Eltrombopag Monoethanolamine Salt Form D1 Stability
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Solution Overview
Problem
Current crystalline forms of Eltrombopag monoethanolamine salt are not thermodynamically stable enough for pharmaceutical applications, lacking the necessary stability and efficacy in formulations.
Innovation Solution
A new crystalline form of Eltrombopag monoethanolamine salt, Form D1, is developed, which is more stable than existing forms, characterized by specific X-ray powder diffraction peaks and higher DSC onset and peak values, prepared from Eltrombopag free acid using a process involving ethanolamine in solvents like 1-pentanol or 1-butanol.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If existing crystalline forms of Eltrombopag monoethanolamine salt are used, then the pharmaceutical formulation can be prepared, but the thermodynamic stability is insufficient for long-term storage and efficacy
Solution Approach 1:
The patent applies parameter changes by developing a new crystalline form (Form D1) with specific crystallographic parameters and molecular packing arrangements that differ from existing forms. This structural parameter change results in enhanced thermodynamic stability while maintaining the required pharmaceutical efficacy, directly resolving the contradiction between stability and reliability
Solution Approach 2:
The invention creates a composite crystalline structure where Eltrombopag molecules are arranged in a specific monoethanolamine salt form with unique intermolecular interactions and hydrogen bonding patterns. This composite molecular arrangement in Form D1 provides superior thermodynamic stability compared to individual molecular forms, while ensuring consistent pharmacological performance
2Ease of manufacture
If existing crystalline forms are used, then the formulation can be manufactured, but the hygroscopicity is too high affecting storage and handling
Solution Approach 1:
The patent applies local quality by modifying the surface properties and crystal lattice structure of the Eltrombopag monoethanolamine salt in Form D1. The specific molecular arrangement in this crystalline form creates a surface structure that is less prone to water adsorption, reducing hygroscopicity while maintaining manufacturability through standard pharmaceutical processing techniques
3Productivity
If existing crystalline forms are used, then the formulation can be prepared, but the solubility characteristics are not optimal for bioavailability
Solution Approach 1:
The patent utilizes parameter changes by optimizing the crystal lattice parameters and molecular packing density in Form D1. These structural parameters directly influence solubility characteristics, and the specific arrangement in Form D1 provides improved dissolution properties and bioavailability while maintaining efficient formulation preparation through standard manufacturing processes
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
Eltrombopag monoethanolamine salt Form D1 exhibits enhanced thermodynamic stability, reduced hygroscopicity, and improved solubility characteristics, making it suitable for pharmaceutical compositions and treatments of chronic immune thrombocytopenia, ensuring efficacy and safety.
Implementation Method 1
A process for a highly stable crystalline Eltrombopag monoethanolamine salt form D1
Implementation Method 2
having characteristic peaks 2-Theta values (2θ) at: 7.6, 11.6 and 16.5, each peak ±0.2
Implementation Method 3
higher DSC onset and peak values
Data Source
AI summary
Object of the present invention is a highly stable crystalline form of Eltrombopag (ETP) monoethanolamine salt, named Form D1, having the highest thermodynamically stability with excellent non-hygroscopicity, and particularly well suitable for pharmaceutical purposes, with related process.