Standard Scale Up Principles and Calculations Guide

Integrated Product Development
ANNEXURE TM-APE-001-A01 Effective date: 01.03.2012
TITTLE STANDARD SCALE UP PRINCIPLES AND CALCULATIONS
STANDARD SCALE UP PRINCIPLES AND

CALCULATIONS
Page No. 1 of 87
S.No. Title Page No.

01 Introduction 4
02 Scale up of Reactions 4
2.1 Reactor selection 4-5
2.2 Material of Construction (MOC) selection 6-10
2.3 Agitator selection 11-15
2.4 Basic approach to Scale up 16-27
2.5 Heat of reaction 28-29
03 Filtration 30
3.1 Agitated Nutsche filter & dryer 30-32
3.2 Pressure / Vacuum Nutsche filter (Non-agitated filter) 33-34
3.3 Centrifuge 34-38
3.4 Plate and Frame Filter Press 39
3.5 Merits & demerits of different filtration equipments 40
3.6 Flow chart for selection of filters 41
04 Drying 43
4.1 Drying Principles 43-45
4.2 Types of dryers & details 45-62
05 Size Reduction 63
5.1 Air Jet Mill 63
5.2 Multi Mill 66
5.3 Selection of Size reduction Equipments 67
06 Crystallization 68
Solubility, Supersaturation and meta-stability
6.1 68-69
(definitions)
6.2 Determination of the solubility curves 69-73
6.3 Scale up factors for crystallization: 74
6.4 Equipment selection for crystallization 75-76
Page No. 2 of 87
07 Distillation 77
7.1 Types of Distillation 77
7.2 Guidelines for distillation 77-79
08 Extraction 80
8.1 Factors to be considered in lab 81-82
8.2 Calculation of Solvent Requirement 82
8.3 Example for Efficient extraction 83
8.4 Scale up approach 86
Page No. 3 of 87
1.0 Introduction:
This document contains brief theory and calculations about the various unit
operations/processes and equipments being used in the API development. Process engineer shall
go through this document during the product development in the lab. This document is intended
to guide process engineer in studying various scale up parameters in the laboratory. It also
provides the selection criteria and calculations to be used for the scale up of various unit
operations/processes like, reaction, filtration, drying, size reduction etc. during the API
development
2.0 Scale up of Reactions

2.1 Reactor selection:
Following diagram depicts preliminary criteria for selection of reactor & type of agitators based
upon nature of reaction mass (Homogeneous/Heterogeneous), pH (Acidic/Basic) and viscosity
of reaction mass:
Page No. 4 of 87
PBT / FLAT /DISK BLADE

LOW µ /RCB
ACIDIC MEDIUM µ PBT / ANCHOR / RCB

GLASS LINED/
HASTELLOY HIGH µ ANCHOR
LOW µ PBT / FLAT /DISK BLADE
BASIC STEEL/HASTELLOY MEDIUM µ PBT / ANCHOR
HIGH µ ANCHOR
HOMOGENEOUS
REACTION
HETEROGENEOUS
SOLIDS
GLASS LINED/ GAS INDUCTION TURBINE /
(HYDROGENATION
HASTELLOY PROPELLER
ETC.)
PBT / FLAT /DISK BLADE

LOW µ /RCB
ACIDIC GLASS LINED/ MEDIUM µ PBT / ANCHOR / RCB
NO SOLIDS
HASTELLOY
HIGH µ ANCHOR
LOW µ PBT / FLAT /DISK BLADE
NO SOLIDS STEEL/HASTELLOY MEDIUM µ PBT / ANCHOR

BASIC
HIGH µ ANCHOR
SOLIDS GAS INDUCTION TURBINE / DISK

(HYDROGENATION STEEL/HASTELLOY TYPE
ETC.)
Figure 2.1
 In above flow diagram,
a. Low viscosity fluids considered having viscosity less than 100 cP
b. Medium viscosity fluids considered having viscosity less than 100 -500 cP
c. Medium viscosity fluids considered having viscosity more than 100 -500 cP
 Special proprietary impellers can be tried for critical cases
 All the mentioned agitators can work for a particular reaction; however final selection shall be
based on lab observations and simulation tool analysis
Page No. 5 of 87
2.2 Material of Construction (MOC) selection

Proper selection of material of construction for reactors and other equipments is an important
factor to ensure equipment compatibility with reaction mass. Chemical compatibility of the
various reagents/ reaction mass should be checked during the optimization study itself and
accordingly appropriate equipment should be planned for the scale up batches. Following are
the most commonly used reactors/equipments MOCs in the API manufacturing.
a. SS-316
b. SS-314
c. Fluropolymers coated vessels/equipments (i.e. Halar/Teflon, etc)
d. MS-GL
e. Superalloys (Hastelloy B, Hastelloy C)
f. Carbon steel
g. Mild steel
For the further details of the compatibility of various categories of chemicals with various
MOCs, refer
 “THE PILOT PLANT REAL BOOK” by Francis X. McConville
 http://www.coleparmer.com/Chemical-Resistance
However, depending upon the compatibility of various categories of reagents with respect to pH
and temperature, appropriate MOC should be selected. Tables 2.1 to table 2.5 describe in brief
the compatibility of various categories of reagents with different MOCs.
Page No. 6 of 87
2.2.1 Properties of common metals:

Thermal Specific
conductivity heat at
Metal Density Characteristics/Identifiers
at 100°C ambient
(BTU/hr-ft-oF) (Btu/lb-oF)
316 SS Excellent corrosion and pitting
resistance and high temperature
(18% Cr, 12% Ni, 8 9.4 0.119
strength. Available as 316-L for
2-3% Mo) welded construction
304 SS Basic, general purpose austenitic type,
(19% Cr, 10% Ni, 7.9 9.4 0.114 good corrosion resistance. Also as 304-
0.08% Mo) L (0.03% C)
Hastelloy B Excellent chemical and oxidation
(63% Ni, 28% mo, 9.24 7.1 0.091 resistance at high temperatures. Very
plus Fe,Co) high strength.
Hastelloy C Excellent resistance but not strong

oxidizing acids or hot mineral acids in
(56% Ni, 17% mo,
9.24 7.1 0.091 the presence of oxidizing cations (i.e.
16.5% Cr plus W, Fe III). High strength. First choice for
Fe) reactors if glass unacceptable.
Table-2.1
Substances known to attack SS-316:
Substance Conc. % Temp.oC Substance Conc. % Temp.oC
Aluminium Chloride 10 20 Hydrochloric acid 2 20
Anilinium HCl 5 20 Hydrofluric 10 20
Aqua Regia - 20 Nitric acid 65 Boiling
Caustic Potash Molten 360 Nitric acid 99 20
Caustic Soda Molten 318 Oxalic acid 10 Boiling
Chlorosulphonic acid 10 20 Phoshoric acid 80 Boiling
Chromium Trioxide 50 Boiling Potasium bisulphate 2 90
Cupric chloride 1 75 Sodium chloride 5 20
Cupric chloride Saturated 20 Stanic chloride Aq. Boiling
Ferric Chloride 10 20 Stannous chloride Sat. Boiling
Formic Acid 80 Boiling Sulphuric acid 10 70
HCl gas Dry 100 Sulphuric acid 2.5 Boiling
HNO3 + H2SO4 mixture 5:30 Boling Tartaric acid 25 Boling
HNO3 + H2SO4 mixture 50:50 20
Trichloroacetic acid any 20
Hydrazinium Sulphate 10 Boiling
Table-2.2
Page No. 7 of 87
Substances known to attack Hastelloy C-276:
Substance Conc. % Temp.oC

Fluorinating agents Any 20
(i.e. Ant.flurochloride)
Chromic acid - 20
Chromic acid/HCl mix. Any 20
Ferric chloride/HCl mix. Any 20
HBr Aq. In presence of O2 or ox. Cations (Fe-III) >50
HCL Aq. In presence of O2 or ox. Cations (Fe-III) >50
Mineral acids In presence of O2 or ox. Cations (Fe-III) >50
HCl 5 Boiling
HCl+ 2.0% HF 5 70
P2O5 44 116
P2O5+ 0.5% HF 38 85
Nitric acid 65 Boiling
Nitric acid+ 6.0% HF 5 60
Nitric acid+25% H2SO4+4% NACl 5 Boiling
H2SO4/HCl 10/1 Boiling
H2SO4/-Cl 10/200 ppm Boiling
H2SO4/Fe2(SO4)3 10/4 Boiling
Ferric chloride 6% 95
Table-2.3
2.2.2 Properties of common Fluropolymers:
Trade Recommended
Type Characteristics/Identifiers
Name temp. range ,0C
ECTFE High heat, flame and abrasion resistance,
low creep, high impact strength, good
(Ethylene-
Halar -100 to 150 dielectric. Subject to attack by amines,
chlorotrifluro esters and ketones, especially at high
ethylene copolymer) temp.
Opaque thermoset, usually white in
colour, low friction, high electrical
resistance, chemically inert, high creep,
Teflon, insoluble in all known solvents, not
PTFE Hostaflon TF, resistant to fluorine gas at high
-195 to 260
(Polytertafluroethylene) Fluon, temperatures, or to molten alkali. Not
Aflon TFE recommended as gasket when high temp
fluctuations are anticipated as it lacks
“elastic memory”. PTFE enveloped
gaskets are preferred.
Table-2.4
Page No. 8 of 87
2.2.3 Properties of Glass

Glass is one of the chemically most inert substances available, and borosilicate glass (typically
~80% SiO2, ~12% B2O3, with Na2O, Al2O3 and other trace compounds is particularly useful in
the chemical process industry because of its relatively low melting point which allows its use in
glass lined steel reactors )
Substances known to attack borosilicate glass

