Pharmaceutical Processing and Manufacturing...

MIXING TECNOLOGIES

PAAN PHARMATECH ENGINEERS

PVT. LTD.

Mr.S. D. Botre

(Managing Director)

CELL-+919820103114

[email protected]

Together thinking engineering

out of the box

ChE702 1

Introduction to Mixing Equipment and Processes in Pharmaceutical Operations

Special Topics - Modules in Pharmaceutical EngineeringChE 702

3

Objectives

Become familiar with the principles of single and multiphase mixing in pharmaceutical processes

Analyze pharmaceutical processes or in which mixing is important

Provide basic tools to conduct process design analysis and scale-up of processes or in which mixing is important

ChE702 4

Relevant Topics

Classification of Mixing Processes and Applications

Mixing Equipment

Liquid Mixing Fundamentals

Mixing and Blending in Low Viscosity Liquids

High Viscosity Mixing in Stirred Tanks

Mass Transfer and Mixing

Solid-Liquid Mixing

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Relevant Topics (continued)

Liquid-Liquid Mixing

Gas-Liquid Mixing

Mixing and Chemical Reactions

Heat Transfer

Jet Mixing

In-Line Mixing

Mechanical Aspects of Mixing Systems

Special Topics and Applications

Classification of Mixing Processes and Applications

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Instructional Objectives of This Section

By the end of this section you will be able to:

Identify basic mixing classes

Develop an appreciation for the importance of mixing in industry

Provide examples of common pharmaceutical mixing processes

ChE702 8

Definition of Mixing

Textbook definition:

The term “mixing” refers to all those operations that tend to reduce non-uniformity in one or more of the properties of a material in bulk (e.g., concentration, temperature)

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Example of Mixing Tanks/Reactors

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Definition of Fluid Mixing

“Fluid mixing” refers to mixing operations in which the continuous phase is a fluid

Although a gas can be used as a fluid (e.g., fluidization) a liquid is typically the continuous phase in fluid mixing processes

In the rest of this course a liquid phase will always be the continuous phase

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Single-Phase vs. Multiphase Mixing

Single-phase mixing refers to mixing of miscible fluids. This operations is typically called “blending”

Multiphase mixing refers to mixing immiscible phases, i.e.:

solid-liquid mixing

liquid-liquid mixing

gas-liquid mixing

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Importance of Mixing in the Pharmaceutical Industry

Mixing of a fluid with other media (solids, liquids) is an extremely common operation encountered in countless applications in the pharmaceutical industry

Many pharmaceutical processes require or are greatly enhanced by:

rapid homogenization of miscible components (in single phase systems)

intimate contact between two or more distinct phases (in multiphase systems)

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Examples of Typical Pharmaceutical Mixing Applications

Blending

Precipitation and Crystallization

Chemical reaction

Fermentation

Solid-liquid suspension

Liquid-liquid emulsification

Gas sparging

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Economic Impact of Mixing-Related Problems

The impact of poor mixing on industrial applications has been estimated to be at 1-10 billion $/year (1989)

The additional economic impact associated with scale-up and start up problems, waste material and by-products generation has not been estimated yet

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Mixing as an Objective or a Means to an End

There are operations where mixing itself is the objective of the process

These operations are required to produce homogenization of a system or a product

Examples:

Blending of gasoline in large storage tanks

Dispersion of pigments in paint

Uniform and stable suspension of API particles in an oral liquid dosage form

Formation of stable liquid-liquid emulsions

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However, in most pharmaceutical processes involving mixing, mixing is just a means to achieve a process objective

In this case mixing is typically required to effectively conduct a primary process (NOT to be limited by mixing)


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Examples of processes possibly affected by mixing:Dissolution of an intermediate in a stirred vessel

prior to reaction (mass transfer) Precipitation of API or intermediate (crystallization)Minimization of impurity formation during

synthesis of a drug product (parallel/consecutive homogeneous reaction)

Suspension of a catalyst during heterogeneous catalysis (mass transfer + heterogeneous reaction)

Preparation of nano/micro-particles or droplets of desired particle size distribution (particle size control)

Achievement of a uniform temperature in a crystallizer and temperature control (heat transfer)


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Mixing operation may involve:

single phase liquids (e.g., blending of miscible solutions, fast chemical parallel reactions and impurity formation)

multiphase systems (e.g., solid dispersion/suspension, emulsification)

