The unexpected dominance of secondary over primary nucleation.

It is still a challenge to control the formation of particles in industrial crystallization processes. In such processes, new crystals can be generated either by primary or secondary nucleation. While in continuous stirred tank crystallization processes, secondary nucleation is thought to occur due to the shear or attrition of already present larger crystals; in antisolvent crystallization processes, where mixing at the inlets locally causes high supersaturations, primary nucleation is understood to be the main mechanism. We aim to show here that secondary nucleation is the dominant nucleation mechanism, even under conditions that are generally considered to be dominated by primary nucleation mechanisms. Measurements of primary and secondary nucleation rates under similar industrial crystallization conditions of sodium bromate in water, sodium chloride in water, glycine in water and isonicotinamide in ethanol show that the secondary nucleation rate is at least 6 orders of magnitude larger in all these systems. Furthermore, seeded fed-batch and continuous antisolvent crystallizations of sodium bromate under high local supersaturation, seeded with crystals of a specific handedness, result in a close to chirally pure crystalline product with the same handedness. This shows that indeed, enantioselective secondary nucleation is the dominant mechanism in these antisolvent crystallizations. It is even possible to use the enantioselective secondary nucleation mechanism to control the product chirality in such a process, making antisolvent crystallization a viable crystallization-enhanced deracemization technique, having a superior productivity compared to other crystallization-enhanced deracemization methods. Our finding of a dominant secondary nucleation mechanism, rather than primary nucleation, will have a strong impact on nucleation control strategies in industrial crystallization processes.

On the Effect of Secondary Nucleation on Deracemization through Temperature Cycles.

Herein, the pivotal role of secondary nucleation in a crystallization-enhanced deracemization process is reported. During this process, complete and rapid deracemization of chiral conglomerate crystals of an isoindolinone is attained through fast microwave-assisted temperature cycling. A parametric study of the main factors that affect the occurrence of secondary nucleation in this process, namely agitation rate, suspension density, and solute supersaturation, confirms that an enhanced stereoselective secondary nucleation rate maximizes the deracemization rate. Analysis of the system during a single temperature cycle showed that, although stereoselective particle production during the crystallization stage leads to enantiomeric enrichment, undesired kinetic dissolution of smaller particles of the preferred enantiomer occurs during the dissolution step. Therefore, secondary nucleation is crucial for the enhancement of deracemization through temperature cycles and as such should be considered in further design and optimization of this process, as well as in other temperature cycling processes commonly applied in particle engineering.

Organic Salts of Pharmaceutical Impurity p-Aminophenol.

The presence of impurities can drastically affect the efficacy and safety of pharmaceutical entities. p-Aminophenol (PAP) is one of the main impurities of paracetamol (PA) that can potentially show toxic effects such as maternal toxicity and nephrotoxicity. The removal of PAP from PA is challenging and difficult to achieve through regular crystallization approaches. In this regard, we report four new salts of PAP with salicylic acid (SA), oxalic acid (OX), l-tartaric acid (TA), and (1S)-(+)-10-camphorsulfonic acid (CSA). All the PAP salts were analyzed using single-crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The presence of minute amounts of PAP in paracetamol solids gives a dark color to the product that was difficult to remove through crystallization. In our study, we found that the addition of small quantities of the aforementioned acids helps to remove PAP from PA during the filtration and washings. This shows that salt formation could be used to efficiently remove challenging impurities.

Viedma ripening: a reliable crystallisation method to reach single chirality.

Crystallisation processes have evolved to practical methods that allow isolation of an enantiopure product in high yield. Viedma ripening in particular enables access to enantiopure products in a reliable way, simply through grinding of crystals in a solution. This tutorial review covers the basic principles behind asymmetric crystallisation processes, with an emphasis on Viedma ripening, and shows that to date many novel organic molecules can be obtained in enantiopure solid form.

Enantiopure isoindolinones through Viedma ripening.

Here we demonstrate that deracemization of isoindolinones using Viedma ripening is possible starting from a racemic mixture of conglomerate crystals. Crystals of the enantiopure isoindolinones lose their chiral identity upon dissolution even without the need for a catalyst. This enabled complete deracemization of the reported isoindolinones without a catalyst.

Emergence of single-molecular chirality from achiral reactants.

The synthesis of enantiopure molecules from achiral precursors without the need for pre-existing chirality is a major challenge associated with the origin of life. We here show that an enantiopure product can be obtained from achiral starting materials in a single organic reaction. An essential characteristic of this reaction is that the chiral product precipitates from the solution, introducing a crystal-solution interface which functions as an asymmetric autocatalytic system that provides sufficient chiral amplification to reach an enantiopure end state. This approach not only provides more insight into the origin of life but also offers a pathway to acquire enantiopure compounds for industrial applications.