Substance Concentration Temp.oC
3.0% 0
Hydrochloric acid
1.0% 20
Sodium Hydroxide Concentrated Boiling
Potassium Hydroxide Concentrated Boiling
Caustic Soda Molten 318
Caustic potash Molten 360
Hydrochloric acid Concentrated 120
Nitric acid Concentrated Boiling
Phosphoric acid Concentrated Boling
Sulphuric acid Concentrated 230
Table-2.5
Comments:
 Hydrofluoric acid is the single most corrosive acid to glass. HF reacts with SIO2 to form
SIF4 which is volatile, thus driving the reaction forward. Since corrosion can occur at
even low concentrations and mild temperatures, HF should be completely avoided in
glass- lined vessels
 For bromination reaction each & every contact part should be of glass i.e. reactor should
be GLR, condenser & other auxiliary equipments should be of glass.
 A number of specially glasses are available that exhibit superior corrosion resistance
under certain specific conditions and over wide temperature ranges. Option should be
discussed in detail with a qualified equipment manufacturer.
Page No. 9 of 87
2.2.4 Corrosion Studies:

However, we may come across the reagents for which the chemical compatibility is not
available with the various MOCs. For the use of such reagents, conduct material compatibility
studies in lab wherever necessary. The corrosion studies for MOC selection can be conducted in
Lab at the desired operating conditions. In a typical method, specimen of a metal is kept for
three weeks in a reaction mass and corrosion rate of materials is estimated with the following
relation:
12𝑤
𝑖𝑝𝑦 =
𝑡𝐴𝜌
w= mass loss in time t (lb)
t= time (years)
A= Surface area (ft2)
ρ=density of material (lb/ft3)
In SI units 1 ipy (inch per year) =25 mm per year
The results of the corrosion test can be compared with the below table to check the
compatibility of the metal for reaction sample (Ref: RC Vol. 6)
Corrosion Rate
Recommendation
Inch per year (ipy) mm/year (mm/y)
Completely satisfactory < 0.01 < 0.25
Use with caution < 0.03 < 0.75
Use only for short exposures < 0.06 < 1.5
Completely unsatisfactory > 0.06 > 1.5
Table 2.6
Page No. 10 of 87
2.3 Agitator selection:

Understanding the types of flow patterns induced by various agitators helps us selecting more
accurate agitator for a given mixing operation. Figures 2-6 shows the various flow patterns
induced by most commonly used agitators in the reactors.
2.3.1 Types of Flow pattern:

The three primary types of flow patterns i.e. axial mixing flow, radial mixing flow and
tangential mixing flow are depicted in below figures.
Figure- 2.2
Page No. 11 of 87
Axial Mixing:
The fluid motion parallel to an axis of rotation. It moves media from the top to the bottom.
Axial flow impellers are used for blending, solids suspension, solids incorporation, or draw
down. It is most common in a low viscosity, high speed application. Propeller and pitched blade
turbine are the impellers which gives axial flow pattern in the reaction vessel. Figure 1 and 4
shows the axial flow pattern obtained in the reactors with propellers and pitched blade turbines.
Power number and flow numbers for this kind of impellers are given in the table No. 2.8
Radial Mixing
The fluid is discharged radially outward to the vessel wall. Compared to axial flow impellers,
radial flow impellers provide higher shear and turbulence levels with lower pumping. Radial
flow draws the media from the top and bottom. The most common impeller styles are the
straight blade. Straight blade and rushton blade turbine are the impellers which gives radial flow
pattern in the reaction vessel. Figure 3 and 6 shows the radial flow pattern obtained in the
reactors with straight blade and Ruston blade turbines. Power number and flow numbers for this
kind of impellers are given in the table No. 2.8
Tangential Mixing
The flow pattern seen when tangential or rotational flow dominates is a swirling of the reactor
contents, often with a surface vortex. It is often used when mixing high viscosity at lower
speeds. The most common impeller styles are the U-shaped anchor and square blade impeller.
Figure 2 shows the tangential flow pattern obtained in the reactors with Anchor. Power number
and flow numbers for this kind of impellers are given in the table No. 2.8
[Reference: http://www.wmprocess.com/mixing-impeller-flow/ ]
Page No. 12 of 87
2.3.2 Relation between flow patterns, type of agitator and its application:
As studied above, various types of flow patterns are induced in reaction mass with different
types of agitators. Below table shows their use for various mixing duties required in the reactor:
Type of
Type of Impeller Type of Reactor Application
Flow
 Homogenization
 Suspension of solid
 Liquid-Liquid
Pitched blade turbine SS  Solid – Liquid
 Gas – Liquid dispersions
 Heat transfer
 Homogenization
 Liquid-Liquid
Retreat curve impeller Glass lined
 Solid – Liquid
 Heat transfer
Axial
 Homogenization
 Liquid-Liquid
Marine blade turbine SS  Solid – Liquid
 Gas – Liquid dispersions
 Heat transfer
 Homogenization
 Liquid-Liquid
Twin Agitator SS  Solid – Liquid
 Heat transfer
 Homogenization
 Liquid-Liquid
Flat / Disk blade turbine SS
 Solid – Liquid
 Heat transfer
Radial
 Homogenization
Anchor SS/Glass  Heat transfer
Table-2.7
Page No. 13 of 87
2.3.3 Power and flow numbers for various agitators:
Name of the Np (Power Nq (Flow

Geometric shape Remarks
agitator number) number)
3 blades- 3.3 3 blades- 0.62 D/T= 0.33, Wb/T= 1/12

Ruston Turbine (RT)

Ruston Turbine
2 blades- 5.4 2 blades- 0.73

Paddle with two and
-
four blades
4 blades- 2.0 4 blades- 1.0
 * down flow- for 2.0 pitch
*D/T= 0.22, Wb/T= 0.1

* blades- 1.0 * blades- 0.5
Propeller
**Up flow- for 2.0 pitch
** blades- 1.35 ** blades- 0.5
 **D/T= 0.22, Wb/T= 0.1
Pitched blade turbine
o 1. Chemineer P-4 1.27 0.79 -

o 2. Lightnin A200
Lightnin A310 or
0.3 0.56 -
Lightnin A510
Page No. 14 of 87
Name of the Diagram Np (Power number) Nq (Flow number) Remarks

agitator
Chemineer 0.2 0.46 for D/T=0.5

HE-3 (Down
pumper) 0.22 0.47 For D/T= 0.4
Chemineer
2.0 0.55 -
BT-6
Bar Turbine 0.65 0.36 -
Anchor 0.6 0.5 -
Retreat Curve
0.4 0.3 -
Marine Blade
- - -
turbine
Table-2.8
D : Diameter of Agitator
T: Diameter of tank
Wb : Width of Blade
Page No. 15 of 87
2.4 Basic approach to Scale up:

Over the years, scientists and engineers have considered many approaches to scaling up mixing
process, with the ultimate goal of successfully matching laboratory results at commercial scale
at a reasonable cost. As a result, numerous scale-up parameters, equations and principles have
been developed, some of which work better or are more reliable than others depending upon the
specific application. No single method has been successful for all the situations and the
characteristics of the system must be understood as well as possible to maximize the chances of
success.
2.4.1 Principles of similarity:
Scale up theory considers two processes similar if they possess geometric, kinematic and
dynamic similarity
 Geometric similarity requires that linear dimensions if two systems are scaled up by the same
ratios at different scales
Fig 2.3: The principle of geometric similarity for stirred tanks. Key ratios (D/T, C/T, B/T, Z/T) are held
equal at both scales
Page No. 16 of 87
Fig 2.4: Typical shape factors or geometric ratios found useful for general mixing application sin
stirred tanks
 Kinematic similarity requires geometric similarity also and the characteristic velocities scaled
up by the same ratio
 Dynamic similarity requires both geometric and kinematic similarity and adds the requirement
that characteristic forces scale by the same ratio
Rigorous application of scale up theory is rarely applied to scale-up of industrial mixing

processes. One reason for this is that when more than two forces properties are important in a
mixing process, full dynamic similarity cannot be achieved. Since most mixing processes
involve three or more force properties, a choice must be made by considering the nature of the
process at hand and applying scaling factors that have been proven to work in similar process.
Page No. 17 of 87
2.4.2 Reaction scale up criteria:

 Energy dissipation per unit Volume- P/V:
A particularly useful and widely used approach to mixing scale-up involves maintaining a
constant rate of turbulent energy dissipation (ε) across the various scales. ε, which is defined
by the following equation in units of W/m3,
ε = P/V
Where P is power input (W) and V is the volume of the reaction mass.
ε is fundamental in describing the interrelationship between turbulence and mass transfer in
mixing operations. P/V can be calculated in the following manner:
1. Calculate the Reynolds number for the reaction mass using following formula,
ND 2
N Re 

Where,
NRe Reynolds Number
ρ Density of reaction mass
N Agitator RPM
µ Reaction mass Viscosity
D Diameter of agitator
 As in any type of fluid flow, fluid motion in mixing can be generally classified as either
turbulent or laminar, depending upon the velocity and other physical properties of the reaction
mass.
 For NRe greater than 104 fluid motion is considered turbulent.
 Under laminar mixing conditions, (NRe<100) and in the transitional region between laminar and
turbulent, power number varies typically increasing with decreasing Reynolds number as shown
by the curves in the below figure.
Page No. 18 of 87
 The values of Reynolds number that delineate the transitional region are only approximate, and
will vary depending upon the system.
2. Find value of Power number from the below graph for a given type of agitator and Reynolds
number
Figure-2.5
3. Power number is given by,
𝑷
𝑵𝒑 =
𝝆𝑵𝟑 𝑫𝟓
Where P is the power dissipated to the reaction mass in W.
Once the power number is calculated for the given system, power dissipation can be calculated
from the above equation.
Page No. 19 of 87
Typical power dissipation Values for different mixing duties:

