FGFR Inhibitor Solid Forms for Stability and Bioavailability
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Solution Overview
Problem
There is a need for new solid forms of FGFR-inhibiting molecules to facilitate the development of pharmaceutically useful formulations and dosage forms with suitable properties for treating FGFR-mediated diseases such as cancer, addressing issues of safety, efficacy, and quality.
Innovation Solution
The development of solid forms, including crystalline and amorphous forms, of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (Compound 1), along with pharmaceutical compositions and methods for preparing and using these forms to inhibit FGFR enzymes and treat diseases like cholangiocarcinoma and myeloid/lymphoid neoplasms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If new solid forms of FGFR-inhibiting molecules are developed, then pharmaceutical usefulness, safety, and efficacy are improved, but development complexity and time are increased
Solution Approach 1:
The patent applies parameter changes by developing multiple solid forms (crystalline forms I-IV, amorphous form, solvates, hydrates) of the FGFR inhibitor molecule, each with different physical and chemical parameters such as crystal structure, solvent content, and molecular arrangement. These parameter variations improve pharmaceutical properties including dissolution rate, bioavailability, and stability, directly resolving the contradiction between pharmaceutical usefulness and development complexity by optimizing the molecular form rather than creating entirely new compounds
Solution Approach 2:
The patent utilizes phase transitions by converting the FGFR inhibitor between different solid states - crystalline phases (Forms I, II, III, IV), amorphous phase, and solvated/hydrated phases. Each phase transition creates a distinct solid form with unique pharmaceutical properties. For example, the amorphous form typically exhibits enhanced dissolution and bioavailability, while specific crystalline forms may offer improved stability. This approach resolves the technical contradiction by leveraging phase transition science to systematically improve pharmaceutical usefulness through controlled modifications of the solid state structure
2Productivity
If solid forms with improved dissolution profile are created, then bioavailability is enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent employs parameter changes by modifying the solid state parameters of the FGFR inhibitor to achieve improved dissolution profiles. The amorphous form and certain crystalline forms (e.g., Form III, IV) are specifically designed with parameters that enhance dissolution rate and bioavailability. This resolves the contradiction by optimizing molecular arrangement and physical state parameters rather than altering the chemical structure, thereby improving bioavailability while maintaining compatibility with existing manufacturing processes
Solution Approach 2:
The patent uses solvents and water as intermediaries to create solvates and hydrates of the FGFR inhibitor. These intermediary substances facilitate the formation of solid forms with improved dissolution properties. For example, solvates with specific solvents can enhance solubility and dissolution rate, thereby improving bioavailability. The intermediary approach resolves the manufacturing complexity issue because these solvates and hydrates can be formed through straightforward solvent evaporation or crystallization processes from existing manufacturing workflows
3Duration of action of stationary object
If stable solid forms are developed, then shelf-life is extended, but formulation flexibility is reduced
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (I, II, III, IV) and solvates with different stability parameters. Each form has optimized parameters for specific applications - some forms prioritize shelf-life stability while others offer enhanced dissolution or formulation compatibility. This systematic parameter optimization resolves the contradiction by providing a portfolio of solid forms, allowing formulators to select the appropriate form for each specific application, thereby maintaining both extended shelf-life and formulation flexibility
Solution Approach 2:
The patent segments the single FGFR inhibitor compound into multiple distinct solid forms, each with specialized properties. Crystalline Forms I-IV are segmented with different stability and dissolution characteristics, while solvates and hydrates are segmented based on solvent/water content. This segmentation resolves the contradiction between shelf-life and formulation flexibility by allowing different segments (solid forms) to be deployed for different formulation needs - highly stable forms for long-term storage and more soluble forms for rapid-release formulations
Data Source
AI summary
The present disclosure relates to 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, solid forms and polymorphs thereof, methods of preparation thereof, and intermediates in the preparation thereof, which are useful in the treatment of the FGFR-associated or mediated diseases such as cancer.