Chiral resolution is common practice in the biomedical and pharmaceutical industry given the large number of chiral drug candidates. Beside diastereomeric salt crystallization and chiral chromatography, a new type of chiral resolution using the enantiospecific behavior of cocrystallization in solution was suggested over recent years.^1-8 This technique has the advantage of being economically and environmentally more interesting compared to chromatography and can furthermore be applied to compounds that do not or not easily form salts.

Prior to the development of this novel technique, it was shown that enantiospecificity can occur during the formation of cocrystal products between two chiral partners.⁹ As a cocrystal can only be formed between a matching pair of enantiomers, this would imply that cocrystallization can be used as a resolution tool, provoking a specific interaction of a coformer of given chirality with the chiral API of interest, the unwanted enantiomer remaining in solution.

We will emphasize on the necessity of phase diagrams in the pursuit of optimal conditions for the development of a resolution. While ternary phase diagrams of cocrystals are nowadays commonly constructed, we are in here confronted with a quaternary phase diagram, as both quantities of R and S API, the quantity of chiral coformer, and the amount of solvent play a role. The overall description of the quaternary phase diagram will be illustrated by experimental results on a model compound. As a model pharmaceutical compound, we decided to use 2-(2-oxopyrrolidin-1-yl) butanamide which is a compound that does not easily form salts and which hitherto required chiral chromatography for effective resolution. This molecule, shown in Figure 1, is a racemic nootropic drug and its biologically activity is essentially associated with the S-enantiomer, marketed under the name Levetiracetam, an active anticonvulsant used to treat epilepsy.

Figure 1. 2-(2-oxopyrrolidin-1-yl) butanamide

References:

1. G. Springuel, T. Leyssens, Cryst. Growth Des., 2012, 12, 3374.

2. C. Kassai, Z. Juvancz, J. Bálint, E. Forgassy, D. Kozma, Tetrahedron, 2000, 56, 8355.

3. S. Hanessian, R. Saladino, R. Margarita, M. Simard, Chem. Eur. J., 1999, 5, 2169.

4. P. Thorey, P. Bombicz, I. M. Szilágyi, P. Molnár, G. Bánsághi, E. Székely, B. Simándi, L. Párkányi, G. Pokol, J. Madarász, Thermochimica Acta, 2010,497, 129.

5. E. Székely, G. Bánsághi, P. Thorey, P. Molnár, J. Madarász, L. Vida, B. Simándi, Ind. Eng. Chem. Res., 2010, 49, 9349.

6. M. Kawashima, A. Hirayama, Chem. Letters, 1991, 763.

7. M. R. Caira, L. R. Nassimbeni, J. L. Scott, A. F. Wildervanck, J. Chem. Crystallogr. 1996, 26, 117.

8. K. Nemák, M. Ács, Z. M. Jászay, D. Kozma, E. Forgassy, Terahedron, 1996, 52, 1637.

9. H. G. Brittain, Cryst. Growth Des., 2011, 11, 2500.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/28738 must be provided.