Below table shows the power dissipations for better performances of some of the mixing duties
required during the reactor operations.
Mixing Duty Power dissipation (W/Kg)
Homogeneous mixing 0.10 to 0.30
Homogeneous mixing with heat transfer 0.3 to 1.0
Liquid – Liquid biphasic >1.0
Blending 0.04 to 0.10
Table-2.9
 Tip speed:
Tip speed is simply tangential velocity of the impeller at its maximum diameter and is
calculated according to the equation,
St= πDN
 Tip speed is related to maximum shear rate in stirred vessel. For this reason, tip speed is often
applied as a scaling parameter for operations where maximum shear is critical determinant of
the process outcome. This includes those processes for which shear can be either beneficial or
detrimental.
 Maintaining sufficiently high shear in the impeller region may be required to rapidly disperse a
reactant fed in to a vessel during a chemical reaction.
 The product of this same reaction may be a solid precipitate whose particles are shear sensitive
and would suffer attrition, creating fines and complicating downstream recovery if high shear
rates are maintained for too long.
Page No. 20 of 87
 Blend time:
Blend time is an empirical factor that describes the time it takes for the contents of a vessel to
become homogenized, particularly important during chemical additions (Fed batch) to a batch.
It is usually determined experimentally by monitoring the dispersion of a dye or other tracer
compound, either visually or by means of detection probes at various points in the vessel.
 Often, acceptable blend time is established base on a practical, realistically achievable value
such as 95% uniformity.
 Although somewhat subjective, blend time is a critical factor in the scale –up of the many
operations, particularly rapid chemical reactions that rely on rapid dispersion during controlled
addition of a reagent.
 Impeller design and number of impellers will have a significant effect on blend time. Some
types of impellers, such as standard anchor-blade impellers, which are not designed for good
bulk mixing, generally result in very long blend times, whereas a pitched-blade turbine operated
at typical speed in the same vessel would result in much shorter blend times.
Following is the most commonly used equation for calculating the blend time.
2
5.2 T 
t 95  0.33  
n  po  D 
Where
t95 Blend time (5% variance)

T Vessel diameter
D Agitator diameter
P0 Power number
n Agitator RPM
Page No. 21 of 87
2.4.3 Semi batch reactions:

A reaction in which one reagent is added slowly to the reaction mass is considered as semi-
batch reaction. To check the mixing regime, conduct following set of experiments and check
the variance in performance of reaction
No
Vary Stirrer speed Mixing unimportant
Yes
No
Yes
Vary Feed rate Micromixing
Yes
No
Vary Feed position Macromixing
Yes
Mesomixing
Figure-2.5
The following table indicates the effect of various operating parameters on mixing:
Mixing sensitivity to parameter change
Mixing Scale Impeller Feed time, No. of feed Feed Viscosity
speed, N tf points, nf position
Micromixing Yes No No Yes Yes
Mesomixing Yes Yes Yes Yes No*
Macromixing Yes Yes Yes No No*
Table-2.10
* Assumes reactor flow in turbulent zone
Once the mixing regime is determined, as per the procedure mentioned above, the scale up
parameters can be determined with the following table:
Page No. 22 of 87
Mixing Reaction Selectivity Scale-up parameter Additional

Regime time constant determined by (to be kept constant) Comment
Mixing is required to
homogenize the
Independent Chemical contents & to provide
10 min.- hr Tip speed
of mixing Kinetics sufficient heat
transfer
Kinetics + Bulk Bulk mixing time Keep feed time

Macromixing Seconds-min. constant (tf)
Circulation (t95)
Kinetics, Addition point: Feed
In between Circulation, to agitator suction
Mesomixing Power/Volume
(Fast feeding) Feed Rate, Local zone, near agitator tip
turbulence
Micromixing Milliseconds Local turbulence Power/Volume Increase nftf ~V8/9
Table-2.11
To achieve equivalent selectivity on scale up:

 If macro mixing limits
Keep blend time (t95) constant as scale up parameter and keep feed time constant
 If micro mixing limits
Keep P/V constant as a scale up parameter and increase nftf V8/9
t95 can be estimated with the following formula:

2
5.2 T 
t 95  0.33  
n  po  D 
Page No. 23 of 87
Conditions for application of above formula:

 NRe > Rec i.e. turbulent mixing
 Applies for single impeller
 Liquid Height/Tank Diameter (H/T) ~ 1
6370
 Re c 
Po0.33
ρ Density of liquid,Kg/m3
N Impeller RPM
µ Viscosity of the fluid, N.S/m2
t95 Mixing time (5% Variance), Sec.
T Tank Diameter, m
D Agitator diameter, m
Po Power Number
Page No. 24 of 87
2.4.4 Gas-Liquid-solid reactions:

The following conditions should ideally be maintained for G-L-S reactions:
 Keep flow regime in turbulent zone
 Use Baffled vessel
 Use induction type agitator
 Ensure gas introduction from bottom
Scale up calculations:
a) Calculate Njs (Just Suspended Speed) for better suspension of catalyst
(It is very important to keep catalyst particles in suspended form in order to have better reaction
rates)
0.45
 g 
S v d
0. 1 0.2
 0.85   X 0.13
p  
N js   1 
D 0.85
Njs Just suspended speed

S a constant depending on the geometry
υ Kinematic Viscosity (m2/s)
dp diameter of catalyst particle
D Agitator diameter
X % mass solid in liquid
ρl Density of liquid
b) Gas dispersion:
 Case 1: For effective Gas dispersion above agitator
Using the following condition, calculate the value of N (At these values gas will be
effectively dispersed above agitator)
Fl ≤ 30Fr (T/D)-3.5
Where,
Flow number= Fl = Q/ND3
Froude number= Fr = N2D/g
Page No. 25 of 87
In above equation,
Q Flow rate of gas in m3/sec.
N Agitator RPM
D Agitator diameter,m
g Gravity, m/s2
 Case 2: Gas fully dispersed
Using the following condition calculate the value of N (At these values gas will be fully
dispersed throughout the reactor)
Fl ≤ 0.2Fr0.5(T/D)0.5
Where,
Flow number= Fl = Q/ND3
Froude number= Fr = N2D/g
Q Flow rate of gas in m3/sec.

N Agitator RPM
D Agitator diameter,m
g Gravity, m/s2
During scale up, keep RPM greater than higher of the two values (Njs and N calculated from
gas dispersion conditions)
The nature of gas dispersion in above two cases is shown in below diagram:
Page No. 26 of 87
Page No. 27 of 87
2.5 Heat of reaction:

Before the reactions are taken at pilot plant or kilo-lab scale, there must be clear understanding
of how the reaction end point will be determined. The effect of heat of reaction on the impurity
profile must be clearly in place before starting.
The best way to minimize excess temperature rise is to control the reaction rate so that it is
matched to the heat removal capacity of the reactor. The most common method of doing so is
by controlled addition of a limiting reagent.
 If the heat of reaction and overall heat transfer coefficient (U) of the reactor are known, the
exact addition rate can be calculated, along with required jacket temperature.
 Heat transfer coefficient can be estimated or easily measured, but the calorimetric
determination of heat of reaction is vital.
Ultimately simplest way is to control the addition rate manually while keeping an eye on the
reactor temperature. Always start the addition very slowly and be aware of the possibility that
un-reacted reagent can accumulate in the reactor if the reaction rate is slow, creating potentially
dangerous situation. Following example elaborates how the addition rate of the limiting reagent
can be calculated using the reaction Calorimetry data.
Example-
An irreversible exothermic reaction, which generates 19664.8 KJ/mol reagent “Z” is to be run at
25oC in a reactor with HTC (U) 312.30 W/m2oC and heat transfer area 1.487 m2 by controlled
addition of reagent “Z”. Jacket temperature is 0oC. Calculate the maximum allowable rate of
5M solution of reagent “Z”.
Approach:
A first pass estimate, assuming constant U, constant heat of reaction, and ignoring
sensible heat of reagent “Z” solution, can be made as follows.
First calculate maximum heat removal rate (Q) using the relation ship
Q = ∆TUA = (T reactor-T jacket) x UA
Q = (250C -00C) x 312.3W/m2C x 1.487m2= 11949.3 W
Page No. 28 of 87
Then, match the addition rate (f) of reagent “Z” to this heat removal rate:
Q 11949 .3W
F=   0.44 L / hr
H  [ A] 19664 .8KJ / mol  5mol / L
Page No. 29 of 87
3 Filtration
Following are the filters commonly used for filtration of pharmaceutical intermediates and finished
APIs.
1. Agitated Nutsche filter & dryer
2. Pressure Nutsche filter
3. Centrifuge
4. Plate and frame filters
3.1 Agitated Nutsche filter & dryer:
Safety requirements and environmental concerns due to solvents evaporation led to development of
this type of filter wherein filtration under vacuum or pressure can be carried out in closed vessels
and solids can be discharged straightaway into drier. Typical unit consists of a dished vessel with a
perforated plate. The entire vessel can be kept at desired temperature by using a limpet jacket,
jacketed bottom dish & stirrer (blade & shaft) through which heat transfer media can flow. The
vessel can be made completely leak proof for vacuum or pressure service.
A multipurpose agitator is the unique feature of this system. The agitator performs a number of
operations through two types of movement. First, it can move parallel to the shaft. Second, it can
rotate with shaft as its axis. The operations performed by agitator are:
 It keeps the slurry contents fluidized until most of the mother liquor is filtered through.
 When filtration is complete, the cake develops cracks causing upsets in the vacuum
operation. This hinders removal of mother liquor. The agitator can be used to maintain a
uniform cake.
 The cake can be washed after filtration by reslurrying the cake with the help of agitator.
 The cake can be discharged by lowering the agitator and rotating it in such a manner that
it brings all the cake towards discharge port.
Page No. 30 of 87
Advantages:
1. Vacuum or pressure filtration possible

