Benzopyran Derivative Crystallization for Purity and Stability
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Solution Overview
Problem
The existing process for purifying a benzopyran derivative results in a product with low purity and high water content, leading to hygroscopicity, making it unsuitable for use as an active pharmaceutical ingredient.
Innovation Solution
Converting the amorphous crude benzopyran derivative to a crystalline form with specific XRPD, DSC, and TGA characteristics, achieved through dissolution in an organic solvent, addition of an antisolvent, or pH control, to enhance purity and reduce water content.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If the benzopyran derivative is prepared using the conventional process, then the production efficiency is maintained, but the purity is low (less than 97 wt/wt%) and water content is high (more than 1 wt/wt%)
Solution Approach 1:
The invention changes the physical state parameter of the product from amorphous to crystalline form. This phase transition fundamentally alters the material properties, enabling high purity (99.0% or more) and low water content (0.5 wt/wt% or less) while maintaining production efficiency through a straightforward crystallization process from the existing amorphous product.
Solution Approach 2:
The core invention utilizes phase transition from amorphous to crystalline state. By inducing crystallization of the amorphous benzopyran derivative, the patent achieves simultaneous improvement in purity, water content reduction, and stability without requiring reoptimization of the entire synthesis pathway, thus resolving the contradiction between manufacturing precision and productivity.
2Reliability
If the amorphous product is used directly, then the process is simple, but the product shows high hygroscopicity with water content increasing to 2.30 wt/wt% in 1 day under accelerated conditions
Solution Approach 1:
The invention applies phase transition from amorphous to crystalline form to fundamentally resolve the hygroscopicity issue. The crystalline structure provides a stable, ordered arrangement that prevents water absorption, achieving less than 0.05 wt/wt% water content increase under accelerated conditions. This single phase change step maintains process simplicity while dramatically improving reliability.
Solution Approach 2:
By changing the physical state parameter from amorphous to crystalline, the invention transforms the material's interaction with moisture. The crystalline form's structured lattice prevents water penetration, eliminating hygroscopicity without adding complex processing steps or equipment, thus improving reliability while keeping process complexity low.
3Manufacturing precision
If the product is obtained in amorphous form, then the initial production is straightforward, but the water content is high and purity is not within the suitable range (99.0% or more)
Solution Approach 1:
The invention uses phase transition from amorphous to crystalline form as a purification mechanism. This single step simultaneously achieves 99.0% or more purity and 0.5 wt/wt% or less water content, eliminating the need for additional purification operations like chromatography. The crystallization process inherently excludes impurities, making high purity achievement easy without complicating the manufacturing process.
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 crystalline form exhibits high purity, reduced water content, and stability, suitable for therapeutic formulations and long-term storage without hygroscopicity, facilitating efficient industrial production.
Implementation Method 1
converting the amorphous crude benzopyran derivative to a crystalline form with specific XRPD, DSC, and TGA characteristics, achieved through dissolution in an organic solvent, addition of an antisolvent, or pH control
Data Source
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AI summary
The present invention provides a process for purifying (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy -2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran, comprising converting an amorphous (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy -2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran to a crystalline form thereof. And also, the present invention provides a novel crystalline form of (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy -2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran and processes for preparing the same.