The oiling out crystallization of a pharmaceutical compound API-T dissolved in acetone/water was conducted using a 100 mL crystallizer, and the effect of oil droplets on the resulting crystal size was investigated. The size of oil droplets was controlled by varying agitation speed, and the resulting crystal size decreased with an increase in the size of oil droplets, namely, with a decrease in agitation speed. The observed phenomenon could be explained by the difference of nucleation rate in large and small droplets. The generation of small crystals was caused by the ease of primary and secondary nucleation in large droplets. A decrease in oil droplet size restrained the primary nucleation and also the secondary nucleation. In this case, the small amount of crystals that were released to the continuous phase grew by absorbing small droplets. On the other hand, in single-phase crystallization without liquid−liquid phase separation, the crystal size did not depend on agitation speed.
A unique semibatch crystallization process, coupling with a
high-speed rotor-stator device, was developed for generation
and control of fine particles. The key underlying mechanism
of this process is controlled secondary nucleation under a high
shear environment during crystallization, in contrast to the
conventional particle breakage mechanism, i.e., milling, after
the crystallization. A recycle mode operation is employed to
control the residence time of the batch in the high shear domain
so as to ensure the scalability of this process. In this work, the
operational sensitivity to the supersaturation and particle size
were first explored in the laboratory. Based on the results of
the laboratory investigation, this process was successfully
demonstrated in multiple 1000-L pilot scale production batches.
The practical issues for the large scale operation are also
illustrated.
Oiling
out crystallization of an active pharmaceutical ingredient, API-T,
was carried out under agitation using a mixed solvent (acetone/water)
system, and the effects of oiling out (liquid [oily droplet phase]/liquid
[continuous phase] separation) on the aspect ratio and size of crystals
were investigated. Acetone composition of the oil phase and API-T
distribution to the oil phase increased with a decrease in charged
acetone composition, and both decreased in the continuous phase. By
utilizing this relationship, API-T crystals with small aspect ratios
were produced under a low charged composition of acetone, at which
a high recovery of product crystals could be expected. Furthermore,
large crystals were obtained in the oiling-out crystallization. Such
performance was never achieved in normal single-phase crystallization,
and thus an advantage of oiling out crystallization was shown.
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