MAT2A Inhibitor Crystal Forms for Stable Drug Production
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Solution Overview
Problem
Existing crystal forms of methionine adenosyltransferase 2A heterocyclic inhibitors exhibit variability in chemical stability, affecting their suitability for industrial production and biological activity, necessitating the development of crystal forms with high purity and stable chemical properties.
Innovation Solution
The development of specific crystal forms of the compound 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyrimido[1,2-b]pyridazin-8-one, characterized by distinct X-ray powder diffraction patterns and thermal profiles, including forms A-Q, to ensure stability and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If different crystalline forms of MAT2A inhibitor are used, then the compound can be produced through various preparation methods, but the chemical stability is affected and crystal structure changes occur
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization parameters (temperature, pH, solvent composition, cooling rate) to obtain specific crystal forms with distinct X-ray powder diffraction patterns. This allows control over crystal structure while maintaining chemical stability through selection of optimal crystallization conditions that prevent unwanted polymorphic transitions.
Solution Approach 2:
The patent employs preliminary action by pre-establishing specific crystallization conditions and storage parameters before production. The crystal forms are characterized and stored under controlled conditions to prevent structural changes during storage and handling, ensuring consistency in chemical stability and biological activity.
2Productivity
If crystal structure changes occur due to storage conditions, then the compound remains producible, but the generation of other crystal forms reduces purity and stability
Solution Approach 1:
The patent implements feedback by monitoring crystal form changes through X-ray powder diffraction analysis during storage. The data from diffraction patterns is used to detect polymorphic transitions early, allowing for corrective measures to be taken that maintain purity and stability while ensuring continuous production capability.
Solution Approach 2:
The patent applies beforehand cushioning by establishing stable crystal forms through optimized crystallization and pre-characterizing them under various storage conditions. This preparation creates a buffer against future structural changes, ensuring that even if storage conditions vary, the crystal form remains stable and pure for continued production.
3Reliability
If multiple crystal forms are generated, then the compound maintains biological activity, but the chemical stability is compromised for industrial production
Solution Approach 1:
The patent applies local quality by focusing on specific crystal forms with distinct X-ray powder diffraction patterns that exhibit both desired biological activity and enhanced chemical stability. Instead of treating all crystal forms equally, the patent identifies and optimizes specific forms that locally possess the qualities needed for both biological efficacy and industrial stability requirements.
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 identified crystal forms provide enhanced chemical stability and purity, supporting the development of drugs with improved industrial production and biological activity.
Implementation Method 1
The crystal form structure used as an active pharmaceutical ingredient often affects the chemical stability of the drug. Differences in the crystalline form, preparation method, and storage conditions may cause changes in the crystal form structure of the compound
Implementation Method 2
conducting in-depth research on the polymorphism of the compound to obtain crystal forms with high purity and stable chemical properties
Implementation Method 3
In one embodiment, a thermogram of the crystal form A measured by differential scanning calorimetry (DSC) has an endothermic peak with an onset temperature of 257-267 °C.
Implementation Method 4
the crystal form structure of the compound and sometimes the generation of other crystal forms
Data Source
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Figure 3~4
Figure 5~6
AI summary
The present invention relates to a crystal form of a methionine adenosyltransferase 2A heterocyclic inhibitor, a preparation method therefor, and a use thereof, and in particular to a crystal form of a compound as represented by the following formula I, a preparation method therefor, and a use thereof. The crystal form has high purity and stable chemical properties, and has important significance for developing drugs which are suitable for industrial production and have good biological activity.