Towards continuous deracemization via racemic crystal transformation monitored by in-situ Raman spectroscopy
Xiouras, Christos and Belletti, Giuseppe and Venkatramanan, Raghunath and Nordon, Alison and Meekes, Hugo and Vlieg, Elias and Stefanidis, Georgios D. and Ter Horst, Joop H. (2019) Towards continuous deracemization via racemic crystal transformation monitored by in-situ Raman spectroscopy. Crystal Growth and Design, 19 (10). pp. 5858-5868. ISSN 1528-7483 (https://doi.org/10.1021/acs.cgd.9b00867)
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Abstract
In this work, we demonstrate a semi-batch solid-state deracemization process for N-(2- chlorobenzylidene)-phenylglycine amide (NCPA), a complex chiral polymorphic system that involves three types of crystalline racemates (racemic compound and conglomerate forms I and II). In this process, gradually fed metastable racemic compound crystals are converted in situ to crystals of the preferred (seeded) enantiomer under grinding conditions through a series of solvent- mediated transformations in a racemizing solution. The phase diagram for this system shows that while conglomerate form II is stable at the conditions examined (acetonitrile at 21°C), form I crystals of a single enantiomer (used as seeds) are unstable at (nearly) racemic compositions and convert to the racemic compound upon addition of the racemization catalyst. Thus, care needs to be exercised in order to fully convert form I to form II before addition of the racemization catalyst in order to prevent the undesired crystallization of the racemic compound. This can be achieved by adding a small amount of water, which is found to enhance the nucleation and growth kinetics of the most stable conglomerate form II, eventually leading to complete deracemization. Importantly, we show that this special deracemization process can be easily monitored online by Raman spectroscopy, which gives access to the evolution of the solid phase composition. For the studied system, this information can in turn be used to directly estimate the solid-phase enantiomeric excess online throughout the process, as long as conglomerate crystals of the counter enantiomer do not form.
ORCID iDs
Xiouras, Christos, Belletti, Giuseppe, Venkatramanan, Raghunath, Nordon, Alison ORCID: https://orcid.org/0000-0001-6553-8993, Meekes, Hugo, Vlieg, Elias, Stefanidis, Georgios D. and Ter Horst, Joop H. ORCID: https://orcid.org/0000-0003-0118-2160;-
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Item type: Article ID code: 70081 Dates: DateEvent2 October 2019Published23 August 2019Published Online23 August 2019AcceptedSubjects: Science > Chemistry
Medicine > Pharmacy and materia medicaDepartment: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Faculty of Science > Pure and Applied ChemistryDepositing user: Pure Administrator Date deposited: 10 Oct 2019 16:44 Last modified: 11 Nov 2024 12:26 URI: https://strathprints.strath.ac.uk/id/eprint/70081