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Crystallizer Design Methods for Direct Crystallization of

Ibuprofen as a Pharmaceutical Formulation


1

1*

A. Rashid , E.T. White , T. Howes , J.D. Litster and I. Marziano


1
School of Chemical Engineering, The University of Queensland, Brisbane, Qld. 4072, Australia.
2
School of Chemical Engineering, Purdue University, West Lafayette IN 47907-2100, USA.
3
Chemical Research & Development, Pfizer Worldwide Research and Development, Sandwich, Kent CT13 9NJ,
United Kingdom..

*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

Racemic (R)/(S) ibuprofen [2-(4-isobutyl-phenyl) propionic


acid] (Figure 1) is a widely used anti-inflammatory drug. In
Figure 1 the asterisk (*) indicates the atom where the
arrangement of the CH3 and COOH entities give the R and S
isomers Ibuprofen is insoluble in water but soluble in many
organics (Gracin & Rasmuson, 2002; Garzon & Martinez,
2004). It is purified by crystallization. Its crystallization from
ethanol and aqueous ethanol is considered here.

Keywords: Ibuprofen; aqueous ethanol; design methods;


crystallizer.
III.

INTRODUCTION

In the pharmaceutical industry, crystallizers are used to


recover or to purify a soluble pharmaceutical. There is an
enormous variety of possible industrial crystallizer
configurations, e.g. tanks or troughs, operated in batch or
continuous mode, run at constant or varying temperatures,
with or without seeding. If the following crystallization data
is available for the range of operating conditions, designs can
be undertaken for all types of crystallizers,
1.
2.
3.
4.
5.

Solubility data and phases


Nucleation metastable region
Growth rate kinetics
Nucleation rate kinetics
Agglomeration and/or breakage
applicable)

kinetics

(if

RESULTS AND DISCUSSIONS

Figure 1: The chemical structure of ibuprofen.


(Lerdkanchanaporn and Dollimore, 1997).
2.5

2.0

Solubility, I*/E (w/w)

I.

1.5

1.0

0.5

0.0

This data is available for the anti-inflammatory drug,


ibuprofen, crystallizing from absolute ethanol and waterethanol mixtures. Most of the data has been presented at
previous Chemeca conferences (Rashid et al., 2008, 2009,

10

20

30

40

Temperature,oC

Figure 2: Solubility of ibuprofen in ethanol.

50

III. REVIEW OF CRYSTALLIZATION DATA


The crystallization data are summarised here. For design
calculations it is convenient to have results in equation form,
so correlating equations are also given.

The values are small compared to the solubility, though still


wide enough to allow acceptable growth rates without
secondary nucleation.
Table 1: Secondary nucleation metastable zone width for ibuprofen in aqueous
ethanol

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

--

3. Growth rate (Rashid et al., 2010)


Ibuprofen crystals from aqueous ethanol show growth rate
dispersion (GRD) (different size crystals have different growth
rates). Figure 4 shows the log Normal distribution of growth
rates for crystals grown from un-sieved ibuprofen nuclei. The
distribution has a coefficient of variation (CVG) of 0.50 (
0.03 %).

2. Nucleation threshold (Rashid et al., 2009)


The nucleation threshold data are expressed as the 1 hour
secondary nucleation metastable zone widths (secondary
nucleation will only begin in solutions with the indicated
supersaturation held for at least 1 h). Table 1 shows the values
for solutions with different water contents (XW = W/(E+W)
by wt.) at different temperatures. These values are expected to
be accurate within 20 %.
2.5

Solubility of ibuprofen, I*/E, by wt.

40o C

Figure 4: Distribution of growth rates for ibuprofen crystals. G is the growth


rate and Gm is the mean growth rate of the crystals.

[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

Water in solvent, W/(E+W), by wt

Figure 3: Solubility of ibuprofen in aqueous ethanol at 10, 25 and 40oC.

Figure 5: Growth rate constants for ibuprofen from aqueous ethanol at 10, 25
and 40oC.

