1,2,4-Oxadiazine Fungicide Form B for Suspension Stability
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Solution Overview
Problem
Existing formulations of (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-1,2,4-oxadiazine are amorphous, leading to instability and potential blockages in application equipment due to polymorphic transitions, which affect solubility, stability, and suspensibility.
Innovation Solution
Development of a stable polymorphic form B, characterized by specific X-ray, Raman, and IR spectra, which is produced through controlled crystallization processes, ensuring high stability and preventing transitions at elevated temperatures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the compound is produced as amorphous solid through known process, then the production process is simple, but the formulation stability deteriorates due to polymorphic transitions
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization process parameters (temperature, solvent composition, cooling rate) to transform the amorphous solid into a stable crystalline polymorph. Specifically, the patent uses controlled cooling from elevated temperatures (e.g., 40-60°C) to ambient temperature, and employs specific solvent systems (e.g., acetonitrile/water mixtures) to induce formation of the stable polymorphic form, thereby resolving the contradiction between simple production and formulation stability.
Solution Approach 2:
The patent utilizes phase transitions by inducing crystallization from the amorphous state to a stable crystalline polymorph through controlled temperature changes and solvent evaporation. The process involves cooling the amorphous solid to trigger polymorphic crystallization, forming stable crystal lattices that prevent further phase changes and ensure formulation stability throughout storage and application.
2Adaptability or versatility
If the compound crystallizes in different polymorphic forms, then the physical properties vary, but the prediction of which form will form is uncertain
Solution Approach 1:
The patent implements feedback by monitoring physical parameters (temperature, viscosity, crystal morphology) during the crystallization process to identify when the stable polymorphic form has formed. The process uses real-time observation of crystal formation and physical property changes to confirm the desired polymorphic form, allowing for process adjustment if necessary to ensure consistent formation of the stable crystalline structure.
Solution Approach 2:
The patent applies preliminary action by pre-establishing optimal crystallization conditions (temperature profiles, solvent ratios, pH levels) before the actual crystallization occurs. By preparing the system in advance with controlled parameters and using pre-tested protocols, the process ensures that the stable polymorphic form forms predictably and consistently, reducing the uncertainty of which form will result.
3Reliability
If metastable polymorphic forms are formed, then the compound can be isolated, but the forms may transform under storage conditions causing formulation issues
Solution Approach 1:
The patent applies preliminary anti-action by taking measures during the crystallization process to prevent the formation of metastable polymorphic forms that could transform later. The process uses controlled nucleation and crystal growth conditions, along with additives or seed crystals, to directly form only the stable polymorphic form from the outset, thereby preventing subsequent phase transformations and ensuring long-term storage stability.
Solution Approach 2:
The patent implements beforehand cushioning by creating a stable crystalline structure with sufficient thermodynamic stability to resist future polymorphic transformations. The crystallization process is designed to produce a polymorph with low free energy and high stability, providing a buffer against environmental changes during storage. This stable crystalline form acts as a cushion that prevents harmful phase transitions even under varying storage conditions.
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
Polymorphic form B exhibits enhanced stability in suspension concentrate formulations, maintaining high suspensibility and preventing recrystallization, thereby improving formulation safety and quality.
Implementation Method 1
Polymorphism is the ability of a compound to crystallize in different crystalline phases with different arrangements and/or conformations of the molecules in the crystal lattice. Hence, polymorphs are different crystalline forms of the same chemical compound.
Implementation Method 2
The process known from the prior art yields (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-1,2,4-oxadiazine as amorphous solid.
Implementation Method 3
FIG. 1a: X-ray powder diffractogram of polymorphic form B of (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-1,2,4-oxadiazine
Implementation Method 4
FIG. 1b: FT Raman spectrum of polymorphic form B of (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-1,2,4-oxadiazine
Implementation Method 5
FIG. 1c: IR spectrum of polymorphic form B of (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-1,2,4-oxadiazine
Data Source
AI summary
The present invention relates to novel crystalline forms of (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-1,2,4-oxadiazine according to formula (I), to a process for its preparation, to agrochemical formulations comprising the novel crystalline form, and to its use in plant protection applications, especially to its use as a fungicide,