1. Introduction to API Process Simulation
Pharmaceutical API Process Development and Design

2. Module Structure Process modeling basics Simulation packages Examples
Model applications
Model types
Modeling procedure
Simulation packages
DynoChem
Examples
Heat transfer
Batch reactor with accumulation effects

3. 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

4. Model Types Mechanistic (white box) Empirical (black box)
Combined models (grey box)
Lumped parameter
Distributed parameter
Continuous
Discrete
Hybrid discrete/continuous

5. Modeling Procedure Problem definition Identify controlling mechanisms
Level of detail
Inputs and outputs
Identify controlling mechanisms
Evaluate problem data
Measured data
Parameter values
Construct model
Solve model

6. Controlling Mechanisms
Chemical reaction
Mass transfer
Diffusion
Boundary layer
Heat transfer
Conduction
Convective
Radiation
Fluid flow
Mixing
Evaporation

7. Model Construction System boundary and balance volumes
Characterizing variables
Balance equations
Transfer rate specifications
Property relations

8. Model Components Model equations and variables Initial conditions
Overall and component mass balances
Energy balance
Momentum balance
Transfer rates
Physical properties
Initial conditions
Parameters

9. Software Packages Examples Desired features
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

10. 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

11. 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

12. Statements Phase Flow Reactions
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

13. Statements (contd.) Heat transfer Mass 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)

14. Statements (contd.) Condense Calculate Integrate Solver
V-L phase equilibrium (Antoine eqn)
Calculate
Set up user defined equations
Integrate
Integrate variables during a simulation
Solver
Solution method, accuracy

15. Example 1: Heat Transfer Through Jacket
(see handout for detailed process description)

16. Balance Volumes
Bulk liquid
Heating fluid

17. Assumptions and Controlling Mechanisms
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

18. Model Variables
Bulk mass Bulk specific heat Bulk temperature Jacket mass flow rate Jacket specific heat Jacket inlet temperature Jacket outlet temperature

19. Heat Transfer Equations

20. Model Objectives Determine UA by fitting experimental data
Estimate time to heat bulk liquid to boiling point for different jacket temperatures

21. 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)

22. Data Sheets

23. Simulation Tool Requires UA value
Obtain by fitting simulated temperature profile to plant data

24. Fitting Tool
Least squares fitting (Levenberg-Marquardt)

25. Scenarios
Compare heating time with different jacket parameters

26. Example 2: Fed-batch reaction with safety constraint
(see handout for detailed process description)

27. Balance Volumes
Bulk liquid
Heating fluid
Header tank

28. 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

29. 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

30. Safety Constraint
MTSR (maximum temperature of synthetic reaction)

31. 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

32. Feed Profile
time
Max flow (1, 3): Volume and safety constraints are inactive
Controlled flow (2): Safety constraint is active
No flow (4): Volume at maximum value
Srinivasan et al., (2003), Computers and Chemical Engineering, 27(2003) 1-26

33. Reaction Equations
Heat transfer equations as in Example 1

34. 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

35. 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

36. 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)

37. Simulation Results
Maximum flow
Controlled flow
No flow

38. Simulation Results Safety constraint active Volume constraint active
Safety and volume constraints inactive

39. Scenarios Increase reactor volume, reduce cycle time
Volume constraint no longer active

40. 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.