Mixing can improve both single-phase and mulpiphase processes

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Example: interfacial mass transfer

CVakCCAkm LvLbulkinterfaceL

Mixing as a Means to an End

Cinterface

Cbulk

A

kL

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Example: interfacial mass transfer

Mixing affects: state of dispersion or suspension of the

dispersed phase, i.e., degree of macroscopic homogeneity of the dispersed phase throughout the continuous phase ( VL, C)

specific interfacial area (av), and overall interfacial area (A)

mass transfer coefficient at the interface (kL)

CVakCCAkm LvLbulkinterfaceL

Mixing as a Means to an End

ChE702 21

Mass Transfer Operations in Mixing Processes

All mass transfer processes are enhanced by:

high mass transfer coefficients

large interfacial area

Mixing can contribute to achieve both

However, most mixing operations are associated with the generation of interfacial (contact) area

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Classification of Mixing Processes

System Operation

Homogeneous liquid

Pumping, recirculation, heat transfer

Miscible liquids Blending

Solid-liquid Suspension

Liquid-liquid (immiscible liquids)

Dispersion

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Mass Transfer Operations in Mixing Processes

System Mass Transfer Operation

Homogeneous liquid

-

Miscible liquids Turbulent and molecular diffusion

Solid-liquid Adsorption, ion exchange leaching, dissolution

Liquid-liquid (immiscible liquids)

Extraction

Gas-liquid Absorption, stripping

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Reactions in Mixing Processes

System Reaction

Homogeneous liquid

-

Miscible liquids Homogeneous reaction

Solid-liquid Heterogeneous reaction, catalysis, precipitation,

crystallization Liquid-liquid

(immiscible liquids) Heterogeneous reaction

Gas-liquid Gas-liquid reaction

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Single vs. Multiple Mixing Requirements

Mixing problems can involve:a single mixing requirement (e.g.,

suspend solids)

multiple simultaneous mixing requirements (e.g., suspend solids, homogenize liquid phase, promote solid-liquid mass transfer, transfer heat)

Even multiple requirements are typically satisfied by the use of a single impeller

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Example of Multiple Mixing Requirements: Crystallizers

In crystallizers a successful process depends on:

heat transfer (for supersaturation)

bulk blending (for homogenization)

solids suspension (for crystal growth)

effective mass transfer (for crystal growth)

possible gas removal (boiling systems)

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Critical Mixing Process

Whenever a process involving a mixing operation is analyzed one should ask:

is mixing a critical component of the process?

if multiple, simultaneous mixing requirements are present which one is the most critical?

Mixing Equipment

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By the end of this section you will be able to:

Identify basic types of mixing equipment

Describe main components of mixing equipment

Describe main features and characteristics of mixing equipment

Instructional Objective of This Section

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Classification of Mixing Equipment

Mixing is typically conducted with:

mechanically stirred tanks

jet mixed tanks

in-line dynamic mixers

in-line static mixers

high-shear mixing equipment

mixing equipment for highly viscous materials (e.g., polymers)

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Mechanically Stirred Tanks and Reactors

Baffle

Motor

Gearbox

Shaft

Impeller

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Drive (Motor-Gearbox) Assembly

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Mechanically Stirred Tanks and Reactors: Symbols

D

T

H

Cb

B

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Mechanically Stirred Tanks and Reactors: Symbols

T

H

Cb

S23

S12

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Tank shape = cylindrical (occasionally square cross section)

T = Internal diameter of tank

HT = Internal height of tank

H = Z = Liquid height

B = Baffle width

Mechanically Stirred Tanks: Nomenclature

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Shape of tank bottom (flat, dished, conical, hemispherical)

Baffle length (full, half)

Number of baffles

Baffle position

Gap between baffles and tank (B)

Gap between baffles and tank bottom

Mechanically Stirred Tanks : Other Geometric Characteristics

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Baffles

Baffles are typically introduced to prevent vortex formation and convert tangential (rotational) flow into axial (vertical) flow

Baffles are always used in turbulent flow systems (low viscosity fluids)

Baffles are not used in laminar flow (high viscosity fluids)

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Baffles

Typically four baffles are used (occasionally three) in fully baffled tanks

In glass-lined tanks a single baffle placed midway between the tank wall and the impeller may be used

A gap between the baffles and the wall is introduced to prevent stagnation behind the baffles and accumulation of material (e.g., solids)

