Febuxostat Form I Crystalline Polymorph for Solubility and Stability
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Solution Overview
Problem
Existing crystal forms of Febuxostat, such as form A, have limited solubility and are difficult to produce in pure form, leading to issues with polymorphic conversion and stability during pharmaceutical formulation, which affects drug product stability and bioavailability.
Innovation Solution
Development of a new crystalline form, designated as form I, with improved solubility and stability, achieved through processes involving novel intermediates like form II and a tert.-amylalcohol solvate, which allows for more efficient production and storage of pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If form A of Febuxostat is used, then it is the preferred solid state form for formulation, but its solubility is limited
Solution Approach 1:
The patent applies parameter changes by discovering and utilizing a new polymorphic form (form I) of Febuxostat with different crystal structure parameters. This polymorph exhibits enhanced solubility (0.45 mg/ml) compared to form A (0.22 mg/ml) while maintaining formulation stability, directly resolving the contradiction between solubility and formulation reliability
2Quantity of substance
If forms other than form A are used, then solubility may be improved, but polymorph conversion during formulation or stability studies results in non uniform dissolution
Solution Approach 1:
Instead of attempting to stabilize unstable polymorphs through conventional means, the patent inverts the approach by identifying and utilizing form I, which naturally possesses both high solubility and polymorphic stability. This inversion resolves the contradiction by finding a polymorph that inherently combines both desired properties without undergoing conversion during formulation
3Reliability
If form A is produced, then it is the preferred formulation form, but it is difficult to make as it requires a narrow window of temperature and methanol/water ratio
Solution Approach 1:
The patent changes the manufacturing parameters by developing form I which can be produced through crystallization from various solvent systems including water, alcohols, and their mixtures. This broadens the processing window and simplifies manufacturing compared to form A's narrow temperature and solvent ratio requirements, while maintaining formulation reliability
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
Form I exhibits higher solubility and improved stability, reducing polymorphic conversion and maintaining its form during storage and use, making it a valuable polymorph for pharmaceutical formulations, particularly for treating hyperuricemia and gout.
Implementation Method 1
Specific crystal forms of Febuxostat designated as forms A, B, C, D and G are disclosed... These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up
Data Source
AI summary
The present invention relates to crystalline form I of Febuxostat as well as to pharmaceutical compositions comprising crystalline form I as an active pharmaceutical ingredient. Furthermore the present invention relates to a further polymorphic form of Febuxostat designated as form II and to a novel solvate of Febuxostat. The present invention also relates to methods of making crystalline form I, form II and the novel solvate of Febuxostat.