Solid-Liquid Separations Pharmaceutical API Process Development and Design

Solid-Liquid Separations Pharmaceutical API Process Development and Design

Solid-Liquid Separations • Filtration Analysis – Flow in packed beds – Cake Filtration – Centrifuges – Deliquoring – Washing • Examples – Cake compressibility – Cycle time calculations

Filtration Options Linear Filtration Centrifugal Filtration Kevin Seibert (2006), Solid-Liquid Separations in the Pharmaceutical Industry

Filtration Options Retentate Stream Backpressure Applied Feed Tank Permeate Stream Cross Flow Filtration Kevin Seibert (2006), Solid-Liquid Separations in the Pharmaceutical Industry

Mechanisms in Filtration • Depth filtration – Particles captured within pore spaces – Slurries with less than 0. 1% solids • Cake filtration – Particles bridge pores in medium – Cake formed on surface of medium • Cross flow filtration – Porous tube with cross flow

Driving Forces • Gravity – Hydrostatic pressure – Free filtering materials • Vacuum – Downstream pressure below atmospheric – Rotary drum, moving belt, disc filters • Pressure – Pumps or compressed gas – Plate and frame, leaf • Centrifugal Force – Perforated bowl centrifuge, peeler centrifuge

Operating Mode • Constant pressure filtration – Vacuum pumps, compressed gas • Constant rate filtration – Positive displacement pumps • Variable pressure, variable rate filtration – Centrifugal pumps

Cake Filtration suspension L, ΔP filter cake membrane Luis Puigjaner (2007), Solid-Liquid Separations

Flow Through Packed Beds Darcy’s Law Permeability Carman-Kozeny Equation Pressure drop Bed height Superficial velocity Porosity Liquor viscosity Specific surface area

Mass Balance Filter area Filtrate density Filtrate volume Solid density Dry solids/unit area Thickness of cake Dry solids/unit volume filtrate Porosity Mass of wet cake/Mass of dry cake Mass fraction of solids in slurry

Cake filtration equation Rewrite Darcy’s law in terms of specific cake resistance, filtrate volume, solids concentration Cake pressure drop Total pressure drop Specific cake resistance Filtrate volume With medium resistance Dry solids/unit area Dry solids/unit volume filtrate Medium Resistance a : Characteristic parameter of a specific solid/liquid system

Ease of Separation Average Specific Cake Resistance (a), m/kg Very Easy 1 x 109 Easy 1 x 1010 Moderate 1 x 1011 Difficult 1 x 1012 Very Difficult 1 x 1013 W Leu (1986), Principles of Compressible Cake Filtration

Filtration Analysis Q = Flow Rate of Eluent t = time of filtration DP = pressure drop A = effective area of filtration μ = viscosity of filtrate aave = average specific cake resistance c = kg of dry cake per volume of filtrate V = volume of filtrate Rm = medium resistance Assumptions: Constant pressure Constant area Ignore gravity

Parabolic Data Analysis Rearranging: Plot t/V vs V – Linear Slope – proportional to average specific cake resistance Intercept – proportional to medium resistance

Filtrate Flowrate Cake Compressibility Incompressible Highly compressible Pressure Drop Incompressible solids - a is independent of pressure

Cake Compressibility ΔP 3, α 3 ΔP 2, α 2 t/V ΔP 1, α 1 V Compressible solids - a varies with pressure

ln a Cake Compressibility ln ΔP Where usually, 0. 1 < s < 0. 8 Sometimes expressed as: Where ao, Po, and s are empirical constants

Medium Resistance • Typically a linear contributor to overall cake pressure drop • May foul if size chosen inappropriately Run 3 Run 2 Run 1 t/V Increase in medium resistance due to blinding V

Experimental Method and Analysis Laboratory Pressure Filtration Representative Slurry Volume vs Time Data Cake Size and dry weight Three-Four Runs at various P’s Various Medium Types Parabolic Data Analysis Ave. Specific Cake Resistance Medium Resistance Porosity (bulk density) Liquor viscosity and density Compute aave, Rm Factory or Pilot Plant Filtration Sample slurry for laboratory Volume vs Time data Cake size and dry weight Different pressures (if possible) Different medium types (if possible) Scale Up Calculations Understand geometric considerations Develop a working model Understand equipment specific issues Optimize operational strategy

Centrifugal Separations Constant Pressure Filtration Centrifugal Filtration R 3 Rc R 1 =Ro Fluid Cake + Fluid Filter Media P 3 Pc P 1 Po

Centrifugal Separations Constant Pressure Filtration Centrifugal Filtration Driving force and surface area are functions of time, feed profile Filtration equation can be integrated numerically

Cross-Flow Filtration Backpressure Applied Retentate Stream Concentrate a dilute two phase (liquid solid) stream Wash out a soluble impurity (diafiltration) Feed Tank Permeate Stream Switch solvents for further processing Scales very easily on filter surface area