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Typical Baffle Arrangement in a Stirred Tank

Baffle

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Typical Baffle Arrangement in a Glass-Lined Tank

Single

Baffle

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Baffles and Vortexing

Baffled tank:

No vortex

Unbaffled tank:

Vortex

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The “Standard” Tank

H/T = 1

D/T = 1/3

C/D = 1

B/T = 1/10 (academic) or 1/12 (industry)

Number of baffles = 4

Baffle length = full

B/T =1/72 or 1/100

Bottom shape = flat

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Impellers

After Oldshue, 1984

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Impeller Types

Impeller can be classified as follows:

radial impellers (e.g, Rushton turbines, paddles, flat-blade turbines, Smith impellers)

axial impellers (e.g., marine propellers, pitched-blade turbines, fluidfoil impellers such as HE-3s, A-310s)

close-clearance impeller (e.g., anchors, helical ribbons, gates)

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Radial Impellers

Radial impellers pump radially.

They are used primarily with low-viscosity liquids in baffled tanks.

Disk turbines can be used for gas dispersion.

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Radial Impellers

Common types include:

Rushton turbine (6-blade disk turbine)

paddle

flat-blade turbines

curve-blade turbine

retreat-blade turbine

Smith impeller

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Examples of Radial Flow Impellers

After Tatterson, 1991

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Disk Turbine (Rushton Turbine)

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Flat-blade turbine (Source: Chemineer)

Piero M. Armenante ChE702 50

Example of Radial Flow Impeller for High Shear Applications

R500 Sawtooth Impeller (Source: Lightnin)

Piero M. Armenante ChE702 51

Example of Radial Flow Impeller for Gas Dispersion

Concave-Blade Turbine (Smith Turbine)

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Example of Radial Flow Impeller for Gas Dispersion

Concave-Blade Turbine (Smith Turbine)

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Flow Generated by Radial Impellers

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Flow Generated by a Radial Impeller in a Stirred Tank


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Axial Impellers

Axial impellers pump primarily (but not exclusively) vertically, either upwards or downwards.

They are used mainly with low-viscosity liquids in baffled tanks.

They are typically used in a downpumping mode.

High-solidity impellers are used with gas.

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Pitch Ratio in Axial Impellers

The pitch-to-diameter ratio (or “pitch ratio”) is the ratio of the distance the impeller would advance per rotation to the impeller diameter

In constant pitch impellers (e.g., propellers) the angle of attach changes along the blade; in variable pitch impellers (e.g, 45° pitched-blade turbine) the angle is constant

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Constant vs. Variable Pitch

Constant Pitch

(Variable angle

of attack)

Variable Pitch

(Constant angle

of attack)

After Oldshue, 1984

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Axial Impellers

Common types include:

marine propeller

pitched-blade turbine

fluidfoil impeller (e.g., Chemineer HE3, Lightning A-310)

high-solidity ratio impellers (e.g., Prochem)

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Examples of Axial Flow Impellers


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Examples of Axial Flow Impellers

Pitched-Blade Turbine

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Example of Axial Flow (Hydrofoil) Impeller

Chemineer SC-3 Impeller

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Chemineer HE-3 Impeller

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Chemineer HE-3 Impeller

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Maxflow W Impeller

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Example of Glassed Impellers

De Dietrich

GlasLock System

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Flow Generated by Axial Impellers

Flow generated by

true axial impellers

(~propeller, A-310, HE-3)

Flow generated by

mixed-flow impellers

(e.g., 45° pitched-

blade turbine)

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Flow Generated by an Axial Impeller in a Stirred Tank


ChE702 68

Close-Clearance Impellers

Close-clearance impellers are primarily used with high-viscosityfluids in unbaffled tanks.

Close-clearance impellers scrape fluid off the tank wall and off the impeller.

They generate a complex flow pattern and have a pumping action similar to that of a displacement pump.

