Chiral Separation by a Combination of Racemization and Crystallization


Chiral Separation by a Combination of Racemization and Crystallization

Supervisor: David Branco Ribeiro

Principal Supervisors: Joop ter Horst, Herman Kramer


Viedma Ripening [1] is a new process that combines grinding and a racemization reaction to achieve an enantiopure product. Both enantiomers of a chiral compound have the same physical properties but may differ in their bioactivity. In pharmaceutical industry it is therefore of utmost importance to separate the two enantiomers. However, this is difficult due to the equal physical behavior (e.g. solubility).

Viedma Ripening combines a racemization reaction and grinding to achieve 100 % of one of the enantiomers from a mixture of both. This method has a high potential for pharmaceutical industry. However, the grinding process is relatively difficult to perform on a larger industrial scale. Recently, it was discovered that the grinding could be replaced by an industrially more convenient temperature cycling.  


We studied Viedma Ripening of acetyl-leucine in acetic acid with the catalyst acetic anhydride. While we had problems getting the grinding method to work, starting from a racemic mixture of acetyl-DL-Leucine and applying the temperature cycling we achieved a single pure enantiomer. The enantiomeric excess of Acetyl-Leucine is measured by measuring the saturation temperature of the produced solid using the Crystal16 equipment. The next step thus is to find the optimal route towards enantiopure acetyl-leucine using temperature cycling during Viedma Ripening.

Research question

What is the optimal route towards an enantiopure product of acetyl-leucine using temperature cycling during Viedma Ripening?


1.      Perform Viedma Ripening of acetyl-leucine using different temperature cycling programs.

2.      Make a process model accounting for temperature cycling during Viedma Ripening.

3.      Optimize the temperature cycling during Viedma Ripening using the experimental data and the process model.

4.      Write report


1.      Articles of Christobald Viedma or Wim Noorduin

2.      Adrian Flood, Gerard Coquerel, Conference paper CGOM 2012