Permeate Flux Filtration Flux Constant Filtration Time Filtrate volume Filtration area

Periodic Operation Permeate Flux Backpressure Applied Filtration Time

Cycle Time Analysis • Cake formation • Operation times that depend on cake thickness – Washing, deliquoring • Operation times independent of cake thickness – Loading, cake discharge, cleaning

Deliquoring • • • Application of vacuum Blowing with compressed gas Centrifugation Compression of the cake Complete drainage is not usually achieved – Final drying with hot gas flow through cake is used • Kinetics and equilibrium of deliquoring – Threshold pressure: minimum pressure to achieve reduction in saturation – Irreducible saturation: limiting value of saturation beyond which no reduction in liquid content is possible

Deliquoring Time Capillary Number Cake permeability Liquid viscosity Irreducible Saturation Cake thickness Threshold Pressure Gas pressure Porosity Mean particle size Dimensionless Time Dimensionless Pressure Difference Reduced Saturation Surface tension

Reduced Saturation SR Deliquoring Time 1 Dimensionless pressure difference 1 Dimensionless time θ

Washing • Remove contaminants in retained liquor • Methods – Displacement washing – Reslurrying followed by refiltering • “Perfect” displacement washing – Wash volume=void volume – Solute concentration=initial concentration • Actual washing – Wash liquor tends to proceed through preferential pathways or cracks in cake – Concentration of solute in wash liquid depends on mixing and mass transport

Displacement Washing Perfect displacement washing c/c 0 1 Actual washing 1 Wash Volume (no. of void volumes)

Washing Curves Saturated cake: displacement followed by mixing and diffusion c/c 0 1 Drained cake: No displacement stage 1 Wash Ratio Washing curve for partially drained cakes will be in between curves for saturated and drained cake

Washing Analysis • “Perfectly Mixed” washing Concentration at end of displacement washing Wash flowrate/area Cake thickness ln c Time from end of displacement washing Time

Washing Analysis • Combined mixing and diffusion effects • Dispersion parameter Wash velocity Cake thickness Axial dispersion Wash ratio Adsorption effects • Perfect mixing

Washing Analysis Washing curves as a function of dispersion parameter c/c 0 1 1 Wash Ratio

Washing Time Cake formation time Wash Ratio Wash ratio Washing time Cake formation time

Examples

Filtration Analysis Example Three pressures, same crystal slurry Kevin Seibert (2006), Solid-Liquid Separations in the Pharmaceutical Industry

Filtration Analysis Example Cake Filtration Cake Deliquoring Start up Effects

Filtration Analysis Example

Filtration Analysis Example Cake Deliquoring Start up Effects

Filtration Analysis Example Slope Intercept

Filtration Analysis Slope Viscosity Example 0. 0031 s/g 2 8. 94 E-04 kg/m-s c 61. 12 kg/m 3 A 0. 002 m 2 ΔP 34474 N/m 2 Density 1. 0 g/cm 3 (5 psi) Alpha = 0. 782 E+10

Compressibility ln a Filtration Analysis ln ΔP DP alpha 5 0. 785 E+10 1. 609438 22. 78378 15 1. 06 E+10 2. 70805 25 1. 39 E+10 3. 218876 23. 35515 ln(p) ln(a) 23. 08412

Filtration Analysis Compressibility Slightly compressible Expect: Some effect of pressure on filtration flux Likely acceptable filtration in centrifuge

Filtration Analysis Scale Up Filtrate volume as a function of time at several pressures Understand the relationship between specific cake resistance and pressure (compressibility) Fully characterized liquid / solid system (physical properties etc. ). How do we scale up to understand plant time cycles?

Filtration Analysis Scale Up Parameters: Rm, a - known from scaled down experiments All else known Assuming: Same slurry composition, same filter medium, 25 psi Filtration Time Kg Product 50 100 200 300 400 500 750 1000 2 m 2 Filter 6 m 25 m 1. 6 h 3. 7 h 6. 5 h 10 h 23 h 41 h 4 m 2 Filter 1. 5 m 6 m 25 m 55 m 1. 6 h 2. 6 h 5. 8 h 10 h

Cycle Time Analysis Example Filtration and wash times for scale-up options based on constant flux (L/M 2 H)

References • W. Leu, Principles of Compressible Cake Filtration, in Encyclopedia of Fluid Mechanics (N. P. Cheremisinoff, ed), Gulf, 1986. • A. Rushton, A. S. Ward, R. G. Holdich, Solid-Liquid Filtration and Separation Technology, VCH, 1996. • A. Rushton, Batch filtration of solid-liquid suspensions, in Handbook of Batch Process Design (P. N. Sharatt, ed), 153 -192, Springer, 1997.