Continuous total spontaneous resolution

We achieved chiral symmetry breaking through continuous crystallizations, 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 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

Scaling up temperature cycling-induced deracemization by suppressing nonstereoselective processes

The scale-up of Temperature Cycling-Induced Deracemization (TCID) of sodium bromate is feasible provided that two nonstereoselective processes are suppressed. Both nonstereoselective processes occur as a result of insufficient crystal breakage or attrition. In the absence of crystal breakage or attrition during the temperature cycles, large crystals emerge and the resulting small total crystal surface area is unable to sufficiently consume the supersaturation during cooling, resulting in nonstereoselective nucleation. This nonstereoselective process can be avoided by applying small temperature cycles involving small dissolving solid fractions. However, this leads to a slow deracemization rate. In addition, crystals undergo nonstereoselective agglomeration, which leads to the formation of large racemic agglomerates constructed of both chiral forms. To counteract their formation, secondary nucleation through crystal breakage was found to be a key requirement. At a large scale, a homogenizer was used to induce crystal breakage which, in combination with temperature cycles, led to the removal of racemic agglomerates as well as a significant increase in the deracemization rate. Overusing the homogenizer, however, caused the enantiomeric excess increase to stop. Our experiments show the importance of secondary nucleation in TCID of sodium bromate. However, secondary nucleation is currently not incorporated in the TCID process models. In the presence of a large amount of crystals which facilitates a sufficiently large crystal surface area at the highest temperature and careful use of the homogenizer, TCID leads to complete deracemization in volumes up to 1 L, demonstrating the potential to extend TCID to industrial applications

Collaborative Writing and Revising: with whom and how?:An experimental study into the interaction between group composition and method of instruction when revising collaboratively in a foreing language in higher education

Wie een vorm van samenwerkend leren in de schrijflessen wil integreren, staat voor de vraag hoe de leerlingen het best te groeperen: welke groepssamenstelling van minder goede en goede reviseerders en schrijvers is de beste? Elke Van Steendam, Gert Rijlaarsdam, Huub van den Bergh en Lies Sercu onderzochten die vraag in twee instructiecondities. De resultaten wijzen uit dat in een meer traditionele leren-door-oefenen conditie zwakkere studenten de meeste leerwinst boeken in een heterogene groepssamenstelling, terwijl de betere studenten het meeste baat hebben bij een homogeen revisiegroepje. In de leren-door-observeren conditie maakt de groepssamenstelling niet uit

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

Microsphere-Based Rapamycin Delivery, Systemic Versus Local Administration in a Rat Model of Renal Ischemia/Reperfusion Injury

The increasing prevalence and treatment costs of kidney diseases call for innovative therapeutic strategies that prevent disease progression at an early stage. We studied a novel method of subcapsular injection of monodisperse microspheres, to use as a local delivery system of drugs to the kidney. We generated placebo- and rapamycin monodisperse microspheres to investigate subcapsular delivery of drugs. Using a rat model of acute kidney injury, subcapsular injection of placebo and rapamycin monodisperse microspheres (monospheres) was compared to subcutaneous injection, mimicking systemic administration. We did not find any adverse effects related to the delivery method. Irrespective of the injection site, a similar low dose of rapamycin was present in the circulation. However, only local intrarenal delivery of rapamycin from monospheres led to decreased macrophage infiltration and a significantly lower amount of myofibroblasts in the kidney, where systemic administration did not. Local delivery of rapamycin did cause a transient increase in the deposition of collagen I, but not of collagen III. We conclude that therapeutic effects can be increased when rapamycin is delivered subcapsularly by monospheres, which, combined with low systemic concentrations, may lead to an effective intrarenal delivery method