Preferential crystallization of a racemic compound via its conglomerate co-crystals

Preferential crystallization of a racemic compound via its conglomerate co-crystals

Villamil Ramirez, O.F.

Kramer, H.J.M. (mentor)

Mechanical, Maritime and Materials Engineering

Process and Energy

2016-08-24

Preferential crystallization, as a powerful chiral resolution technique, is intrinsically limited to chiral molecules that crystallize as conglomerates. Many studies have been conducted on using chemical reactions to convert the target molecules, which originally form racemic compounds, into conglomerate-forming derivatives salts or by creating solvate, for the application of preferential crystallization. Up to this date conglomerate co-crystals of racemic compounds have never been applied as the intermediate for chiral resolution. In this study, preferential crystallization of the model compound Ibuprofen (IBU), originally a racemic compound, was carried out via its conglomerate co-crystal with 2,4-bipyridine ethylene (BPE) in heptane. Suitable operation conditions were selected based on pseudobinary phase diagram of the model compound system constructed under different IBU-BPE ratio. A unique measurement method combining polarimeter and Nuclear Magnetic Resonance (NMR) measurements was developed to identify the enantiopurity and the yield of the final product, which was a mixture of racemic IBU and IBU-BPE co-crystals, a likely result from this complex system. With respect to the results, preferential crystallization of IBU was successfully performed by slowly cooling down a saturated solution of racemic IBU-BPE, initially at T=57.5°C, after seeding it with S-IBU/BPE crystals to T=53°C with a cooling rate of 0.3°C/min. The recovered crystalline product contained pure IBU and a mixture of R-co-crystals and S-co-crystals with a yield of 44%, with the amount of S-co-crystals recovered four times higher than the amount of R-co-crystals present in the final product. The existence of R-IBU/BPE indicates that the primary nucleation of the undesired enantiomer still took place. This can be minimized by performing the experiment at bigger scale, where samples of the mother liquor can be taken during the process in order to monitor the evolution of the enantiomeric excess enabling the defining of an optimum filtration time. The crystallization of racemic IBU along with the cocrystals lowered the purity of S-IBU. By using new ratios of IBU/BPE close to the stoichiometric co-crystal ratio and with IBU in excess, this impurity can be diminished. Additionally a comprehensive study of the Metastable Zone Width (MSZW) in a bigger volume and the exploration of mixture of solvents can improve the definition of the final temperature in order to avoid the presence of racemic IBU and R-co-crystals in the crystals produced.

conglomerate co-crystal
preferential crystallization
chiral resolution

http://resolver.tudelft.nl/uuid:14154bd2-d5a5-46bb-8d37-172725d6953b

2017-08-24

Student theses

master thesis

(c) 2016 Villamil Ramirez, O.F.