The formation of conglomerate salts from chiral molecules, which crystallize as racemic compounds, expands the theoretical application range of Viedma Ripening roughly 10 fold. In the present study, on the use of conglomerate forming salts was studied for temperature cycling, an alternative technique for Viedma ripening. The racemic compound Phenyalanine (Phe) was successfully deracemized via its conglomerate-forming salt with 2,5-xylenesulfonic acid (XSA) by continuous heating-cooling cycles applied to its suspension in glacial acetic acid, coupled with a solution racemization reaction. In addition, the dependence of the deracemization rate on the operational parameters was studies. The results can be used as guidelines for process optimization as well as for the understanding of the mechanism behind temperature cycling. The advantages and disadvantages of temperature cycling and Viedma Ripening, as deracemization methods in an industrial setting are discussed.

Viedma ripening is a process in which a compound that forms a stable racemic conglomerate can be converted to an enantiomerically pure solid state. Combining this deracemization process with Ostwald’s rule of stages, allows Viedma ripening to be extended to a racemic compound for which the conglomerate exists only in a metastable form. This is demonstrated for glutamic acid, a proteinogenic amino acid. Since Ostwald ripening is one of the processes occurring during Viedma ripening, we thus make use of Ostwald twice.

Chiral purification is a very important step in the production of many products such as active pharmaceutical ingredients (API). These procedures are typically limited to a maximum yield of 50%. Methods that include a racemization method, such as Viedma ripening, offer a theoretical yield of 100%. Racemic conglomerate formation is a necessary condition for chiral purification processes that exploit crystallization, such as Viedma ripening. This condition forms a limiting factor because only 10% of the chiral organic molecules crystallize in this way; the other 90% form racemic compounds. For two compounds that crystallize as racemic compounds we demonstrate that salt formation can transform these into racemic conglomerates and show that these can subsequently be fully deracemized using Viedma ripening. Salt formation thus promises to be a crystal engineering tool to significantly extend the applicability of Viedma ripening.

During Viedma ripening experiments on alanine 4-chlorobenzenesulfonic acid, the solution shows a small enantiomeric excess ee l with the reverse sign as compared to the solid state enantiomeric excess. This reverse solution ee l is persistent, even after the deracemization is complete, as long as the grinding is maintained. A model that includes thermodynamic chiral clusters and their incorporation into larger crystals of the same chirality explains this behavior. The size of the reverse ee l is in good agreement with the estimated subcritical cluster distribution calculated on the basis of a Boltzmann distribution and classical nucleation theory.

A coupled batch grinding method is used to obtain resolution of a scalemic mixture of asparagine monohydrate conglomerate crystals, which are not racemizable in solution. For this method in two separate vessels a scalemic mixture of crystals is vigorously ground, while the two saturated solutions in contact with the crystals are continuously exchanged. Application of the method yields a 100% resolution with a yield of 50% (S) and 50% (R) crystals in the two vessels. To obtain a successful outcome, the grinding rates, temperatures and the amount of solids must be similar in both vessels. The experimental results are supported by a simple analytical model. It confirms that the process parameters are quite critical and that the incorporation of small clusters formed by grinding into the larger crystals of the same chirality is a prerequisite to obtain complete resolution.