Amisulpride Crystalline Form Preparation via Coupling and Isolation
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Solution Overview
Problem
There is a need for a reliable and reproducible method to prepare enantiomerically pure crystalline forms of amisulpride, as existing methods often result in amorphous or kinetically favored crystalline forms, complicating the production of high-yield, stable crystalline products with specific particle size distributions.
Innovation Solution
A method involving coupling 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with (R)-(1-ethylpyrrolidin-2-yl)methanamine or (S)-(1-ethylpyrrolidin-2-yl)methanamine in the presence of a tertiary amine and an acid activating reagent, followed by isolation using a specific reagent, to produce enantiomerically pure crystalline amisulpride without forming solvates, characterized by distinct XRPD patterns and controlled crystallization processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional methods are used to prepare amisulpride, then the production process is simple, but the product is amorphous or kinetically favored crystalline form with poor stability and narrow particle size distribution
Solution Approach 1:
The patent applies parameter changes by modifying crystallization conditions including temperature profiles, solvent selection, and cooling rates to transform amorphous or kinetically favored crystalline forms into thermodynamically stable crystalline forms with desired particle size distributions. The method controls supersaturation levels and cooling rates to achieve controlled nucleation and crystal growth.
Solution Approach 2:
The patent utilizes phase transitions during crystallization processes, including controlled melting and solidification, to convert amorphous materials into crystalline forms. The method employs controlled cooling through phase change regions to achieve polymorphic transformation and stabilize specific crystalline forms with narrow particle size distributions.
2Reliability
If conventional crystallization methods are used, then the process is fast, but the crystalline forms are kinetically favored with poor reproducibility
Solution Approach 1:
The patent implements feedback control in crystallization processes by monitoring temperature, pressure, and supersaturation levels in real-time. The method uses feedback mechanisms to adjust cooling rates, agitation speeds, and solvent addition rates to maintain optimal conditions for reproducible crystalline form formation with narrow particle size distributions.
Solution Approach 2:
The patent applies preliminary action by pre-equilibrating solutions, pre-cooling crystallization vessels, and pre-preparing seed crystals before the main crystallization process. This ensures consistent nucleation conditions and reproducible crystal growth, achieving both high reliability and maintained productivity.
3Manufacturing precision
If solvate formation is allowed during isolation, then the isolation process is simple, but the crystalline form purity and stability are compromised
Solution Approach 1:
The patent applies the taking out principle by selectively removing solvents and mother liquids from the crystalline product through controlled filtration and drying processes. The method extracts and eliminates solvate molecules from the crystal structure, achieving high purity crystalline forms without compromising stability or requiring complex isolation procedures.
Solution Approach 2:
The patent uses intermediary substances such as anti-solvents and filtration media to facilitate isolation without solvate formation. The method employs intermediary agents that promote selective precipitation and filtration, enabling easy isolation of pure crystalline forms while preventing solvate incorporation through controlled solvent removal.
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 method achieves high yields of enantiomerically pure (R)-amisulpride and (S)-amisulpride with stable, scalable, and cost-effective production, providing crystalline products with narrower particle size distributions, improving manufacturability and product purity.
Implementation Method 1
coupling, in the presence of a tertiary amine and an acid activating reagent, 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and (R)-(1-ethylpyrrolidin-2-yl) methanamine to form a reaction mixture
Implementation Method 2
isolating from the reaction mixture of step (a), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (R)-(+)-amisulpride
Data Source
AI summary
Provided are methods for making crystalline forms of (S)-(−)-amisulpride and (R)-(+)-amisulpride. Also provided are pharmaceutical compositions comprising the crystalline forms of (S)-(−)-amisulpride and (R)-(+)-amisulpride and methods of using the crystalline forms.