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Close-Clearance Impellers

Common close-clearance impeller types include:

anchors

helical ribbons

gates

kneaders

Z- and sigma-blade impellers

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Examples of Close Clearance Impellers

Anchor Impeller

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Double Helical Ribbon Impeller

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Auger Impeller

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Examples of Close Clearance Agitation System

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Blending Capabilities of Different Impellers

Impeller Viscosity Range

Open Impellers < 100,000 cP

- Propellers < 200 cP

- Turbines < 5000 cP

- Paddles < 100,000 cP

Anchors < 50,000

Helical Ribbons > 30,000

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Characteristics of Common Radial Impellers

Rushton turbines (Disk turbine, R-100). Strong radial flow, high power consumption, significant shear, good for gas dispersion

Smith impeller. Similar in performance to Rushton turbine, but particularly well suited for gas dispersion

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Paddles. Simple and inexpensive, medium-to-strong radial flow and shear, intermediate power consumption, good for simple applications at small-to-medium scales

Flat-blade turbines. Similar to paddles but with stronger radial flow power, consumption, and shear. Used in transition flow.

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Curve-blade turbine. Similar to flat-blade turbines

Retreat-blade impeller (Pfaudler, De Dietrich types). Simpler construction suitable for glass-lined vessels; reduced power and flow

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Characteristics of Common Axial Impellers

Marine propeller (A-100). Oldest constant-pitched impeller, usually cast (cannot be easily inserted in a manhole), expensive, low power consumption, high pumping rate

Pitched-blade turbine (A-200).Very common, simple, usually 45°, effective for solid suspension; mixed flow; medium power consumption, good pumping rate

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Characteristics of Common Axial Impellers

Fluidfoil impellers. Many types exist (Chemineer HE-3, Lightning A-310); expensive, near constant pitch for improved axial flow, low power consumption, high pumping rate

High-solidity ratio impellers.Many types exist (e.g., Maxchem); low-to-medium power consumption, high pumping rate, “streamlined”

ChE702 83

Characteristics of Common Close-Clearance Impellers

Anchor impellers (A-400). Good for blending and heat transfer for liquids with 5000 cP < < 50,000 cP

Helical ribbon. Good for blending high viscosity liquids (up to 25·106

cP)

Gates. Used in large “squat” tanks.

Kneaders, Z- and sigma-blade impellers. Used to mix pastes

ChE702 84

D = Impeller diameter

C = Impeller clearance off the tank bottom measured from the impeller center

Cb = Impeller clearance off the tank bottom measured from the bottom of the impeller

Sij = distance between i and jimpellers

Impellers: Nomenclature

ChE702 85

L = Impeller blade length

w = Impeller blade width

wb = Impeller blade width projected along the vertical axis

Sij = distance between impellers i and j

= Blade angle of attack (if constant)

Pitch

Impellers: Nomenclature

ChE702 86

Rushton Turbine

L/D=1/4

w/D=1/5

Disk diameter=

3/4·D or 2/3 ·D

ChE702 87

45° Pitched-Blade Turbine

ChE702 88

Typical Ranges for Geometric Variables

T = 0.1 m to 10 m (0.3’-33’)

H/T = 0.3 to 1.2 for single impeller systems

D/T = 1/5 to 2/3

C/D 1

B/T = 1/10 to 1/12

ChE702 89

Jet Mixers

Jet mixers rely on the use of a jet, i.e., a stream of liquid injected at high velocity in the bulk of another miscible liquid.

This is typically achieved with an external recirculation pump

Jet mixers are used in:

tanks

tubes and pipes

ChE702 90

Jet Mixer

External recirculation line

Pump

ChE702 91

Jet Mixers in Tanks

Jet mixers are typically used in large tanks.

Jet mixers are used for blending purposes (e.g., gasoline) or to suspend solids in unusual processes (e.g., radioactive material slurry).

Typically one or more jets are placed at an angle to provide good recirculation.

ChE702 92

Axial Jets in Mixing Tanks

Poorly mixed zone

ChE702 93

Angled Jets in Mixing Tanks

Poorly mixed zone

ChE702 94

In-Line Mixers

In-line mixers are small mixing devices placed in the same line where the materials to be mixed are flowing.

Two types of in-line mixers exist:

dynamic mixers, where the mixing energy is provided from the outside

static (motionless) mixers where the fluid itself provides the mixing energy

ChE702 95

In-Line Dynamic Mixers

In-line dynamic mixers consist of small high-speed mixers placed inside a casing fed with a continuous stream of the materials to be mixed.

The residence time of in-line mixers is usually of the order of seconds.

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Example of a Dynamic In-Line Mixer

ChE702 97

Example of In-Line, High Shear, Homogenizing Mixer

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Example of a Two-Stage Rotor Stator for In-Line High Shear Mixer

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Applications of Dynamic In-Line Mixers

ChE702 100

In-Line Static Mixers

Static mixers consist of mirror image inserts (elements) placed inside a pipe, capable of altering the fluid flow, and rearranging the distribution of fluid elements across the pipe cross section.

