Batch Distillation Pharmaceutical API Process Development and Design

Batch Distillation Pharmaceutical API Process Development and Design

Module Structure • • • Vapor Liquid Equilibrium Curves Rayleigh Distillation Column Configurations Column Operation Simulation Design of Batch Columns

Distillation • Used for separating a mixture of two or more liquids • Takes advantage of the differences in volatilities (vapor pressure) • For a binary mixture, αij – relative volatility, Pi 0 – vapor pressure of pure liquid i

VLE Curve and BP/DP Curves 1 T Saturated Vapor y Saturated Liquid 0 x. A 1 0 Mixture of A and B x. A 1

Homogeneous Azeotropes For non-ideal mixtures, the activity coefficients are different from unity: If the mixture has a minimum-boiling azeotrope minimum Phase diagrams for Isopropyl ether – Isopropyl Alcohol

Homogeneous Azeotropes For non-ideal mixtures, the activity coefficients are different from unity: If the mixture has a maximum-boiling azeotrope maximum Phase diagrams for Acetone – Chloroform

Heterogeneous Azeotropes For a minimum-boiling azeotrope with large deviation from Raoult’s law ( ), phase splitting may occur and a minimum-boiling heterogeneous azeotrope forms, having a vapor phase in equilibrium with two liquid phases. Homogeneous Azeotrope Heterogeneous Azeotrope

Thermo Properties Calculations • Important properties of pure components, mixtures – Vapor liquid equilibria – Y-X diagrams, T-X, T-Y diagrams – Existence of multiple liquid phases • Commercial packages – Part of process simulators – Activity++, PPDS etc • Helps you identify distillation boundaries

Rayleigh Distillation Vapor Heat Liquid Charge L’, xi – remaining liquid and mole fraction at any subsequent time L’ 0, xi 0 – initial liquid amount and mole fraction

Rayleigh Distillation (Contd) • For binary mixture when ij is constant

Batch Evaporation Qc Accum 1 Qr Accum 2

Batch Evaporation Example

Batch Distillation • Preferred method for separation when – Feed quantities are small – Feed composition varies widely – Product purity specification change with time – High purity streams are required – Product tracking is important – Feed has solids

Batch Distillation Advantages • Advantages – Flexible – Accurate implementation of recipe specific to a given mixture – Several components separated using one column – Requires least amount of capital

Conventional Batch Distillation Column Qc 1 L D • • Accum 1 Accum n N Qr

Column Configurations Inverted BD Qc Qr F F Qr Accum 1 Accum n

Column Configurations Middle Vessel BD Qc Qc Accum 1 F Qr Accum n+1 Accum m Accum n

Dual Column Configuration • Side stream from the main column fed to a second column 260 Q 2 262 A • Can be used for mixtures with 3 or more components • Take advantage of the build up of medium volatile component in the column • Eliminate slop cut • Reduce cycle time, energy consumption 2 266 217 270 216 Main Column 218 3 Side Column 219 222 B 220 1 214 Q 3 232 223 224 228 C 230 240 Q 1

Column Operation • Start-up period • Vapor boilup rate policy – Constant vapor boilup rate – Constant condenser vapor load – Constant distillate rate – Constant reboiler duty • Product period: Reflux ratio policy • Shutdown period

Column Operation • Operate under total reflux until the column reaches steady state (L / V = 1, R = ) • Change reflux ratio to the desired value • Collect distillate in accumulator • End the ‘cut’ when certain criteria are satisfied – Duration Qc – Condenser composition 1 – Accumulator composition, amount L D • • Accum 1 Accum n – Reboiler composition, amount N Qr

Effect of Reflux Ratio • Increasing reflux ratio – Improves separation – Increases cycle time – Increases energy consumption • Profile optimization – Trade-off between cycle time and value of recovered material – Maximize profit

Staged Separation Qc V 1 – vapor rate leaving plate 1 V 1 L / V – Internal reflux ratio D Vj, yj L / D – Reflux ratio N Qr L Lj-1, xj-1 Mj, xj Plate j Vj+1, yj+1 Lj, xj

Packed Columns • HETP – Height equivalent to one theoretical plate – Characteristic of packing • Number of plates = packed bed height/HETP

Simulation of Batch Distillation • • Simulation of startup period Simulation of product period Column model Examples – Benzene–toluene–ortho-xylene – Acetone–chloroform

Simulation of Start-up Period • Dynamics of column during start-up are very difficult to model – Rigorous model of tray hydraulics – Rigorous model of heating column internals • Typical simulation of start-up period – Run column under total reflux until column reaches steady state – At the beginning, assume that liquid compositions on plates and in the condenser are same as feed composition

Simulation of Product Period • Total condenser without sub-cooling • Perfect mixing of liquid and vapor on plates • Negligible heat losses • Condenser material balance

Column Model • Mass balance equations on plate j • Constant volume holdup • Constant molar holdup • VLE on each plate • Constraint

Column Model (Contd) • Enthalpy balance equations on plate j • Physical properties

Solution of Dynamic Model • Vapor boilup rate from plate 1 is constant • Quasi steady-state approximation – During a small time interval, plate temperature, K values, vapor and liquid flowrates remain constant • Solve the set of ODEs numerically up to the next update interval • After each update interval, recompute – bubble point, K values, plate enthalpies – Vapor compositions – Reboiler composition from mass balance – Liquid and vapor flowrates from enthalpy derivatives

Benzene–Toluene Distillation • Equimolar mixture of Benzene and Toluene • 8000 liters charge • Vapor boilup rate 20 kmol/hr • Number of plates = 20 • Plate holdup 4 liters • Condenser holdup 180 liters • Recover 99% mole fr Benzene and Toluene • Simulated using BDIST-Sim. Opt – Uses Activity++ physical properties package

Benzene–Toluene–O-Xylene 20 plates

Acetone–Chloroform Azeotropic system

Use of Simulation in Batch Distillation • Synthesis of operating recipe and rapid characterization of batch distillations • Accurate determination of operating and design parameters of a batch column • Use in column operation to determine cut amounts and switching policy for each batch

Role of Simulation in Column Operation Model Developer Simulator Components Cut Sequence For each cut: • Starting and stopping criteria • Reflux ratio Verified Model Operator Simulator DCS Feed Amount Feed Composition Column

Problems Related to Batch Distillation • Design of a batch column • Operating policy determination for individual column batches • Design and operation issues are interdependent

Design of Batch Columns • Main design parameters – Number of stages – Vapor boilup rate – Diameter – Still capacity (batch size) – Reboiler and condenser size heat transfer areas • Single separation duty • Multiple separation duties