Fruquintinib Hydrate Crystal Form for Stable Drug Development
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Solution Overview
Problem
There is a need to develop a hydrate form of fruquintinib, a VEGFR inhibitor, with good druggability, as existing crystal forms are either anhydrates or organic solvates, which are unsuitable for drug development and unstable under moisture exposure.
Innovation Solution
The development of a fruquintinib hydrate and its crystal form α, characterized by specific X-ray powder diffraction peaks and water content, prepared through methods involving solvent mixing and crystallization with additives like xylitol in solvents such as tetrahydrofuran.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystal forms (anhydrates or organic solvates) are used, then the formulation can be maintained, but the druggability and stability for drug development are insufficient
Solution Approach 1:
The patent changes the crystal form parameter from anhydrate/organic solvate to hydrate (specifically monohydrate, dihydrate, or trihydrate forms). This parameter change in crystal structure enables both improved stability and enhanced druggability, resolving the contradiction by finding an optimal crystal form that satisfies both requirements simultaneously.
2Stability of the object's composition
If organic solvate crystal forms are used, then the crystal structure is stable, but the presence of organic solvents makes them unsuitable for drug development
Solution Approach 1:
The patent extracts and removes the harmful organic solvent component from the crystal structure. By developing hydrate forms that contain only water molecules (without organic solvents), the invention eliminates the harmful factor while maintaining crystal structure stability through the water-of-crystallization framework.
Solution Approach 2:
Water in the hydrate crystal structure creates an inert environment that protects the active pharmaceutical ingredient from degradation. The water molecules in the crystal lattice provide a stable, non-reactive environment that enhances drug stability without introducing harmful organic solvents.
3Device complexity
If anhydrate crystal forms are used, then the formulation is simple, but the forms are unstable and prone to hydration during processing and storage
Solution Approach 1:
The patent applies beforehand cushioning by pre-incorporating water molecules into the crystal structure during formulation. By developing hydrate forms that already contain the appropriate amount of water (monohydrate, dihydrate, or trihydrate), the invention prevents unwanted hydration during storage and processing, effectively cushioning against environmental moisture.
4Reliability
If hydrate crystal forms are developed, then stability and bioavailability are improved, but the preparation process complexity increases
Solution Approach 1:
The patent uses parameter changes in the crystallization process (such as temperature, pH, solvent composition, and presence of additives) to control the formation of specific hydrate forms. By optimizing these parameters, the invention achieves stable and bioavailable hydrate crystal forms through controlled crystallization rather than complex multi-step processes.
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 fruquintinib hydrate exhibits improved physicochemical properties, including stability, solubility, bioavailability, and hygroscopicity, facilitating wider medicament preparation and reducing reagent costs, with a simple, repeatable, and environmentally friendly preparation process.
Implementation Method 1
an X-ray powder diffraction pattern of the crystal form has characteristic peaks at 20 angles of 7.2±0.2°, 8.6±0.2°, 14.4±0.2°, 15.2±0.2°, 20.4±0.2°, 22.3±0.2°, 24.0±0.2°, 26.1±0.2°, 26.4±0.2°, and 29.1±0.2°
Implementation Method 2
preparation method therefor... mixing fruquintinib and an additive in a solvent A and crystallizing
Data Source
AI summary
A hydrate of a VEGFR inhibitor, a crystal form thereof and a preparation method therefor are provided. The VEGFR inhibitor is 6-(6,7-dimethoxyquinazolin-4-yl-oxy)-N,2-dimethylbenzofuran-3-carboxamide, and the hydrate and the crystal form thereof have good physicochemical properties, and have good flowability, solubility, stability and bioavailability, and alleviated hygroscopicity. In addition, the preparation method is simple, has good repeatability, achieves high yield, and is easy to perform and environment-friendly, and the method requires only a small amount of solvents and facilitates recycling use, thus effectively reducing the cost on reagents, and enabling easy implementation of large-scale mass production.