2. Inert gas atmosphere can be maintained
3. Very high solvent recovery
4. Solvents are in closed systems, so no toxic vapors are let off in the atmosphere
5. Personal safety is maintained and heat transfer surfaces can be provided to maintain
filtration temperature
Figure 3.1 : ANFD
Page No. 31 of 87
Different operations involved in ANFD:
Figure 3.2
Page No. 32 of 87
3.2 Pressure / Vacuum Nutsche filter (Non-agitated filter):

They are similar to Agitated Nutsche filter & dryer except that they are not fitted with agitators.
The absence of agitator may necessitate the manual mixing of the cake during washing for
content uniformity. In case of crack formation in the cake, the lid needs to be opened to
manually smoothen the cake. For this reason, operating a non-agitated filter requires more
personal protection (such as full suit, face shield, supplied breathing air etc.) for the operator to
avoid material exposure. These are usually fitted with a jacket.
Figure 3.3 :PNF
3.2.1 Constant Pressure filtration calculations (Vacuum / Pressure Nutsche filter

(Incompressible cakes)):
 Conduct experiment and measure filtrate volume at different time intervals at constant
pressure
 Plot graph of t/V vs V
 Calculate slope and intercept from graph
 Use the slope and intercept values for calculating Specific cake resistance and filter medium
resistance
 Keep these two parameters constant as a scale up parameter
 Use following formula for calculating filtration time in scaled up operations
Page No. 33 of 87
t
= 𝑚V + 𝑛
V
𝛼𝜂𝑐
𝑚= 2
2𝐴 𝛥𝑃𝑓
(𝑅𝑀)𝜂
𝑛=
𝐴𝛥𝑃𝑓
𝜂 = 𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑒 𝑣𝑖𝑠𝑐𝑜𝑠𝑖𝑡𝑦 (𝑃𝑎. 𝑠)

𝛼 = 𝑆𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑐𝑎𝑘𝑒 𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 (m/kg)
𝑐 = 𝑀𝑎𝑠𝑠 𝑜𝑓 𝑑𝑟𝑦 𝑐𝑎𝑘𝑒 𝑝𝑒𝑟 𝑢𝑛𝑖𝑡 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑓𝑖𝑙𝑡𝑟𝑎𝑡𝑒 (𝐾𝑔/𝑚3 )
𝐴 = 𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑠𝑢𝑟𝑓𝑎𝑐𝑒 𝑎𝑟𝑒𝑎 (𝑚2 )
𝛥𝑃𝑓 = 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒 (𝑃𝑎)
𝑅𝑀 = 𝐹𝑖𝑙𝑡𝑒𝑟 𝑚𝑒𝑑𝑖𝑢𝑚 𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 (𝑚−1 )
𝑉 = 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑓𝑖𝑙𝑡𝑟𝑎𝑡𝑒 𝑐𝑜𝑙𝑙𝑒𝑐𝑡𝑒𝑑 𝑎𝑡 𝑡𝑕𝑒 𝑒𝑛𝑑 𝑜𝑓 𝑡𝑖𝑚𝑒 𝑡
3.3 Centrifuge:
Pharmaceutical industry uses various types of centrifuges. Commonly used ones are
listed below:
a) Vertical axis batch mode centrifuge:
It uses a perforated basket rotating on a vertical axis to produce a centrifugal force on the
slurry that is fed to the basket through the feed pipe. The perforated basket is lined with a
filter bag of desired pore size. This filter bag retains the solid particles as wet cake, while the
filtrate passes through the filter medium. The filtrate flows out of the basket through the
perforations and gets collected outside through the outlet valve. Cake washes can then be
performed through similar steps by feeding the wash solvent to the basket.
Page No. 34 of 87
Figure 3.4
b) Peeler centrifuge:
The mode of discharge in this type of centrifuge is through mechanical peeling action.
Typical operation involves equipment setup (fitting the filter bag of appropriate pore size and
material of construction, performing leak check), initiating the spinning, loading the slurry,
de-liquoring the mother liquor, loading the wash, de-liquoring the wash, peeling, discharging
and removing the heel before initiating the next load. Isolation starts as soon as the slurry is
loaded as the basket is already spinning, yielding the necessary centrifugal force for the
separation. After the liquid layer goes below the cake surface, cake washing can be initiated.
After completely de-liquoring the wash solvents, the cake is peeled off using a hydraulically
activated peeler. The peeled solids are then discharged through a chute for the next unit
operation. Often, there is an offset between the peeler‟s closest position and the cloth,
resulting in a residual heel. The operating parameters of the peeler centrifuge such as the load
size and the spin speed are adjusted according to the process requirements. For example, a
lower spin speed may be chosen to isolate a compressible cake, to prevent the formation of a
highly compressed cake the heel of which might be difficult to remove.
Page No. 35 of 87
Figure 3.5
c) Inverting bag centrifuge:

The order of operation in this centrifuge is very similar to the peeler centrifuge except the
mode of discharge. In this case, after completing the filtration and washing, the filter bag is
stroked forward by a hydraulically controlled piston, turning the bag inside out, allowing the
solids to be discharged. The filter bag is secured to the basket wall at the front end,
preventing it from completely detaching from the basket. These centrifuges offer an efficient
and faster cake removal as the bag is turned inside out.
Page No. 36 of 87
Figure 3.6
Centrifuge filtration calculations:
Figure 3.7
a) Calculate the centrifugal force (mrω2)

b) Calculate gravitational force (mg)
Ratio of centrifugal to gravitational force (rω2/g) is measure of the separating

power of the machine
So for small scale and commercial scale centrifuge:
r1ω12/g = r2ω22/g
Page No. 37 of 87
i.e. r1ω12 = r2ω22

Using this formula we can calculate the speed of rotation of desired size of machine
either for scale up or scale down operation
 Below relation can be used to calculate flow rate of filtrate in centrifuge operation
𝜌𝜔2 (𝑟2 2 − 𝑟1 2 )
𝑄=
𝑚 𝛼 𝑅
2µ(𝐴 𝑐𝐴 + 𝐴𝑚 )
𝐿 𝑎 2
𝜌 = Solution density
𝜔 = Angular velocity of centrifuge (rad/s)
µ = Viscosity of solution
𝑚𝑐 = Mass of solid in the solution
𝛼 = 𝑆𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑐𝑎𝑘𝑒 𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 (m/kg)
𝑅𝑀 = 𝐹𝑖𝑙𝑡𝑒𝑟 𝑚𝑒𝑑𝑖𝑢𝑚 𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 (𝑚−1 )
2𝜋𝑏(𝑟2 − 𝑟𝑖 )
𝐴𝐿 = 𝑟
( 𝑟2 )
ln⁡
𝑖
(Logarithmic cake area)

𝐴𝑎 =( 𝑟𝑖 + 𝑟2 ) πb (Arithmetic mean cake area)
𝐴2 =2π𝑟2 𝑏 (Area of filter medium)
Page No. 38 of 87
3.4 Plate and Frame Filter Press
A filter press consists of a series of chambers containing square or rectangular filter plates
supported in a frame. Once the filter chambers are loaded with slurry, the plates are forced
together with hydraulic rams that generate pressures typically in the region of 70,000 kg/m 2.
Each plate is covered by a material or membrane that acts as the initial filter when the press is in
operation. As the solid filter cake builds up, the cake adds to the retrieval of fine particles from
the slurry. At the end of the compression, the solid filter cake can be removed. The whole
process is often computer controlled to make it automatic or semi-automatic.
Figure 3.8
General notes:
1. In case of compressible cakes the specific resistance will vary with ΔP, generally the
relationship is of following two forms:
𝛼 = 𝛼𝑜 𝑃 𝑛
𝛼 = 𝛼𝑜 (1 + 𝑘𝑃)𝑛
2. To keep constant filtration rate, ΔP needs to be increased as filtration progresses
Page No. 39 of 87
3.5 Merits & demerits of different filtration equipments:
Table 3.1
Page No. 40 of 87
3.6 Flow chart for selection of filters
Assemble data and

physical properties
Select filter medium from those with A

suitable chemical resistance
Filtration lab test Record the data in lab data

sheet
Is filtrate
clarity
satisfactory
?
Select another
medium
No
Will be used during
Yes scaleup
Try grade either side of chosen medium

and choose fastest permissible grade
Collect filtrate vol. vs time

A Calculate Rm & α
data & rate of cake buildup
Rate of cake
Continuous Centrifuge, Nutsche
buildup is 0.1 - 10 α = 1x107 _ 1x108
Filter
cm/sec
Settling rate
(> 5 cm/s)
Rate of cake Peeler / Basket Type Centrifuge,

buildup is 0.1 - 10 Vacuum Nutsche Filter, Agitated α = 1x108 _ 1x1010
cm/min Nutsche Filter, Rotary Pressure
Filter
Settling rate
(0.1-5 cm/s)
Rate of cake Plate and Frame Filter Press,

buildup is 0.1 - 10 Pressure Nutsche Filter, Agitated α > 1x1010
cm/hr Nutsche Filter or combination of
both in critical cases
Settling rate
(< 0.1 cm/s)
Note:
1. Centrifuge should be avoided for flammable solvents
2. If toxic vapours are realeased during filtration operation then it should be carried out under closed conditions (PNF, ANFD etc.)
Figure 3.9
Page No. 41 of 87
Table 3.2: Equipment selection based on rate of cake build up

