ABCA1-Inducing Crystalline Forms for Kidney Disease Therapy
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Solution Overview
Problem
Existing treatments for chronic kidney disease are limited, and there is a need for new therapeutics, particularly small molecule compounds that can stabilize the expression and activity of ATP-binding cassette transporter Al protein (ABCA1) to address kidney function loss.
Innovation Solution
Development of crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy) nicotinamide, including anhydrates, hydrates, and solvates, which act as ABCA1 inducers, formulated into pharmaceutical compositions for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple crystalline forms are developed to optimize pharmaceutical properties, then the therapeutic effectiveness and bioavailability are improved, but the manufacturing complexity and characterization difficulty increase
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs, solvates, hydrates) of the same compound with different physical and chemical parameters. Each crystalline form has distinct XRPD patterns, stability profiles, and solubility characteristics, allowing optimization of therapeutic effectiveness and bioavailability while managing manufacturing complexity through systematic characterization
Solution Approach 2:
The patent creates composite crystalline structures by forming solvates and hydrates of the compound with different solvents and water molecules. These composite crystalline forms combine the active compound with specific solvent molecules in defined stoichiometric ratios, enabling optimization of pharmaceutical properties while maintaining structural integrity for manufacturing
2Productivity
If crystalline forms with specific XRPD patterns are selected for formulation, then the dissolution rate and bioavailability are improved, but the difficulty of detecting and measuring the correct form increases
Solution Approach 1:
The patent uses X-ray powder diffraction (XRPD) patterns as characteristic fingerprints for each crystalline form. Each polymorph, solvate, and hydrate exhibits distinct diffraction peak patterns at specific 2θ angles, enabling easy detection and measurement of the correct crystalline form through routine XRPD analysis, thus resolving the characterization difficulty while ensuring optimal dissolution rate and bioavailability
3Duration of action of stationary object
If stable crystalline forms are used for long-term storage, then the shelf life and stability are improved, but the solubility and dissolution rate may be reduced
Solution Approach 1:
The patent systematically varies crystalline packing parameters and intermolecular interaction parameters to create different crystalline forms with optimized balances between stability and dissolution rate. By changing crystal lattice parameters, solvent inclusion, and hydration states, the patent achieves forms that maintain stability during storage while ensuring adequate dissolution rate upon administration
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 crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy) nicotinamide effectively stabilize ABCA1 expression and activity, providing a therapeutic option for treating kidney diseases.
Implementation Method 1
Polymorphism is the ability of a substance to crystallize in more than one crystal lattice arrangement. Crystallization, or polymorphism, can influence many aspects of the solid-state properties of a drug substance.
Data Source
AI summary
The disclosure is in part directed to crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide and pharmaceutical compositions thereof.