Febuxostat Crystalline Forms Enhancing Solubility and Stability
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Solution Overview
Problem
Current forms of Febuxostat, a xanthine oxidase inhibitor for gout, lack optimal solid-state physical properties such as solubility, stability, and processing characteristics, necessitating the discovery of new polymorphic forms that enhance its pharmaceutical performance.
Innovation Solution
Development of new crystalline forms (F1-F14) of Febuxostat characterized by specific XRD patterns and 13C NMR spectra, which offer improved crystallinity, solubility, stability, and handling properties, including anhydrous forms and specific preparation methods using solvents like methylisobutylketone and hydrocarbons.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms of Febuxostat are used, then the basic pharmaceutical function is achieved, but the solid-state physical properties such as solubility, stability, and processing characteristics are suboptimal
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple new polymorphic forms (F1-F14) of Febuxostat with different crystal structures. Each polymorph exhibits distinct physical properties including solubility, stability, and processing characteristics. By changing the crystalline form parameter, the patent optimizes the balance between stability and manufacturability for pharmaceutical applications
Solution Approach 2:
The patent employs composite material principles by creating specific crystalline structures with defined molecular arrangements. The new polymorphic forms represent composite organizational states of the Febuxostat molecules, where the spatial arrangement and intermolecular interactions are optimized to achieve both stability and desirable processing characteristics
2Reliability
If existing crystalline forms of Febuxostat are used, then the basic pharmaceutical function is achieved, but the solubility properties are insufficient for optimal formulation
Solution Approach 1:
The patent utilizes parameter changes by identifying polymorphic forms with enhanced solubility properties while maintaining storage stability. The different crystal packing arrangements in polymorphs F1-F14 create variations in lattice energy and molecular accessibility to solvent, thereby tuning solubility without sacrificing stability
Solution Approach 2:
The patent applies local quality principles by creating polymorphic forms with specific local molecular environments and intermolecular interactions. The distinct hydrogen bonding patterns, pi-stacking arrangements, and van der Waals contacts in different polymorphs create localized structural features that influence overall solubility while preserving global stability
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
These new forms provide enhanced chemical purity, flowability, solubility, and stability, improving the pharmaceutical properties of Febuxostat, including storage stability and compactability, making them suitable for tablet formulation and effective in treating hyperuricemia.
Implementation Method 1
a powder XRD pattern with peaks at 5.8°, 6.8°, 8.1°, 11.8° and 17.4°±0.2° 2θ
Implementation Method 2
X-ray powder diffraction pattern having peaks at: 6.7°, 7.7°, 12.8°, 13.3° and 20.0°±0.2° 2θ
Implementation Method 3
a solid-state 13C NMR spectrum with signals at 123.8, 163.1 and 168.5±0.2 ppm
Data Source
AI summary
New forms of Febuxostat have bean, prepared and characterized. These forms are useful for examples in the chronic management of hyperuricemia in patients with gout.