A laminar-flow tubular crystallizer
was used for seedless continuous
flow crystallization of an active pharmaceutical ingredient, namely,
Brivaracetam, which has a polymorphic behavior: rod-shaped crystals
and a pseudo-polymorphic solvated, needle-like crystal. The combination
of fast cooling at 20 °C/s and high supersaturation values between
4 and 11 resulted in the discrimination of nucleation and growth of
only the desired crystalline form even though its solubility curve
is very close to the one of the undesired needle shape. Crystal nucleation
and the start of crystal growth occur inside the tubular crystallizer;
high flow rates prevent clogging of the crystallizer. Further crystal
growth may be, if desired, stopped via immediate filtration. In this
way, an industrially applicable continuous crystallizer is proposed.
It is also demonstrated that the presence of restrictions in the tubing
drastically increases the nucleation rate. A literature survey points
out that induced turbulence can occur under current flow conditions
using said restrictions.
The study presents the use of a continuous crystallization device that can be directly incorporated into flow chemistry setups. Inside this device spontaneous nucleation and growth of organic molecules are controlled and maintained, using Aspirin as model molecule. The identification of the optimal crystallization scenario is discussed in view of the chemical stability of Aspirin and based on the determination of the solubility and the metastable zone width corresponding to the presented experimental setups. Physicochemical analyses combined with heat transfer modeling of the solution whilst flowing through a capillary placed inside a thermostated water bath provide the desired cooling profile and hence the degree of supersaturation along the system. The crystalline quality and stability of the crystalline output is evidenced for two different pump setups having distinguished flow patterns to show the independence on the flow stability, an important parameter for the success rate of the complete reaction scheme and in the perspective of operation scale-up. Reproducible output of material with narrow size distributions is obtained throughout all experiments.
This paper discusses theoretical and experimental considerations of organic molecules nucleating inside tubular reactors or nucleators. Temperature evolution of these liquid systems is experimentally shown for different flow rates as a function of distance when these nucleators are immersed into a water bath set at spontaneous nucleating conditions. When different restrictions in the flow path are introduced before the cooling phase of the liquid; important differences on the nucleation rates are observed. For this study, Aspirin was dissolved in a blend of water and ethanol in a 50/50 vol%. At a concentration of 200 mg/mL and a nucleation temperature of 10°C, demonstrated to be close to the metastable zonewidth, these flow restrictions show an antagonistic effect on the nucleation rate. One restriction, placed right before the nucleator enters the cooling bath, induces a reduction in nucleation rate. Putting more restrictions into the flow path with an equal separation of 5 cm in between, the nucleation recovers back to its initial value when a second restriction of an expansion ratio 2 is applied. Restrictions with an expansion ratio of 4 exceed this nucleation rate up to an order of magnitude when more than 2 restrictions are put in place.At a higher kinetic driving force defined KDF, at a concentration of 300 mg/mL of Aspirin, the influence of the restriction becomes invariant as a function of the expansion ratio. For all experiments, the nucleation rates is highly increased with the number of restrictions introduced into the flow path. A thermal gradient difference by using the restrictions on the cooling rate of the liquid flowing inside the tubing was not observed experimentally. Therefore only hydrodynamic changes of the flow seems a plausible cause for this nucleation rate -restriction dependence as it is expected that finite amplitude perturbations, amplified by the use of restrictions, cause vortex shedding in current experimental setup.
Crystallization is one of the major steps in industrial production and environmental settings. According to thermodynamics and nucleation theories, the crystallization kinetics can be controlled by adjusting the temperature and concentration. The supersaturated liquid is almost always flown into a crystallization device due to stirring, injection, or other reasons. The role of shear flow on the crystallization kinetics therefore plays a crucial role, but the precise shear-induced nucleation mechanism has so far remained elusive.Here we present a detailed mechanism for the example of glycine, and we validate it by comparing experimental data to theory. A major result is the confirmation that nucleation has a maximum as a function of shear, which can lead to a dramatic enhancement of industrial production.
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