Diaminopyrimidine Salt Crystal Forms for P2X3 Bioavailability
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Solution Overview
Problem
Existing 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 salts with specific molar ratios, such as hydrochloride, citrate, sulfate, and mesylate, which enhance physical properties, stability, and bioavailability, facilitating better pharmaceutical formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing P2X3 and/or P2X2/3 receptor antagonists are used, then the therapeutic effect is achieved, but the physical properties, solubility, dissolution rate, and stability are insufficient
Solution Approach 1:
The patent applies parameter changes by converting the compound into different salt forms (hydrochloride, citrate, sulfate, mesylate) with specific molar ratios. This chemical parameter modification fundamentally alters the physical properties including solubility, dissolution rate, and stability while preserving the core therapeutic activity against P2X3 and/or P2X2/3 receptors.
Solution Approach 2:
The invention creates composite crystalline structures by combining the diaminopyrimidine compound with various counterions in specific stoichiometric ratios. These composite crystalline forms integrate multiple components into a unified solid structure that exhibits improved physical properties compared to the parent compound alone.
2Reliability
If existing P2X3 and/or P2X2/3 receptor antagonists are used, then the pain treatment effect is achieved, but the bioavailability is limited
Solution Approach 1:
By changing the salt form parameters of the compound, the patent optimizes bioavailability. The selected salt forms (particularly hydrochloride, citrate, sulfate, and mesylate) exhibit enhanced solubility and dissolution characteristics that directly improve absorption and bioavailability while maintaining the pain treatment efficacy.
3Reliability
If existing P2X3 and/or P2X2/3 receptor antagonists are used, then the receptor antagonism is achieved, but the toxicity from drug accumulation occurs
Solution Approach 1:
The patent modifies the chemical parameters by forming salts with specific counterions, which alters the pharmacokinetic profile. The new crystalline forms exhibit reduced drug accumulation and lower toxicity while preserving the desired receptor antagonism, likely due to improved solubility and metabolic characteristics.
4Reliability
If existing P2X3 and/or P2X2/3 receptor antagonists are used, then the therapeutic activity is achieved, but the dissolution rate is insufficient
Solution Approach 1:
The invention changes the physical-chemical parameters by creating salt forms with specific counterions and molar ratios. This fundamentally improves the dissolution rate of the compound while maintaining therapeutic activity, as the ionic interactions in the salt forms enhance solubility and breakdown in aqueous environments compared to the parent compound.
Data Source
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AI summary
The present invention relates to a salt of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine and a solid form thereof, a method for preparing the solid form and a pharmaceutical composition comprising the solid form, as well as a use of the solid form for preventing or treating diseases modulated by P2X3 and/or P2X2/3 receptor antagonists.