Diaminopyrimidine Crystal Forms for Solubility and Stability
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Solution Overview
Problem
Existing diaminopyrimidine compounds used as P2X3 and/or P2X2/3 receptor antagonists face challenges in terms of physical properties, solubility, dissolution rate, stability, and bioavailability, which affect their efficacy and safety in treating pain-related diseases.
Innovation Solution
Development of crystalline forms of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine with specific XRPD patterns and DSC/TGA characteristics, offering improved solubility, stability, and bioavailability, along with methods for their preparation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing diaminopyrimidine compounds are used as P2X3 and/or P2X2/3 receptor antagonists, then they can block ATP-gated cation channels to treat pain-related diseases, but they suffer from poor physical properties including low solubility, slow dissolution rate, and low bioavailability
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (Form I through Form VIII) with different physical and chemical properties. Each crystalline form has distinct XRPD patterns, solubility characteristics, and dissolution rates. This allows selection of the most appropriate form for specific pharmaceutical applications, resolving the contradiction between maintaining therapeutic efficacy and improving formulation properties.
Solution Approach 2:
The patent creates composite pharmaceutical compositions by combining specific crystalline forms with excipients and carriers. For example, Form I is combined with pharmaceutically acceptable carriers to create formulations with improved bioavailability. The composite approach allows optimization of both therapeutic effect and physical properties through careful selection of crystal form and formulation components.
2Reliability
If existing diaminopyrimidine compounds are administered, then they can achieve P2X3 and/or P2X2/3 receptor antagonism, but they exhibit high toxicity due to poor absorption and drug accumulation
Solution Approach 1:
The patent utilizes parameter changes in the physical form of the compound to improve absorption characteristics. Crystalline Form II and Form III exhibit different dissolution rates and absorption profiles compared to other forms, leading to reduced drug accumulation and lower toxicity while maintaining effective receptor antagonism. The selection of appropriate crystalline form directly impacts the toxicity profile.
3Reliability
If existing diaminopyrimidine compounds are used, then they can function as P2X3 and/or P2X2/3 receptor antagonists, but they show poor stability under various storage conditions
Solution Approach 1:
The patent demonstrates that different crystalline forms have different stability characteristics under various storage conditions. Form I shows high stability under humid conditions, while other forms may be more stable under different temperature or moisture conditions. This allows selection of the most stable form for specific storage and handling requirements, ensuring both long-term stability and effective receptor antagonism.
Data Source
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AI summary
The present invention relates to a solid form of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine or a hydrate thereof, a method for preparing the solid form, a pharmaceutical composition comprising the solid form, and a use of the solid form for the prevention or treatment of a disease modulated by P2X3 and/or P2X2/3 receptor antagonists.