Crystalline OAD2 Acid Salts for Stability and Low Hygroscopicity
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Solution Overview
Problem
Existing acid salts of OAD2, including OAD2 dihydrochloride, have not been systematically studied for pharmaceutically acceptable alternatives with improved stability and hygroscopicity.
Innovation Solution
Development of crystalline acid salts of OAD2, such as hydrochloride, p-toluenesulfonate, tartrate, citrate, glycollate, methanesulfonate, hydrobromide, and sulfate forms, which exhibit superior stability and hygroscopicity compared to OAD2 dihydrochloride.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If OAD2 dihydrochloride is used as the acid salt form, then the compound is orally available and active, but it exhibits poor stability and poor hygroscopicity
Solution Approach 1:
The patent applies parameter changes by systematically varying the acid component in salt formation with OAD2 free base. Different acids (hydrochloric acid, p-toluenesulfonic acid, tartaric acid, citric acid, glycolic acid, methanesulfonic acid, hydrobromic acid, sulfuric acid) were tested to produce different salt forms with improved stability and hygroscopicity profiles while maintaining oral availability and GLP-1 receptor agonist activity.
Solution Approach 2:
The patent utilizes phase transitions by forming crystalline salt forms from the OAD2 free base. The acid salts were isolated as crystalline materials through controlled crystallization processes, transforming the amorphous or less stable free base into stable crystalline phases with defined melting points and improved physical properties including reduced hygroscopicity and enhanced stability.
2Reliability
If multiple acid salts are synthesized and characterized, then superior stability and hygroscopicity profiles are achieved, but the development process becomes more complex
Solution Approach 1:
The patent applies universality by developing a systematic salt formation approach that can be applied to any GLP-1 receptor agonist with a basic nitrogen atom. The methodology established through screening multiple acids creates a universal platform for optimizing the physical properties of peptide-mimetic compounds, where the same principles and procedures can be reused for different compounds in the series.
Solution Approach 2:
The patent systematically varies the acid component parameter to optimize multiple properties simultaneously. By changing the acid counterion, the patent achieves improvements in stability, hygroscopicity, solubility, and crystallinity in a coordinated manner, demonstrating that a single parameter change (acid selection) can influence multiple critical quality attributes of the pharmaceutical compound.
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 new acid salts demonstrate enhanced stability and hygroscopicity, making them suitable for pharmaceutical applications, particularly in treating conditions where GLP-1 receptor activation is beneficial, such as type 2 diabetes.
Implementation Method 1
the pharmaceutically acceptable acid salts of OAD2 may be crystalline
Implementation Method 2
pharmaceutically acceptable acid salts of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid
Data Source
AI summary
The invention provides pharmaceutically acceptable acid salts of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl) propionic acid (“OAD2”) and the preparation method thereof. The pharmaceutically acceptable acid salts of OAD2 provided herein may be useful in the treatment of various conditions and metabolic disorders including, but not limited to, type 2 diabetes.