Ref. : Page-306, Chemical Process Equipment- Selection and Design, Stanley M. Walas
Table 3.3
Ref. : Page-318, Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing, edited by
David J. am Ende
Page No. 42 of 87
4 Drying
4.1 Drying principles
The drying characteristics, i.e., drying curve, of any product can be found experimentally.
Virtually for any product, drying occurs in three phases. The typical drying curve is shown in
the figure below:
Three different phases of drying are:
 Initial Period: Where sensible heat is transferred to the product and the contained
moisture. The rate of evaporation increases dramatically during this period with mostly
free moisture being removed.
 Constant rate period: free moisture persists on the surfaces and the rate of evaporation
alters very little as the moisture content reduces. There is a gradual and relatively small
increase in the product temperature during this period.
 Falling rate period: phase during which migration of moisture from the inner
interstices of each particle to the outer surface becomes the limiting factor that reduces
the drying rate.
Page No. 43 of 87
The above graph of drying rate vs time is constructed by the following steps:
1. Moisture content is evaluated at certain regular time intervals. The more the number of
points the better.
2. Forward difference method is applied to the selected points. Say at time t1 the moisture
content is X1 and at time t2 the moisture content was X2. The difference between the
moisture content i.e. X2 – X1 and the corresponding time interval t2 – t1 is calculated.
3. Step 2 is done for all the values of moisture content. Then, a new table is constructed having
the three columns, moisture content difference (X2 – X1), time interval (t2 – t1) and average
time interval (t2 + t1)/2.
The drying rate is the rate of vaporization of solvents per unit area of solid. It is given by:
𝑀 𝑑𝑋
𝑁=
𝐴 𝑑𝑡
M: Mass of completely dried solid
A: Total surface area of particles
X: Moisture content
N: Drying Rate
t: Time
𝑑𝑋 (𝑋2 − 𝑋1 )
=
𝑑𝑡 (𝑡 1 +𝑡 2 )
2
(𝑡2 − 𝑡1 )
4. In order to evaluate the total surface area of the particles, the following steps are followed:
i. Assuming spherical particles, their diameter (d) is calculated.
ii. The ratio of bulk weight to the weight of a single particle would provide us
the number of particles.
𝑊 𝑊 𝑊
𝑁𝑝 = = =
𝑊𝑝 𝜌𝑝 𝑉𝑝
3
𝜌𝑝 𝜋𝑑 6
iii. 𝐴 = 𝑁𝑝 (𝜋𝑑2 )
Page No. 44 of 87
5. The value of N is calculated at every point in the table. Then, a desired graph is plotted
using the values of N and the values in the average time interval column.
This curve is generally used to calculate the efficiency of the dryer.
4.2 Types of dryers

Based on the mode of heating, Dryers are classified in to following categories:
 Indirect heating dryers: in which heating medium do not come in direct contact with
material to be dried. Examples are Rotary Cone Vacuum Dryer (RCVD), Agitated Thin
Film Dryer (ATFD), Nauta dryer etc.
 Direct heating dryers: in which heating medium (Air or N2) directly comes in contact with
material to be dried. Examples are Air Tray Dryer (ATD), Fluid Bed Dryer (FBD), Spray
Dryer etc.
Common dryers used in pharmaceutical industry are:

1. Vacuum Tray Dryer (VTD
2. Air tray dryers
3. Rotary cone vacuum dryers
4. Fluidized bed dryers
5. Spray dryers
6. Agitated thin film dryers
7. Nauta dryers
Page No. 45 of 87
4.2.1 Vacuum Tray Dryer (VTD):
Figure 4.2
The Vacuum tray dryer is basically a tray dryer working under vacuum conditions. It dries on
the conduction principle. It is used mainly for drying of temperature and oxygen sensitive
products. It‟s a clean, simple and effective method of drying wet cake. The drying is under
vacuum and hence it is possible to dry heat sensitive materials at lower temperatures. Valuable
organic solvents can also be conveniently condensed and recovered.
There are a number of shelves inside the dryer on which the product laden trays are placed. The
top most shelf is a dummy shelf to ensure proper heating and to block dried powder from
escaping into the solvent extraction system.
The shelves are manufactured in hollow construction with baffles cum stiffeners placed in
between. Each shelf has an inlet and outlet nozzle. Each shelf is connected through these
nozzles to an Inlet and Outlet Header. Hot media is passed through the Inlet Header and in turn
to each shelf. The hot media flows through the shelves in a serpentine fashion ensuring faster
heat transfer to the surface, which in turn heats up the trays placed on the shelves. The hot
media flows out from the shelves through the Outlet Header.
Page No. 46 of 87
Scale up:
During scale up keep the following parameters constant (i.e. same as small scale):
1) Vacuum
2) Utility inlet temperature
Effect of cake thickness on drying time should be simulated at lab/kilo lab scale (based on cake
thickness at plant driers)
4.2.2 Air Tray Dryer (ATD):
The cabinet of ATD is a simple large box fitted with internal runners to support the trays of
product being processed. The trays are loaded into the chamber, the doors closed and heated air
is blown through the stack of trays until the entire product is dry. The construction is almost
similar to VTD.
Scale up:
1) Air (N2) inlet temperature
2) RH of Air (N2)
Flow rate of air
3) Mass of wet cake
(Wet cake LOD should be almost same for small as well as large scale)
Page No. 47 of 87
4.2.3 Rotary Cone Vacuum Dryer (RCVD):

RCVD consists of a rotating vessel in the shape of a double-cone supported by two stationary
trunnions. The vessel is surrounded by a heated jacket and a small vacuum line is installed
within one of the trunnions and extends into the vessel (angled in the upward direction). The
dryer can also be equipped with a delumping bar that extends into the vessel from one of the
trunnions. The double-cone drying chamber rotates about the axis of the trunnions, causing the
material to cascade inside. Through gentle tumbling and folding, the material is contacted with
the heated wall to facilitate drying without a significant amount of shear being imparted to the
material.
Scale up:
2) Vacuum
3) RPM
4) % Occupancy (from Kilo lab to plant scale)
Figure 4.3
Page No. 48 of 87
4.2.4 Fluid bed dryer:

Fluid bed dryers are not suitable for drying very wet materials that have a pasty or liquid like
consistency. In a fluid bed dryer, a hot gas stream is introduced into the bottom of a chamber
filled with the material to be dried. The gas stream expands the bed of material to create
turbulence and the solid particles attain a fluid like state – a phenomenon known as fluidization.
Heat transfer is extremely efficient and uniform since the solid particles are surrounded by hot
gas, leading to fast drying times. The exhaust to the chamber is equipped with particulate filters
to prevent the product from escaping the chamber
Figure 4.4
Figure 4.5
Page No. 49 of 87
Scale up of Fluidized bed dryers:

1) Inlet Air (N2) temperature
2) Inlet Air (N2) RH
During scale up, aim is that each particle should undergo the same experience independent of
scale of operation. This means mainly:
 The same exposure to temperature and humidity for the same time
 The same mechanical stress (characterized by the fluidization velocity)
In most real fluid bed systems, typically the bed height h2 in larger processors will be bigger
than the bed height h1 in a smaller processor. This already means that there is more mechanical
stress to the materials due to the increased product bed height, which might for delicate granules
lead to a certain degree of breakage and therefore to an increased amount of fines.
As a second consequence, it is no longer possible to maintain both mechanical and

thermodynamic conditions identical. Therefore it has to be decided what is more critical to a
particular product.
 Keeping exposure to temperature and humidity same: For satisfying this condition, amount
of air (N2) per unit mass of product and time should be kept same in both the cases. As a
consequence the fluidization velocity in larger fluid bed processor will be larger. If this option is
selected the overall drying time and the exposure of the product to temperature and moisture
will be same.
Downside of this option is that there is not only an increased mechanical stress by the increased
height of the product bed but additionally by the higher fluidization velocity. For most granules
this will lead to a finer particle size distribution and especially to an increased amount of fines.
This option is attractive if the granules are very robust or if the particle size distribution is not
critical for the downstream processing.
Page No. 50 of 87
 Keeping mechanical stress same: For satisfying this condition, fluidization velocity should be
kept identical in both the cases.
This has two effects:
 Drying phase 1 (Zero Order drying) will be prolonged. The end of drying phase 1 is reached
when a rise in product/outlet temperature can be detected. One can try to compensate for this by
selecting a higher inlet air temperature.
 Drying Phase 2 (First Order Drying) will be affected in 2 ways. As there is more material
(moisture) per amount of process air the product temperature will be lower and the absolute
humidity of the process air will be higher (and of course also the relative humidity). Second the
duration of drying phase 1 will be prolonged, as already discussed. Which of these 2 effects will
be how significant is product dependent. How much the characteristics (chemical stability, form
etc.) of the final product will be affected is also product dependent.
 Calculating the minimum fluidization velocity:

 Theoretical method:
2
𝜌𝑓 𝑢𝑚𝑓 150(1 − 𝜀𝑚𝑓 )µ
(𝜌𝑝 − 𝜌𝑓 )𝑔 = 3 + 1.75
𝛷𝑠 𝐷𝑝 𝜀𝑚𝑓 𝛷𝑠 𝐷𝑝 𝑢𝑚𝑓 𝜌𝑓
If εmf (and maybe Φs) is not known then following correlation can be used:
2
𝐷𝑝3 𝜌𝑓 (𝜌𝑝 − 𝜌𝑓 )𝑔
𝑅𝑒𝑚𝑓 = 33.7 + 0.0408 − 33.7
µ2
𝜌𝑝 = Density of particle
𝜌𝑓 = Density of fluid
𝑔 = acceleration due to gravity
𝑢𝑚𝑓 = minimum fluidization velocity
𝛷𝑠 = sphericity of the particle
Page No. 51 of 87
6
𝑎𝑠𝑝 𝑕𝑒𝑟𝑒 𝐷𝑝
𝛷𝑠 = =
𝑎𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒
𝑆𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒
𝑉𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒
Sparticle = Surface area of the particle

Vparticle = Volume of the particle
𝐷𝑝 = effective diameter (diameter of a sphere having the equivalent volume as the particle)
𝜀𝑚𝑓 = void fraction at minimum fluidization
µ= Viscosity of fluid
𝑅𝑒𝑚𝑓 =Reynolds number at the minimum fluidization velocity
𝑢𝑚𝑓 𝜌𝑓 𝛷𝑠 𝐷𝑝
𝑅𝑒𝑚𝑓 =
µ
Experimental method:
1) Take a vertical tube & partially fill it with wet cake. (The tube should be open at the top with
a porous plate at the bottom for air distribution)
2) Now increase the air velocity slowly from 0 till the bed is fluidized vigorously and note down
the height of the bed as a function of air velocity.
3) Now decrease the air velocity slowly till 0 and again note down the height of the bed as a
function of air velocity.
4) Plot the graph between bed height and air velocity for both the cases 2 & 3.
5) Typical graph will look like this:
Figure 4.6
Page No. 52 of 87
6) Velocity corresponding to point B is the minimum fluidization velocity.

