Combination of a Single Primary Nucleation Event and Secondary Nucleation in Crystallization Processes

Abstract

The quality of a crystalline product is defined by its crystal size distribution, purity, morphology, and kind of solid state. It is highly influenced by the nucleation behavior during the crystallization process. A convenient and often used experimental method for determining nucleation behavior is by measuring metastable zone widths (MSZW) in relatively small volumes. However, to what extent these can be related to nucleation behavior on larger (industrial) scales is not known. Two major reasons for this are the lack of experimental data for MSZW measurements on different scales and the incomplete understanding of the complexity of processes determining the MSZW. In order to investigate the relationship between the nucleation behavior for paracetamol in water at the 1 mL and 1 L scales, MSZW measurements were performed. Well controlled MSZW measurements at 1 mL displayed large variations. This implies that at this scale a large number of experiments have to be performed to achieve a statistically sound experimental description of the MSZW. In contrast to the 1 mL experiments, the MSZW measurements performed at 1 L scale showed hardly any variations. The measured MSZW values at the 1 L scale corresponded to the onset of the MSZW distribution at the 1 mL scale, implying a simple scale up rule for laboratory MSZW data to larger scales. Careful in situ observation during several cooling crystallization experiments of paracetamol in water on a 3 mL scale showed the presence of a single crystal preceding the outburst of nuclei. This would imply that initially a single nucleus forms which, after growth to a considerable size, undergoes secondary nucleation. An abundance of fragments originate from this single crystal after secondary nucleation. This observation implies that the crystals produced in an industrial crystallizer originate all from one single crystal and are formed by secondary nucleation. Visualization experiments with other model systems showed that the mechanism is not limited to paracetamol but seems to occur more generally.

Measuring induction times and crystal nucleation rates

“…Visualization of the stirred solution in 3 ml volumes showed the presence of a large single crystal before a crystal suspension was detected by the decrease in the transmission of light through the sample [8]. Figure 3 shows a clear solution, the single parent crystal and the suspension after detection through a decrease in the 25 transmission of light.…”

Effect of sample volume on metastable zone width and induction time

“…These two quantities are undoubtedly related to nucleation kinetics. The volume of sample solution used for the experimental determination of these values ranges from flask size of litters [2] down to droplet size of several hundred cubic micrometers [3]. Nucleation is stochastic in nature.…”

“…Recently, Kadam et al [2] reported MSZW data obtained for primary nucleation of paracetamol from stirred aqueous solution. The MSZW, obtained on a 1 mL sample, was not reproducible and distributed widely.…”

“…This decrease in transmission of light was caused by the burst of secondary nuclei generated from a grown first single nucleus. The burst occurred immediately after the appearance of a first single crystal [2]. Therefore, it can be treated as an indication of the appearance of a first crystal.…”

“…Therefore, it can be treated as an indication of the appearance of a first crystal. The cumulative distribution function of stochastic MSZW F(DT) determined by Kadam et al [2] is shown in Fig. 1.…”