Ivabradine Hydrochloride Polymorph ε Preparation
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Solution Overview
Problem
Current methods for preparing polymorphic forms of ivabradine hydrochloride, such as forms δ and δd, often result in high residual solvent levels, which are not acceptable for pharmaceutical use and require complex drying conditions, making them unsuitable for industrial application.
Innovation Solution
A process involving the use of anhydrous ivabradine hydrochloride mixed with C4-C7 ketones containing a specific water content, followed by controlled temperature and stirring conditions, to produce the stable polymorphic form ε, which can be seeded to promote crystallization, reducing solvent residues and simplifying the process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If crystallization is carried out in acetonitrile to produce polymorphic forms δ or δd, then the polymorphic form is obtained, but high residual solvent levels are present which are not acceptable for pharmaceutical use
Solution Approach 1:
The patent extracts the harmful acetonitrile solvent from the crystallization process by replacing it with water or water-miscible solvents. This eliminates the residual solvent issue while maintaining the ability to produce the desired polymorphic forms δ or δd, directly resolving the contradiction between obtaining pure polymorphic form and avoiding harmful residual solvents.
Solution Approach 2:
The patent changes the solvent parameter from organic acetonitrile to aqueous systems (water or water-miscible solvents). This parameter change fundamentally alters the solvent composition to eliminate harmful residues while preserving the crystallization capability to produce the required polymorphic forms.
2Object-affected harmful factors
If complex drying conditions are used to reduce residual solvent levels, then solvent residues are reduced, but the process complexity increases making it unsuitable for industrial application
Solution Approach 1:
The patent applies preliminary action by selecting aqueous or water-miscible solvents from the beginning of the crystallization process. This prevents the formation of problematic residual organic solvents that would require complex drying, thereby eliminating the need for complex drying conditions while still achieving low residual solvent levels suitable for pharmaceutical use.
3Ease of manufacture
If standard crystallization procedures are used, then the process is simple, but the polymorphic form obtained may not be stable or suitable for pharmaceutical formulations
Solution Approach 1:
The patent changes the solvent system parameter to aqueous or water-miscible solvents, which enables the formation of stable polymorphic forms δ or δd that are suitable for pharmaceutical formulations. This parameter change maintains process simplicity while ensuring the stability and suitability of the resulting polymorphic form.
Solution Approach 2:
The patent utilizes controlled phase transitions during crystallization from aqueous systems to obtain stable polymorphic forms. The controlled solid-liquid phase transition in the aqueous medium promotes the formation of thermodynamically stable polymorphic forms that are suitable for pharmaceutical applications while maintaining manufacturing simplicity.
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 process effectively produces the ε form of ivabradine hydrochloride with enhanced stability and reproducibility, suitable for large-scale production, and achieves chemical purity greater than 99.5%, suitable for pharmaceutical formulations with reduced environmental impact.
Implementation Method 1
a process involving the use of anhydrous ivabradine hydrochloride mixed with C4-C7 ketones containing a specific water content, followed by controlled temperature and stirring conditions, to produce the stable polymorphic form ε
Data Source
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AI summary
The present invention relates to a new polymorph, ε (epsilon), of ivabradine hydrochloride, having the formula shown below, and two methods for its preparation: