Nebivolol Isomer Separation via Controlled Crystallization

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Existing methods for preparing and separating Nebivolol intermediates, such as RRRS and SSSR configurations, face inefficiencies and complexities, including low yield and residual isomer contamination, making them inconvenient for industrial-scale operations.

Innovation Solution

A process involving the use of alcohol and precipitation solvents, where the mixture of RRRS, SSSR, RRSR, and SSRS configurations is heated, cooled, and filtered to precipitate crystals, effectively separating RRRS and SSSR configurations with high purity and efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If fractional crystallization is used to separate Nebivolol isomers, then separation can be achieved, but the yield is quite low (6.6%)

Engineering Contradiction:

Improveseparation efficiencyVSAvoidyield

Core Design Contradiction:

Manufacturing precisionVSProductivity

Solution Approach 1:

The patent changes the physical parameters of the separation process by using a two-solvent system (ether solvent and alcohol solvent) with specific volume ratios, controlling temperature during cooling, and adjusting solvent composition to optimize both separation efficiency and yield of desired isomers

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transition through controlled cooling of the solvent mixture to precipitate crystals of desired isomers, leveraging the temperature-dependent solubility differences between isomers to achieve efficient separation with high yield

Inventive Principle:

Principle #36Phase transitions

2Manufacturing precision

If multiple recrystallization treatments are performed to remove residual isomers, then purity is improved, but the process becomes complex and time-consuming

Engineering Contradiction:

ImprovepurityVSAvoidprocess complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent performs preliminary action by carefully optimizing the initial crystallization conditions (solvent ratio, temperature control, cooling rate) to achieve high purity in a single step, preventing the need for multiple subsequent recrystallization treatments and simplifying the overall process

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent creates a universal separation method that achieves both high purity and high yield simultaneously through a single optimized crystallization process, making the process applicable to different isomer separations without requiring multiple specialized treatment steps

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Manufacturing precision

If conventional separation methods are used, then isomers can be separated, but residual isomers remain causing inconvenience to subsequent operations

Engineering Contradiction:

Improveseparation efficiencyVSAvoidconvenience of subsequent operations

Core Design Contradiction:

Manufacturing precisionVSEase of operation

Solution Approach 1:

The patent changes the separation parameters by using a two-solvent system with specific volume ratios and controlled temperature profiles, achieving complete separation of isomers with no residual contamination, thereby ensuring ease of subsequent operations

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces conventional mechanical separation methods with a thermodynamically-controlled crystallization process that uses solvent-solute interactions and temperature-dependent solubility to achieve complete separation, eliminating residual isomer contamination that would complicate subsequent operations

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

This method simplifies the process, enhances separation efficiency, and allows for convenient scaling up to industrial levels with high purity products, overcoming previous method limitations.

Implementation Method 1

after heating, cooling down to precipitate crystals and filtrating, the product can be obtained

Methodology Applied

Scientific EffectCrystallisation: Crystallisation

Implementation Method 2

the mixture of RRRS, SSSR, RRSR, and SSRS configurations is heated, cooled, and filtered to precipitate crystals

Methodology Applied

Scientific EffectSolubility: Solvation

Data Source

PatentEP2236510B1Process for isolation of a mixture of RRRS and SSSR configurations of nebivolol intermediates

Publication Date: 2014.04.30 SHANGHAI SHYNDEC PHARMA CO LTD

AI summary

The invention discloses a process for isolation of a mixture of RRRS and SSSR configurations of nebivolol intermediates represented by formulae II and III respectively, which is optionally selected from one of the following two manners: (1) precipitation solvent is added to alcohol solvent comprising the mixture of RRRS, SSSR, RRSR and SSRS configurations of nebivolol intermediates represented by formula I, heating, cooling to precipitate crystals and filtrating; (2) the mixture of RRRS, SSSR, RRSR and SSRS configurations of nebivolol intermediates represented by formula I is added into the mixture solvent of alcohol solvent and precipitation solvent, heating, cooling to precipitate crystals and filtrating. In formulae I, II and III, X is H, C1-C6 alkyl or C1-C6 alkoxy, n is 1-5.