(219g) 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.