Spontaneous resolution, preferential

Another important but non-synthetic method involves harvesting crops of enan-tioenriched crystals by seeding a supersaturated racemate and is known as resolution by entrainment, or preferential crystallization. These approaches have been well reviewed and will not be covered here [8]. Rare (but spectacular) examples where crystallizations of conglomerates are observed combined with racemization events in solution, leading to total spontaneous resolutions [9], are briefly mentioned in Chapter 7 as there have been interesting recent developments on that front. Included therein are special cases where diastereomeric interactions in solution combined with racemization may yield more than a 50% yield of one enantiomer. 

Spontaneous Resolution and Preferential Crystallization The identification and characterization of the solid-state properties of chiral drugs with regard to the relationships between the racemic mixture and the (/ )- and (5)-enan-tiomers are essential for drug development and manufacture... 

FIGURE 1.41. Application of spontaneous resolution or preferential crystallization. 

Gonnade RG, Iwama S, Sugiwake R, Manoj K, Takahashi H, Tsue H, Tamura R. Occurrence of spontaneous resolution of ketoprofen with a racemic crystal structure by simple crystallization under nonequiUbrium preferential enrichment conditions. Chem. Commun. 2012 48(22) 2791-2793. 

Phenomena of purity drop in preferential crystallization for resolution of racemic mixtures are first surveyed, and proposed mechanisms relevant to the purity drop are then summarized to understand properly the phenomena. Finally with the aid of additional experimental data a possible mechanism of such spontaneous crystallization resulting in the purity drop is discussed and a process to prevent purity drop is also proposed. 

Occurrence of Spontaneous Crystallization of an Unseeded Enantiomer. When we consider the purity drop on the phase diagram, it is the prerequisite that the seeds added to cause the preferential resolution are completely pure. However if the seeds are contaminated by the undesired enantiomer, the phenomena could be completely different. Since in general seeds are taken from a previous batch, they are likely to have been contaminated by the adhered mother liquor due to incomplete phase separation or by some non-equilibrium crystallization phenomena such as inclusion of mother liquor or agglomeration of crystalline particles. For the case of the former, drying of the crystals generates small particles of the undesired enantiomer which will then be introduced to a racemic solution as seeds. 

Phenomena of purity drop in racemic resolution by preferential crystallization were surveyed and factors relevant to spontaneous crystallization and their significance were quantitatively summarized. It was empirically concluded that washing of seed crystals would be the best way to prevent such purity drop, although it could not completely suppress the occurrence. With additional experiments on the preparation method of seed crystals, adequate procedures were found. However, recrystallization under these conditions could only prolong the start of purity drop but could not prevent it. A combined process to produce optically pure enantiomers consisting of preferential crystallization, racemization reaction and solvent evaporation steps was proposed. 

---