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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
0
50
100
150
200
250
0 2 4 6 8 10
In
ten
sit
y
Time (hours)
Alpha peak 877 cm-1
Beta peak 872 cm-1
0
20
40
60
80
100
120
140
160
0 5 10 15 20 25 30 35
In
ten
sit
y
Time (hours)
Alpha peak 877 cm-1Beta peak 872 cm-1
Blockage
-50
-30
-10
10
30
50
70
90
110
130
0 2 4 6 8 10 12 14
In
ten
sit
y
Time (hours)
Alpha peak 877 cm-1
Beta peak 872 cm-1
Complete transformation:
low yield of beta form
0
50
100
150
200
250
300
350
400
450
0 1 2 3 4 5
In
ten
sit
y
Time (hours)
Alpha peak 877 cm-1
Beta peak 872 cm-1Seeded with 5%
Beta before nucleation
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20
In
ten
sit
yTime (hours)
Alpha peak 877 cm-1
Beta peak 872 cm-1
Seeded with 10%
Beta before nucleation Beta form washed out,
alpha form nucleates
Transformation to
beta form quicker than unseeded
experiment
-50
0
50
100
150
200
250
300
0 5 10 15 20 25 30
In
ten
sit
y
Time (hours)
Alpha peak 877 cm-1
Beta peak 872 cm-1
MSMPRstarted
Beta form washed out, nucleation of alpha form
0
50
100
150
200
250
300
350
400
450
0 1 2 3 4 5 6
In
ten
sit
y
Time (hours)
Alpha peak 877 cm-1
Beta peak 872 cm-1
MSMPRstarted
0
5
10
15
20
25
30
35
40
45
10 20 30 40 50 60 70 80
So
lute
co
nce
ntr
ati
on
(g
/kg
so
lven
t)
Temperature (oC)
alpha
beta
Start Temp80oC
Jacket Temp45oC
Jacket Temp25oC
-20
0
20
40
60
80
100
120
0 0.5 1 1.5 2
In
ten
sit
y
Time (hours)
Raman: Liquid Phase