CDK4/6 Inhibitor Solid-State Forms for Solubility and Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need to identify a suitable solid-state form of the CDK4/6 inhibitor Compound 1 that exhibits desirable chemical and physical properties, such as solubility, stability, and bioavailability, and to develop reliable methods for its manufacture and purification to create effective therapeutic formulations.
Innovation Solution
The development of various crystalline and amorphous forms of Compound 1, including freebase and pharmaceutically acceptable salts like HCl, H2SO4, H3PO4, methanesulfonic acid, and p-toluenesulfonic acid salts, along with methods for their preparation, to enhance solubility, stability, and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If a suitable solid-state form of Compound 1 is identified, then solubility and bioavailability are improved, but the complexity of identifying and characterizing multiple crystalline and amorphous forms increases
Solution Approach 1:
The patent applies parameter changes by systematically varying physical and chemical parameters to transform Compound 1 into different solid-state forms. Specifically, the invention creates multiple crystalline polymorphs (Forms A-F) and amorphous forms with distinct X-ray diffraction patterns, melting points, and solubility characteristics. Salt formation with various acids (HCl, H2SO4, H3PO4, methanesulfonic acid, p-toluenesulfonic acid) further modifies the physical and chemical parameters to optimize solubility and bioavailability while maintaining the core molecular structure
Solution Approach 2:
The patent utilizes phase transitions by deliberately inducing transitions between different solid-state forms of Compound 1. The invention describes methods to transition between crystalline polymorphs and amorphous forms through controlled crystallization, solvent selection, and processing conditions. These phase transitions enable optimization of solubility and bioavailability properties without altering the fundamental molecular identity of the compound
2Ease of operation
If multiple salt forms and crystalline polymorphs are developed, then solubility and bioavailability are enhanced, but the manufacturing and purification processes become more complex
Solution Approach 1:
The patent applies segmentation by separating the development of different salt forms and crystalline polymorphs into distinct, independently optimized manufacturing pathways. Each salt form (HCl, H2SO4, H3PO4, methanesulfonic acid, p-toluenesulfonic acid salts) and crystalline polymorph (Forms A-F) is characterized and processed through specific purification methods tailored to its unique properties. This segmentation allows parallel development and selection of the most suitable form for manufacturing without requiring complex integrated processes
Solution Approach 2:
The patent employs intermediaries in the form of specific solvents and counterions that facilitate the formation and purification of different salt forms. For example, hydrochloric acid serves as an intermediary to form the HCl salt, which then can be further processed into specific crystalline polymorphs. These intermediary substances enable controlled transformation between different solid-state forms while simplifying the overall manufacturing and purification processes
3Stability of the object's composition
If crystalline and amorphous forms are prepared for formulation, then stability and solubility are optimized, but the time and resources required for characterization and development increase
Solution Approach 1:
The patent applies preliminary action by conducting comprehensive characterization of all crystalline polymorphs (Forms A-F) and salt forms during the early development stage. The invention provides advance data on X-ray diffraction patterns, melting points, solubility profiles, and stability characteristics for each form. This preliminary characterization enables informed selection of the most suitable form for formulation development, avoiding time-consuming trial-and-error processes later in the development cycle
Solution Approach 2:
The patent implements feedback mechanisms through systematic comparison and evaluation of different solid-state forms based on their characterized properties. The invention uses feedback from solubility measurements, stability studies, and bioavailability data to guide the selection and optimization of specific crystalline polymorphs and salt forms. This feedback-driven approach accelerates the development process by quickly identifying and eliminating less promising forms while focusing resources on the most viable options
Data Source
AI summary
Crystalline and amorphous forms of N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl-5-fluoro-4-(3-iso-propyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine (Compound 1) and various salts thereof, preparation methods of these crystalline and amorphous forms, pharmaceutical compositions containing these crystalline or amorphous forms, and use of these crystalline and amorphous forms, or pharmaceutical compositions thereof, for treatment of diseases or disorders associated with cyclin-dependent kinase (CDK), especially CDK4 and CDK6, activities, such as various cancers, are disclosed.