Crystalline Form Stabilization for Antitumor Drug Storage
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Solution Overview
Problem
There is a need to investigate crystalline forms of the antitumor drug 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)aminoformyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy] hexanoic acid, as good properties related to drug processing, preparation, storage stability, and usefulness are crucial for drug development.
Innovation Solution
The patent describes three crystalline forms (AB, M, and F) of the compound, along with methods for preparing them. These methods involve dissolving the compound in an alcohol solvent, precipitating crystals at low temperatures, and filtering and drying to obtain the crystalline forms. The crystalline forms are characterized by their X-ray powder diffraction patterns and thermal analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the compound is processed as an amorphous solid or non-crystalline form, then it may be easier to process initially, but it exhibits poor storage stability and chemical degradation under high temperature and humidity conditions
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of the compound from amorphous to crystalline form. Specifically, three distinct crystalline forms (AB, M, and F) are developed with different crystal structures, each exhibiting superior stability under high temperature and humidity conditions compared to the amorphous form. The crystalline forms are achieved through controlled crystallization processes from various solvents, fundamentally changing the molecular arrangement and intermolecular forces to enhance storage stability.
Solution Approach 2:
The patent utilizes phase transitions by inducing the compound to transition from an amorphous or solution state into defined crystalline phases. The crystallization process involves controlled cooling, solvent evaporation, or anti-solvent addition to nucleate and grow stable crystal structures. This phase transition from disordered to ordered molecular arrangement is the key mechanism that confers enhanced storage stability and chemical resistance to the crystalline forms.
2Stability of the object's composition
If multiple crystalline forms are developed and characterized, then storage stability and chemical resistance are improved, but the complexity of characterization and analysis increases
Solution Approach 1:
The patent applies segmentation by dividing the crystalline forms into three distinct categories (Form AB, Form M, and Form F), each with uniquely identified diffraction patterns and characteristic properties. This segmentation allows for systematic characterization and differentiation of each polymorph using standard techniques like XRPD, DSC, and HPLC. By segmenting the crystalline forms into discrete, well-defined categories, the patent simplifies the overall characterization process compared to dealing with undefined amorphous variations.
Solution Approach 2:
The patent uses parameter changes to differentiate and characterize the three crystalline forms through their distinct physical and chemical parameters. Each form has unique X-ray powder diffraction patterns with characteristic peak positions and intensities, distinct melting points and thermal behaviors in DSC analysis, and different solubility profiles. These parameter variations provide clear fingerprints for identifying and characterizing each polymorph, making the characterization process more manageable despite the presence of multiple forms.
3Reliability
If the compound is formulated without defined crystalline structure, then formulation flexibility may be higher, but bioavailability and drug performance are reduced
Solution Approach 1:
The patent applies parameter changes by establishing defined crystalline structures with specific physical parameters that optimize drug performance. The three crystalline forms exhibit different solubility, dissolution rate, and bioavailability characteristics compared to the amorphous form. Through selecting appropriate crystalline forms and controlling their physical parameters (particle size, crystal habit, polymorph selection), the patent achieves reliable and reproducible drug performance while maintaining formulation flexibility through the availability of multiple crystalline options.
Solution Approach 2:
The patent effectively creates composite pharmaceutical materials by combining the active compound in defined crystalline forms with excipients and formulation components. The crystalline forms serve as stable, well-defined matrices that can be reliably formulated into various dosage forms (tablets, capsules, suspensions). The defined crystal structures provide a stable foundation for formulation development, enabling flexible combination with different excipients while ensuring consistent drug performance and bioavailability.
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 crystalline forms AB, M, and F exhibit good chemical stability, high yield, and purity, making them suitable for pharmaceutical use. They maintain stability even under high temperature, high humidity, and oxidizing conditions, facilitating storage, transportation, and industrial production. Additionally, the crystalline form AB shows high bioavailability.
Implementation Method 1
adding the compound 1 to an alcohol solvent, and heating at a temperature ranging from 75° C. to 80° C. to dissolving the compound 1
Implementation Method 2
precipitating crystals at a temperature below −5° C., stirring at a temperature ranging from −10° C. to −15° C. to further precipitate crystals
Implementation Method 3
an X-ray powder diffraction pattern of the crystalline form AB represented by an angle of 2θ has diffraction peaks at 4.6±0.1°, 6.7±0.1°, 10.7±0.1°, 16.2±0.1°, 17.0±0.1°, 17.4±0.1°, 19.5±0.1°, 20.7±0.1°, 21.9±0.1°, 22.5±0.1°, 23.8±0.1°, and 25.1±0.1°
Data Source
AI summary
The present disclosure relates to the field of pharmaceutical technology, providing three crystalline forms, i.e., a crystalline form AB, a crystalline form M and a crystalline form F, of the compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)aminoformyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid for treatment of diseases related to protein kinases AXL and/or VEGFR2. The present disclosure also provides methods for preparing these three crystalline forms and pharmaceutical compositions comprising these three crystalline forms. The crystalline form AB, the crystalline form M and the crystalline form F of the present disclosure all have good chemical stability, and the preparation processes of the three crystalline forms of the present disclosure are simple for implementation with high product yield and purity, allowing stable and mass production that facilitates promotion and application.