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
P 
  v Darcy’s Law
L k
3
k
k1 (1   ) 2 S o2 Permeability
P k1 1    S o2 
2
  Carman-Kozeny Equation
L 3

P Pressure drop L Bed height

v Superficial velocity  Porosity
 Liquor viscosity So Specific surface area
 Mass Balance
 mass of slurry   mass of cake   mass of filtrate 

s V V
w c
1  ms A A

w   s 1    L

A Filter area  Filtrate density

V Filtrate volume s Solid density
w Dry solids/unit area L Thickness of cake
c Dry solids/unit volume filtrate  Porosity
m Mass of wet cake/Mass of dry cake
s Mass fraction of solids in slurry
 Cake filtration equation
Rewrite Darcy’s law in terms of specific cake
resistance, filtrate volume, solids concentration
Pc  1 dV Pc Cake pressure drop
 v  
w k s 1    A dt
P Total pressure drop
dV Pc A Pc A 1  Specific cake resistance
  
dt w c V k (1   )  s V Filtrate volume
A
w Dry solids/unit area
With medium resistance
c Dry solids/unit volume
dV PA PA filtrate
 
dt   w  Rm   cV  Rm Medium Resistance
  Rm 
 A 
: Characteristic parameter of a specific solid/liquid system
 Ease of Separation

Ease of Separation Average Specific Cake Resistance (, m/kg

Very Easy 1x109
Easy 1x1010
Moderate 1x1011
Difficult 1x1012
Very Difficult 1x1013

W Leu (1986), Principles of Compressible Cake Filtration

 Filtration Analysis
dV P A
Q 
dt   ave cV 
  Rm 
 A 

Q = Flow Rate of Eluent

t = time of filtration
P = pressure drop Assumptions:
A = effective area of filtration Constant pressure
μ = viscosity of filtrate Constant area
ave = average specific cake resistance Ignore gravity
c = kg of dry cake per volume of filtrate
V = volume of filtrate
Rm = medium resistance
 Parabolic Data Analysis
 c  2   
t   ave  V  Rm  V
 2 A2 P   AP 
 driving   driving 

Rearranging:

t  c    
  ave  V  Rm  
V  2 A2 P   AP 
 driving   driving 

Plot t/V vs V – Linear

Slope – proportional to average specific cake resistance
Intercept – proportional to medium resistance
 Cake Compressibility

Filtrate Flowrate
Incompressible

Highly
compressible

Pressure Drop

Incompressible solids -  is independent of pressure

 Cake Compressibility

ΔP3, α3

ΔP2, α2
ΔP1, α1
t/V

Compressible solids -  varies with pressure

Cake Compressibility

ln 

ln ΔP

   o  P 
s
Where usually, 0.1 < s < 0.8

Sometimes expressed as:

s
 P 
   o 1  
 Po 

Where o, 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

Increase in
t/V

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 ave, 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

dV P dV Pdriving
Q  Q 
dt   cV R  dt   cV R 
  ave  m    ave  m 
 Ao Ao Ao   Alm Am Ao 

2h ro  rc  2h ro  rc 
Ao  cloth area Am  Alm 
2 r 
ln o 
 rc 

R3 Rc R1 =Ro

P3
Fluid
Pc
Cake + Fluid
P1
Filter Media
Po
 Centrifugal Separations
Constant
Centrifugal Filtration
Pressure Filtration

dV Pdriving Pdriving
Q  dV
dt   cV R  Q 
  ave  m  dt   cV R 
  ave  m 
 Ao Ao Ao 
 Alm Am Ao 
 fluid  2  R32  R12 
Pdriving  applied pressure Pdriving 
2

Driving force and surface area are

  2   functions of time, feed profile
c 
t   ave  2 V  Rm  V
 2 A P   AP 
 driving   driving  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

 Filtration Flux
t
 k1t  k 2
V
1 dV 1 k2
Permeate Flux

J 
A dt A  k1t  k 2  2

J Filtration Flux

k1 Constant
k2 Constant
V Filtrate volume
Filtration Time A Filtration area
 Periodic Operation
Backpressure Applied
Permeate Flux

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 Pb
– Irreducible saturation: limiting value of saturation beyond which
no reduction in liquid content is possible S 
 Deliquoring Time
 3 x 2  gL  P  Capillary k Cake permeability
Nc  Number
1   2 L  Liquid viscosity


S   0.155 1  0.031N 0.49
c  Irreducible
Saturation
L Cake thickness
 Porosity
4.61    Threshold
Pb  Pa Gas pressure
x Pressure
kPb t x Mean particle size
 Dimensionless

L(1  S  ) Time
Surface tension

 Pa   Pa  Dimensionless
Pa       Pressure
 Pb inlet  Pb  outlet Difference
S  S
SR  Reduced
1  S Saturation
 Deliquoring Time
Reduced Saturation SR 1

Dimensionless pressure
difference
Pa

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

c  c0 Perfect displacement
1
c/c0 washing

c  c0
Actual washing

1
Wash Volume
(no. of void volumes)
 Washing Curves
Saturated cake: displacement
followed by mixing and diffusion
1
c/c0

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
  kFt 
  c Concentration at end
 c c   e  L  of displacement
washing
F Wash flowrate/area
L Cake thickness
t Time from end of
displacement washing
ln c

Time
 Washing Analysis
• Combined mixing and diffusion effects
• Dispersion parameter  uL 
D

cs  uL  u Wash velocity
 f  , , n 
co D  L Cake thickness
D Axial dispersion
n Wash ratio
 Adsorption effects
 uL 
• Perfect mixing  0
D
cs
 en
co
Washing Analysis
Washing curves as a
function of dispersion
1 parameter

 uL 
  0.1  500
D
c/c0

1
Wash Ratio
 Washing Time
Washing Time Cake formation time

Wash Ratio

n Wash ratio
t w  nt f tw Washing time
tf Cake formation time
Examples
 Filtration Analysis Example
5 PSI delta P

