GLP-1 Agonist Salt Forms for Stable Crystallization
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Solution Overview
Problem
Developing stable and soluble forms of GLP-1 agonists like Compound I and Compound II for pharmaceutical use is challenging due to issues with isolation, purification, large-scale manufacture, storage stability, and bioavailability, particularly in forms that can be effectively absorbed and remain stable in gastric fluids.
Innovation Solution
The development of 1:1 tris salts and citrate salts of Compound I and Compound II, which exhibit high solubility, solid stability, and suitable melting points, enabling effective crystallization and large-scale synthesis, and are suitable for pharmaceutical formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 agonists are developed for pharmaceutical use, then therapeutic efficacy is improved, but isolation and purification difficulty increases
Solution Approach 1:
The patent applies parameter changes by converting the GLP-1 agonist compounds into salt forms with different solubility and stability characteristics. This chemical modification enables improved isolation and purification while maintaining therapeutic efficacy, directly resolving the technical contradiction between drug effectiveness and manufacturing ease.
2Reliability
If GLP-1 agonists are developed for pharmaceutical use, then therapeutic activity is improved, but storage stability deteriorates
Solution Approach 1:
The patent employs parameter changes by developing specific salt forms of GLP-1 agonists that exhibit enhanced storage stability while preserving therapeutic activity. The salt forms demonstrate improved solid-state stability and reduced hygroscopicity, directly addressing the contradiction between maintaining drug activity and ensuring storage stability.
3Reliability
If GLP-1 agonists are developed for pharmaceutical use, then bioavailability is improved, but solubility issues arise
Solution Approach 1:
The patent resolves the solubility-bioavailability contradiction through parameter changes by creating salt forms with optimized solubility characteristics. The disclosed salt forms exhibit improved water and gastric fluid solubility, which directly enhances bioavailability while maintaining compositional stability.
4Productivity
If GLP-1 agonists are developed for large-scale manufacture, then productivity is improved, but manufacturing complexity increases
Solution Approach 1:
The patent addresses manufacturing complexity versus productivity by developing salt forms that enable simplified large-scale synthesis. The salt forms facilitate easier isolation, purification, and formulation processes, directly reducing manufacturing complexity while improving productivity for large-scale production.
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
These salt forms provide enhanced stability, solubility, and bioavailability, making them suitable for pharmaceutical applications and improving glycemic control in conditions like T2DM by maintaining efficacy and reducing side effects.
Implementation Method 1
the 1:1 Compound I tris salt, 1:1 Compound II tris salt, and 1:1 Compound II citrate salt can be crystallized under well-defined conditions to provide desired crystalline forms
Data Source
Figure 1~2A
Figure 2B
Figure 3
AI summary
Various salt forms of Compound I and Compound II represented by the following structural formulae, and their corresponding pharmaceutical compositions, are disclosed. (I), (II) Particular single crystalline forms of 1:1 Compound I tris salt, 1 : 1 Compound II tris salt, and 1:1 Compound II citrate salt are characterized by a variety of properties and physical measurements. Methods of preparing specific crystalline forms are also disclosed. The present disclosure also provides methods of treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease in a subject.