Crystalline Salt Forms for Low Melting Point API
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Solution Overview
Problem
1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone is difficult to crystallize due to its low melting point, making it challenging for pharmaceutical development and formulation, and existing acids do not form solid salts with this compound, necessitating alternative forms with improved stability and bioavailability.
Innovation Solution
The development of crystalline salts such as hydrochloride, maleate, succinate, oxalate, and hydrobromide of 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone, which offer enhanced thermodynamic stability, solubility, and bioavailability, facilitating better pharmaceutical formulations and therapeutic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the compound 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone is used in its free base form, then it exhibits strong analgesic activity and sigma-1 receptor antagonism, but it is difficult to crystallize due to its low melting point (46°C), which complicates pharmaceutical development and formulation
Solution Approach 1:
The patent applies parameter changes by converting the free base compound into salt forms with different physical properties. Specifically, the compound is converted into hydrochloride, hydrobromide, and other salt forms that have higher melting points and improved crystallization characteristics, thereby resolving the manufacturing difficulty while preserving the pharmacological activity
Solution Approach 2:
The patent creates composite material forms by combining the active pharmaceutical ingredient with counterions to form stable salt compounds. These composite salt forms (e.g., hydrochloride salt, hydrobromide salt) exhibit improved physical properties including enhanced crystallinity, stability, and manufacturability compared to the free base form
2Ease of manufacture
If alternative forms of the compound are developed to improve crystallization, then manufacturing and handling are facilitated, but the complexity of the invention increases due to the need to characterize multiple salt forms
Solution Approach 1:
The patent employs universality by developing a systematic approach that can be applied to create multiple salt forms from a single active pharmaceutical ingredient. The methodology demonstrated for creating hydrochloride, hydrobromide, and other salts provides a universal framework that simplifies future formulation development while maintaining consistent characterization protocols across different salt forms
3Reliability
If the free base form is used, then the compound structure is simple, but the bioavailability and dissolution patterns are suboptimal for pharmaceutical use
Solution Approach 1:
The patent applies parameter changes by modifying the chemical form of the compound through salt formation. This changes the solubility and dissolution characteristics of the compound, thereby improving bioavailability. The salt forms exhibit enhanced dissolution patterns compared to the free base, allowing for better pharmaceutical performance
Data Source
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AI summary
The present invention relates to 1 -(4-(2-((1 -(3,4-difluorophenyl)-1 H-pyrazol-3-yl)methoxy)ethyl)piperazin-1 -yl)ethanone salts, specifically to the hydrochloride and to the maleate, to pharmaceutical compositions comprising them, and to their use in therapy and/or prophylaxis of sigma receptor associated diseases.