Methanesulfonate Crystal Forms for Soluble Stable C-Met Inhibitors
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Solution Overview
Problem
Existing formulations of the 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-thio)-4-methyl-2H-[1,4]oxazino[3,2-c]quinoline-3(4H)-one methanesulfonate do not adequately address the need for stable and effective pharmaceutical forms suitable for treating C-Met/HGFR kinase-related cancers.
Innovation Solution
Development of nine distinct crystal forms (A to I) of the methanesulfonate compound, each with specific X-ray diffraction patterns and proton nuclear magnetic resonance spectra, enhancing stability and solubility, and a method for their preparation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing formulations of the methanesulfonate compound are used, then the basic pharmaceutical need is met, but the solubility and stability are insufficient for effective treatment
Solution Approach 1:
The patent applies parameter changes by developing nine distinct crystal forms (polymorphs) of the methanesulfonate compound, each with different crystal structures characterized by specific X-ray diffraction patterns. These polymorphic forms exhibit varying solubility and stability parameters, allowing selection of the optimal form for pharmaceutical application. The different packing arrangements in each crystal form directly alter the physicochemical properties including solubility, melting point, and stability without changing the chemical composition.
Solution Approach 2:
The patent utilizes phase transitions by creating multiple solid-state polymorphic forms of the compound. Each crystal form represents a different solid phase with distinct molecular packing and intermolecular interactions. The ability to transition between these phases through controlled crystallization conditions enables optimization of solubility and stability for pharmaceutical formulation.
2Ease of operation
If a single crystal form is used, then the formulation is simple, but the bioavailability and pharmaceutical processing are limited
Solution Approach 1:
By providing nine different crystal forms with systematically varied properties, the patent enables selection of the specific polymorph that best balances formulation simplicity with bioavailability requirements. Each crystal form offers different dissolution rates, solubility profiles, and stability characteristics, allowing optimization of the drug product performance while maintaining manageable formulation complexity.
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 crystal forms exhibit improved physicochemical properties, including solubility and stability, facilitating bioavailability and pharmaceutical processing, making them suitable for treating C-Met/HGFR kinase-related cancers effectively.
Implementation Method 1
Development of nine distinct crystal forms (A to I) of the methanesulfonate compound, each with specific X-ray diffraction patterns and proton nuclear magnetic resonance spectra
Data Source
Figure 1~1A
Figure 2~3
Figure 3A~3B
AI summary
Disclosed in the present invention are a triazolo ring compound methanesulfonate crystal form, a preparation method therefor and a use thereof. Specifically, disclosed are a crystal form of a compound methanesulfonate of formula (I), and a preparation method therefor and a use thereof, wherein the methanesulfonate crystal form is selected from crystal forms A-I; and disclosed are a preparation method for the crystal form and a pharmaceutical composition containing the crystal form. The preparation method of the present invention is simple and easy to implement and suitable for industrial large-scale production; the crystal forms A-I of the compound methanesulfonate of formula (I) prepared have good solubility and stability, thereby facilitating the preparation and storage of pharmaceutical preparations.