AZD1656 Therapeutic Cocrystals for Dissolution and Stability
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Solution Overview
Problem
Existing benzamide compounds, such as AZD1656, face challenges with polymorphic forms that affect drug stability, dissolution, and bioavailability, and micronization processes are inefficient due to material buildup, limiting their use in certain delivery methods.
Innovation Solution
Formation of novel cocrystals with acids like fumaric, maleic, malonic, L-tartaric, and gentisic acids, which offer distinct crystallographic and spectroscopic properties, enhancing dissolution and solubility, and allowing for efficient processing without the need for co-milling excipients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If micronization is performed on benzamide compound, then dissolution rate is improved, but material builds up on milling equipment surfaces reducing process efficiency
Solution Approach 1:
The patent introduces co-milling excipients (lactose, mannitol, or surfactants) as intermediary substances that prevent direct adhesion of the benzamide compound to the milling equipment surfaces. These excipients act as a mediating layer that reduces cohesive and adhesive forces between the drug material and steel surfaces, enabling efficient micronization without material buildup.
2Ease of manufacture
If co-milling excipients are used to prevent material buildup, then milling efficiency is improved, but tablet formulation has limit to amount of benzamide compound
Solution Approach 1:
The patent extracts the problematic cohesive and adhesive properties of the benzamide compound by forming a cocrystal with a coformer substance. This cocrystal formation removes the surface properties that cause material buildup during milling, allowing the active ingredient to be milled efficiently without requiring co-milling excipients, thereby eliminating the limitation on benzamide compound amount in tablet formulation.
3Adaptability or versatility
If polymorphic forms are present in benzamide compound, then chemical and physical properties vary, but form transitions during manufacture and storage occur
Solution Approach 1:
The patent creates a cocrystal composite material combining the benzamide compound with a coformer in a defined stoichiometric ratio. This composite crystalline structure locks the molecules in a stable arrangement that prevents polymorphic transitions, providing consistent chemical and physical properties during manufacture and storage while eliminating the instability associated with polymorphic form changes.
Data Source
AI summary
Cocrystals of a benzamide compound, specifically 3-{[5-(azetidine-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide, therapeutic uses of the benzamide cocrystals and pharmaceutical compositions containing them are disclosed. For purposes of this disclosure and for case of understanding. “benzamide” or “benzamide compound” as well as “AZD 1656” refer to 3-{[5-(azetidine-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide. The benzamide cocrystals of the invention include a 1:1 benzamide fumaric acid (Cocrystal 1), a 1:1 benzamide maleic acid (Cocrystal 2), a 1:1 benzamide malonic acid (Cocrystal 3), a 1:1 benzamide L-tartaric acid hydrate (Cocrystal 4), and a 1:1 benzamide gentisic acid (Cocrystal 5), which includes a 1:1 benzamide gentisic acid form 1 (Cocrystal 5A), a 1:1 benzamide gentisic acid form 2 (Cocrystal 5B), a 1:1 benzamide gentisic acid form 3 (Cocrystal 5C), and a 1:1 benzamide gentisic acid form 4 (Cocrystal 5D).