Stable Crystal Form I for 1,4-Bisbenzisoselenazolone Butane
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Solution Overview
Problem
Existing crystalline forms of 1,4-bis[1,2-benzisoselenazol-3(2H)-one]-butane lack stability and uniformity, affecting the solubility, bioavailability, and efficacy of drugs used for treating fibrosis and inflammatory diseases, particularly liver cancer.
Innovation Solution
Development of a crystalline form I with specific X-ray diffraction peaks and monoclinic monocrystalline properties, prepared by dissolving the compound in solvents like DMSO and adding antisolvents such as water or acetonitrile, ensuring stability and high solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms are used, then the compound can be applied in medicaments, but the lack of stability and uniformity affects solubility, bioavailability, and efficacy
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent type (DMSO, ethanol, isopropanol, acetonitrile), temperature (4°C, room temperature, refrigeration), and concentration to obtain different crystalline forms with distinct stability and uniformity characteristics. This allows selection of optimal crystalline form parameters for reliable drug performance
Solution Approach 2:
The patent utilizes phase transitions through controlled crystallization processes where the compound transitions from solution phase to solid crystalline phase. By controlling cooling rates, solvent evaporation, and crystallization temperature, the patent achieves uniform crystalline structures with improved stability and predictable bioavailability
2Ease of operation
If different crystalline forms are developed, then solubility and bioavailability can be improved, but the complexity of identifying and characterizing stable forms increases
Solution Approach 1:
The patent employs X-ray diffraction (XRD) technology to replace complex manual characterization methods. The XRD system automatically identifies crystalline forms through diffraction patterns, providing rapid and accurate characterization of solubility-related crystalline properties without requiring complex manual analysis
Solution Approach 2:
The patent creates reference crystalline forms with characterized properties that serve as templates for future developments. Once a crystalline form with desirable solubility is identified and characterized, it can be replicated using the same crystallization parameters, simplifying subsequent work without requiring re-characterization
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 I exhibits good stability, high solubility, reasonable bioavailability, and excellent tumor inhibitory activity, particularly against HBV-associated liver cancer, with improved therapeutic activity and safety for pharmaceutical use.
Implementation Method 1
dissolving 1,4-bis[1,2-benzisoselenazol-3(2H)-one]-butane in a solvent S1, and adding an antisolvent S2 to give the crystalline form I
Implementation Method 2
having characteristic peaks at 2θ angles of 6.15±0.20°, 12.28±0.20°, 18.44±0.20°, 19.09±0.20°, 22.20±0.20°, 23.68±0.20°, 25.92±0.20°, 30.95±0.20° and 32.45±0.20° by X-ray powder diffraction using Cu-Kα radiation
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
Disclosed herein is a crystalline form I of 1,4-BIS[1,2-BENZISOSELENAZOL-3(2H)-one]-butane having characteristic peaks at 2θ angles of 6.17±0.20°, 12.28±0.20°, 18.44±0.20°, 25.92±0.20° and 30.95±0.20° by X-ray powder diffraction using Cu-Kα radiation. The crystalline form has good stability, is not susceptible to polymorphic transition, is beneficial to the preparation, use, shipping and preservation of pharmaceutical compositions and preparations, and fully ensures the safety of medication and the quality of medicaments. In addition, the crystalline form features high solubility, reasonable bioavailability, low toxicity and excellent tumor inhibitory activity.