SSAO Inhibitor Salt Forms for Thermal Stability and Hygroscopicity Control
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Solution Overview
Problem
Current SSAO inhibitors, such as (3S)-Tetrahydrofuran-3-yl (4S)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate, face challenges with hygroscopicity and thermal stability, making them difficult to handle and process effectively in pharmaceutical applications.
Innovation Solution
Development of new salt forms, specifically the mesylate and sulphate salts, which exhibit improved thermal stability and reduced hygroscopicity, allowing for better handling and processing during milling and tablet pressing procedures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If the free base form of SSAO inhibitor is used, then the compound can be synthesized and isolated, but it exhibits high hygroscopicity and poor thermal stability making it difficult to handle
Solution Approach 1:
The patent applies parameter changes by converting the free base form of the SSAO inhibitor into salt forms with different physical and chemical properties. Specifically, the compound is converted into hydrochloride, phosphate, sulphate, and mesylate salts, each exhibiting improved thermal stability and reduced hygroscopicity compared to the free base form. This chemical form transformation resolves the handling difficulties while maintaining pharmacological activity.
Solution Approach 2:
The patent uses salt-forming agents (hydrochloric acid, phosphoric acid, sulphuric acid, methanesulphonic acid) as intermediaries to transform the free base compound into stable salt forms. These intermediaries facilitate the conversion process and enable the final product to exhibit improved handling properties, solubility, and thermal stability without altering the core pharmacological structure.
2Productivity
If standard milling and tablet pressing procedures are used, then pharmaceutical processing can be performed, but temperatures exceed the melting point causing drug particles to clump and aggregate
Solution Approach 1:
The patent raises the thermal stability parameter by converting the compound into salt forms with higher melting points. The hydrochloride salt melts at 168°C, phosphate at 205°C, sulphate at 106°C, and mesylate at 189°C. These elevated melting points allow standard pharmaceutical processing temperatures to remain below the compound's melting point, preventing aggregation and ensuring formulation consistency while maintaining processing efficiency.
3Ease of operation
If the free base form is used, then the compound structure is simple, but it is hygroscopic and sticky making it difficult to weigh and handle
Solution Approach 1:
The patent changes the physical and chemical parameters of the compound by forming salts with different hygroscopicity characteristics. The resulting salt forms exhibit reduced water absorption compared to the hygroscopic free base form. This parameter change eliminates the stickiness and weighing difficulties while maintaining the compound's pharmacological identity and activity.
Data Source
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AI summary
The mesylate and sulphate salts of (3S)-Tetrahydrofuran-3-yl (4S)-4-isopropyl-,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate mesylate, and hydrates thereof, and their use in medicine.