Lenvatinib Mesylate Form M Crystallization
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Solution Overview
Problem
Existing crystalline forms of lenvatinib mesylate vary in solubility and stability, affecting absorption, bioavailability, and therapeutic efficacy, necessitating a comprehensive screening for a suitable form.
Innovation Solution
A novel crystalline form of lenvatinib mesylate, designated as Form M, with specific X-ray powder diffraction peaks and a preparation process involving the addition of methanesulfonic acid in acetonitrile, offering improved solubility, stability, and purification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms of lenvatinib mesylate are used, then the drug can be manufactured, but the solubility and stability vary leading to inconsistent absorption and bioavailability
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent type (acetonitrile, ethanol, isopropanol, etc.), temperature ranges (0-25°C), and pH levels (adjusted with methanesulfonic acid) to transform lenvatinib mesylate from existing crystalline forms with inconsistent properties into a new Form M with optimized and consistent solubility, stability, and bioavailability parameters
2Reliability
If comprehensive polymorph screening is conducted to find the most suitable crystalline form, then the most suitable form can be selected, but the development process becomes more complex and time-consuming
Solution Approach 1:
The patent applies preliminary action by pre-establishing a systematic crystallization methodology using specific solvents (particularly acetonitrile), controlled temperature ranges (0-25°C), and pH adjustment protocols with methanesulfonic acid. This pre-defined approach directly yields Form M with optimized properties, eliminating the need for extensive preliminary polymorph screening while ensuring reliable therapeutic effect
Solution Approach 2:
By systematically varying and controlling crystallization parameters (solvent selection, temperature, pH), the patent efficiently screens and identifies Form M as the optimal crystalline form, resolving the contradiction between comprehensive screening and process complexity
3Reliability
If multiple crystalline forms are developed through systematic screening, then the most suitable form for development can be selected, but the development time and cost increase
Solution Approach 1:
The patent applies preliminary action by pre-defining an efficient crystallization protocol using acetonitrile as the primary solvent, controlled temperature (0-25°C), and methanesulfonic acid for pH adjustment. This pre-established methodology directly produces Form M with improved solubility and stability, significantly reducing development time while ensuring reliable drug properties
Solution Approach 2:
The patent efficiently resolves the contradiction by systematically optimizing key crystallization parameters (solvent type, temperature, pH) to directly obtain Form M with superior solubility and stability, avoiding the time-consuming process of developing and evaluating multiple crystalline forms
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 M exhibits enhanced solubility, stability, and purification, simplifying the drug development process while maintaining therapeutic efficacy, avoiding bioavailability and efficacy changes during storage.
Implementation Method 1
adding compound (I) and methanesulfonic acid into an appropriate crystallizing solvent, stirring to get Form M
Implementation Method 2
its X-ray powder diffraction pattern shows at least three characteristic peaks at 2theta values of 11.3°±0.2°, 6.1°±0.2°, 15.2°±0.2°
Data Source
AI summary
The present disclosure relates to a novel crystalline form of lenvatinib mesylate and the preparation method thereof. The novel crystalline form of mesylate of the present disclosure can be used for treating invasive and differentiated thyroid cancer. The novel crystalline form of mesylate of the present disclosure has good solubility, stability, and remarkable purification effect in process. The preparation method of this novel crystalline form is simple, low cost, and has an important value for future optimization and development of the drug.