7) Keep velocity more than minimum fluidization velocity during drying operation.
4.2.5. Spray Dryer:

Spray dryer is used to evaporate liquid solutions to get the dissolved product out of it. The
liquid stream is sprayed via a nozzle into a cylindrical chamber (often with a conical bottom) as
a mist of fine droplets. These droplets get dispersed into a stream of hot gas and the solvent is
vaporized rapidly to leave a residue of dry solid product particles in the chamber. It is
important to ensure that particles of product are not wet with solvent when they touch the walls
of the chamber and hence spray drying chambers tend to have large diameters. The heating
period is very short, hence functional damage to the product is usually not an issue.
Figure 4.7
Page No. 53 of 87
Dependence of Responses on process parameters:
Table 4.1
Page No. 54 of 87
Table 4.2
During scale up of spray dryer, the aim is to get a powder with similar residual moisture or OVI
content, similar particle size and same form as we have got at small scale, but at a higher production
rate.
Scale up of spray dryer:
1) Hot air (N2) temperature
2) Chamber pressure
Feed flow rate
3) Hot air (N
2 ) flow rate
Page No. 55 of 87
4) Nozzle geometry & diameter

5) Droplet size (if possible to measure)
Phase Doppler Particle Analyzers can be used for measuring droplet size during the
experiment.
Droplet size and solution solids content directly correlate to the final size of the dried particle
based on the following correlation:
1/3
ρdroplet
𝐷𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒 ≈ 𝐷𝑑𝑟𝑜𝑝𝑙𝑒𝑡 xsolids
ρparticle
Dparticle = diameter of the dried particle

Ddroplet = diameter of the droplet
ρparticle = density of the dried particle
ρdroplet = density of the spray solution
xsolids = solution solids content
 Mass & Energy balance:
1) First of all calculate EVR

𝑅𝑆
𝐸𝑉𝑅 = 𝐹𝑅 1 − 𝑇𝑆 − 𝐹𝑅. 𝑇𝑆
1 − 𝑅𝑆
2) Define T0 based on following conditions:

 Maximum T0 is determined based on thermal degradation/inactivation of the product or
property constraints such as specific density etc.
 Minimum T0 is determined based upon the relationship of the product Tg to the relative
saturation at the dryer outlet. Below this percentage relative saturation (at outlet) value,
insufficient drying leads to low collection yields because product buildup inside the
drying chamber takes place when “wet” or “sticky” particles come in contact with the
dryer walls.
Page No. 56 of 87
 After defining T0, calculate MG from the following relation:
𝐸𝑉𝑅. 𝛥𝐻𝑣𝑎𝑝
𝑇0 = 𝑇𝑖 − 𝑔
𝑀𝐺. 𝐶𝑝
3) Calculate Yout from the following relation:
𝑌𝑖𝑛 𝑌𝑇𝐹𝑁
𝐺𝑖𝑛 + 𝐺𝑇𝐹𝑁 + 𝐸𝑉𝑅
1 + 𝑌𝑖𝑛 1 + 𝑌𝑇𝐹𝑁
𝑌𝑜𝑢𝑡 =
𝐺𝑖𝑛 𝐺𝑇𝐹𝑁
+
1 + 𝑌𝑖𝑛 1 + 𝑌𝑇𝐹𝑁
EVR = Evaporation rate of solvent (kg/h)

FR = Feed flow rate (kg/h)
TS = Total solids in the feed (kg solids/kg feed)
RS = Residual solvent in the powder (kg solvent/kg wet powder)
T0 = Outlet temperature of drying air (N2)
Ti = Inlet temperature of drying air (N2)
MG (Gin ) = Mass flow rate of air (N2) (Kg/h)
g
Cp = Heat capacity of drying air (N2)
ΔHvap = Heat of vaporization of solvent
Yout = Outlet drying air solvent concentration (kg solvent/kg dry air)
Yin = Inlet drying air solvent concentration (kg solvent/kg dry air)
GTFN = Two fluid nozzle atomization air flow rate (including solvent) (kg/h)
YTFN = Two fluid nozzle atomization air solvent concentration (kg solvent/kg dry air)
Page No. 57 of 87
4.2.6. Agitated Thin Film Dryer (ATFD):

ATFD consists of a cylindrical, vertical body with heating jacket and a rotor inside of the shell
which is equipped with rows of pendulum blades (hinged blades) all over the length of the
dryer. A well designed dynamically balanced rotor develops a centrifugal force to distribute the
feed uniformly against heated wall of jacketed cylinder. The thin film created between the blade
and heated wall covers the entire heated surface continuously.
Figure 4.8
The thickness of the film is defined by the clearance between the blade and the wall. A highly
agitated bow wave is formed in front of the rotor blades. The turbulence increases as the product
passes through the clearance before entering a calming zone situated behind the blades. The
volatile component evaporates continuously. The product layer is typically less than a
Page No. 58 of 87
millimeter in thickness. The hinged pendulum blades are designed to give a minimum clearance
with the dryer wall to prevent fouling of the heating surface by product.
Figure 4.9
Normally, the drying process in ATFD consists of a preheating, a slurry and a powder zone. In
the preheating zone the solvent evaporation starts and solids are formed. In the slurry zone, the
concentration of solids increases. Many products during this phase tend to form agglomerates
which are crushed by the pendulum blades. In the final powder zone surface solvent content is
further removed and the drying process is completed. Based on the feed liquor characteristic
drying can be accomplished at desired temperature by maintaining the corresponding vacuum
inside the dryer.
The length of the various zones depends for a given product largely on the feed rates and
solvent content. With increasing feed rate the preheating and the slurry zone increase due to the
increased heat demand. As a result the powder zone decreases in size and the final OVI in
powder may increase.
Vapors moves through the dryer counter-current to the product flow and is condensed in an
external condenser. The free flowing powder gets collected at the bottom, which can be taken
out once the cycle is complete.
Page No. 59 of 87
Scale up of ATFD:
Feed flow rate
1) Heat transfer area
2) Vacuum
4.2.7 Nauta Dryer:
A nauta dryer is a jacketed dryer with an internal agitator. The screws of the Nauta mixer are
rotating along the self-axis meanwhile revoluting along the central axis of a conical
container. The screw conveys the material upwards along the vessel wall and that material sinks
down by gravity at the centre of the mixing chamber. The revolving motion ensures that entire
material is turned over. Because of uniform mixing inside the dryer, heat transfer is better and
temperature remains uniform throughout the material. Final solvent content (OVI) is uniform
everywhere because of better mixing and uniform heat transfer.
Figure 4.10
Page No. 60 of 87
Figure 4.11
Advantages and disadvantages of various dryers:
Table 4.3
Note: 1. Conical dryer mentioned in the above table is Nauta dryer
2. Tumble dryer mentioned in the above table is RCVD
Page No. 61 of 87
An example illustrating the selection of dryers:
Note: 1. Conical dryer mentioned in the above example is Nauta dryer

2. Tumble dryer mentioned in the above example is RCVD
Page No. 62 of 87
5. Size Reduction
5.1 Air Jet Mills
Jet Milling is a concept of feeding of the powder particles into a flat circular milling chamber
and subjecting the same tangentially with pressurized air or nitrogen through a venturi. The
powder particles are accelerated in a spiral movement inside the milling chamber by number of
angular holes in a ring and placed around the periphery of the chamber. The micronization takes
place due to the collision between the incoming particles and the particles, which are already
accelerated into the spiral path. The larger particles of the product get retained at the periphery
of the chamber by centrifugal force and the smaller particles exit with the exhaust air from the
central portion of the chamber. The particle size distribution is controlled by adjusting pressure
and feed rate. The particles are trapped by specially designed cyclonic separator and finger-bag.
Figure 5.1
Page No. 63 of 87
Figure 5.2
Xc: cut-off size (Particle Size Distribution of Finished Product):

It is governed by the following relation:
𝑿𝒄 ∝ √((𝑫𝟑 /𝑽)(𝒅/𝑫)[(𝟏 − 𝑫𝒆/𝑫) − 𝟐𝑪(𝒅/𝑫)𝒄𝒐𝒔𝜶])
Xc – Cut-off size (d10, d90) (cm)

D – Jet Mill Diameter (cm)
De – Outlet Diameter (cm)
V – Volumetric Flow Rate of Air Introduced (cm3/sec)
d – Nozzle diameter (cm)
α – Angle of Jet Injection (degree)
C – Dimensionless Constant
𝐶 = 𝑙/𝑑
l – Length of free jet (C ~ 10-20)
According to the above relation:
𝑋𝑐 ∝ (𝐷3 /𝑉)
When d/D, De/D and α are kept constant
To keep cut off size same at different scales, (D3/V) must be kept constant
Page No. 64 of 87
Figure 5.3
Calculation of Feed-Flow Requirement (Milling Capacity):
𝐹 ∝ 𝑉 2 [(𝐷3 /V).(d/D)]1/2
Where F – Feed Flow or Milling Capacity (gm/sec)

