Benzamide Cocrystals for Stable Dissolution and Reduced-Adhesion Micronization
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Solution Overview
Problem
Existing benzamide compounds, such as AZD1656, face challenges with polymorphic forms affecting drug stability, dissolution, and bioavailability, and micronization processes are inefficient due to cohesive properties, 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, improving dissolution and solubility, and facilitating easier processing without the need for co-milling excipients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If micronization is performed on benzamide compound, then dissolution behavior is improved, but material builds up on milling equipment surfaces resulting in loss of material and reduced process efficiency
Solution Approach 1:
The patent uses co-milling excipients (lactose, mannitol, or microcrystalline cellulose) as intermediary materials that prevent adhesion between the benzamide compound and milling equipment surfaces. These excipients act as a mediating layer that reduces cohesive and adhesive forces, allowing efficient micronization without material loss while maintaining improved dissolution behavior.
2Productivity
If co-milling excipients are used to prevent material buildup, then milling efficiency is improved, but the tablet formulation reaches a limit on the amount of benzamide compound that can be included
Solution Approach 1:
The patent extracts the problematic cohesive and adhesive properties from the benzamide compound by forming a cocrystal with a coformer molecule. This cocrystal formation removes the surface properties that cause adhesion to milling equipment, eliminating the need for co-milling excipients and thereby removing the limitation on the amount of active compound that can be included in the tablet formulation.
3Manufacturing precision
If different polymorphic forms of benzamide compound are used, then solubility and dissolution rate are affected, but polymorphic transition during manufacture or storage can affect quality and stability
Solution Approach 1:
The patent creates a cocrystal composite material combining the benzamide compound with a coformer in a defined stoichiometric ratio. This composite structure produces a new crystalline form with distinct crystallographic properties that provide consistent solubility and dissolution rate while being stable against polymorphic transition during manufacture and storage, thereby improving both manufacturing precision and reliability.
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 ease of understanding, “benzamide” or “benzamide compound” as well as “AZD1656” 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).