Wee1 Inhibitor Crystal Forms for Stability and Solubility
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Solution Overview
Problem
Current Wee1 inhibitors, such as AZD1775, while showing promise in clinical trials for treating cancer, may face challenges related to stability, solubility, and druggability, which can affect their efficacy and usability as medicaments.
Innovation Solution
The development of specific crystal forms (Crystal Forms A, B, C, D, E, and F) of a compound of formula (I), characterized by distinct X-ray powder diffraction patterns, Differential Scanning calorimetry curves, and Thermogravimetric Analysis profiles, which enhance stability, solubility, and druggability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Wee1 inhibitors are developed for cancer treatment, then therapeutic effectiveness is improved, but stability and solubility issues arise that affect medicament usability
Solution Approach 1:
The patent applies parameter changes by developing multiple crystal forms (Crystal Forms A-F) with different physical and chemical parameters. Each crystal form has distinct XRPD patterns, DSC curves, and TGA profiles, representing different solid-state arrangements of the same Wee1 inhibitor compound. This allows optimization of stability and solubility parameters while maintaining the core therapeutic activity against Wee1 kinase.
Solution Approach 2:
The patent creates composite material structures through different crystal forms of the Wee1 inhibitor. Each crystal form represents a unique composite arrangement of molecules in the solid state, with Crystal Forms A-F exhibiting different packing densities, intermolecular interactions, and lattice energies. These composite structures directly influence the drug's stability, solubility, and bioavailability characteristics.
2Reliability
If Wee1 inhibitors are developed for cancer treatment, then therapeutic effectiveness is improved, but solubility issues arise that affect medicament usability
Solution Approach 1:
The patent utilizes parameter changes by establishing six distinct crystal forms with varying solubility parameters. Crystal Forms A-F exhibit different dissolution rates and solubility profiles due to their unique crystal lattice structures, allowing selection of the most suitable form for specific formulation requirements and manufacturing processes.
Solution Approach 2:
The patent exploits phase transitions between different crystal forms to optimize solubility characteristics. By controlling crystallization conditions, the patent enables transition between stable and metastable crystal forms, each with distinct solubility behaviors. This phase transition capability provides flexibility in manufacturing and formulation development.
3Stability of the object's composition
If crystal forms are developed to improve stability, then sensitivity to light, heat, and humidity is reduced, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by optimizing crystallization parameters such as solvent selection, temperature profiles, and cooling rates to produce stable crystal forms. Each crystal form (A-F) represents an optimized parameter set that enhances resistance to degradation from light, heat, and humidity while establishing reproducible manufacturing protocols.
Solution Approach 2:
The patent implements preliminary action by pre-establishing stable crystal forms with known stability profiles before final formulation and manufacturing. The characterization data (XRPD, DSC, TGA) for each crystal form provides advance information about stability under various conditions, allowing selection of the most robust form for manufacturing without requiring extensive trial-and-error during production.
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
These crystal forms demonstrate improved stability and solubility, reducing sensitivity to light, heat, and humidity, and offering promising druggability, which can enhance the therapeutic effectiveness of Wee1 inhibitors in treating Wee1-related diseases.
Implementation Method 1
Crystal Form A has an X-ray powder diffraction (XRPD) pattern having characteristic diffraction peaks at the following 2θ angles: 5.71±0.2°, 12.68±0.2° and 15.32±0.2°
Implementation Method 2
Crystal Form A has an X-ray powder diffraction (XRPD) pattern having characteristic diffraction peaks
Implementation Method 3
Crystal Form A has a Differential Scanning calorimetry curve (DSC) having one onset point of endothermic peak at 34.95±3° C., 174.75±3° C. and 219.12±3° C.
Implementation Method 4
Crystal Form A has a Thermogravimetric_analysis curve (TGA), wherein the weight loss at 70.33±3° C. is 0.7367%; and the weight loss at 209.42±3° C. is 3.123%
Data Source
AI summary
Disclosed is a crystal form of a compound of formula (I) and the use of the crystal form in the preparation of a drug for treating Wee1-related diseases.