CRYSTALLIZATION IN A STIRRED TANK REACTOR

Introduction
Stirred Tank Reactor (STR) of sizes ranging from 10 liters to 100,000 liters is the
traditional "work horse" in various fine chemicals and pharmaceutical operations. STRs
are frequently employed for mixing and gas-liquid contacting. Most of the operations
carried out in a properly baffled cylindrical vessels equipped with an agitator depend
primarily on high rates of fluid shear, high fluid recirculation rates due to the impellers on
the agitators, or a combination of both. For example, emulsification processes require
primarily a high intensity of the shearing action to reduce droplet size, and high rates of
heat transfer depend upon large flow rates of the fluid past the heated surfaces. Chemical
reactions require both large flow rates to distribute reactant streams throughout the vessel
and a high intensity of turbulence to aid the mixing of the reactant streams to the desired
degree of completeness on a molecular level. Turbulence is also needed to enhance mass
transfer between gas and liquid inside a STR (or bioreactor) for various biological
processes. For example, oxygen transfer is enhanced in a stirred reactor (usually called a
fermentor or bioreactor) for various biological processes.

Theory
The concept of mechanical agitation imparted to Newtonian fluids was advanced
by Rushton et al (1950). They found that the power absorption can be characterized by a
dimensionless power number. This dimensionless number Np represents the ratio of
external force exerted to the inertial force imparted to the fluid.
Po gc External force
Np = = 1
N Di ρ
3 5
Inertial force
where
Np is the power number (dimensionless),
P0 is the external power from the agitator in g-cm/sec,
gc is the Newton conversion factor in cm/sec2,
N is the impeller rotational speed in sec-1,
Di is the impeller diameter in cm,
ρ is the density of the fluid in g/cm3.
Fluid motion in an agitated vessel can also be characterized similar to that for
fluid flow in a pipe, using a dimensionless number, NRe which depicts the ratio of inertial
force to the viscous force for the fluids in motion. The NRe for a stirred tank reactor is
defined as:
ρ N Di 2 Inertial force
NRe = = 2
µ Viscous force

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where
NRe is the impeller Reynolds number (dimensionless),
µ is the viscosity of the fluid in g/cm-sec.
Rushton et al. (1950) were able to demonstrate experimentally that the power
number (Np) is correlated to the Reynolds number (NRe) over a wide range of operating
conditions. The Np is also dependent on the number and the types of impellers used. It
should also be clear that these STR's are fully baffled and thus the Froude number on
power absorption has been neglected.

Fig 1 Relationship of Power number to Reynolds Number of non-gassed Newtonian

fluid.

Power (P0) is the rate of doing work or the rate of energy flow. The traditional
unit of power is the horsepower, HP (550 ft lbf/sec) which is related to the SI system by 1
HP = 745.7 W. Table 1 shows the power requirements for some typical applications.

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Table 1: Suggested Horsepower Requirements (HP/1000 gal) in STRs.
Agitation type HP Application
Mild 0.5-2 Mixing, blending
Medium 2-5 Heat transfer, suspension, gas absorption
Turbulent 5-10 Reactions, emulsification, suspension of devices

Mixing Time
Many different kinds of reactors may exhibit non-uniform characteristics. While
small STRs (<500 L) are essentially well mixed, larger STRs (> 5000 L) are usually
poorly mixed. For example, differences in dissolved oxygen levels can be readily shown
in the larger STRs.
Using dimensional analysis techniques, Fox and Gex (1956) have been able to
work out a correlation for time to mix a solution on a molecular scale
ft = tm ( NDi 2 )
2/3
g1 / 6 Di1 / 2Y 3 / 2 = Constant for NRe > 105 3
Where ft is a mixing function, tm is the experimentally observed molecular mixing
time, Y is the liquid depth and T is the tank diameter.
For geometrically similar vessels equation 3 reduces to
1/ 6
tm1  Ns 4 Di1 
=  4
tm 2  Nl 4 Di 2 
where tm1 and tm2 represent mixing time for large and small reactors respectively.
Since geometrically similar reactors with same volumetric agitated input (i.e.
3
P/Di = constant)
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tm1  Di1 
=  5
tm 2  Di 2 
As expected, the mixing time increases with increasing scale.
Despite its intrinsic limitation, mixing time is still the most commonly used
parameter to quantify the mixing behavior of a reactor. Many attempts have been made
to correlate the mixing time in unaerated mixing vessels to the impeller speed and the
geometry of vessels and stirrers. For a low-viscosity medium, the mixing time in stirred
tanks with standard geometry is not too far away from what can be predicted based on the
information in the literature. The following is an example of the correlation (Riet and
Tremper, 1991).
1/ 3
3 T
N t95% = 1/ 3   NRe > 104 6
N p  Di 

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t95% is the time span to reach 95% homogeneity, N is the rotation speed (sec-1), Np is the
power number, T is the tank diameter, Di is the impeller diameter (m).
The mixing time for multiphase systems is less understood. Riet (1991)
concluded that aeration would lead to approximately a doubling of the mixing time
compared to unaerated conditions at the same stirrer speed, while others concluded the
mixing time actually decreased under aerated conditions. Therefore the mixing time for
unaerated conditions can only be used as a first approximation.

Crystals and Crystallization

A crystal is the most highly organized particular matter of non-living origin. It is
characterized by an orderly 3 dimensional lattice made of either atoms, ions or molecules.
Crystal formation is an important unit operation in various fine chemical and
pharmaceutical industries. Crystallization occurs when the molecular species reach
above saturation, which is the maximum concentration of solutes (So) which is
thermodynamically stable in solution. Saturation is the result of phase equilibria from
equal chemical potentials between the solid crystal phase and the mother liquor. In many
cases, solutions can contain more solute than that present in saturation. Such
supersaturated solutions are thermodynamically unstable. Yet, they are often metastable
and remain unaltered for long periods of time. Precipitation is quite similar to
crystallization with a major difference in that crystallization yields particles of well-
defined shape and size, while precipitation results in amorphous solids of ill-defined
shape and size.
The main objective of a crystallization process is to produce crystals with
properties such as crystal size distribution (CSD), shape and purity. The CSD is often
determined by the rates of nucleation, attrition and breakage, agglomeration and growth.
Batch and continuous crystallization are usually done in a stirred reactor and is a relative
simple operation in which a clear, warm, concentrated solute solution near its solubility
limit is manipulated (such as cooling) slowly until small crystals are formed. These small
crystals are often induced by adding “seeds” or smaller crystals. After crystallization, the
crystal product is recovered by filtration or centrifugation from mother liquor. Scale
translation of crystallization is often difficult because large scale crystallization occurs in
reactors of ill-defined geometry, with simultaneous mass and heat transfer in a multi
phase, multi component system that is also thermodynamically unstable. It is also
profoundly affected by small trace impurities.
The primary and secondary nucleation rates (Bp, Bs) are often described by power
laws:
np
Bp = K p ∆C
Bs = Ks (t ) W ∆C ns
Kp and Ks are constants. The secondary nucleation rate constant Ks is a function
of time. W is the magma density and ∆C is the degree of supersaturation.

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 One unique characteristics of the crystal quality is the distribution of the crystal
sizes during this crystallization process or CSD. A typical crystal size distribution can be
related to a population density (Randolph and Larson, 1988). The population balances
can be solved using method of moments, which is based on the evaluation of the time
variations of the crystal size distribution moments. Other methods are based on a size
discretization of the population balances or method of classes (Marchal et al, 1988,
Rawlings et al, 1993). It consists of integrating the population balance equation along the
size. Several measurement techniques for on-line crystal size distribution are available.
Image analyses and microscopy will be used in this lab to determine the crystal size and
its distribution.
The size distribution and concentration of crystals vary within an agitated
suspension. In batch crystallization, often the optimal agitation is the minimum stirring
rate needed to keep all crystals just suspended from the bottom. At such conditions, a
homogeneous suspension is not necessarily obtained, but especially axial variations in
particle concentration and size distribution are significant. The hydrodynamics vary
significantly in an agitated vessel. The local energy dissipation rate may vary by two
orders of magnitude and the highest values are found close to the agitator. Previous
results indicate that the rate of secondary nucleation is approximately proportional to the
mean specific power input to the fluid (Garside and Davey, 1980). It is thus likely that
the rate of secondary nucleation may vary significantly within the reactor and thus affect
the crystal quality.

Model System: L-glutamic acid and crystal formation.

L-glutamic acid, a common natural amino acid will be used as a model crystal in
this experimental investigation. We are interested in examining the crystal size
distribution in a well-agitated stirred tank reactor. The quality of these crystals will be
dependent on the processing conditions during the batch crystallization. Polymorphism
exists in L-glutamic acid crystals where the α form is a coarse pyramidal crystal, while
the β form crystal usually has shapes like needles or leaflets with a high moisture content
(Sugita, 1988). You are being asked to develop an experimental protocol to obtain
consistently good quality α form crystal using pH neutralization in the stirred reactor
based on your understanding of the crystallization process.
The experiments have to be carried out by collecting as much information on both
the liquid and solid phases. For the liquid phase, the pH and the conductivity of the
solution should be monitored during crystallization while for the solid phase, the final
amount of the crystal formed and the crystal size distribution should be determined.
After mixing and establishing equilibria, the conductivity of the solution first remains
constant but decreases after the induction period with corresponding increases in the
+
amount of crystals in the solution. Owing to the high ionic conductivity of H and the
conductivity of the solution can be safely assumed to be proportional to the concentration
+ +
of H ions. Therefore, H ions and afterwards, all other chemical species present in the
stirred reactor can be estimated due to mass conservation and equilibrium relationships.
Thus, the supersaturation should be known as a function of time. Crystal size distribution

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(CSD) can be estimated by taking a representative sample from the reactor at the end of
the experiment. The crystals can be filtered out and viewed with a microscope. A
characteristic size L should be estimated through multiple measurements and estimation
of a shape factor (Jones et al, 1986).

Equipment Description
A 10 liter stirred tank reactor (STR) donated by Dow-Elanco (Harbor Beach,
Michigan) has been modified with the necessary computer and process instrumentation
and data acquisition systems to evaluate its performance. This modification is based on a
financial contribution from Abbott Laboratories (N. Chicago, Ill.). Figure 2 shows a
schematic diagram of the reactor setup.
Syringe
valve
Flow

From thermostat
meter
To thermostat

Filter
Water
Quick-connect
supply

Rotameter

Heating Coil/Baffles
Air
supply
Top Propeller
drain

Bottom drain STR Vessel

Fig 2: Stirred Tank Reactor Diagram

The CSTR reactor consists of a glass cylindrical vessel 9 inches internal diameter
and 12 inches high. The CSTR is equipped with the following equipment and
instrumentation:
1. Top-entry variable-speed agitator, with a 4-inch diameter 3-blade marine propeller.
2. Integral internal coil/baffles for heating purposes and efficient mixing.
3. Resistance Temperature Detector (RTD) for reaction temperature monitoring.

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4. Conductivity probe and pH probe to monitor the conductivity and pH of the reactor
contents
5. Feed flow meter
6. Tachometer to measure agitation speed
7. Current meter to measure the power used by the agitator motor.
8. Two feed inlet ports (one ear the top, one near the bottom)
9. Two air inlet ports (one above the liquid, one just below the propeller).
10. Two product discharge ports (one from the top, one from the bottom).

EXPERIMENTAL PROCEDURES
Use of Personal Protection Equipment (PPE)
Safety glasses must be worn at all times in the laboratory.
When handling corrosive liquids (such as Sulfuric Acid solutions) appropriate
rubber gloves should be used. N-Dex nitrile rubber gloves are provided for this purpose.
When handling a container of more than 1-liter of Concentrated Sulfuric Acid
(30% or higher). A chemical resistant apron, face shield and heavy resistant gloves
should be used.

I. Equipment Start-up:
The reactor needs to be plugged into a 208-volt electric outlet and the additional
instrumentation for data acquisition needs to be plugged into a 110-volt electric outlet
(the display on the conductivity transmitter lights-up when the instrumentation is on).
Reactor Agitator: A knob located in the control panel is used to control the agitator
speed. The agitator speed is displayed in the built-in tachometer. Note that the motor
will overheat and shutdown if it is operated at currents above 2.5 amps. The load of the
motor varies with RP, liquid viscosity, density, impeller type, gas-liquid ratio, etc. The
user must be careful to monitor the motor current usage during operation to prevent
overload. Currently there is a single 4-inch propeller installed. A second 4-inch
propeller and two 4-inch flat-blade impellers are also available.
Water flow: Water feed rate can be controlled with a valve located prior to the water
inlet filter, and it can be introduced into the reactor trough one of two possible locations.
One enters at the top, near the liquid surface, the other at a position near the bottom of the
vessel. A tee in the water feed-line is fitted with a valve with a syringe adapter. This
port can be used to introduce an additional component in the feed stream.
Air flow: The air feed to the reactor can be controlled with the valve located at the top of
the air rotameter. A tee in the air line allow the air to be introduced into the reactor at
two locations. The top location (above the water surface) can be used by opening the
pinch-clamp on the plastic hose directing air to the appropriate port. Closing the pinch-

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clamp forces the air to flow through the dip-tube located directly below the lower
impeller.
Product Discharge: The product from the reactor can be discharged from the bottom of
the tank or from the top. The bottom drain can be opened by loosening the pinch-clamp
located on the plastic tube that discharges the bottom of the reactor to the drain. The top
drain can be activated by introducing a positive air pressure into the reactor and allowing
the liquid to overflow through the siphon tube located at the top of the reactor.
Temperature Control: The temperature can be controlled from the thermostatically
controlled recirculating water to the internal coils. The maximum possible water
temperature in the recirculation loop is 60 °C. The maximum temperature achievable in
the reactor is determined by the heat load, heat-loses and heat-transfer characteristic of
the internal coil.

II Data Acquisition and Data Logging

A computer is connected to the reactor hardware and instrumentation for Data
logging purposes. The IBM compatible computer uses “LABTECH CONTROL”
software (produced by Laboratory Technologies Corporation, Wilmington MA), to
control the process and display all the information received from the sensors. This
information can be stored in user-configured data files, which can be stored in the
computer hard disk or in floppy diskettes provided by the user.
The analog signals from each one of the instruments are converted to equivalent
analog signals ranging from 0 to 5 volts. These signals are then used by the analog-to-
digital (A/D) conversion card in the computer to generate a digital signal that is read by
the computer. The CONTROL program converts the digital signal (in volts) to the value
of the measured variables in the desired engineering units (i.e. l/min., degrees C, etc.).
Data File Storage
A file named “RTDnnn.XLS” is generated every time the data acquisition
program is invoked. The “nnn” indicate the numerical order of the file and it is
incremented by one each time a new file is saved. Flow rate, conductivity, temperature,
RPM, current to the agitator motor and time values are stored in this file every 15
seconds. Note that the data written to the file are not the actual readings at every 15-
second mark; instead, they are the calculated average of the values read over the previous
15 seconds. To stop the data acquisition program, simply select “Exit” from the
application “File” menu.
If a faster rate of data acquisition is desired, click-hold on the “FAST
ACQUISITION” toggle switch (located on the lower-right corner of the Process Control
screen) until it changes status from the OFF to the ON position. While this switch is in
the ON position, all values are recorded every second, and stored in a file named
“FASTnnn.XLS”. It is recommended that this be used only when necessary since it will
create very large data files in a relatively short period of time.
To retrieve these files at the end of your work, double-click on the “DATA” icon
in the “STIRRED TANK REACTOR” Folder. The files list can be sorted by date with

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the most recently created file at the top of the list. Your files can be recognized by their
creation date and time.
When you are done with the computer, please double-click on the “Shut Down”
icon on the “Start” menu.

III. Monitoring Reactor Conditions.

CONTROL operates under Microsoft WINDOWS® 95 operating system. To
start the program, turn the computer on if it is not already. The computer is not
connected to the network, so click "Cancel" in the "Enter network password" dialog box.
Double-click on the “STIRRED TANK REACTOR” folder if it is not open already. This
folder contains icons for the CONTROL set-up, the 5 calibration files, a file to reset the
calibration and a folder for the storage of the data from the experimental runs. Before
each lab session, be sure to double-click on the “reset calibration” icon to erase any
changes that the previous lab group may have made. In order to start the data acquisition
program double-click on the "REACTOR" icon. A product identification screen and the
CONTROL setup will start the data acquisition and control functions.
The program produces a window that displays the values for all the sensor outputs
on the right-hand side of the screen, and analog traces for the sensor outputs on the left-
hand side of the screen.
When you are finished using the computer please do not shut it down. There is an
anti-virus program which is set to run every night at midnight and the computer must be
left on for this event.

IV. Sensor Calibration

The electronic signals produced by the flow meters, RTDs, etc., are converted to a
standard voltage signal and sent to the computer. The sensor calibration is done by
means of a regression (either linear or non-linear) between the variable measured (flow
rate or temperature) and the voltage signal produced by the sensor. These calibrations
can be implemented with the computer by means of a polynomial fit. For sensors with a
linear response, a 1st. order polynomial is sufficient for the calibration. For sensors with a
non-linear response, a higher order polynomial will be required. The software
implements polynomial fits using:
y = a0 + a1V + a2V 2 + a3V 3 + a4V 4 + ..... + anV n 6
where:
y = Variable being monitored (temperature, flow, etc.)
V = Volts produced by the measuring instrument (flow meter,
RTDs, etc.)
ao, a1, a2, ... , an = correlation constants

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 All calibrations can be implemented in this manner. For example, an instrument
that has a linear relationship between the monitored variable and the voltage produced,
can be calibrated with:
y = a0 + a1V 7
This has the same form as equation 6 where: a2 = a3 = a4 = ..... = an = 0 .
Similarly for any ith. order polynomial (i ≤ 10 in the current data acquisition setup) can
be implemented by setting aj = 0 (where j>i).
Several instruments have been calibrated and fitted with an equation. The
parameters ai for each instrument calibration are located in text files with the same name
as the instrument, and can be edited by double clicking on the file icon1. These files
consist of 11 numbers in a column where a0 is at the top, and a10 is at the bottom. Table
2 shows the units for each of the calibrations and the sensor range:

Table 2: Sensor calibration ranges

Variable Calibration Units

Range
Conductivity: 0 - 9.99 mS
Motor Current 0 - 4.2 Amps
Rotation speed: 0 - 550 RPM
Temperature: 0 - 100 °C

The flow meter and pH transmitter need to be calibrated.

Calibration of the pH Electrode

In order to calibrate the pH electrodes, a two-point calibration is generally carried
out with the help of two standard buffer solutions of known pH. This type of calibration
generally produces a straight-line correlation between the pH electrode response to the H+
ion concentration and the transmitter output. Note that this will not correct for any non-
linearity of the electrode response. Standard buffer solutions of pH 7 and 4 are provided
for this calibration.
In order to calibrate the pH electrode/transmitter pair between pH 7 and 4, use the
following procedure:
1 To edit the calibration files, double-click on the file icon and enter the ai numbers in the appropriate
positions (note that each one of these files has to have 11 numbers in a single column or an error message
will be generated during data acquisition). Save each file by selecting “Save” from the “File” menu, and
exit the text editor by selecting “Exit” from the “File” menu.

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1. Fill a 250-ml beaker with 200 ml of DI water and rinse the pH electrode.
2. Fill a 50 ml beaker with Standard buffer pH = 7. Insert the pH electrode in the beaker
until the pH reading is stable. Mild agitation with a stirring plate and magnet may be
useful.
3. Once the reading is stable, adjust the "CALIB" screw in the transmitter until the pH
value of 7 registers in the transmitter display.
4. Rinse the pH electrode with DI water.
5. Fill a 50 ml beaker with Standard buffer pH = 4. Insert the pH electrode in the beaker
until the pH reading is stable.
6. Once the reading is stable adjust the "SLOPE" screw in the transmitter until the pH
value of 4 registers in the transmitter display.
Note: pH 7 is the neutral point for the slope of the pH transmitter. That means that the
pH reading at 7 should not change when adjusting the “SLOPE” screw. If calibration at
points other than pH 7 and 4 is desired (i.e. between pH 8 and 10 or between pH 4 and1);
use the buffer closer to pH 7 in step 2, the buffer farthest from pH 7 in step 5, and repeat
steps 1 to 6 until both pH readings match the pH of the buffer solutions.
pH Electrode Storage
When all your daily experiments have been completed the pH electrodes must be
stored in pH 7 buffer solution.

Calibration of the pH Transmitter and Flow meter

The pH tranmitter generates a current signal which is converted to a voltage
sisgnal and sent to the computer. The flow meter generates a pulse that in turn is
converted to a voltage signal. This signal is sent to the computer. A calibration is needed
to convert these voltage signals to pH units and flow units.
Procedure:
1. Turn the computer ON and double-click on each one of the pH and flow
calibration files icons (located in the “LABTECH CONTROL” group window) to
ascertain that the parameter values are a1 = 1, and
a0 = a2 = a3 = a4 = ..... = a10 = 0 (edit the files if they are not)
2. Double-click on the “STR”. If conditions shown in step 1 are met, then the pH
and flow values displayed and saved to the file by this setup represent the direct
instruments output and have units of VOLTS.
3 . Make several measures of pH values displayed by the transmitter and the
corresponding voltages sent to the computer. Create a table correlating pH
displayed vs. volts. Note that both pH calibrations (pH electrode/transmitter and
Computer Data Acquisition) can be performed simultaneously to save both time
and buffer solutions
4. Make several measurements of flow rates and the corresponding voltages sent to
the computer. Create a table correlating Flow vs. volts.

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 5. Plot the pH values against the voltage for the pH transmitter, plot the flow rate
values against the voltage and conduct appropriate curve fits, using either your
calculator, Delta-Graph, Excel or other programs, or graph paper, pencil and ruler.
Calculate the parameters ai in equation 6 (or equation 7 for linear relationships)
for each the pH transmitter and the flow meter.
6. Enter the values for the parameters ai in each of the calibration files. To do this,
double-click on the file icon and enter the ai numbers in the appropriate positions
(note that each one of these files has to have 11 numbers in a single column or an
error message will be generated during data acquisition). Save each file by
selecting “Save” from the “File” menu, and exit the text editor by selecting “Exit”
from the “File” menu. Once this is done for all calibration files, the computer will
display and store the sensor data in the appropriate engineering units (such as pH
units and l/min).
Once the calibration procedure is completed, dispose of all used buffer solutions.
NEVER return used solutions to the original container.

Residence Time and Mixing Time Characterization.

Section 8 of this manual include theory on residence time distribution and suggest
method to characterize the residence time frequency function of a stirred tank utilizing a
step function on the concentration of the feed. A similar method can be used here to
determine the residence time frequency function by applying a pulse function in the
concentration of the feed (Fogler Chapter 13). Mixing times can be analyzed in a similar
manner during batch operation of the reactor.

References
Rushton, J. H., E. W. Costich, and H. J. Everet, “Power Characteristics of Mixing
Impellers I and II,” Chem. Eng. Progr., 46, 395 and 467 (1950)
Fox, E. A. and Gex,V. E. AIChE Journal 2:539 (1956)
Fogler, H. S. Elements of Chemical Reaction Engineering, Chapter 13.Prntice-Hall,
Englewood Clifs, New Jersey (1986)
Randolph, A.D. and M.A. Larson. Theory of Particulate Processes. 2nd edition ,
Academic Press, New York, 1988.
Marchal P., David, R., Klein, J.P., and Villermaux, J., “Crystallization and Precipitation
Engineering - I. An Efficient Method for Solving Population Balance in Crystallization
with Agglomeration” Chem. Eng. Sci., 43:59- 67, 1988.
Rawlings, J.B., S.M. Miller and W.R. Witkowski. “Model Identification and control of
solution Crystallization Processes: A Review” Ind. Eng. Chem. Res. 32:1275-1296,
1993.
Garside, J. and R.J. Davey. “Secondary Contact Nucleation: Kientics, Growth and Scale-
Up” Chem Eng Commun., 4:393, 1980.

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Y. H. Sugita. “Polymorphism of L-Glutamic acid Crystals and Inhibitory Substance for β
Transition in beet Molasses” Agric. Biol. Chem. 52:3081-3085, 1988.
Jones, A.G., Budz, J. and J.W. Mullin. “Crystallization Kinetics of Potassium Sulfate in
an MSMPR Agitated Vessel” AIChE J. 32:2002-2008, 1986.
Riet,K. and Tramper, J. 1991. “Basic Bioreactor Design”, (Marcel Dekker, New York).

Henry Y. Wang, Pablo La Valle, January 7, 2002

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