The growth rate G is first order with supersaturation s, i.e G =


kG * s, where kG is the growth rate constant. The dependence
of kG on growth conditions is shown in Figure 5. The overall
correlation fitting the data is G = 5.3 * exp(0.024 * T) *
exp[(7.2 0.21 * T) * XW]* s, where G is the growth rate in
m/min, T is the temperature in oC, XW is the fractional water
content of the solvent and s is the supersaturation measured as
I/E (by wt.). This correlation fits 95% of the experimental
data within 80%.
4. Nucleation rate (Rashid et al., 2011)
Nucleation rate data is only needed if crystallizer operation is
at supersaturations above the nucleation metastable threshold.
Above this limit the secondary nucleation rate B (#/min/kg
slurry) has been taken as first order with supersaturation s, i.e.
B = kB * s, where kB is the nucleation rate constant.
Figure 6 shows the dependence of the secondary nucleation
rate constants on water content and temperature. The chosen
fitting correlation is nucleation rate B = 1.73 108 ( 65%)
*exp[- XW/0.12 ( 90%)] * s. The errors shown are 95%
uncertainties on the parameters. This relation fitted 95% of
the experimental results within a factor of 3.

5. Agglomeration and breakage


No evidence of agglomeration or breakage was seen in all the
crystallization trials, under the agitation conditions used, so
these mechanisms are not involved.

Figure 6: Nucleation rate coefficient for ibuprofen from aqueous ethanol at


10, 25 and 40oC.

IV. GENERATION OF SUPERSATURATION


Crystallization is usually carried out to purify a material from
any impurities in the solution, so impurities must be
considered in discussion of the crystallization process. Even if
a material is being re-crystallised just to improve its crystal
size or shape, there are usually still impurities present, but at
much lower levels. For the following it will be assumed that
the particular impurities (undefined) do not affect the
crystallization equilibrium and kinetics, i.e. do not change the
solubility, growth or nucleation relations. In practice the
major impurity and other impurities would be known and the
experiments data would have been obtained with the
impurities present. The primary concern is at what conditions
the impurity will come out of solution (co-crystallize) and thus
contaminate the crystal product.
In designing a crystallizer, the first decision is the choice of
the means of generating the supersaturation for the
crystallization, e.g. changing temperature, evaporating solvent,
adding an anti-solvent. All three are relevant for the
crystallization of ibuprofen from ethanol.
For ibuprofen crystallization from water free ethanol solutions
the change of solubility with temperature is very large (Figure
2). For negligible effect of any impurity on the solubility I*/E,
cooling a saturated solution from say 35 oC to 25 oC could
crystallize 0.62 kg of ibuprofen per kg of ethanol in the
solvent.
This would correspond to a crystal content
(crystal/total slurry) of 22% w/w which is moderately high.
However there would still be a large amount of ibuprofen in
the mother liquor (1.14 kg of ibuprofen per kg of ethanol in
the liquor at 25 oC). The second method, evaporation of
ethanol (under vacuum) at say 50oC could remove 3.06 kg of
ibuprofen per kg of ethanol evaporated. Evaporation could be
continued until the impurity started to co-crystallize. In the
third method an anti-solvent (e.g. water) could be added. For
water addition at say 25oC to increases the water content of the
solvent XW from 0 to 60%, 1.08 kg of ibuprofen could be
recovered per kg of ethanol in solution. The limiting water
addition again would be constrained by the co-crystallization
of the impurity or too high a crystal content.
To illustrate the design methods, two examples will be
considered, (i) a non-nucleating well mixed batch crystallizer
and (ii) a well mixed continuous (MSMPR) crystallizer. For
the sample calculations, the feed solution will be considered to
contain 1% w/w of impurity Z and at 25oC, it will be assumed
Z will co-crystallise at the 5% level, both as Z/E ratios.

V. NON-NUCLEATING BATCH CRYSTALLIZATION


A well mixed seeded batch crystallization operating without
nucleation (operating below the nucleation threshold) will be
considered. It will be assumed the seeds selected are SPG
(size proportional growth, i.e. growth rate proportional to
size). If GRD occurs and non-SPG seeds were used,
calculations can still be done but a further characterisation of
the seeds to give a bivariate distribution in terms of size and
relative growth rate (White et al., 1998) would be required.
Mass of crystal
For theoretical and design purposes the basic size distribution
is that given on a number basis. The size distribution density
function f(L) is defined by f(L) dL as the fraction of the total
number of crystals considered with sizes between L dL/2 to
L + dL/2. The size distribution has a mean size L10 (the
number mean), a coefficient of variation CV (= standard
deviation / mean i.e. / L10) and a skewness Sk (= third
3).
moment about mean / standard deviation3 i.e. m3/
The mass of a crystal of size L is V C L3, where C is the
crystal density and V is the volumetric shape factor. If size is
taken as the volume equivalent size (as is often the case in
crystallization) then by definition V = /6 for all crystals and
is constant.
Consider a collection of N crystals having a size distribution
f(L) then the mass of those crystals with sizes between L
dL/2 to L + dL/2 is N V C L3 f(L) dL. Summing over all
crystals (sizes L from 0 to ), the total mass M = N V C
L3 f(L) dL if all crystals have the same V and C. The
integral is the definition of the third moment about the origin,
i.e. 3 = L3 f(L) dL, so M = N V C 3. The third moment
about the origin can be expressed in terms of moments about
the mean, mi as 3 = L103 + 3 m2 L10 + m3, i.e. 3 = L103 (1 + 3
CV2 + Sk CV3). So the mass of N crystals may be evaluated
by,
M = N V C L103 (1 + 3 CV2 + Sk CV3)
where L10, CV and Sk are properties of the crystal size
distribution (on a number basis) and are measured in a simple
size analysis. If it is convenient to use some other central
reference size measure Lr rather than L10 then the equation
becomes,
M = N V C Lr3 (L10/Lr)3 (1 + 3 CV2 + Sk CV3) = N V C F Lr3

For SIG (size independent growth) crystals, equation [1] could


be written as
M = N V C L303 = F L303
(1)
where L30 is the volume number mean of the distribution (L30
= L103 + 3 m2 L10 + m3) and F = N V C. For non-nucleating
growth, F will be unchanged.
The ratio of the mass of product to the mass of seed M/Ms = N
V C F Lr3 / Ns Vs Cs Fs Lrs3. If the crystals have the same
shape (or if volume equivalent size is used) V = Vs. Also the
density is unchanged so C = Cs. If there is no nucleation (or
agglomeration or breakage) then N = Ns. If the seeds are
selected as SPG (size proportional growth) then from above F
= Fs. Hence M/Ms = (Lr/Lrs)3. This relation is illustrated in
Figure 7.
The more seed that is used for a given solute deposition, the
smaller the crystal size. So this relation gives the reference
size change with growth and thus the size distribution. This
calculation applies irrespective of the growth kinetics.
Mass balance
During the course of a batch crystallization, a material balance
can be undertaken at any time to link the mass of crystal
deposited to concentration changes in the solution. There are
many ways the mass change due to the concentration drop can
be written. For example and for this analysis, the mass of
crystal corresponding to the change in concentration will be
written as E (Ci C) where E is the amount of the selected
solvent species in solution, C is the concentration of interest
and Ci the initial concentration. Care is required in the choice
of units for E. Here E is the mass of a tie substance whose
amount is unchanged during the crystallization. If the crystals
contain solvent (e.g. water of crystallization) then the tie
substance can be taken as the free solvent, the mass of
solvent minus the total mass of solvent if all solute
crystallized.

(1)

where F = (L10/Lr)3 (1 + 3 CV2 + Sk CV3). For growth on


SPG (size proportional growth) seeds where the growth rate is
proportional to crystal size, the size distribution on a log size
scale retains the same shape and all ratios associated with the
size distribution remain constant as the crystals grow, so with
no nucleation (operating below the SNT), F is unchanged
during growth.

Figure 7: Mass of seed needed to give the size increase.

. The concentrations C are then expressed as the mass ratio of


the solute to the tie substance. For this study, concentrations
are expressed as the mass ratio of ibuprofen to ethanol (I/E),
so E would then be the mass of ethanol in the crystallizer.

1.0
0.9
0.8
0.7

The material balance then becomes M Ms = E (Ci C)


where M is the mass of crystal and Ms the initial mass of seed
used. Further M Ms = E [(Ci C*) (C C*)] = E (si s)
where C* is the solubility and s the absolute supersaturation.
Thus,

0.6

= L r/L roo, dimensionless size

0.5

0.4

= M/M oo , dimensionless crystal mass


-X*), dimensionless concn
= (X-X*)/(X
(
t

0.3
0.2

N V C F Lr3 - Ns Vs Cs Fs Lrs3 = E (si s)

0.1
0.0

If the crystals are SPG with a non-nucleating batch,

N V C F (Lr - Lrs ) = (Ms / Lrs ) (Lr - Lrs ) = E (si s) (2)


3

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)

For integer order kinetics, analytical solutions exist (White et


al., 2006). For example, Figure 8 illustrates the analytical
results for first order kinetics.
A numerical solution is
necessary for non-integer orders.
For the terms in Figure 8, at the end of the batch (at
equilibrium, time ) the crystal size is Lr, the product
mass M and the concentration (here designated as X) is the
solubility X*. Xt is the total amount of solute (including
crystals) in the crystallizer. The dimensionless time is 1 =
(kG/ Lr) M/ E) * t. C1 is an integration constant. For a
particular application, C1 should be taken so that time is zero
for the particular seed size used. For example if = Lrs/Lr is
0.30, C1 should be taken as 0.60.

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

Figure 8. Analytical solution for time dependence of dimensionless size,


crystal mass and solution concentration for non-nucleating batch crystallizers
seeded with SPG crystals first order kinetics (White et al., 2006).

Since SPG the seed size distribution will be of identical shape


to the growth distribution, i.e. lognormal having a volume
median size of say 20 m. It is desired to grow the crystals to
have a volume median size of 100 m in a non-nucleating
crystallizer (initial supersaturation below the secondary
nucleation threshold relative supersaturation of 0.052 i.e. an
absolute supersaturation of 0.055 kg of I per kg of E). Since
SPG the product distribution will also be lognormal. The size
ratio of the product to the seed L/Ls = 5. Thus the mass of
seed / mass of product = 1/125. Suppose the feed is a solution
saturated at 35oC, then the equilibrium yield is 0.616 kg
ibuprofen per kg ethanol in the crystallizer.
The operation of the crystallizer would have to be controlled
to maintain the operating supersaturation below the secondary
nucleation threshold. This could be done by (a) controlled
addition of the solution at 35oC added to an initial footing
containing the seeds or (b) by having a temperature
programmed cooling crystallizer. Both will be considered.
(a) Controlled solution addition
The crystallizer at 25oC is to produce say 500 kg of crystal.
So the mass of seed needed is 500 / 125 = 4.0 kg. The
crystallizer starts with a saturated footing containing say 100
kg of ethanol (214 kg of solution) at 25 oC. First sufficient
feed (saturated solution at 35 oC) is added very rapidly to
obtain the operating supersaturation at s = 0.040 kg of I per kg
of E (~ 70% of the MSZW to allow a safety zone from the
nucleation threshold). This amount is 19.1 [=
100*0.040/(0.616-0.040)*2.754] kg of feed, since every kg of
feed supplies 0.616 0.040 kg of I / kg E above the operating
supersaturation. The seed is then added and feeding
commenced to maintain the supersaturation constant at s =
0.040. At the end, the feed is stopped and the solution
retained for a time to de-supersaturate the solution to near
equilibrium (solubility).

