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**Introduction to API Process Simulation**

Pharmaceutical API Process Development and Design

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**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

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**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

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**Model Types Mechanistic (white box) Empirical (black box)**

Combined models (grey box) Lumped parameter Distributed parameter Continuous Discrete Hybrid discrete/continuous

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**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

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**Controlling Mechanisms**

Chemical reaction Mass transfer Diffusion Boundary layer Heat transfer Conduction Convective Radiation Fluid flow Mixing Evaporation

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**Model Construction System boundary and balance volumes**

Characterizing variables Balance equations Transfer rate specifications Property relations

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**Model Components Model equations and variables Initial conditions**

Overall and component mass balances Energy balance Momentum balance Transfer rates Physical properties Initial conditions Parameters

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**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

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**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

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**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

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**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

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**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)

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**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

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**Example 1: Heat Transfer Through Jacket**

(see handout for detailed process description)

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Balance Volumes Bulk liquid Heating fluid

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**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

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

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**Heat Transfer Equations**

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**Model Objectives Determine UA by fitting experimental data**

Estimate time to heat bulk liquid to boiling point for different jacket temperatures

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**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)

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Data Sheets

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**Simulation Tool Requires UA value**

Obtain by fitting simulated temperature profile to plant data

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Fitting Tool Least squares fitting (Levenberg-Marquardt)

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Scenarios Compare heating time with different jacket parameters

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**Example 2: Fed-batch reaction with safety constraint**

(see handout for detailed process description)

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Balance Volumes Bulk liquid Heating fluid Header tank

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**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

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**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

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Safety Constraint MTSR (maximum temperature of synthetic reaction)

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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

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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

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Reaction Equations Heat transfer equations as in Example 1

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**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

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**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

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**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)

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Simulation Results Maximum flow Controlled flow No flow

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**Simulation Results Safety constraint active Volume constraint active**

Safety and volume constraints inactive

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**Scenarios Increase reactor volume, reduce cycle time**

Volume constraint no longer active

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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.

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