In-situ monitoring of crystallisation processes in MSMPR

reactors using non-invasive Raman spectrometry

1. Introduction Conventional crystallisation is carried out in batch

reactors with the use of off-line analytical techniques commonly

resulting in problems with product quality and consistency

MSMPR reactors can be employed for continuous crystallisation

and are commonly used to study the kinetics of different polymorphs

in crystallisation processes

The aims of the project were to operate at a point supersaturated

with respect to either alpha or beta L-glutamic acid to obtain the

pure forms. This can be achieved by changing the temperature,

concentration or residence time.

In this work in-situ Raman spectrometry has been employed to

provide information on how changes in reactor temperature or

residence time and the addition of seeds affect the formation and

growth of particles in real time. The measurements were able to

show differences in the nucleation temperature, polymorphic

composition and growth profiles of the crystals

2. Experimental

Aqueous solutions of L-glutamic acid prepared (40 g/L)

Heated to 80°C and added at a constant flow rate to a vessel at a

fixed temperature of either 25°C or 45°C. The residence time was

determined by the flow rate and 10% of the reactor contents was

removed at fixed time intervals.

Operating conditions determined the initial polymorph obtained

and the transformation time to the stable form.

Experiments were repeated by seeding with either 5, 10 or 100%

alpha or beta form.

Raman spectra recorded using Kaiser Raman PhAT probe (6 mm

spot size) through wall of vessel every 70 s.

Figure 1 a): Set up of MSMPR b) Phase diagram of alpha and beta

LGA showing the liquid phase concentrations at 25°C and 45°C

using a 30 min RT

3. Results and Discussion

Figure 2 a) Crystallisation profile showing transformation from

majority alpha to beta LGA in a batch STR at 45°C b)

Crystallisation profile showing transformation from majority

alpha to beta in a MSMPR at 45°C and 30 min RT

a) In-situ analysis: unseeded experiments-45oC

b) Effect of residence time on polymorphic form and transformation

time

Figure 3 a) Crystallisation profile showing transformation from

alpha to beta LGA in an MSMPR using a 60 min RT b) Crystallisation

profile of LGA solution obtained in a MSMPR using a 15 min RT

c) Effect of seeding on nucleation and growth (5 and 10% beta)

Figure 5 a) Crystallisation profiles of alpha and beta LGA when an

MSMPR was seeded with 100% beta b) Crystallisation profiles of

alpha and beta LGA when an MSMPR was seeded with 100% alpha

4. Conclusions Alpha form was obtained at 25°C and remained after 65 hours, a

mixture of forms was obtained at 45oC which transformed to beta

after 23 hours

Pure beta form obtained using seeding but quickly washed out and

a mixture of forms nucleated as in the unseeded experiments

Acknowledgements Scottish Funding Council SPIRIT scheme, Mac Robertson Scholarship

Figure 4 a) Crystallisation profiles of alpha and beta LGA when a

MSMPR was seeded with 5% beta using a 30 min RT b)

Crystallisation profiles for alpha and beta LGA when a MSMPR was

seeded with 10% beta using a 30 min RT

5. Further Work

Investigate results further using nucleation kinetics and

MSMPR model to explain outcome of experiments

Compare results to those obtained in batch and continuous

OBR using L-glutamic acid

d) Effect of seeding (100% alpha and beta)

Laura Palmer1, David Littlejohn1, Alison Nordon1, Steven Ferguson2, Tsai-ta Lai2, Allan Myerson2

1 WestCHEM/Department of Pure and Applied Chemistry and CPACT, University of Strathclyde,

295 Cathedral Street, Glasgow, G1 1XL

2 Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts

Avenue, Cambridge , MA

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Raman: Liquid Phase