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

A material balance (Table 2) can be undertaken for initial to


the final equilibrium conditions. Thus 2218 kg of feed will be
used to give a total crystallizer mass of 2435 kg. The feed
would be stopped with 36.2 kg of I remaining in solution (at s
= 0.040), i.e. the product mass = 463.8 kg and the product
volume equivalent size = 97.5 m. The feeding time of the
batch will be (97.5-20)/0.39 = 201 min. The size will increase
linearly during this time (Figure 9) and the masses of product
and feed will rise rapidly. The supersaturation (the units here
are g I/ kg E) is also shown on Figure 9. The Z impurity
concentration will rise from the initial 1% to 1.26% which is
well below the assumed 5% co-crystallization concentration,
so there are no problems with impurities.
After the feed addition is stopped after 201 min, the solution
de-supersaturates as a batch. This stage will take about 30
min. The conditions during this part of the batch as shown in
Figure 9 can be calculated by solving equations 2 and 3 or else
by using the analytical solutions for a batch with first order
growth kinetics (Figure 8).

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 9. Conditions during batch experiment with controlled feed addition.


The vertical dotted line shows the end of feed addition.
Figure 10. Conditions during batch experiment with controlled temperature.

VI. CONTINUOUS CRYSTALLIZER


The most common industrial type of crystallizer is the selfnucleating continuous well mixed vessel (the MSMPR
Mixed Suspension Mixed Product Removal crystallizer). A
good review is given in Randolph and Larson (1988). For
size independent growth (SIG) systems, the theory is very
simple the product has an exponential size distribution on
a number basis and a third order Gamma distribution on a
mass basis. For size dependent growth (SDG) which
includes growth rate dispersion (GRD), the analysis is more
complex. The product size distribution has to be obtained
by numerical integration.
Assumptions
The assumptions for the MSMPR crystallizer modelling are,
Steady
state
operation
(constant
temperature, feed, flow rate, etc.)
Well mixed contents
Representative overflow (the product is
identical to the contents)
No seeding (particle generation by
nucleation only)
Nuclei initially are of negligible size
(compared to product)
No agglomeration or breakage (only
nucleation and growth)
and for size independent growth (SIG),
There is no SDG (size dependent growth).
At any time the growth rate is the same for
all crystals,
alternatively for size dependent growth (SDG),
Nuclei have a distribution of growth rates
G given by f(z) where z = G/Gm, where
Gm is the mean growth rate of the nuclei.

Review of simple SIG theory


The methods for SDG material will build on that for SIG,
so this will be summarised first. For SIG (size independent
growth) materials, the calculations are relatively simple
(Randolph and Larson, 1988).
The number size
distribution is exponential i.e. f(x) = exp(-x), where x =
L/Gm and Gm is the SIG growth rate (change in volume
equivalent size with time), is the mean residence time in
the crystallizer and Gm the number mean size . The
distribution by mass then is third order Gamma. The total
number of crystals in the crystallizer is N = B where B is
the secondary nucleation rate (number per unit time per unit
volume of contents) so the mass of crystal per unit contents
volume MT = 6 V C N (Gm)3. Now B and Gm are