Assuming (D3/V) to be constant
𝐹 ∝ (𝑉)2
Reference: Scale up theory of Jet Mills on the basis of communition kinetics – Tatsuo Tanaka
Page No. 65 of 87
5.2 Multi Mills
The multi mill is a highly versatile machine suitable for dry pulverizing of lumps to small
particles of desired size by high shear action. The machine is provided with a vertical rotor
assembly with knife type swinging blades for pulverizing the lumps. The rotor is provided with
two bottom scrapper blades for scrapping the material from the bottom plate and pushing it in
the upward direction towards the knife blades. It has a circular perforated screen around the
blades for better pulverizing action. The main shaft of the rotor assembly is coupled to a step
pulley through a bearing housing which in turn is coupled to a suitable motor through a belt
assembly. The speed of the rotor can be changed by changing the position of the belt in the step
pulley. The speed selection is made depending on the material and the final size of the particles.
Figure 5.4
Determination of Feed Rate:

𝑭∝𝑵𝝎
Where N: Number of Knives
ω: Rotor Speed (rad/sec)
F: Feed Rate (gm/sec)
Page No. 66 of 87
5.3 Selection of Size reduction Equipments
High PSD Multi Mill
Solid
Powder
Low PSD Air Jet Mill

Size reduction
Suspension Colloid Mill
Figure 5.5
Page No. 67 of 87
6. Crystallization
Crystallization operation is performed to isolate the product as solid. It can be used for different
objectives as purify by leaving impurities in the liquid phase (re-crystallization) and create
particles of correct form (polymorphs creation) and desired physical properties. The driving
force for crystallization is the Supersaturation of the solution.
6.1 Solubility, Supersaturation and meta-stability (definitions)

Solubility: Solubility of a solute in a given solvent is the concentration at which the solid solute
and the liquid solution are at equilibrium. This is important because it allows calculation of the
maximum yield of product crystals accompanying a change of state from one set of
concentration to another in which crystals form.
For example, if we look at Figure 1, which gives us the solubility diagram for KCl, if we start
with 1000 kg of a solution at 100 °C and a concentration of 567g/kg water and cool it to 10 °C
at equilibrium, we will have 836 kg of solution with a KCl concentration of 310g/kg water and
164 kg of solid KCl.
Figure 6.1
Page No. 68 of 87
Supersaturation: A solution that contains a higher than saturation concentration of solute;

slight disturbance or seeding causes crystallization of excess solute. Supersaturation is the
fundamental driving force for crystallization and can be expressed in dimensionless form as
Where µ is the chemical potential, c is the concentration, a is the activity, γ is the activity
coefficient, and * represents the property at saturation. Supersaturation is also often expressed
as a concentration differences
∆C = C - C*
Where C is the concentration, and C* is the concentration at equilibrium or saturation.
Supersaturation is can also expressed as a ratio of concentrations
S = C / C*
Nucleation: The generation of a new solid phase either on an inert material in solution or in the
solution itself.
Crystal Growth: Growth is the increase in size of this nucleus with layer by layer addition of
solute.
Meta Stable Zone Width: The metastable zone width results from the Specific characteristics
of nucleation in a supersaturated solution of soluble substances.
6.2 Determination of the solubility curves

Experimentally, the solubility is determined as a function of concentration and temperature by
the following steps (figure below):
• Dissolution of the product to form a homogeneous solution (point S),
• Slow cooling until the onset of crystallization; the appearance of the first crystals defines point
N on curve n
• Slow heating until a homogeneous solution is again attained; the disappearance of the last
crystals defines point D and hence the solubility curve d.
Page No. 69 of 87
• Addition of solvent or product to change the concentration.

Steps (2) through (4) are repeated a number of times to obtain several experimental points to
establish curves d and n.
Figure 6.2
Schematic representation of the solubility curves. C: Concentration of product in the solution, T:

Temperature, d: Solubility curve, D: Clear point, n: Supersaturation curve, N: Cloud point, m: Metastable
region (no primary nucleation), S: Start point (homogeneous solution) for the measurement cycle at
concentration C1, HS: Region of homogenous solution (below curve d), CS: Region of crystal suspension
(above curve n).
Page No. 70 of 87
The below table can be prepared during lab experiment, to generate the solubility plot for
various solvent and for determination of Meta stable zone width.
Exp. No: __________

Product : __________
Stage : __________
B.No __________
Solvent __________
B.No __________
Aim: To evaluate solubility/MSZW for __________ in __________
Table
S.No Solvent Solubility Conc Nueclation Volume
mL (mg) Temp °C mg/mL
1
2
3
4
5
Graph
Solubility and MSZW for XXXX in XXXX
1.2
1 Sol Nucleation
0.8
Conc
0.6
0.4
0.2
0
0 0.2 0.4 0.6 0.8 1 1.2
Temp °C
Remarks/Observations (if Any)

________________________________________________________________________
________________________________________________________________________
Figure 6.3
Page No. 71 of 87
Supersaturated solutions are metastable. This means that supersaturating a solution some
amount will not necessarily result in crystallization. Referring to the solubility diagram shown
in Figure 6.4, if we were to start with a solution at point A and cool to point B just below
saturation, the solution would be supersaturated. If we allowed that solution to sit, it might take
days before crystals formed. If we took another sample, cooled it to point C. and let it sit, this
might crystallize in a matter of hours; eventually we will get to a point where the solution
crystallized rapidly and no longer appears to be stable. As we can see from this experiment, the
metastability of a solution decreases as the supersaturation increases.
Figure 6.4
Supersaturation is the fundamental driving force for crystallization. There are four main
methods to generate supersaturation, and hence four types of crystallization associated
accordingly:
1. By Temperature change - Cooling crystallization
2. By Evaporation of solvent - Evaporative crystallization
Page No. 72 of 87
3. By Chemical reaction - Reactive crystallization

4. By changing the solvent composition - Anti solvent crystallization
Crystallization consist several physical phenomena, the most important of which are nucleation
(tiny particle generation) and growth. Supersaturation is required for nucleation and growth.
Generally very high supersaturation favors nucleation over growth, and low supersaturation
favors growth over nucleation. Some time seeds can be added to start nucleation in the
supersaturation zone.
Page No. 73 of 87
6.3 Scale up factors for crystallization:

Factor In Lab At scale Impact Means to Evaluate
Generally narrower Narrower meta stable zone width may result Test metastable zone width in the lab as a function
in spontaneous nucleation prior to seeding, of agitation, cooling (as described in above plot)
Metastable zone thus lack of control over polymorph. and anti solvent addition (as applicable).
Generally broader
width Generally, to grow large particles of a desired
polymorph, it is best to seed the batch under
conditions of very low supersaturation.
For some equipment solid Polymorph control and particle size Evaluate effect of amount of seed (loading),
charge is difficult and the distribution control seeding point, and the dry versus slurry transfer.
seeds are transferred as
Either is possible and
Seeded / unseeded slurry. seed charges is small
easy to add
quantity, and sometime it is
challenging to ensure that
seed reaches the batch.
Stir bar, or overhead Various agitator, vessel, and Inadequate mixing can result in hot spots of Evaluate the impact of mixing in scale-down
baffle configurations. high supersaturation, and thus uncontrolled experiment.
Mixing stirring. Generally
nucleation. High agitation may reduce
good mixing. metastable zone width.
Variable Some particles are easily broken. This Explore the particle size distribution as a function
process may be sensitive to agitation of agitation using overhead stirring, or stress the
Attrition Variable parameters (including time). This may affect process by using a high shear mixer.
the particle size distribution, filterability,
and ultimate powder properties.
Temperature probes can If jacket temperature control is used, this Observe the tendency for coating during the
sometimes be coated with may not be a processing issue, but accurate crystallization. Specify jacket temperature control
crystals and provide false temperature data will not be collected. If rather than batch temperature control mode.
Measurement of By thermocouple, not
information operating in batch control mode, the control
temperature typically a problem. system may adjust the jacket temperature
and thus move the batch temperature outside
the normal operating range.
Page No. 74 of 87
6.4 Equipment selection for crystallization:

Some of the basic calculations for selection of size of vessel and utility requirement for
crystallization,
Energy balance: To calculate the utility requirements.
Compounds whose solubility increases with increasing temperature (normal solubility), there is
usually an absorption of heat when the compound dissolves, which is called the heat of solution.
For materials having normal solubility the separation of a crystalline phase is accompanied by
the release of heat. At equilibrium the heat of crystallization is equal and opposite in sign to the
heat of solution.
 Generally the total heat released on crystallization is insignificant in comparison to heat
removed in cooling-type crystallization. In some typical case it may be a substantial
portion of the total heat removed in cooling-type crystallization.
 In evaporative-type crystallizers, the heat of crystallization is usually negligible when
compared with the heat required for vaporizing the solvent.
 A heat balance can be made wherein the individual heat effects, such as the sensible heat
required for heating or cooling the solution, the heat of crystallization of the product
formed, and the latent heat of vaporization for liquid vaporized can be combined into an
equation for the total heat effects.
Mass Balance: To calculate the yield of a crystallization process and size of the equipment
Theoretical yield from a crystallization process can be calcuted by below equation
Where,
Page No. 75 of 87
Selection of Reactor and agitator
Figure 6.5
Page No. 76 of 87
7. DISTILLATION:
Distillation covers a number of operations involving boiling and vaporizing a liquid, and then
separating and condensing the vapors. Broadly it can be divided in two type, continuous or batch.
Mostly we are dealing here is single stage batch distillation without reflux, which sometimes
called flash distillation. It carried out in reactors for volume reduction, solvent exchange, or
removal of residual water by azeotropic drying.
7.1 Types of Distillation