Static mixers are only capable of homogenizing the content of the pipe across its cross section but not along its length.

ChE702 101

Static Mixers

Source: Chemineer

ChE702 102

Classification of Static Mixers

Static mixers are classified according to the flow regime under which they operate.

Static mixers are available for:

laminar flow

transitional flow

turbulent flow

ChE702 103

Static Mixers for Laminar Flow

In laminar flow the only mechanism for radial mixing is molecular diffusion.

Each element in a laminar static mixers typically produces spit and a rotation (90°or 180°) of the flow, which is then fed to the next element.

Such actions result in further sub-divisions of the flow and the generation of striations leading to mixing.

ChE702 104

Static Helical Mixer for Laminar Flow

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Static Mixers forTurbulent Flow

In turbulent flow, turbulent eddies are responsible for radial mixing

Flow in open pipes produces radial mixing if enough pipe length is provided (at least 100 pipe diameters)

Static mixers for turbulent flow rely on vortex generation to produce mixing

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Static Vortex Mixer forTurbulent Flow

ChE702 109


Source: Chemineer

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ChE702 111

High-Shear Mixing Equipment

High-shear mixers are devices used to generate high velocity gradients across small distances (resulting in high shear stress and shear rates) in order to disperse, break up, or homogenize a second immiscible phase.

Different devices base on different physical mechanisms are used to produce high shear.

ChE702 112

High-Shear Equipment

High shear equipment include:

(high speed) rotor-stator devices

valve homogeneizers, such as:

valve homogeneizers

ultrasonic homogenizers

ChE702 113

High-Speed, High-Shear Rotor-Stator Mixer

High-speed rotor-stator mixers are devices in which a rotor rotates at high speed inside a casing provided with slots. A small gap exists between the rotor and the stator.

As the liquid (and its dispersed phase) move through the rotor-stator assembly they are subjected to high shear, resulting in break up effects.

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High-Speed, High-Shear Rotor-Stator Mixer

ChE702 115

Example of High-Speed, High-Shear Rotor-Stator Mixer

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Colloid Mills

Colloid mills are in-line machines designed to finely homogenize, disperse solids, and emulsify immiscible liquids

Mixing head consist of a rotor and a stator separated by an extremely small gap (0.001-0.03 in.)

Stirring speed are usually extremely high (2000-14,000 rpm)

Flow rates are usually small (as a result of the small rotor-stator gap)

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Colloid Mill

ChE702 120

Colloid Mill

ChE702 121

Colloid Mill

ChE702 122

Colloid Mill

ChE702 123

Valve Homogenizers

Valve homogenizers pump material at high pressure (30-500 bar) through small orifices.

The high velocity in the orifices produces high shear.

The equipment operates in line and can be used to produce emulsions, dispersion, and suspensions.

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Valve Homogenizer

ChE702 125

Example of Valve Homogenizer

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Ultrasonic Homogenizers

Ultrasonic homogenizers pump material at high pressure (up to 150 bar) through a small orifice placed in front of a vibrating ultrasonic blade.

The high velocity in the orifice produces high shear, and the blade produces microcavitation that results in emulsions, dispersion, and suspensions of the dispersed phase.

ChE702 127

Ultrasonic Homogenizer

ChE702 128

Basic Mechanisms in Laminar Flow Mixing

Laminar shear

Elongation and extensional flow

Distributive mixing

Molecular diffusion

Stresses in laminar flow

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Mixing Equipment for Highly Viscous Materials

Equipment for highly viscous material (such as pastes, dough, plastics) include:

kneaders

single-screw extruders

twin-screw extruders

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Double-Arm Kneader

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Single-Screw Extruder

Feed

Hopper

Die

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Twin-Screw Extruder

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Single-Screw Extruder

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Screw Design to Enhance Mixing/Compounding Capability in Single Screw Extruders

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Twin-Screw Extruder with Clam-Shell Barrel Design

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Gear Mixing Elements in a Twin-Screw Extruder

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Kneading Paddles in a Twin-Screw Extruder

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Final Remarks About Impellers

No universal “optimal” impeller design exists

Each process needs to be analyzed to determine what are the controlling mechanisms

Impellers can be designed to optimize the process

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