Piperazine Salt Solubility for Dopamine Antagonist Formulation
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Solution Overview
Problem
The base form of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine is substantially insoluble in water, making it difficult to formulate into pharmaceutical compositions that meet solubility, handling, and stability requirements for effective treatment of dopamine receptor-related conditions.
Innovation Solution
The development of monohydrochloride salts and their hydrates/solvates, which are prepared by suspending or dissolving the base form in a solvent and adding hydrochloric acid, followed by concentration and filtration, resulting in a compound with excellent stability, isolability, and solubility properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the base form of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine is used, then the compound exhibits dopamine receptor antagonist activity, but it is substantially insoluble in water making it difficult to formulate into pharmaceutical compositions
Solution Approach 1:
The patent applies parameter changes by converting the base form of the compound into its monohydrochloride salt form. This chemical modification changes the physical and chemical parameters of the compound, specifically improving water solubility while preserving the dopamine receptor antagonist activity. The salt form allows the compound to be formulated into pharmaceutical compositions that meet solubility requirements for effective treatment.
2Productivity
If the base form is used for industrial scale synthesis, then the compound can be produced, but it requires complicated multistep recovery processes that decrease yields and increase production costs
Solution Approach 1:
The invention changes the physical and chemical parameters of the compound by forming the monohydrochloride salt. This transformation significantly improves handling properties and isolability during industrial scale synthesis. The salt form enables simpler recovery processes, reduces the number of steps required, improves yields, and decreases production costs while maintaining production capability.
3Ease of operation
If different salt forms are used for the same active agent, then solubility properties may be improved, but the properties of salts formed with the same salt forming agent may differ greatly making selection difficult
Solution Approach 1:
The patent applies the self-service principle by demonstrating that the monohydrochloride salt form inherently provides the optimal balance of solubility, stability, and handling properties without requiring complex selection processes. The systematic evaluation shows that this specific salt form self-evidently meets all pharmaceutical requirements, simplifying the selection process for formulators.
4Device complexity
If the base form is used, then the compound structure is simple, but it lacks adequate stability for pharmaceutical composition durability and quality control
Solution Approach 1:
The patent applies parameter changes by converting the base form into the monohydrochloride salt form, which fundamentally improves the stability parameter. This chemical modification enhances the durability of the pharmaceutical composition and ensures better quality control while maintaining the essential structural characteristics needed for dopamine receptor antagonist activity.
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 monohydrochloride salts exhibit improved stability, isolability, and solubility, allowing for high-purity production and effective use in treating conditions requiring modulation of dopamine D3/D2 receptors, such as schizophrenia and drug abuse, with reduced side effects compared to traditional D2 antagonists.
Implementation Method 1
trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine base is suspended or dissolved in an appropriate solvent or mixture of solvents, then HCl, or a salt thereof prepared with a base which is weaker base than the trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, or a solution thereof is added
Data Source
AI summary
The present invention relates to novel monohydrochloride, dihydrochloride, monohydrobromide, maleate and methanesulphonate salts of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine and/or their hydrates and/or solvates. Moreover, the invention relates to the process for preparing the salts and their hydrates and/or solvates, to their use in the treatment and/or prevention of conditions which require modulation of dopamine receptor and to pharmaceutical compositions containing them.