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 physical properties, solubility, dissolution rate, stability, and bioavailability, leading to issues in drug efficacy and safety.

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, enhancing properties such as solubility, stability, and bioavailability, and providing methods for their preparation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing diaminopyrimidine compounds are used as P2X3 and/or P2X2/3 receptor antagonists, then the therapeutic effect is achieved, but the physical properties, solubility, dissolution rate, stability, and bioavailability are insufficient

Engineering Contradiction:

Improvetherapeutic effectVSAvoidphysical and chemical stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by developing multiple crystalline forms (Form I through Form XII) with different physical and chemical parameters. Each crystalline form has distinct XRPD patterns, DSC characteristics, and solubility profiles. This allows optimization of therapeutic effect while improving physical stability, solubility, and dissolution rate through selection of appropriate crystalline polymorphs

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite pharmaceutical formulations containing the diaminopyrimidine compound in combination with specific excipients and carriers. These composite materials enhance the overall stability, bioavailability, and therapeutic performance while mitigating the limitations of the pure compound through synergistic interactions with formulation components

Inventive Principle:

Principle #40Composite materials

2Reliability

If existing diaminopyrimidine compounds are used, then the receptor antagonist activity is maintained, but the solubility and dissolution rate are poor

Engineering Contradiction:

Improvereceptor antagonist activityVSAvoidsolubility and dissolution rate

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent utilizes parameter changes by identifying and characterizing twelve distinct crystalline forms with varying solubility and dissolution characteristics. Specific forms exhibit enhanced solubility profiles compared to the parent compound, allowing improved bioavailability while maintaining P2X3 and/or P2X2/3 receptor antagonist activity through selective crystalline polymorph selection

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by creating pharmaceutical formulations with spatially differentiated properties - the active compound maintains its receptor-binding capability while the formulation matrix provides localized enhancement of solubility and dissolution rate through specific excipient interactions and delivery system design

Inventive Principle:

Principle #3Local quality

3Reliability

If existing diaminopyrimidine compounds are used, then the pharmacological activity is achieved, but the toxicity from drug accumulation increases

Engineering Contradiction:

Improvepharmacological activityVSAvoidtoxicity from drug accumulation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by selecting crystalline forms with optimized pharmacokinetic properties that enhance metabolic clearance and reduce drug accumulation. The different crystalline polymorphs exhibit varying solubility and dissolution rates that influence absorption and elimination profiles, allowing selection of forms that maintain pharmacological activity while minimizing toxic accumulation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs short-living crystalline forms that are designed to be rapidly metabolized and eliminated from the body. These crystalline polymorphs provide transient therapeutic effect with minimal accumulation, analogous to disposable use, thereby reducing long-term toxicity while maintaining necessary pharmacological activity during treatment periods

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentUS12365665B2Solid form of diaminopyrimidine compound or hydrate thereof, preparation method therefor, and application thereof

Publication Date: 2025.07.22 BEIJING TIDE PHARMACEUTICAL CO LTD

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.