Pyrimidine RET Inhibitor Salt Forms for Bioavailability and Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current RET inhibitors lack high efficacy and low toxicity, and there is a need for crystalline forms of RET inhibitors with improved bioavailability, stability, and manufacturability for medical and pharmaceutical use.
Innovation Solution
Development of fumarate and p-toluenesulfonate salts and various crystal forms of the pyrimidine compound 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine, including specific crystal forms A to VI and amorphous forms, with methods for preparation and pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple crystal forms and salts of compound I are developed, then bioavailability and physical/chemical stability are improved, but device complexity and manufacturing complexity increase
Solution Approach 1:
The patent applies parameter changes by developing multiple crystal forms (Forms I-VI) and salt forms (fumarate, p-toluenesulfonate) of compound I, each with distinct physical and chemical properties. Different crystal forms exhibit varying solubility, stability, and bioavailability characteristics, allowing optimization of these parameters for specific therapeutic applications without changing the core molecular structure.
Solution Approach 2:
The invention segments compound I into multiple distinct crystal forms and salt forms, each with unique properties. This segmentation allows the same active pharmaceutical ingredient to be delivered in forms optimized for different routes of administration, storage conditions, and patient populations, thereby improving overall reliability while managing complexity through systematic classification.
2Ease of manufacture
If various crystal forms are developed for RET inhibitors, then manufacturability and purity are improved, but device complexity increases
Solution Approach 1:
The patent utilizes parameter changes by establishing six different crystal forms and multiple salt forms of compound I, each with distinct crystallization behaviors, solubility profiles, and purification characteristics. These parameter variations enable manufacturers to select the most suitable form for specific production requirements, improving ease of manufacture while maintaining systematic control over complexity.
Solution Approach 2:
The invention applies local quality by optimizing specific properties of each crystal form for particular manufacturing needs. For example, certain crystal forms may be optimized for high purity through controlled crystallization, while others may be optimized for scalability or specific route of administration, allowing tailored manufacturing approaches for different market needs.
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 developed salts and crystal forms exhibit desirable inhibitory effects on RET, enhancing pharmacokinetic properties and safety, improving bioavailability, stability, and manufacturing processes, suitable for treating conditions associated with RET activity such as cancer and irritable bowel syndrome.
Implementation Method 1
reacting the compound I in any solid form with an inorganic acid or an organic acid, precipitating a solid
Implementation Method 2
precipitating a solid, and subsequently separating and drying the precipitated solid
Data Source
AI summary
Provided are a salt and a crystal form of a pyrimidine compound, and preparation methods therefor. Specifically, provided are a salt and a crystal form of a compound I, including a crystal form of the salt, and preparation methods therefor.