2.

Review of Related Literature

2.1 Batch Crystallizer

Batch crystallizers are predominantly used in chemical industries like pharmaceuticals, food industries and specialty
chemicals. The nonlinear nature of the batch process leads to difficulties when the objective is to obtain a uniform Crystal Size
Distribution (CSD). In this study, a linear PI controller is designed using classical controller tuning methods for controlling the
crystallizer outlet temperature by manipulating the inlet jacket temperature; however, the response is not satisfactory. A simple PID
controller cannot guarantee a satisfactory response that is why an optimal controller is designed to keep the concentration and
temperature in a range that suits our needs. Any typical process operation has constraints on states, inputs and outputs. So, a nonlinear
process needs to be operated satisfying the constraints. Hence, a nonlinear controller like Generic Model Controller (GMC) which is
similar in structure to the PI controller is implemented. It minimizes the derivative of the squared error, thus improving the output
response of the process. Minimization of crystal size variation is considered as an objective function in this study. Model predictive
control is also designed that uses advanced optimization algorithm to minimize the error while linearizing the process. Constraints are
fed into the MPC toolbox in MATLAB and Prediction, Control horizons and Performance weights are tuned using Sridhar and Cooper
Method. Performances of all the three controllers (PID, GMC and MPC) are compared and it is found that MPC is the most superior
one in terms of settling time and percentage overshoot

2.2 Parameters used in Batch Crystallizer

Parameters Definition Value Units

b Nucleation rate exponent 1.78
Kb Nucleation rate constant 4.64*1011 1/m3.s
g Growth rate exponent 1.32
Kg Growth rate constant 1.1612*10-4 m/s
Co Initial concentration of solution 18 Kg KNO3/kg H2O
Pc Density of crystals 2110 Kg/m3
Pi Density of water 1000 Kg/m3
Kv Volume shape factor 1
M Mass of slurry 30 Kg
Cp Specific heat capacity of solution 95.06 J/kg.K
Cpi Specific heat capacity of water 4184 J/kg.K
Vi Volume shape factor 0.905 m3
Fi Flow rate of water 0.001 Kg/s
U.A. Areas times overall heat transfer coefficient 0.125 J/K.s
μ0 (0) Zeroth moments (total no. of crystals) 10-6
μ1 (0) First moment (total length of Crystals) 10-6
μ2 (0) Second moment (total area of crystals) 10-6
μ3 (0) Third moment (total volume of crystals) 10-6
n (L, t) Number density function which describes the number of crystals per crystal (1/m4)
length and volume of slurry
S Supersaturation which defines the driving potential for the nucleation and growth
to occur

2.3 Design of Batch Crystallizer

The design of a batch crystallizer is mainly a consideration of the size of the equipment, the operating conditions and measurement of
the performance. The size of crystallizer is determined by time spend and the cooling rate (occasioned by suspension of solids).
Operating conditions depends on the cooling curves formations and times spent in the batch. Basically time is important since it
ensure the correct size of crystals is reached. The quality of the products is usually measured on the amount of crystals formed and
Crystal Size Distribution (CSD). A part from the ideal design, other factors such as the supersaturation affects the design of the
equipment. The major parameters in the control of the crystallizer are the feed that is the feed for the batch process should be in the
ratio stated in the design. The operating condition for the feed also has a hand in control. The feed is expected to reach the crystallizer
a temperature of 90 degrees Celsius from the batch reactor. The temperature has to be reduced to zero degrees Celsius. The mixing
process should be moderate to avoid turbulence which might disturb the crystal from forming (Houson 2011). All the conditions affect
the most important parameter which under the control of the engineer. The quality of the crystal is considered the output. From the
chemical engineering design, the crystals formed should have some specific shape and size from them to be considered quality. From
modeling of various mathematical models, the control of the parameters in the crystallizer design can be obtained and have an
effective control of the crystallization process (Silla 2003).

Mass and energy balance in the crystallizer includes: yielding of crystals and the heat load (Crundwell 2008). The mass balance is
based on the population distribution. Among other factors the mass balance can be obtained through the nucleation rate calculations.
The mass balance of the population is important in enhancing the control of the parameters in the crystallizer (Richardson, Coulson,
Harker, & Backhurst 2002).

2.4 Control

The most important parameter to consider in the crystallizer control design is the supersaturation. The parameter is responsible is
responsible for the scaling of the heat transfer areas (Letcher 2004). It is also responsible for the nucleation process and the CSD.
When the natural cooling is considered in cooling slurry in the crystallizer, the level of supersaturation is rapidly increased thus slurry
reaches metastable state in the early stage of crystallization. Basically the resulting crystals formed are finer and of poor quality
(Branan 2005).

When seeding a controlled cooling is applied, the desired crystal size is then obtained. In this case the cooling rate is under control
therefore a metastable state is maintained throughout the process of nucleation. Also the CSD and large particles are formed with the
effects of fouling in the heat transfer areas being catered for. Basically the cooling in the crystallizer is an important factor and has
been subjected to mathematic modeling to ensure a good controlled system is established. Secondary nucleation can occur at
metastable state therefore a mass balance for the crystallization can be obtained by taking into account the control parameters (Woo
2007).
From the mass balance equation, a correct graph equation can be obtained. In comparison with the natural cooling, the graph obtained
from the equation forms a convex curve which is a contrast to the system under natural cooling.

2.4.1 Automatic Control System

An automatic control system is a preset closed-loop control system that requires no operation action. This assumes the process
remains in the normal range for the control system. An automatic control system has two process variables associated with it: a
controlled variable and a manipulated variable.

A controlled variable is the process that is maintained at a specific value or within specific range.

A manipulated variable is the process variable that is acted on by the control system to maintain the controlled variable at the
specific value or within specific range.

Functions of Automatic Control

In any automatic control system, the four basic functions that occur are:

-Measurement

-Comparison

-Computation

-Correction

2.4.2 Operating at Maximum control

Though the main aim of nucleation controlling cooling in crystallizer is to obtained large size crystals, natural cooling forms
the largest crystals overall (Coulson 2011). The problem is because the formation is uneven. Nucleation happens at some point in the
process. Basically that complicates the process since the crystal growth integral cannot be easily estimated with the time taken in the
batch. Batch process can only be defined in terms operating at optimum over a period of time and not an instant performance.

In the case where the graph of the cooling rate between the natural cooling and the controlled cooling is drawn, a natural
cooling shows a rapid temperature drop whereas controlled cooling evenly and slowly drop (Jones 2002). The principle of maximum
cooling is used.

The variables for the cooling rate can be stated in the principle of maximum cooling. The principle is used in the design of a
control system for the crystallizer. The variables are mainly the size of the crystals while the control parameter is the temperature of
the solution. Since the aim of the process is to maximize the size of the crystals, an ordinary deferential equation is obtained for the
process (Barbosa-Póvoa, Matos, & Matos 2004). It can be deduced that maintaining a constant temperature throughout the operation
in the crystallizer maximizes the final outcome of the particles size and the CSD. It prevents an early nucleation and maintains an
optimum operating condition (Silla 2003). Optimization is not ideal however the process has maximum operating conditions.

2.4.3 Feedback controllers

In the control system, there is either a positive or a negative feedback. Whenever there is a negative feedback, the controllers
are used to rectify the arising problem. In the case of positive feedback, the system will just operate in the same condition. The
integrated controller is an important element in control since the controlled variables are brought back to the set point so that the
offsets are rectified (Crundwell 2008).

2.4.4 PID controller design

Crystallization process can be controlled by two ways; either by controlling the crystallizer temperature or by controlling the
crystallizer concentration. Inlet jacket temperature is used as the manipulated variable. As the jacket temperature is changed,
concentration and temperature of the crystallizer is changed. Since, concentration control requires some expensive sensors temperature
control is widely adopted in literatures. A basic PID controller is designed for temperature control strategy. Output temperature of the
crystallizer is fed back and difference between the set point and measured output is calculated. This error signal is then fed to the
controller and an actuating signal is then generated from the controller so that the output reaches the set point. Zeigler–Nichols tuning
setting are used fortuning the PID parameters

2.4.5 Temperature Control

Control and manipulation of temperature during the screening, optimization and production of crystals is a prerequisite for
successful and reproducible crystal growth of proteins with temperature dependent solubility. Christopher et al., testing 30 randomly
chosen proteins, found 86% demonstrated a temperature dependent solubility and suggested that temperature induced crystallization
could be a generally useful technique. Temperature was shown to affect quantity, size, and quality of the crystals as well as sample
solubility and preliminary crystallization data.

One advantage of temperature is that temperature provides precise, quick, and reversible control of relative supersaturation.
Using temperature in addition to standard crystallization variables such as sample concentration, reagent composition and
concentration, as well as pH can increase the probability of producing crystals as well as uncover new crystallization conditions for a
sample. Additional crystallization conditions may uncover reagent formulations more amicable to heavy atom derivatization,
cryoprotection, and optimization or at least offer options. Temperature is amenable to control and can be used to carefully manipulate
crystal nucleation and growth. This control can also be used to etch or partially dissolve then grow back the crystal in an attempt to
improve crystal size, morphology, and quality or assist with seeding. Temperature control is noninvasive and can manipulate sample
solubility and crystallization with altering reagent formulation

Traditionally, crystallization screens and experiments are performed at room temperature and sometimes 4 degrees Celsius. A
reasonable range of temperature to screen and optimize for protein crystallization is 4 to 45 degrees Celsius and some proteins have
been crystallized at 60 (glucagon and choriomammotropin) degrees Celsius. A practical strategy would be to screen at 10, 20 (or room
temperature) and 30 degrees Celsius when the sample volume permits. Temperature incubations above room temperature should be
monitored closely for evaporation from the drop and reservoir.

References

Z.K. Nagy, R.D. Braatz, Advances and new directions in crystallization control, Ann Rev Chem Biomol Eng 3 (2012) 55–75.
J.B. Rawlings, S.M. Miller, W.R. Witkowski, Model identification and control of solution crystallization process: a review, Ind. Eng.
Chem. Res. 32 (1993) 1275–1296.
S.M. Miller, Modeling and quality control strategies for batch cooling crystallizers, Ph.D. thesis, University of Texas at Austin 1993.
A. Ducruix and R. Giege, Editors, Crystallization of Nucleic Acids and Proteins: A Practical Approach, IRL Press at Oxford
University Press, 1991
Haser, R., et al., Journal of Crystal Growth (1992) 123, 109-120.

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