Continuous Total Spontaneous Resolution

Abstract

We achieved chiral symmetry breaking through continuous crystallization, which enables the continuous industrial production of chirally pure crystals. For this, a novel recycling platform that mimics a continuous cooling crystallization process with a hot concentrated feed and an outflow of cold suspension was developed and tested. A virtually enantiopure steady-state was realized by seeding a clear supersaturated achiral solution with enantiopure seed crystals at the start of the experiment. Seeding with the enantiopure form ensured that fragments of the seeded form were continuously created through secondary nucleation. Below the metastable zone limit, the product continued to consist of crystals of the same handedness as the seeded form provided that long residence times were applied in combination with sufficiently high feed concentrations. Short residence times in combination with low feed concentrations led to fouling-induced formation of both chiral forms and a decrease in the product's enantiomeric excess. Overall these results demonstrate the feasibility of Continuous Total Spontaneous Resolution of chiral 2 pharmaceutical products in an industrial setting. This continuous manufacturing approach provides many benefits including ease of operation, consistent product quality and a high degree of process control.

Interference-contrast optical activity: a new technique for probing the chirality of anisotropic samples and more

“…It has recently been shown that PlasDIC can be applied to help monitor crystal growth, with potential applications in the pharmaceutical industry [26,28]. The results presented above lead us to suggest that ICOA-GOR might be applied to provide chiral sensitivity in this context, an important addition given the importance of chirality to the pharmaceutical industry [42]. We envisage using ICOA-GOR to determine the sign of the optical rotation of a crystal in conjunction with a computer algorithm trained with knowledge of the crystal's habit to determine the crystal's orientation; together, this information will reveal the chirality of the crystal.…”

Secondary Nucleation of Sodium Chlorate: The Role of Initial Breeding

“…As a result, secondary nucleation is an excellent approach to make new crystals in continuous crystallization experiments as seed crystals would continuously convert a supersaturated feed solution into secondary nuclei. 16 A proof of concept of the continuous generation of secondary nuclei has been reported for glycine and paracetamol, where secondary nuclei were formed through continuous contact nucleation. 17 Alternatively, continuous shear-induced secondary nucleation through fluid shear should also be feasible.…”

“…After the formation and dispersion of secondary nuclei, the crystal surface becomes available to induce secondary nucleation again, provided that the solution remains sufficiently supersaturated. As a result, secondary nucleation is an excellent approach to make new crystals in continuous crystallization experiments as seed crystals would continuously convert a supersaturated feed solution into secondary nuclei . A proof of concept of the continuous generation of secondary nuclei has been reported for glycine and paracetamol, where secondary nuclei were formed through continuous contact nucleation .…”

Chiral Recognition of Racemic Proline based on Chiral Macrocyclic Nickel(II) Complex: Synthesis and Crystal Structures

“…Chiral resolution, occurring during the spontaneous resolution or chiral symmetry breaking, continues to be a subject of great interest in the pharmaceutical industry and material sciences . In our previous report, we observed chiral resolution of β‐ dl –phenylalanine by [Ni( RR ‐L)] 2+ and [Ni( SS ‐L)] 2+ (Scheme ) enantiomers selectively binding β‐ d ‐phenylalanine and β‐ l ‐phenylalanine to form [Ni( RR ‐L)(β‐ d ‐HPhe)](ClO 4 ) 2 and [Ni( SS ‐L)(β‐ l ‐HPhe)](ClO 4 ) 2 (L = 5,5,7,12,12,14‐hexamethyl‐1,4,8,11‐tetraazacyclotetradecane, Phe = phenylalanine), respectively.…”