Solid Forms of JNK Inhibitor Compound 1

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Solution Overview

Problem

The development of stable and effective solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (Compound 1) is challenging due to the unpredictability of crystalline forms and polymorphs, which affects physical and chemical properties crucial for pharmaceutical applications, particularly in inhibiting JNK kinases and treating related diseases.

Innovation Solution

The patent describes methods for preparing and characterizing solid forms of Compound 1, including crystalline and amorphous forms, using techniques like X-ray powder diffractometry, thermal analysis, and nuclear magnetic resonance spectroscopy to ensure purity and stability, and provides specific conditions for recrystallization and solvation processes to achieve suitable pharmaceutical properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If multiple solid forms (polymorphs) of a pharmaceutical compound are discovered, then physical and chemical properties can be optimized for specific applications, but the complexity of selecting and characterizing the appropriate solid form increases significantly

Engineering Contradiction:

Improveoptimization of physical and chemical propertiesVSAvoidcomplexity of solid form selection and characterization

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent systematically varies crystallization parameters including solvent type, temperature, pH, and concentration to generate and characterize multiple solid forms of the compound. This approach allows optimization of specific physical and chemical properties (solubility, stability, bioavailability) by selecting appropriate crystallization conditions while providing a structured method to manage the complexity of solid form selection.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs phase transition techniques such as solvate formation, hydrate formation, and polymorphic transitions to generate different solid forms of the compound. By controlling phase transitions through temperature, pressure, and solvent conditions, the patent enables systematic exploration of solid forms with optimized properties while maintaining a controlled approach to characterization.

Inventive Principle:

Principle #36Phase transitions

2Reliability

If crystalline forms are prepared through systematic variation of crystallization parameters, then desired solid forms with optimized properties can be obtained, but the time and resources required for preparation and characterization increase

Engineering Contradiction:

Improvestability and bioavailability of solid formVSAvoidtime for preparation and characterization

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent performs preliminary screening of crystallization conditions using small-scale experiments to identify promising solid forms before conducting extensive characterization. This preliminary action includes rapid assessment of solubility, crystallization behavior, and initial stability data, which guides subsequent resource allocation and reduces overall development time while ensuring reliable solid form selection.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent implements a feedback-driven approach where characterization data from each solid form (XRD patterns, DSC thermograms, solubility measurements) is used to inform and optimize subsequent crystallization experiments. This iterative feedback process accelerates the identification of optimal solid forms by learning from previous results and adjusting crystallization parameters systematically.

Inventive Principle:

Principle #23Feedback

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 described methods enable the production of stable and effective solid forms of Compound 1, enhancing its bioavailability, solubility, and therapeutic efficacy as a JNK inhibitor for treating conditions like interstitial pulmonary fibrosis, systemic sclerosis, and liver fibrotic disorders.

Implementation Method 1

X-ray powder diffractometry

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 2

The importance of discovering polymorphs was underscored by the case of RitonavirTM

Methodology Applied

Scientific EffectPolymorphism:

Implementation Method 3

thermal analysis

Methodology Applied

Scientific EffectThermal analysis:

Implementation Method 4

nuclear magnetic resonance spectroscopy

Methodology Applied

Scientific EffectNuclear magnetic resonance:

Implementation Method 5

specific conditions for recrystallization and solvation processes

Methodology Applied

Scientific EffectCrystallisation: Crystallisation

Implementation Method 6

specific conditions for recrystallization and solvation processes

Methodology Applied

Scientific EffectSolvation: Solvation

Data Source

PatentUS20250000860A1Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use

Publication Date: 2025.01.02 SIGNAL PHARMACEUTICALS LLC

AI summary

Provided herein are formulations, processes, solid forms and methods of use relating to 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide.