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Introduction to API Process

Simulation
Pharmaceutical API Process
Development and Design
Module Structure
Process modeling basics
Model applications
Model types
Modeling procedure
Simulation packages
DynoChem
Examples
Heat transfer
Batch reactor with accumulation effects
Model Applications
Effects of process parameter changes
Optimal operating policies for batch
operations
Compare different reactant or solvent feed
strategies
Maximization of yield in crystallization
Minimize side-product formation in batch
reaction
Safety
Loss of cooling
Model Types
Mechanistic (white box)
Empirical (black box)
Combined models (grey box)
Lumped parameter
Distributed parameter
Continuous
Discrete
Hybrid discrete/continuous
Modeling Procedure
1. Problem definition
a. Level of detail
b. Inputs and outputs
2. Identify controlling mechanisms
3. Evaluate problem data
a. Measured data
b. Parameter values
4. Construct model
5. Solve model
Controlling Mechanisms
1. Chemical reaction
2. Mass transfer
a. Diffusion
b. Boundary layer
3. Heat transfer
a. Conduction
b. Convective
c. Radiation
4. Fluid flow
5. Mixing
6. Evaporation
Model Construction
1. System boundary and balance volumes
2. Characterizing variables
3. Balance equations
4. Transfer rate specifications
5. Property relations
Model Components
1. Model equations and variables
a. Overall and component mass balances
b. Energy balance
c. Momentum balance
d. Transfer rates
e. Physical properties
2. Initial conditions
3. Parameters
Software Packages
Examples
gPROMS, DynoChem, Daesim Studio, MATLAB
Desired features
Solution of differential algebraic equation systems
Parameter estimation
Optimization
Model templates, physical properties estimation
Software used for examples in this module
DynoChem
DynoChem Features
Tools for simulation, optimization and
fitting
Excel spreadsheets for data entry and
utility calculations
Model library
Templates for common API Unit Operations
Utilities for physical properties, vessel
characterization
DynoChem Model Structure
Component Definitions
Name, molecular weight, functional groups for
property calculations
Process Definition
Statements
Scenarios
Initial values, parameters
Data sheets
Profiles for measured variables
Statements
Phase
Represents vessel (e.g. header tank,
condenser, receiving vessel) or compartment
(e.g. headspace)
Solid, liquid, gas
Flow
Transfer, feed, remove
Reactions
Take place in phases or flows
Statements (contd.)
Heat transfer
Heat or cool a phase with a jacket (flow)
Heat exchange between phases
Heat duty
Mass transfer
Liquid-liquid (transfer between immiscible
phases)
Gas-liquid (e.g. hydrogen into solvent)
Solid-liquid (e.g. dissolution)
Statements (contd.)
Condense
V-L phase equilibrium (Antoine eqn)
Calculate
Set up user defined equations
Integrate
Integrate variables during a simulation
Solver
Solution method, accuracy
Example 1: Heat Transfer
Through Jacket
(see handout for detailed process
description)
Balance Volumes
1. Bulk liquid
2. Heating fluid
bulk
jacket
jacket
bulk
Assumptions and Controlling
Mechanisms
Assumptions
Neglect agitator work
Neglect heat losses to environment
Neglect evaporation
Constant properties
Controlling Mechanisms
Flow of heating liquid
Heat transfer between jacket and tank
Perfect mixing
Model Variables
Bulk mass
Bulk specific heat
Bulk temperature
Jacket mass flow rate
Jacket specific heat
Jacket inlet temperature
Jacket outlet temperature
bulk
M
bulk p
c
,
bulk
T
jacket p
c
,
jacket
F
in jacket
T
,
out jacket
T
,
Heat Transfer Equations
, p bulk
c specified =
, p jacket
c specified =
jacket
F specified =
bulk
M specified =
)
, bulk p bulk bulk
d
M c T q
dt
=
) q T UA T T c F
lm in jacket out jacket jacket p jacket
= A = ) (
, , ,
) ) ) . J
out jacket bulk in jacket bulk in jacket out jacket lm
T T T T T T T
, , , ,
ln = A
Model Objectives
1. Determine UA by fitting experimental data
2. Estimate time to heat bulk liquid to boiling
point for different jacket temperatures
DynoChem Model Summary
Components
solvent (methanol), htfluid
Process definition (statements)
Phase bulk liquid
Heat bulk liquid with jacket
Scenarios (initial values and parameters)
Bulk liquid: Initial temperature, solvent mass,
specific heat
Jacket: Inlet temperature, flow, specific heat
UA (to be determined by fitting data)
Jacket and Bulk temperature profiles
0
20
40
60
80
100
120
12/8/06 6:57 AM 12/8/06 7:04 AM 12/8/06 7:12 AM 12/8/06 7:19 AM 12/8/06 7:26 AM 12/8/06 7:33 AM
Time, min
s
e
e

l
e
g
e
n
d Jacket
Temperature C
Bulk liquid
Temperature C
Data Sheets
Simulation Tool
Requires UA value
Obtain by fitting simulated temperature
profile to plant data
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35
Jacket Temperature (Imp)
Bulk liquid Temperature (Exp)
Bulk liquid Temperature
(UA=400)
Bulk liquid Temperature
(UA=100)
Fitting Tool
Least squares fitting (Levenberg-Marquardt)
Scenarios
Compare heating time with different jacket
parameters
Heating time
20
30
40
50
60
70
0 10 20 30 40 50 60
Time (minutes)
T
e
m
p
e
r
a
t
u
r
e

(
C
)
Jacket Temperature=104
Jacket Temperature=120
Jacket Temperature=88
Example 2: Fed-batch
reaction with safety constraint
(see handout for detailed process
description)
Balance Volumes
1. Bulk liquid
2. Heating fluid
3. Header tank
header
jacket
bulk
header
jacket
bulk
1 feed
Process Description
Exothermic reaction
substrate + reagent product
Isothermal operation, fed-batch
Objective
Minimize time to produce given amount of
product
Manipulated variable
Feed rate of reagent
Model Variables
concentration of species X in reactor;
volume of material in reactor;
maximum volume;
feed rate;
concentration of X in header tank;
kinetic rate constant;
reactor temperature (normal process operation);
Maximum temperature of synthetic reaction
(temperature attained after cooling failure);
maximum allowable temperature;
heat of reaction;
Reaction heat generation;
density;
heat capacity of material in reactor
bulk X
c
,
bulk
V
max
V
in
q
header X
c
,
k
bulk
T
MTSR
max
T
r
H A
p
bulk p
c
,
r
q
Safety Constraint
MTSR (maximum temperature of synthetic reaction)
max
T T T MTSR
ad bulk
A + =
bulk
T
Safety Constraint
Cooling failure Stop feed Reaction
continues till unreacted components are
exhausted
Maximum attainable temperature
Without safety constraint, batch operation
(add all B at t=0) is optimal
extent of reaction after feed is stopped
Srinivasan et al., (2003), Computers and Chemical Engineering, 27(2003) 1-26
p r bulk reagent bulk substrate bulk
c H t c t c T t MTSR p ) ( )) ( ), ( min( ) (
, ,
A + =
Feed Profile
Max flow (1, 3): Volume and safety constraints
are inactive
Controlled flow (2): Safety constraint is active
No flow (4): Volume at maximum value
time
Min
in
q
Max
in
q
in
q
con
in
q
Max
in
q
1
2
3
4
Srinivasan et al., (2003), Computers and Chemical Engineering, 27(2003) 1-26
Reaction Equations
B A bulk
c kc V rate =
r r
H rate q A - =
Heat transfer equations as in Example 1
p r bulk reagent bulk substrate bulk
c H t c t c T t MTSR p ) ( )) ( ), ( min( ) (
, ,
A + =
DynoChem Model Summary
Components
solvent, coolant, reagent, substrate, product
Process definition (statements)
Phase bulk liquid
Heat bulk liquid with jacket
Phase header tank
Transfer to bulk liquid from header tank
Reactions in bulk liquid
Calculate MTSR
DynoChem Model Summary
Scenarios (initial values and parameters)
Bulk liquid: Initial temperature, solvent mass,
specific heat, substrate moles, reagent moles
Header tank: Temperature, solvent mass,
reagent moles
Jacket: Inlet temperature, flow, specific heat,
UA
Feed and Temperature Profiles for Fed Batch Reactor
0
10
20
30
40
50
60
70
80
0 200 400 600 800 1000 1200 1400
Time, min
s
e
e

l
e
g
e
n
d
Qin L/hr
Temperature C
Data Sheet for Simulation
Adjust feed profile to satisfy MTSR and volume
constraints
Isothermal temperature profile is imposed through data
sheet (DynoChem calculates required jacket temperature internally)
Simulation Results
Volume (l)
60
70
80
90
100
110
0 200 400 600 800 1000 1200 1400
Time (min)
Volume (l)
Maximum flow
Controlled flow
No flow
Simulation Results
MTSR
76.5
77
77.5
78
78.5
79
79.5
80
80.5
0 200 400 600 800 1000 1200 1400
Time (min)
T
e
m
p
e
r
a
t
u
r
e

(
C
)
MTSR
Safety constraint active
Volume constraint active
Safety and volume constraints inactive
Scenarios
Increase reactor volume, reduce cycle time
0
10
20
30
40
50
60
70
0 200 400 600 800 1000 1200 1400
Time (min)
P
r
o
d
u
c
t

(
m
o
l
)
Run1
Run2
60
70
80
90
100
110
120
0 200 400 600 800 1000 1200 1400
Time (min)
V
o
l

(
l
)
Run1
Run2
Volume constraint no longer active
References
Katalin Hangos and Ian Cameron, Process
Modeling and Model Analysis, Academic Press,
2001, London.
P.E. Burke, Experiences in Heat-Flow
Calorimetry and Thermal Analysis, in W. Hoyle
(ed), Pilot Plants and Scale-Up of Chemical
Processes, Royal Society of Chemistry, 1997,
Cambridge.