Preferential crystallization of a racemic compound via its conglomerate co-crystals Master Thesis Oscar F. Villamil R August 24th 2016 Faculty of 3ME Department: Process & Energy Section: Intensified Reaction & Separation Systems Graduation Committee Ir. W. Li PDeng Dr. ir. H.J.M Kramer Dr. ir. H.W.Nugteren Dr. ir. A. van der Heijden 1 Abstract 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 pseudo- binary 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 co- crystals 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. Key words: conglomerate co-crystal, preferential crystallization, chiral resolution 2 3 Acknowledgements Firstly thank you to the Process and Energy Department of TU Delft for giving me the scholarship that allowed me to pursue my master of science in Sustainable Process and Energy Technologies. Thanks to the Intensified Reactions and Separation (IRS) group for its support during the development of my project, especially to my daily supervisor, Weiwei Li, for guiding me during the experiments and for having a positive and enthusiastic attitude regarding my work, making always a space on his agenda for my project, even when he was out of the country. I would also like to thank Marloes Reus for dedicating me time, explaining me good practice in the laboratory and for organizing the group meetings and sharing her knowledge with nice tutorials. I want to thank Debby den Besten (DDB) for motivating me with her hard work attitude, for explaining me the equipment and procedures and for the countless technical discussions. Herman Kramer, my supervisor, I want to thank you for introducing me into the crystallization world initially through your lectures during the first year and afterwards with your advices, guidelines and feedback during the execution of my project, thank you for your positive attitude and for being always willing to help me when I needed it. Stephen Eustace, thank you for all your help with the NMR measurements. Moj and Priya, thank you for all the emotional support and for making the office a nice place to be. I would also like to thank Henk Nugteren and Antoine van der Heijden for being part of my thesis committee. I also want to thank Silvia for bringing me all the joy from Colombia especially in the most hectic period of my project. Dennis, thank you for encouraging me and for being literally always there in the long days of work. Yeyo, thank you because without all your help I would have never been able to succeed during my master. Oscar Villamil 4 Contents Abstract ........................................................................................................................................... 2 Acknowledgements ......................................................................................................................... 4 1. Abbreviations .................................................................................................................................. 9 2. Introduction................................................................................................................................... 10 3. Theory............................................................................................................................................ 12 3.1 Chirality.................................................................................................................................. 12 3.2 Crystallization ........................................................................................................................ 13 3.2.1 Nucleation ..................................................................................................................... 14 3.2.2 Metastable zone (MSZ) ................................................................................................. 16 3.2.3 Crystal growth ............................................................................................................... 18 3.3 Preferential crystallization .................................................................................................... 18 3.3.1 Enantiopurification from a conglomerate forming system........................................... 21 3.4 co-crystals.............................................................................................................................. 23 3.5 Screening of conglomerates.................................................................................................. 25 3.5.1 Specific Optical rotation and its use for the determination of the enantiomeric excess 27 4. Materials and methods ................................................................................................................. 28 4.1 Materials................................................................................................................................ 28 4.2 Methods ................................................................................................................................ 28 4.2.1 Solubility determination................................................................................................ 28 4.3 Seeds synthesis...................................................................................................................... 29 4.3.1 XRPD patterns................................................................................................................ 29 4.4 Purity measurement.............................................................................................................. 29 4.4.1 Determination of the ratio IBU/BPE with the NMR ...................................................... 30 4.4.2 Specific Optical rotation and its use for the determination of the enantiomeric excess 30 4.5 Preferential crystallization .................................................................................................... 31 5. Results and discussion................................................................................................................... 33 5.1 Initial system.......................................................................................................................... 33 5.2 Influence of the ratio IBU/BPE in the system........................................................................ 36 5.3 New solvent selection ........................................................................................................... 38 5.4 Phase diagram of IBU/BPE..................................................................................................... 40 5.5 MSZW (Metastable Zone Width) definition .......................................................................... 42 5 5.6 Calibration lines for specific optical rotation measurement................................................. 44 5.7 The preferential crystallization in different batches............................................................. 45 6. Conclusions.................................................................................................................................... 55 7. Recommendations........................................................................................................................