Case – Viedma ripening for Naproxen

Obtaining enantiopure compounds from a racemic mixture without any additional chiral reagent. Not a dream, but a new reality. By using racemizing conditions and specific crystallization behavior the solid phase of a racemic mixture can be fully converted into the enantiomerically pure form of the chiral compound.

By in situ racemization in solution the solid phase of the racemic mixture can be fully converted into the enantiomerically pure form of the chiral compound

This crystallization technology is limited to chiral compounds that show conglomerate behavior, i.e. separate crystalline phases for each of the enantiomers

By screening of various derivatives of the desired compounds it is in general possible to identify a compound with the required conglomerate behavior and racemization conditions

Over the last 10 years this new technology has been applied for many different chiral compounds and is now quoted as Viedma ripening (to the person who described this phenomena first).

One of the main driving forces is ‘Ostwald ripening’ – bigger crystals are more favorable than smaller ones. “The rich get richer and the poor get poorer.”


Below this unique crystallization technique is shown for Naproxen.

For more details, see
Angew. Chem. Int. Ed. 2009, 48, 4581–4583
Org. Proc. Res. Dev. 2010, 14, 908–911








The non-steroidal anti-infective OTC drug naproxen is marketed as the (S)-enantiomer

In the current production process racemic naproxen is resolved via diastereomeric salt formation, combined with ex situ racemization

Via Viedma ripening the methyl ester of naproxen the (S)-enantiomer could be obtained in single process operation without the use of (stoichiometric) chiral auxiliaries and in quantitative crystallization yield

By the use of specific milling equipment and beads the Viedma ripening has been scaled up to kg volumes successfully, while reducing process times to several hours only.