Dasatinib Polymorphs: Solvent Reduction via Crystallization Control
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Solution Overview
Problem
Dasatinib's insolubility in water and organic solvents makes industrial production challenging, and existing methods fail to effectively reduce related substances, leading to poor product quality and stability issues.
Innovation Solution
New polymorphs of Dasatinib, specifically Polymorph I and Polymorph II, are developed with improved physical and chemical properties, including controlled crystallization conditions and solvent systems, which facilitate easier and more efficient production and purification, reducing the amount of organic solvents required.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If existing preparation methods are used to produce Dasatinib polymorphs, then Dasatinib can be obtained, but a large amount of organic solvent is required due to poor solubility
Solution Approach 1:
The patent applies parameter changes by modifying the solvent system composition and crystallization conditions. Specifically, it uses a mixed solvent system (water-organic solvent) with optimized ratios, controls temperature parameters during crystallization, and adjusts pH values to achieve optimal solubility and polymorph formation, thereby reducing the total amount of organic solvent required while maintaining ease of manufacture
Solution Approach 2:
The patent introduces water as an intermediary substance to mediate the solubility problem. By using a water-organic solvent mixed system where water acts as a co-solvent, the overall organic solvent requirement is reduced. The water component facilitates dissolution and crystallization processes, serving as a bridge that allows Dasatinib to be processed with lower organic solvent content
2Manufacturing precision
If existing preparation methods are used, then Dasatinib polymorphs can be obtained, but related substances cannot be effectively reduced, leading to poor product quality
Solution Approach 1:
The patent applies preliminary action by optimizing the crystallization process parameters before the actual polymorph formation. This includes pre-adjusting the solvent composition, temperature profile, and addition rate to ensure that related substances are minimized during the crystallization process itself, rather than requiring extensive post-processing. The method establishes optimal conditions in advance that favor pure polymorph formation
Solution Approach 2:
The patent uses parameter changes to improve manufacturing precision by carefully controlling crystallization temperature, solvent ratio, and pH during the polymorph formation process. These parameter optimizations ensure that Dasatinib crystallizes in the desired polymorphic form with minimal related substances, achieving high product quality without requiring excessive purification steps
3Stability of the object's composition
If existing preparation methods are used, then Dasatinib can be produced, but stability issues occur during storage
Solution Approach 1:
The patent applies parameter changes to improve storage stability by optimizing the polymorphic form selection and controlling the crystallization conditions. The specific polymorphs obtained through the patented method exhibit enhanced stability characteristics. Additionally, the method controls moisture content and solvent residue through optimized drying parameters, ensuring long-term storage stability
Solution Approach 2:
The patent employs a water-organic solvent mixed system where water serves as a stable, non-toxic component that enhances long-term storage stability. The use of water as a co-solvent creates a more stable final product compared to methods using only organic solvents, extending the storage duration without compromising composition stability
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 new polymorphs exhibit enhanced stability, improved solubility, and better manufacturing processes, making them suitable for industrial production and long-term storage, while minimizing organic solvent usage and toxic effects.
Implementation Method 1
dissolved by heating to 75° C.
Implementation Method 2
cooling to 5° C. within 2 h and keeping the temperature at 0 ̃5° C. for 2 h
Implementation Method 3
The slurry was filtrated and the filter cake was washed
Implementation Method 4
after being dried under vacuum≦50° C. 41 g of solid was obtained
Data Source
AI summary
Polymorph I of dasatinib monohydrate and Polymorph II of dasatinib, their preparation methods and pharmaceutical compositions containing the same are provided. These polymorphs have better physicochemical properties, are more stable and are more suitable for industrial scale production.