CDK4 Inhibitor Solid Forms With Low Hygroscopicity and Stability
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Solution Overview
Problem
Existing forms of the CDK4 inhibitor PF-07220060 lack desirable properties such as high crystallinity, purity, low hygroscopicity, favorable dissolution, mechanical properties, and stability, which are crucial for effective pharmaceutical applications.
Innovation Solution
Development of crystalline forms (Form 2), anhydrous crystalline forms (Form 6), and amorphous forms (Form 8) of PF-07220060, characterized by specific PXRD, Raman, 13C solid state NMR, and 19F solid state NMR patterns, enhancing properties like high crystallinity, purity, and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline hydrate Form 1 is used, then the compound can be isolated and obtained, but it exhibits high hygroscopicity and poor stability
Solution Approach 1:
The patent applies parameter changes by transforming the crystalline form from hydrate to anhydrous state, fundamentally altering the physical and chemical properties of the compound. This parameter change eliminates water of crystallization, thereby reducing hygroscopicity and improving stability without changing the molecular structure of PF-07220060 itself
Solution Approach 2:
The invention utilizes phase transitions by converting the compound from a crystalline hydrate phase to an anhydrous crystalline phase. This phase transition results in a new solid form with different properties, specifically lower hygroscopicity and enhanced stability, while maintaining the therapeutic activity of the compound
2Manufacturing precision
If existing solid forms are used, then the compound is available for pharmaceutical use, but they lack high crystallinity and purity
Solution Approach 1:
The patent applies preliminary action by implementing a multi-step crystallization process that pre-establishes high purity and crystallinity before final product formation. The process includes preliminary filtration, washing with specific solvents, and controlled drying conditions that ensure the anhydrous form achieves superior crystallinity and purity from the outset
Solution Approach 2:
The invention uses intermediary substances, specifically organic solvents like ethanol or isopropanol, as mediators during the crystallization process. These intermediaries facilitate the formation of high-quality anhydrous crystals by controlling solubility and crystal growth, resulting in products with enhanced crystallinity and purity
3Ease of operation
If existing forms are used, then the compound can be administered, but they exhibit poor dissolution and mechanical properties
Solution Approach 1:
The patent applies parameter changes by modifying the physical state from hydrate to anhydrous form, which fundamentally alters dissolution characteristics and mechanical properties. The anhydrous crystalline form exhibits improved dissolution rate and enhanced mechanical strength, making it more suitable for pharmaceutical formulations and tablet pressing
Data Source
AI summary
This invention relates to crystalline and amorphous forms of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol, to pharmaceutical compositions comprising such solid forms, and to use of such solid forms and pharmaceutical compositions for the treatment of cancer.