functions of supersaturation s, e.g G = kG*sa, B = kB*sb. So


a selected material balance (MT = si s) linking the mass of
crystal to the drop in solution supersaturation (si s) will
allow s to be evaluated and hence Gm and thus the number
and mass distributions and the crystal content.
Example of Design
Consider an MSMPR crystallizer operating at 25 oC, fed
with a solution of ibuprofen in water-free ethanol saturated
at 35 oC. From the solubility relation the ibuprofen
concentration in the feed ci = 1.754 kg I / kg E and at
equilibrium at 25 oC, c* = 1.138. So the maximum yield
will be 0.616 kg of crystal per kg of ethanol in solution.
This corresponds to a crystal content again of 22% w/w.
Assuming SIG behaviour, we can write si - s = kG3 kB C
4 s (3a+b) F1 10-18, where si is the inlet supersaturation as
(I/E) w/w, s is the exit supersaturation, G = kG*sa with a =
1 and kG = 10.6 m/min/unit (I/E), B = kB*sb with b = 1
and kB = 1.73 * 108 #/min/(kg slurry)/(unit of (I/E)), C is
the crystal density, F1 = 0.363 kg E/kg init. solution is a
conversion factor to allow for nucleation being based on
slurry and supersaturation on ethanol,
10-18 is the
conversion from m to m and is the mean residence time
of crystals in the vessel. This equation may be solved for s,
from which the recovery (above the solubility), the mean
size and the growth rate may be evaluated. The mean size
does not change much with residence time and is predicted
to have a value as volume median size L[v, 0.5] of ~ 270
m corresponding to a number mean size L10 of 73 m.
The recovery and steady growth rates are shown as a
function of chosen mean residence times in Figure 11.
Figure 11 suggests it may be economic to operate the
MSMPR crystallizer at about 3 h mean residence time. This
would be decided after an economic analysis of the value of
the extra recovery against the extra capital cost.

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

Figure 12 shows the size analysis by mass for the product


for mean residence times 2 h or greater. The spread given
by the coefficient of variation on a volume basis CVV is
0.50.
Theory for SDG material
Now the nuclei have a distribution of growth rates G given
by the distribution f(z), where f(z) dz is the fraction of the
nuclei having dimensionless growth rates z = (G/Gm)
between z - dz/2 and z + dz/2, and Gm is the mean of the
distribution of growth rates.
Figure 13 shows the
distribution of growth rates for nuclei having a log Normal
distribution of growth rates with a CVG (coefficient of
variation = standard deviation/mean) of 0.50. Now each
growth range fraction f(z) dz will give an exponential size
distribution with L (i.e. each behaves like a simple SIG
MSMPR) which is given by f(z) dz e-L/zGm where is the
mean residence time in the crystallizer. So adding all these
growth fractions the product size distribution is given by,

- L

f(L) = 0 f(z) e zGm dz


(4)

Figure 14. Product number distributions from continuous self seeding


crystallizers.

If all nuclei have the same growth rate Gm (SIG), this


collapses to the usual MSMPR exponential size distribution
f(L) = e-x, as above. With SDG the product number size
distribution may be found by numerical integration. Figure
14 (red curve) shows the distribution of crystal sizes f(L)
plotted against crystal size L from a continuous well mixed
crystallizer. This was obtained by numerically integrating
the above equation.
For SIG, Figure 14 the log (f[L]) (number density) vs. size
would be a straight line (the blue line, the simple MSMPR
solution). The typical concave upward curvature of the
number distribution for SDG (the red curve in Figure 14) is
the result of size dependent growth. Note that the SDG
curve lies below the simple result at low sizes and above at
lower.
Sample calculation
Considering the above MSMPR case (Figure 12) the
corresponding mass (volume) distribution (satisfying the
material balance) can be calculated. The two curves are
shown in Figure 15. The SDG has a wider spread of sizes
CVV = 0.73 compared with the SIG case with CVV = 0.50.
The impurity concentration is again 1.26%.

VII.

OTHER CASES

The calculations shown can be extended to handle most


other cases, e.g. aqueous ethanol solutions, evaporation of
solvent, salting out with water, fed batch, plug flow or
classifying crystallizers. The information found in this
study provides sufficient information for the majority of
cases to be modelled.

Figure 13. Distribution of growth rates with a log Normal


distribution.

IX. REFERENCES

Figure 15. Product mass size distribution from a continuous


self seeding crystallizer.
VIII.

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

volumetric shape factor


ith moment about zero size
crystal density, g/cc
standard deviation

Other subscripts and superscripts


growth
G
mean
m
r
reference
s
seed
volume
V
*
equilibrium

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