 Atmospheric Distillation
 Vacuum/ High Vacuum Distillation
 Fractional Distillation
 Azeotropic Distillation
7.2 Guidelines for distillation
Atmospheric distillation
 Check the solvent boiling point and thermal stability of product
 Ensure distillation equipment should contain thermometer to check the temperature
of reaction mass and vapor
 Use the silicon oil for distillation temperature above 150.0°C
 The volume of reaction mass or solvent to be distilled should not be more than
50.0% of the capacity of equipment.
 Heat the reaction mass slowly by controlling the distillation rate and to avoid
reaction mass/ solvent blow-out.
Vacuum distillation
 Establish the optimum vacuum range for distillation to get maximum recovery.
 Ensure the receiver should have 50.0% free space on vacuum distillation.
 Avoid the vapor loss providing vacuum trap between receiver and vacuum pump.
 Ensure the vacuum trap chilled properly.
 Apply the vacuum before heating the reaction mass
Page No. 77 of 87
reaction mass/ solvent blow-out
 Break the vacuum slowly by applying nitrogen only
Fractional distillation
 Check the solvent boiling point and thermal stability of product.
 Select the column size based on difference in solvent boiling point and to attain the
desired quality.
 Ensure the receiver should have 25.0% free space and chilled properly by keeping
in ice bath.
reaction mass/ solvent blow-out
Scale up factors for distillation:

 Agitation should be set as high as practical to maximize heat transfer. Apply heat
slowly to prevent flooding the condenser by exceeding its capacity. If using vacuum,
try to establish the desired pressure in the reactor first (a vacuum controller is a
must), and then slowly apply heat to the reactor. This will help minimize foaming.
 Foam/Bumping: A very small nitrogen bleed into the reactor can also be helpful to
knock down a high head of foam. When stopping the distillation, always shut off the
heat first. Then, once the batch is cooled, vacuum and agitation can be turned off.
 Time: The time taken for distillation in plant can very in great extent from lab.
Stability of process stream at must be velauted by refluxing at the highest antiicpated
pressure, and at both extremes of composition.
 Vacuum control: some process strems have a tendency to foam, or to “bump”.
Carefully test the effect of decresed pressure on distillation.
 Jacket temperaure: The diffeernce of temperature between jacket and boiling point
drives the distillation. We should asses the stability of the product at high
temperature to see if high jacket temperaure is an issue.
Page No. 78 of 87
 Minimum volume: There may be safety issues associated with highly concentrated
process streams, and it needs to be evaluated.
 End point volume: May be difficult to see volume landmarks in the vessel. Need to
asses the effect of under distillaton ( some solvent remains in stream) and over
distillation (dry distillation) in the next operation.
Page No. 79 of 87
8. Extraction
The objective of extraction is to bring the product from aqueous phase to organic phase for
further reactions. It can be used to remove organic impurities or remove inorganic salts or to
quench the reaction mass generally referred as Washing. In principle washing and extraction is
same, where one substance moves from one phase to another phase. Generally the reaction
mixture is organic and the added liquid is water or an aqueous salt solution but the reverse is
also possible.
Definition:
Liquid extraction is a mass transfer operation in which a liquid solution (the feed-F) is
contacted with an immiscible or nearly immiscible liquid (solvent-S) that exhibits preferential
affinity or selectivity towards one or more of the components in the feed.
Figure 8.1
The basic steps involved include:

1. Contacting the feed with the extraction solvent
2. Separation of the resulting phases
3. Removal/recovery of solvent from each phase
Page No. 80 of 87
8.1 Factors to be considered during extraction optimization in lab:
1. Solvent selection:
a. Selectivity: The ability of the solvent to pick up the desired component in the feed as
compared to other components. Good selectivity towards solute and little or no
miscibility with feed solution.
b. Recoverability: The solvent should be easily recoverable for recycle.
c. Density: Must be different so that phases can be separated by settling
d. Chemical Reactivity: Solvent should be inert and stable
e. Safety : Should be non toxic
f. Cost : Should be low
g. Environmental : it should be class -2 or 3 solvent
2. Operating Condition:
a. Temperature: can also be used as a variable to alter selectivity. Elevated
temperatures are sometimes used in order to keep viscosity low and thereby
minimizing mass-transfer resistance
b. pH :The pH becomes significant in metal and bio-extractions. pH is maintained to
improve distribution coefficient and minimize degradation of product.
c. Agitation & Mixing is an important parameter in extraction processes , where
Axial and Radial circulation required (e.g. propeller and Turbine )
3. Agitator type: Adequate mixing needed to properly mix the phases and equilibrate
compositions. Excessive agitation may promote stable emulsion formation.
Page No. 81 of 87
4. Mode of Operation: batch or continuous

A single-stage extractor can be represented as:
Figure 8.2
Where,
F = Feed quantity / rate, mass
R = Raffinate quantity / rate, mass
S = Solvent quantity / rate, mass
E = Extract quantity / rate, mass
Xf, Xr, Ys, and Ye are the weight fractions of solute in the feed, Raffinate, solvent and
extract, respectively.
Partition coefficient „m‟ is defined as the ratio of Ye to Xr at equilibrium conditions
8.2 Calculation of Solvent Requirement:

Mass balance can be represented as:
F Xf + S Ys = R Xr + E Ye
Assumption:
The initial solvent is free of solute, i.e., F = R. S, E and Ys = 0 and using the equilibrium
relation of Ye = m Xr.
This equation simplifies to: S = F/m (Xf /Xr–1)
Calculation of No of Stages Requirement:
Amount of Product present after extraction (Q):
=1- (m*(Vol of Org/Vol of Aq)) /(m* (Vol of Org/Vol of Aq)+1)
No of Stages (N):
= Log (1-Efficiency)/Log (Q)
Efficiency: 99%
Page No. 82 of 87
8.3 Example for Efficient extraction

If there are 300 particles of compound and let the distribution ratio is 2 for the compound in
solvent 2 to solvent 1. For example 100 ml of solvent 2 is added in after mixing the compound
will distribute themselves in two phases with 200 particles in solvent 2 (Extract)and leaving 100
particles in solvent 1 (Raffinate).
The optimization between numbers of extractions to solvent quantity: the below pictorial
example will tell us that it is more efficient to carry out two extractions with 1/2 volume of
extraction solvent than one large volume. But more number of extractions will increase the
cycle time, so we have to optimize these two.
Figure 8.3
Page No. 83 of 87
Guideline for checking emulsification and treatment:

 Tendency to form emulsion: It may be very insignificant in lab but in plant additional
factors (like increased addition power) may cause emulsion formation.
 To check this, conduct experiment at extremes of composition i.e. high concentration of
organic compound in solvent.
 To check the mixing effect to form emulsion, conduct experiment at vigorous mixing in
lab.
 A final consideration is the position of the agitator blade relative to the phase boundary.
This can influence which phase is dispersed in which, potentially affecting the stability
of the dispersed phase.
 If an emulsion is formed methods to break the emulsion should be studied. Typical
means of breaking an emulsion include addition of either solvent or water to change the
composition, heating, filtration (to remove stabilizing entities such as tiny particles), pH
adjustment, salt addition and in rare cases addition of a demulsifier.
 Settling time (settling velocity) of phase boundary: Settling velocity of phase boundary
should be same in lab and plant. Settling time therefore will be much longer in plant vessel.
Guideline to check the settling time:

 Collect 100-200 ml volume of mixed phases in the cylindrical flask.
 Mix/shake the mixture well in the cylindrical flask.
 Allow the phases to settle.
 Note down the settling rate of the phase boundary in the extraction data sheets.
 Based on the settling rate of the phase in the cylindrical flask, settling time will be
calculated for lab vessel and plant vessel.
 Mixing: Adequate mixing needed to properly mix the phases and equilibrate compositions.
Excessive agitation may promote stable emulsion formation. Determine at-scale blend time
to ensure that phases will be adequately mixed. To know the other extreme, allow the
process by mixing as vigorously as possible to check the formation of emulsions.
Page No. 84 of 87
 Ability to catch the split of boundary: It is easy to see the phase boundary in lab glass
reactors but may be difficult to see through small sight glass in plant scale. Mass meters can
be employed to detect the density difference to determine the split. Another precaution (for
phases which are having same color and opacity) is to calculate the expected phase volumes
before plant run, so that the rate of discharge can be adjusted depending on how close the
phase boundary is.
 Rag layer: Minimal or not seen in lab, but at significant volume may present at plant scale.
We must determine disposition of rag layer in advance, its inclusion can affect purity and
exclusion can affect yield. Generally rag layer is kept with the product phase, except for the
final phase split.
Page No. 85 of 87
8.4 Scale up approach for extraction
Assemble data and physical properties
Extraction lab test

Measure P/V value
Measure Kla value
Measure settling time /unit liquid depth
Is layer
separation
clear?
check phase
continuity/solvent qty
No
Yes
No
Yes Conduct PP trials and

Pilot trial required ?
compare with lab data
Yes
Commercial T&V batches
compare data with Lab,PP,commercial

T&V
END
NOTES : 1. KEEP FLUID FLOW IN TURBULENT ZONE

2. USE BAFFLED VESSEL ONLY
3. USE PROPELLER / PBT (OTHER AGITATORS WITH AXIAL FLOW)
4. ESTIMATE Kla EXPERIMENTALLY
Figure 8.4
Page No. 86 of 87
9. Others:
Angle of Repose:
Page No. 87 of 87

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ANNEXURE TM-APE-001-A01 Effective date: 01.03.2012

TITTLE STANDARD SCALE UP PRINCIPLES AND CALCULATIONS