Crystalline FGFR Inhibitor Salts for Stability and Dissolution
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Solution Overview
Problem
There is a need for new salts of FGFR-inhibiting molecules to facilitate the development of pharmaceutically useful formulations with suitable properties for the treatment of FGFR-mediated diseases such as cancer, addressing issues related to safety, efficacy, and quality of drug products.
Innovation Solution
The development of various acid salts of the FGFR inhibitor 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, including D-(−)-tartaric, L-(+)-tartaric, salicylic, hydrochloric, hydrobromic, fumaric, phosphoric, benzenesulfonic, ethanesulfonic, maleic, and adipic acid salts, which can be isolated in crystalline forms for improved handling, stability, and pharmaceutical performance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the FGFR inhibitor is used in its original form, then the drug can be administered, but the handling ease, storage stability, and purification difficulty are insufficient
Solution Approach 1:
The patent applies parameter changes by converting the FGFR inhibitor into different salt forms (hydrochloride, hydrobromide, sulfate, phosphate, etc.), which changes the chemical parameters of the compound. This transformation improves storage stability and facilitates purification while maintaining the pharmacological activity of the original molecule.
Solution Approach 2:
The patent creates composite materials by forming salts of the FGFR inhibitor with various acids. These salt forms combine the active pharmaceutical ingredient with counterions to produce compounds with improved physical and chemical properties, including enhanced stability and easier purification characteristics.
2Reliability
If the FGFR inhibitor is administered, then therapeutic effect is achieved, but the dissolution profile and bioavailability are suboptimal
Solution Approach 1:
The patent changes the physical and chemical parameters of the FGFR inhibitor by forming various salt compounds. This parameter change directly impacts the dissolution profile and bioavailability of the drug, enabling better absorption and therapeutic efficacy while maintaining the core pharmacological activity.
3Adaptability or versatility
If multiple salt forms are developed, then pharmaceutical formulation options increase, but the device complexity and development time increase
Solution Approach 1:
The patent segments the development process by isolating and characterizing each salt form independently. Each salt (hydrochloride, hydrobromide, sulfate, phosphate, etc.) is prepared and evaluated as a separate entity, allowing systematic optimization of formulation options without overwhelming complexity.
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 crystalline acid salts enhance the ease of handling, storage stability, and purification of the FGFR inhibitor, improving dissolution profile and bioavailability, making them suitable for pharmaceutical formulations.
Implementation Method 1
The compound of Formula (I) can be isolated as one or more solid forms including, but not limited to, crystalline forms
Data Source
AI summary
The present invention relates to salt forms of the Fibroblast Growth Factor Receptors (FGFR) inhibitor 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, including methods of preparation thereof, where the compound is useful in the treatment of FGFR mediated diseases such as cancer.