140
Weight of Filtrate (g)

120
100
80 25 PSI data
60
40 400
20 350
0 300
0 10 20 30 40 50 250

weight (g)
Time (s) 200
150
15 PSI filtration data 100
50
140
0
120
0 20 40 60 80 100 120
100
time (s)
80

60

40

20

0 Three pressures, same crystal

slurry
0 5 10 15 20

Ti m e ( s )

Kevin Seibert (2006), Solid-Liquid Separations in the Pharmaceutical Industry

Filtration Analysis Example
5 PSI delta P
Cake Filtration
140
Weight of Filtrate (g)

120
100
80
60
40 Cake Deliquoring
20
0
0 10 20 30 40 50
Time (s)

Start up Effects
 Filtration Analysis Example
dt/dw vs w for 5 PSI dt/dw vs w for 15 PSI data

0.5 0.25
y = 0.0031x + 0.0473 y = 0.0014x + 0.0362
0.4 R2 = 0.8251 R2 = 0.9334
0.2
dt/dw (s/g)

dt/dw (s/g)
0.3 0.15

0.2 0.1

0.1 0.05
0
0
0 20 40 60 80 100 120 0 20 40 60 80 100 120
Weight (g) w eight (g)

dt/dw vs w for 25 psi data

dt  c R 
0.45

0.4 y = 0.0011x + 0.0468    ave 2 V  m 

0.35
R2 = 0.7117
dV  PA PA 
dt/dw (s/g)

dt   c Rm 
   2 ave 2  V  
0.3


d  V    PA PA 
0.25

0.2

V  weight of filtrate
0.15
100 150 200 250 300
w (g)
Filtration Analysis Example
dt/dw vs w for 5 PSI

1.5
y = 0.006x - 0.127
dt/dw (s/g)

1
R2 = 0.4515
0.5

0
0 50 100 150
Cake Deliquoring
-0.5
Weight (g)

Start up Effects
Filtration Analysis Example
dt/dw vs w for 5 PSI

0.5 y = 0.0031x + 0.0473

0.4 R2 = 0.8251
dt/dw (s/g)

0.3

0.2

0.1

0 Slope
0 20 40 60 80 100 120
Weight (g)
Intercept

Slope Intercept

dt   c Rm 
  2 ave 2  V   
d  V    PA PA 
Filtration Analysis Example

Slope 0.0031 s/g2

Viscosity 8.94E-04 kg/m-s

c 61.12 kg/m3

A 0.002 m2  ave c
slope  2
 PA 2
ΔP 34474 N/m2 (5 psi)

Density 1.0 g/cm3 Alpha = 0.782E+10

Filtration Analysis Compressibility

   o  P 

ln 
s

ln   ln  o  s ln P 

ln ΔP

P alpha ln(p) ln()

5 0.785E+10 1.609438 22.78378
15 1.06E+10 2.70805 23.08412
25 1.39E+10 3.218876 23.35515
 Filtration Analysis Compressibility
ln   ln  o  s ln P  s  0.342

ln (alpha) vs ln (dp)

Slightly compressible
23.4 y = 0.342x + 22.215
23.3 R2 = 0.9686
Expect:
ln (alpha)

23.2
23.1 Some effect of
23
22.9
pressure on
22.8 filtration flux
22.7
1.5 2 2.5 3 3.5
Likely acceptable
filtration in
ln (dp) centrifuge

Series1
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
 
 
 c  2   
 
  t   ave  V  Rm  V
 2 A2 P   AP 
 driving   driving 
Parameters: Rm,  - 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 m2 Filter 6m 25 m 1.6 h 3.7 h 6.5h 10 h 23 h 41 h

4 m2 Filter 1.5m 6m 25 m 55m 1.6 h 2.6 h 5.8 h 10 h

Cycle Time Analysis Example
Base Scale-Up Options
A (2x) B C D E F G
Batch Size (kg) 11.0 50.0 100.0 100.0 100.0 200.0 200.0 200.0
FD Area (m2) 0.2 0.6 0.6 2.0 4.0 0.6 2.0 4.0
Mother Liquor Volume (L) 86.0 390.9 781.8 781.8 781.8 1563.6 1563.6 1563.6
Mother Liquor Filtration Time (Hr) 3.3 5.0 10.0 3.0 1.5 20.0 6.0 3.0
Wash 1 Volume (L) 50.0 227.3 454.5 454.5 454.5 909.1 909.1 909.1
Wash 1 Filtration Time (hr) 7.3 11.0 22.0 6.6 3.3 43.9 13.2 6.6
Wash 2 Volume (L) 50.0 227.3 454.5 454.5 454.5 909.1 909.1 909.1
Wash 2 Filtration Time (hr) 20.0 30.3 60.6 18.2 9.1 121.2 36.4 18.2
Wash 3 Volume (L) 50.0 227.3 454.5 454.5 454.5 909.1 909.1 909.1
Wash 3 Filtration Time (hr) 5.7 8.6 17.2 5.1 2.6 34.3 10.3 5.1
Cake Depth (ratio to base) 1.5 3.0 0.9 0.5 6.1 1.8 0.9

Filtration Cycle Time 36.21 110 109.7 32.9 16.5 219.5 65.8 32.9
Milling Time per slurry mill (hr) 3.0 27.3 27.3 27.3 27.3 54.5 54.5 54.5
Total Time Cycle (hr) 39.2 137.0 137.0 60.2 43.7 274.0 120.4 87.5

Filtration and wash times for scale-up options based on constant flux
(L/M2H)
 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.