(300e) Separation of Enantiomers By Temperature Swing Viedma Ripening

Chiral resolutions are an important process step in the pharmaceutical industry. The term 'chiral resolutions' is a collective name for a number of methods with the aim of obtaining optically pure substances from mixtures of two enantiomers. Notable examples include chiral chromatography, preferential crystallization and resolution via formation of diastereomers. Most such methods require either auxiliary chiral substances, which are usually expensive, or detailed knowledge of thermodynamics and kinetics as well as exact control of process conditions in order to be operated successfully.

Viedma ripening is a process in which a suspension of a racemic or scalemic conglomerate in contact with a solution containing a racemizing agent is subjected to grinding by, for example, glass beads. Upon stirring for some time, this process results in the conversion of the whole solid phase to one of the enantiomers. In other words, one obtains an enantiomerically pure solid phase at a high yield through a relatively simple experimental protocol, without using auxiliary chiral substances. The first demonstrations of this process were published for sodium chlorate (NaClO ), which is an achiral substance in solution but forms optically active crystals [1] and for a small organic molecule which is induced to racemize by the organic base DBU [2].

The mechanisms behind this process are believed to be racemization, growth and dissolution due to the size-dependence of solubility, agglomeration and breakage. The racemization reaction is often induced by a catalyst, such as an acid or a base. In the case of sodium chlorate, there is no racemization reaction since the substance is achiral in solution. The growth and dissolution is caused by the same thermodynamic phenomenon which causes Ostwald ripening: the higher solubility of small crystals compared to larger ones [3]. Agglomeration and breakage are processes which affect the crystals and crystal size distributions, but not the solution phase directly.

We have previously presented a mathematical model for Viedma ripening based on population balance equations incorporating all of the mechanisms mentioned above [4,5]. This model includes two particle size distributions and two population balances describing the change of these due to action of the various mechanisms. The solution phase is modelled using a solute mass balance. The mechanisms of breakage and agglomeration are governed by the choice of the constitutive equations, however, the general behaviour of the simulations is not affected by the exact form of these equations, or by the exact values of the rate parameters used. This lets us conclude that the simulations are generally valid and thus that a size-dependence of solubility, agglomeration and racemization are indeed responsible for the observed behaviour. Breakage serves to speed up the process. Simulations carried out using this model are able to reproduce experimentally observed behaviour. For example, it is possible to direct the evolution of the system towards one of the enantiomers by starting with an enantiomeric excess by mass in the solid phase, or by starting differently sized crystals for the two enantiomers [1,2,6,7]. Our model also successfully reproduces the observation that an increase in the breakage rate leads to faster deracemisation [1,6].

The use of glass beads for grinding is a barrier to the implementation of Viedma ripening industrially. The beads can introduce impurities, which is a problem especially in the pharmaceutical industry. Furthermore, the glass beads need to be separated from the solid product after the process is completed. Recently, it has been shown that temperature swings are another alternative to grinding: cycles of heating and cooling lead to the same exponential increase in the enantiomeric excess as observed with grinding. A change in temperature affects the growth and dissolution of crystals by changing the solubility and critical size, in contrast to grinding which affects the crystal size directly.

The use of temperature swings would overcome the problems caused by the glass beads, but poses other challenges. There are, in principle, infinitely many possible temperature profiles possible, varying in the temperature range which is exploited and in the rate of heating and cooling. Choosing an optimal temperature profile requires the understanding of how temperature changes affect the particle size distributions of the two enantiomers and the solution phase concentration. Other factors that need to be considered are the thermal stability of the substance of interest, which may limit the maximum temperature which can be applied. Furthermore, the optimal rate of heating or cooling is affected by growth and dissolution kinetics, as well as by nucleation kinetics – since nucleation should be avoided, this effectively limits the rate of cooling applicable. The number of heating and cooling cycles, the absolute temperature difference and the rate of heating and cooling all affect the energy input required. Besides minimizing the time required to reach an optically pure solid phase, this energy input should of course be kept as low as possible.

We have extended our model to be able to simulate the effects of temperature changes. We use a combination of experiments and simulations in order to improve our understanding of how Viedma ripening by temperature swings works and how a process can be optimally designed in order to minimize the time required to reach an optically pure solid phase.

[1] Viedma, Phys. Rev. Lett. 94 (2005) 065504
[2] Noorduin et al., J. Am. Chem. Soc. 130 (2008) 1158
[3] Iggland and Mazzotti, Cryst. Growth Des. 12 (2012) 1489
[4] Iggland and Mazzotti, Cryst. Growth Des. 11 (2011) 4611
[5] Iggland and Mazzotti, CrystEngComm 15 (2013) 2319
[6] Cheung et al., Chem. Commun. (2008) 987
[7] Noorduin et al., Org. Process Res. Dev. 14 (2010) 908