crystalline form while providing clear quality control criteria.
2Productivity
If reproducible synthesis methods are developed, then productivity and manufacturing efficiency are improved, but the number of process parameters to control increases
Solution Approach 1:
The patent employs parameter changes by specifying precise crystallization conditions including solvent composition (ethanol/ethyl acetate ratios), temperature ranges, and concentration parameters to reliably produce Crystalline Form 1. These standardized process parameters enable reproducible synthesis while providing a controlled framework for manufacturing.
Solution Approach 2:
The patent uses ethanol and ethyl acetate as intermediary solvents to facilitate the crystallization process. These solvents act as mediators that enable the transformation of ABT-869 from amorphous or other crystalline forms to the desired Crystalline Form 1, providing a controlled pathway for reproducible synthesis.
3Reliability
If specific crystalline form is produced, then therapeutic efficacy and stability are improved, but the difficulty of detecting and measuring crystallinity increases
Solution Approach 1:
The patent employs X-ray diffraction as an intermediary detection method to characterize and verify Crystalline Form 1. The PXRD pattern serves as a fingerprint that indirectly confirms the presence of the desired crystalline form through characteristic peak positions, making detection feasible despite the complexity of direct crystallinity measurement.
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
This approach allows for the reproducible production of a stable crystalline form of N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, enhancing its therapeutic efficacy and manufacturing efficiency, particularly for treating cancer with or without additional anticancer drugs.
Implementation Method 1
when measured at 25°C ± 2 °C with radiation at 1.54178 Å, is characterized by a powder diffraction pattern
Implementation Method 2
methods for its production involving solvents like ethanol and ethyl acetate, along with crystallization processes
Data Source
Figure 1
AI summary
N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea ¼ Ethanolate Crystalline Form 1, ways to make it, formulations comprising it and made with it and methods of treating patients having disease using it is disclosed.