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1*
*E-mail: uqewhit1@uq.edu.au
Abstract. To design a crystallizer for producing an active
pharmaceutical ingredient (API) of the desired crystal size,
it is necessary to know the solubility, the nucleation
metastable zone widths (MSZW), the crystal growth rates
and the nucleation rates. These data have been measured
(and presented in previous conferences) for the popular
anti-inflammatory drug ibuprofen crystallized from
absolute ethanol and water-ethanol mixtures. Using this
data, methods will be outlined to design industrial
crystallizers to recover ibuprofen crystals. From ethanol,
as the solubility increases greatly with temperature,
cooling crystallizers can be used industrially. Both seeded
batch and continuous (MSMPR) designs are considered
2010, 2011). The present paper uses this data and outlines the
procedures for carrying out typical design calculations.
II.
IBUPROFEN
INTRODUCTION
kinetics
(if
2.0
I.
1.5
1.0
0.5
0.0
10
20
30
40
Temperature,oC
50
Temperature, C
1. Phases and Solubility (Rashid et al., 2008)
Form I ibuprofen, as used in this study, exists as two
enantiomers (R and S). The industrial material is a racemate
and this was used here. A rare Form II ibuprofen has recently
been reported (Dudgnon et al., 2008, Arlin et al., 2009).
Figure 2 shows the solubility in I/E mass units of Form I
ibuprofen (I) in ethanol (E). They are in broad agreement
(Rashid, 2011; Rashid et al., 2008) with previous studies. The
data was correlated by I*/E = 0.497 + 0.001026 * T2, with T =
temperature in oC. This correlation is considered to fit the true
solubility within 1% in the range 10 oC to 40 oC.
Figure 3 shows the solubility of racemic ibuprofen in aqueous
ethanol at 10, 25 and 40oC. No correlation was derived for
this data so any required values will be interpolated from the
figure. At 25 and 40oC, the solubility first rises (salting in)
then falls (salting out) finally to negligible levels. Thus water
(W) overall is an anti-solvent.
XW
10
25
40
0
0.2
0.4
0.5
0.071
0.220
-0.358
0.052
0.008
0.0014
--
0.057
0.021
---
0.6
--
0.0003
--
40o C
[0.339, 2.048]
2.0
Locus of
two liquid
layers 40 oC
Construction
line for tie lines
1.5
25oC
1.0
10o C
0.5
[0.642, 0.080]
0.0
0.0
0.2
0.4
0.6
0.8
1.0
Figure 5: Growth rate constants for ibuprofen from aqueous ethanol at 10, 25
and 40oC.
(1)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Batch time
The growth kinetics are necessary to calculate the batch time.
For consistency, the growth rate G should be expressed as the
rate of change of the reference size (G = dLr/dt) and the
supersaturation should be in the same units as used in the
material balance above. The kinetics are usually expressed as
a power law on supersaturation G = kG sn, where n is the order
of the dependence and the growth rate constant kG depends on
operating conditions (temperature, impurity, stirring speed,
etc.).
This equation and the material balance give two equations
with two unknowns (Lr and s) and may be solved. The
equations are,
dLr/dt = kG sn
(3)
(Ms / Lrs3) (Lr3 - Lrs3) = E (si s)
(2)
Sample calculation
Consider ibuprofen SPG seed with the lognormal growth rate
distribution shown in Figure 4 (CVG = 0.50) growing from
ethanol in a batch crystallizer at 25oC.
1 + C 1 , Dimensionless time
Table 2 Material balance for controlled feed addition crystallizer (mass in kg).
Initial
Final
Total
Total
Footing
213.8
113.8
100
---
500
500
Crystal
Seed
4.00
4.00
---
905.2
1030.1
1935.3
Solution
Feed
2217.5
1412.3
805.2
Total
2435.3
1530.1
905.2
905.2
1530.1
2435.3
Total
b. Controlled cooling
In this case the 4.0 kg of seed is added initially to the total
amount of saturated solution (2218 kg) at 35 oC and the batch
is cooled to lower temperatures to maintain the supersaturation
at s = 0.040. No footing is required. The behavior of the
crystallizer can be predicted again by solving equations 2 and
3 numerically, but first by altering the temperature to keep the
supersaturation at 0.040 kg I / kg E. Once the temperature
reaches 25 oC the solution is allowed to de-supersaturate to
near equilibrium, but now allowing s to fall. The variation of
size, supersaturation and mass of crystal against time are
shown in Figure 10.
As is usual with cooled batches, the temperature (purple line)
falls slowly at first then more rapidly at the end (the reverse of
natural cooling). The batch time before the final desupersaturation stage (173 min) is less than for the controlled
feed addition case because now most of the growth is at
temperatures > 25 oC and thus higher than before. The final
crystal content is 22% kg crystal per kg slurry or 19 % v/v,
which may be approaching the slurry circulation limit for
irregularly shaped crystals.
Figure 11. Recovery and growth rate for MSMPR crystallizer without
GRD.
Figure 12. Size distribution by mass of product from MSMPR. The dotted
vertical line is the volume (mass) median size of the distribution
- L
VII.
OTHER CASES
IX. REFERENCES
NOMENCLATURE
a,b
order of growth and nucleation rates
B
nucleation rate, #/min/kg slurry
C
ibuprofen concentration, kg I/kg E
CV
coefficient of variation = std. dev./mean
E
ethanol and mass of ethanol
f(L)
number size distribution density function, m-1
F, F, F1 factors
G
growth rate, m/min
I
ibuprofen
nucleation rate constant, #/min/kg sl./(I/E)
kB
kG
growth rate constant, m/min/(I/E)
L
crystal size (vol. equiv.), m
mi
ith moment about mean
M
mass of crystals, kg
suspension density, kg crystals/cryst. vol.
MT
N
number of crystals
s
supersaturation = (I/E)
Sk
skewness, m3/3
T
temperature, oC
XW
water content = W/(E+W)
W
water
z
dimensionless growth rate
Z
impurity
V
i
C