FXR Agonist Crystalline Forms for Stable Therapeutic Formulation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for metabolic disorders, liver diseases, and inflammatory conditions associated with farnesoid X receptor (FXR) activity lack effective and specific compounds that can modulate FXR activity to address these conditions.

Innovation Solution

Development of crystalline forms of the farnesoid X receptor agonist, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, including pharmaceutically acceptable solvates and polymorphs, to enhance FXR modulation for therapeutic applications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If crystalline forms of the FXR agonist are developed, then therapeutic efficacy is enhanced, but manufacturing complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmanufacturing complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by developing multiple crystalline forms (polymorphs) of the FXR agonist compound. Each polymorph represents a different crystal structure with distinct physical and chemical parameters such as melting point, solubility, and stability. By optimizing these parameters, the patent enhances therapeutic efficacy while providing options for manufacturing optimization.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions by characterizing and utilizing different solid-state phases (polymorphs) of the active pharmaceutical ingredient. The identification of multiple crystalline forms allows selection of the most suitable phase for formulation and manufacturing, balancing efficacy requirements with manufacturing feasibility.

Inventive Principle:

Principle #36Phase transitions

2Adaptability or versatility

If multiple crystalline forms are characterized and utilized, then formulation flexibility is improved, but characterization and analysis difficulty increases

Engineering Contradiction:

Improveformulation flexibilityVSAvoidcharacterization difficulty

Core Design Contradiction:

Adaptability or versatilityVSDifficulty of detecting and measuring

Solution Approach 1:

The patent employs multiple characterization techniques that serve universal purposes in solid-state analysis. Methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) are used to simultaneously identify polymorphs, determine their stability, and characterize their physical properties, thereby providing formulation flexibility while managing characterization complexity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Stability of the object's composition

If specific crystalline forms with defined properties are selected, then product stability is improved, but manufacturing precision requirements increase

Engineering Contradiction:

Improveproduct stabilityVSAvoidmanufacturing precision

Core Design Contradiction:

Stability of the object's compositionVSManufacturing precision

Solution Approach 1:

The patent applies preliminary action by pre-characterizing multiple crystalline forms and selecting the most stable polymorph for development before large-scale manufacturing. This advance characterization allows optimization of manufacturing processes to maintain the desired crystal structure, ensuring product stability while establishing precise manufacturing protocols.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12545660B2Crystalline forms of a farnesoid X receptor agonist

Publication Date: 2026.02.10 ELI LILLY & CO

AI summary

Described herein is the farnesoid X receptor agonist, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, including crystalline forms and pharmaceutically acceptable salts, solvates, and formulations thereof.