Apremilast Crystalline Forms via Toluene Precipitation
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Solution Overview
Problem
Current methods for producing apremilast are inefficient due to high reaction temperatures and complex solvent replacement processes, which affect yield and purity, and there is a lack of characterization of its polymorphs and amorphous forms.
Innovation Solution
Apremilast is produced by heating (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine and 3-acetamidophthalic anhydride in toluene with acetic acid at a lower temperature, allowing for direct precipitation of crystalline forms without solvent replacement, and characterized using XRPD, TGA, and DSC to define novel crystalline and amorphous forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If heating is conducted at high temperature (118°C) in HOAc, then the reaction proceeds to completion, but the process requires complex solvent replacement and aqueous workup, increasing process time and reducing efficiency
Solution Approach 1:
The patent changes the reaction parameters by using toluene as solvent instead of HOAc, and conducting the reaction at a lower temperature (90°C) with shorter time (3 hours), which eliminates the need for complex solvent replacement and aqueous workup procedures while maintaining high purity
Solution Approach 2:
The patent extracts and eliminates the problematic solvent replacement and aqueous workup steps from the process by choosing toluene as the reaction solvent, which allows direct precipitation of the product without requiring removal of HOAc or additional washing steps
2Manufacturing precision
If solvent replacement and aqueous workup are performed, then purity is improved, but manufacturing complexity and process time increase
Solution Approach 1:
The patent removes the complex solvent replacement and aqueous workup steps by selecting toluene as the reaction solvent, which enables direct precipitation of apremilast upon cooling without requiring additional purification steps
Solution Approach 2:
The reaction system self-purifies through selective precipitation of apremilast from the toluene solution upon cooling, eliminating the need for external purification operations such as solvent replacement and aqueous workup
3Loss of time
If reaction is conducted at lower temperature (90°C) in toluene, then process time is reduced and simplicity is improved, but reaction completion and yield may be affected
Solution Approach 1:
The patent optimizes the reaction parameters by using toluene as solvent and conducting the reaction at 90°C for 3 hours, which achieves both reduced process time and high yield through the unique properties of toluene as a reaction medium
Solution Approach 2:
The patent utilizes the phase transition of apremilast from dissolved state in hot toluene to precipitated solid upon cooling, which drives the reaction to completion and ensures high yield while maintaining low reaction temperature and short reaction time
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 reduces process time, increases stability, and achieves high yields and purity of apremilast, with specific crystalline and amorphous forms (Forms I, II, 3, and 4) that are stable at elevated temperatures and humidity, improving the production efficiency and characterization of apremilast.
Implementation Method 1
Apremilast solids precipitated from the mixture with cooling to 20-30° C.
Implementation Method 2
The apremilast obtained directly from the precipitation is the crystalline form of apremilast hemitoluene (Form I)
Data Source
AI summary
The present invention provides novel crystalline forms of apremilast hemitoluene solvate, apremilast hydrate, and apremilast anhydrate and an amorphous form of apremilast, and processes for the preparation of these forms.