L-Glutamic Acid Crystallization in a Mesoscale Oscillatory Baffled Crystallizer

Background

It is well-known that mixing conditions play a key role in affecting the product properties and qualities during crystallization processes. Many crystallization processes are however carried out in stirred tanks which are known to provide non-uniform mixing conditions. This can result in a product that requires downstream processing to meet the desired specification. In recent years the advantages of oscillatory baffled reactors (OBRs), such as more uniform mixing and heat transfer conditions than in stirred tank reactors, have been identified as being beneficial for use in crystallization. OBRs are capable of achieving plug flow conditions when used in continuous mode of operation which would in theory allow for a continuous crystallization process that has consistent product properties over time. The quality of crystals formed using oscillatory flow mixing conditions has also been found to be higher than those produced using ‘conventional' mixing in a stirred tank due to the formation of fewer inclusions (Ristic, 2007).  Mesoscale OBRs are OBRs scaled down to a 5 mm internal diameter, with applications in screening of conditions and low volume, continuous manufacture (Reis et al., 2005). Advantages of using this type of reactor for screening include the ability to handle solids, having a compact reactor design and achieving plug flow conditions at laminar flow rates, all of which are applicable to crystallization screening.

Aims

The aims of this research were to determine the viability of continuous crystallization in mesoscale OBRs by studying the crystallization of l-glutamic acid and to investigate the effect that variables including the oscillation conditions have on the crystal properties, such as size statistics and crystal polymorph. These results were compared with those of published crystallization experiments in larger scale OBRs.

Methodology

A solution of known concentration of l-glutamic acid was continuously pumped through a series of mesoscale OBRs, cooling the solution from 80°C to 20°C with a residence time of 20 minutes. The amplitude and frequency of oscillation in the OBR were varied between experimental runs. Product samples were collected from the outlet of the final mesoscale OBR and were analysed by light microscopy, Raman spectroscopy and X-ray powder diffraction to determine the crystal properties such as the polymorph, crystal habit, and size characteristics. A series of jacketed stirred tanks experiments with the same cooling profile and solution concentration were then used to provide a comparison between oscillatory and ‘conventional' mixing.

Results

It was established that cooling crystallization can be successfully carried out using mesoscale OBRs. The most dramatic finding was the occurrence of previously unreported tetrahedral shaped crystals coexisting with the typical α polymorph shape when samples from the mesoscale OBR were viewed under a light microscope as seen in Figure 1. This occurred in the samples produced using the lower oscillation conditions. In samples from the stirred tank experiments this crystal habit was not detected indicating that its existence may be due to the hydrodynamic conditions that occur in the mesoscale OBR. The tetrahedral crystals were able to grow and/or then subsequently change in to the α polymorph shape. This transformation is shown in Figure 2.

Figure 1 – Microscope image of crystal products from the mesoscale OBR

Figure 2 – Microscope images illustrating tetrahedral crystal transformation (different magnifications are used as images progress)

The crystal size measurements have shown that the l-glutamic acid crystals produced in the mesoscale OBR follow the same trends as in the larger OBRs, with more vigorous mixing conditions producing smaller average crystal sizes. This shows that it should be possible to produce crystals of a given average size by selecting the appropriate oscillation conditions after sufficient experimental data has been obtained. Based on the microscope images, the tetrahedral crystal habit was found to have a critical size of approximately 20 μm at which the transformation into the characteristic α polymorph shape begins to occur.

The samples taken from the stirred tank crystallization experiments showed that many of crystals had some degree of physical damage. This was not observed in the crystals sampled from the mesoscale OBR even at the most vigorous achievable mixing conditions demonstrating that the oscillatory mixing conditions in this situation result less damage to the crystals.

Conclusions

Cooling crystallization has been successfully carried out for the first time in mesoscale OBRs, producing l-glutamic acid crystals. Mean crystal sizes of samples from the mesoscale OBR were found to decrease with an increase in mixing intensity. A previously unreported crystal habit of l-glutamic acid was observed, which was witnessed transforming into the typical α polymorph shape. This tetrahedral crystal habit was not found to occur in experiments performed using a stirred tank suggesting that the mesoscale OBR could be used as a platform to investigate existing crystallization processes and potentially expose novel findings.

References

REIS, N., HARVEY, A. P., MACKLEY, M. R., VICENTE, A. A. & TEIXEIRA, J. A. 2005. Fluid Mechanics and Design Aspects of a Novel Oscillatory Flow Screening Mesoreactor. Chemical Engineering Research and Design, 83, 357-371.

RISTIC, R. I. 2007. Oscillatory mixing for crystallization of high crystal perfection pharmaceuticals. Chemical Engineering Research and Design, 85, 937-944.