GLP-1 Receptor Agonist Crystal Form A for Moisture-Resistant Processing
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Solution Overview
Problem
The dihydrochloride salt of OAD2 absorbs moisture, making it difficult to filter, dry, and process, which affects its purity and production cost.
Innovation Solution
Development of a crystal form A of OAD2 with improved stability and morphology, characterized by specific X-ray powder diffraction peaks and thermal properties, prepared through solvent crystallization using alkaline neutralization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If OAD2 dihydrochloride salt is used, then the compound is orally available and active, but it absorbs moisture and is difficult to filter and dry
Solution Approach 1:
The patent changes the physical and chemical parameters of OAD2 by converting it from dihydrochloride salt form to a free base crystal form (Crystal Form A). This parameter change eliminates the hygroscopic nature and filtration difficulties while preserving the oral availability and biological activity through appropriate salt formation or formulation strategies.
Solution Approach 2:
The patent creates a composite approach by developing Crystal Form A of the free base, which combines the pharmacologically active OAD2 molecule with a specific crystalline structure that provides improved processing characteristics. The crystal form acts as a composite material that integrates both therapeutic function and manufacturing advantages.
2Reliability
If OAD2 dihydrochloride salt is used, then the compound has desired pharmacological activity, but purity and production cost are adversely affected
Solution Approach 1:
The patent applies parameter changes by transitioning from the dihydrochloride salt form to Crystal Form A of the free base. This change in chemical form and crystalline structure improves purity by eliminating the hygroscopicity that complicates purification, while maintaining pharmacological activity through the preserved molecular structure of the active compound.
3Reliability
If OAD2 dihydrochloride salt is used, then the compound is pharmacologically active, but production cost increases
Solution Approach 1:
The patent reduces production cost through parameter changes by developing Crystal Form A of the free base, which simplifies the manufacturing process. The improved filterability and drying characteristics reduce processing time and energy consumption, while the enhanced stability reduces waste and rework, all while maintaining the pharmacologically active OAD2 structure.
4Ease of operation
If OAD2 dihydrochloride salt is used, then the compound is orally available, but stability and morphology are compromised
Solution Approach 1:
The patent creates a stable composite material in the form of Crystal Form A, where the OAD2 free base is organized in a specific crystalline structure. This composite approach provides enhanced stability and defined morphology while maintaining oral availability, as the crystalline form can be converted to appropriate salt forms for pharmaceutical formulation.
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
Crystal form A exhibits reduced water absorption, simpler purification, and lower production costs, maintaining high purity and stability, suitable for pharmaceutical compositions and treatments activating the GLP-1 receptor.
Implementation Method 1
The invention provides a crystal form A 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
Implementation Method 2
an X-ray powder diffraction pattern comprising peaks at the following 2θ angles: 9.53°, 12.32°, 13.80°, 17.84°, 18.56°, 19.40°, 20.38°, 20.99°, 21.78°, and 24.69°±0.2
Implementation Method 3
an X-ray powder diffraction pattern comprising peaks at the following 2θ angles
Data Source
AI summary
The invention relates to a crystal form A 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 methods of preparation thereof. Crystal form A may be useful in the treatment of various conditions and metabolic disorders including, but not limited to, type 2 diabetes.