Sulfonamide Crystal Forms for Stability and Anti-Agglomeration
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Solution Overview
Problem
Existing crystal forms of the sulfonamide derivative N-(5-((1H-pyrazol-1-yl)methyl)-3,4-dihydro-2H-benzopyran[8,7-d]isoxazol-9-yl)-2,6-dimethoxybenzenesulfonamide exhibit poor stability and agglomeration, posing challenges in production and storage, and require improved polymorphs for better clinical efficacy.
Innovation Solution
Development of six distinct crystal forms (A, B, C, D, E, F, G, and H) characterized by specific X-ray powder diffraction patterns, each prepared through various solvent-based crystallization methods, including trituration, stirring, and antisolvent crystallization, to enhance stability and clinical prospects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous drug products are used, then the compound can be obtained without crystallization, but the product stability is poor and agglomeration occurs
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent type (water, organic solvents), temperature (room temperature, refrigeration, heating), and concentration to obtain different crystal forms with improved stability. This resolves the contradiction by transforming the amorphous product into structured crystal forms through controlled parameter changes.
Solution Approach 2:
The patent utilizes phase transitions by inducing crystallization from amorphous or dissolved states to ordered crystal structures. The transformation from amorphous compound to crystalline forms (Forms I-X) through controlled crystallization processes eliminates agglomeration and improves product stability while maintaining manufacturability.
2Manufacturing precision
If conventional crystallization conditions are used, then the compound can be crystallized, but fine particles are generated and filtration is difficult
Solution Approach 1:
The patent optimizes crystallization parameters including solvent selection, temperature control, and concentration to produce crystal forms with appropriate particle size and morphology. This enables easier filtration while maintaining defined crystal structures, resolving the contradiction between manufacturing precision and ease of manufacture.
3Duration of action of stationary object
If crystal form variations occur due to storage conditions, then the compound can be stored, but other crystal forms are generated causing product inconsistency
Solution Approach 1:
The patent employs preliminary action by pre-selecting and characterizing stable crystal forms (Forms I-X) that are resistant to polymorphic transformation during storage. By establishing the most stable crystal forms beforehand and optimizing storage conditions, the patent prevents generation of other crystal forms during the storage period, ensuring product consistency.
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 new crystal forms exhibit improved stability and flowability, addressing the issues of agglomeration and enhancing the drug's suitability for pharmaceutical applications, particularly in the treatment of cancers such as breast, ovarian, pancreatic, and lung cancer.
Implementation Method 1
adding the compound of formula 1 to a solvent (I), and triturating for crystallization
Implementation Method 2
an X-ray powder diffraction pattern represented by diffraction angles 2θ having characteristic peaks
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The present disclosure relates to a crystalline form of a sulfonamide derivative and a preparation method therefor. Specifically, the present disclosure provides a new crystalline form of a compound as represented by formula (1) and a preparation method therefor.