Introduction to Mixing Equipment and Processes in Pharmaceutical Operations Piero M. Armenante 2008 © Special Topics - Modules in Pharmaceutical Engineering

Introduction to Mixing Equipment and Processes in Pharmaceutical Operations Piero M. Armenante 2008 Special Topics - Modules in Pharmaceutical Engineering ChE 702

Piero M. ArmenanteChE7022 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

Piero M. ArmenanteChE7023 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

Piero M. ArmenanteChE7024 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

Piero M. ArmenanteChE7026 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

Piero M. ArmenanteChE7027 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)

Piero M. ArmenanteChE7028 Example of Mixing Tanks/Reactors

Piero M. ArmenanteChE7029 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

Piero M. ArmenanteChE70210 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

Piero M. ArmenanteChE70211 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)

Piero M. ArmenanteChE70212 Examples of Typical Pharmaceutical Mixing Applications Blending Precipitation and Crystallization Chemical reaction Fermentation Solid-liquid suspension Liquid-liquid emulsification Gas sparging

Piero M. ArmenanteChE70213 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

Piero M. ArmenanteChE70214 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

Piero M. ArmenanteChE70215 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) Mixing as an Objective or a Means to an End

Piero M. ArmenanteChE70216 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) Mixing as an Objective or a Means to an End

Piero M. ArmenanteChE70217 Mixing as an Objective or a Means to an End 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

Piero M. ArmenanteChE70218 Example: interfacial mass transfer Mixing as a Means to an End C interface C bulk A kLkL

Piero M. ArmenanteChE70219 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 ( V L, C) specific interfacial area (a v ), and overall interfacial area (A) mass transfer coefficient at the interface (k L ) Mixing as a Means to an End

Piero M. ArmenanteChE70220 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

Piero M. ArmenanteChE70221 Classification of Mixing Processes

Piero M. ArmenanteChE70222 Mass Transfer Operations in Mixing Processes

Piero M. ArmenanteChE70223 Reactions in Mixing Processes

Piero M. ArmenanteChE70224 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

Piero M. ArmenanteChE70225 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)

Piero M. ArmenanteChE70226 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

Piero M. ArmenanteChE70228 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

Piero M. ArmenanteChE70229 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)

Piero M. ArmenanteChE70230 Mechanically Stirred Tanks and Reactors Baffle Motor Gearbox Shaft Impeller

Piero M. ArmenanteChE70231 Drive (Motor-Gearbox) Assembly After Chemineer

Piero M. ArmenanteChE70232 Mechanically Stirred Tanks and Reactors: Symbols D T H CbCb B

Piero M. ArmenanteChE70233 Mechanically Stirred Tanks and Reactors: Symbols T H CbCb S 23 S 12

Piero M. ArmenanteChE70234 Tank shape = cylindrical (occasionally square cross section) T = Internal diameter of tank H T = Internal height of tank H = Z = Liquid height B = Baffle width Mechanically Stirred Tanks: Nomenclature

Piero M. ArmenanteChE70235 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

Piero M. ArmenanteChE70236 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)

Piero M. ArmenanteChE70237 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)

Piero M. ArmenanteChE70238 Typical Baffle Arrangement in a Stirred Tank Baffle

Piero M. ArmenanteChE70239 Typical Baffle Arrangement in a Glass-Lined Tank De Dietrich Vessel Single Baffle

Piero M. ArmenanteChE70240 Baffles and Vortexing Baffled tank: No vortex Unbaffled tank: Vortex

Piero M. ArmenanteChE70241 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

Piero M. ArmenanteChE70242 Impellers After Oldshue, 1984

Piero M. ArmenanteChE70243 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)

Piero M. ArmenanteChE70244 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.

Piero M. ArmenanteChE70245 Radial Impellers Common types include: Rushton turbine (6-blade disk turbine) paddle flat-blade turbines curve-blade turbine retreat-blade turbine Smith impeller

Piero M. ArmenanteChE70246 Examples of Radial Flow Impellers After Tatterson, 1991

Piero M. ArmenanteChE70247 Examples of Radial Flow Impellers Disk Turbine (Rushton Turbine)

Piero M. ArmenanteChE70248 Examples of Radial Flow Impellers Flat-blade turbine (Source: Chemineer)

Piero M. ArmenanteChE70249 Example of Radial Flow Impeller for High Shear Applications R500 Sawtooth Impeller (Source: Lightnin)

Piero M. ArmenanteChE70250 Example of Radial Flow Impeller for Gas Dispersion Concave-Blade Turbine (Smith Turbine)

Piero M. ArmenanteChE70251 Example of Radial Flow Impeller for Gas Dispersion Concave-Blade Turbine (Smith Turbine)

Piero M. ArmenanteChE70252 Flow Generated by Radial Impellers

Piero M. ArmenanteChE70253 Flow Generated by a Radial Impeller in a Stirred Tank After Tatterson, 1991

Piero M. ArmenanteChE70254 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.

Piero M. ArmenanteChE70255 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

Piero M. ArmenanteChE70256 Constant vs. Variable Pitch Constant Pitch (Variable angle of attack) Variable Pitch (Constant angle of attack) After Oldshue, 1984

Piero M. ArmenanteChE70257 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)

Piero M. ArmenanteChE70258 Examples of Axial Flow Impellers After Tatterson, 1991

Piero M. ArmenanteChE70259 Examples of Axial Flow Impellers Pitched-Blade Turbine

Piero M. ArmenanteChE70260 Example of Axial Flow (Hydrofoil) Impeller Chemineer SC-3 Impeller

Piero M. ArmenanteChE70261 Example of Axial Flow (Hydrofoil) Impeller Chemineer HE-3 Impeller

Piero M. ArmenanteChE70262 Example of Axial Flow (Hydrofoil) Impeller Chemineer HE-3 Impeller

Piero M. ArmenanteChE70263 Example of Axial Flow (Hydrofoil) Impeller Maxflow W Impeller

Piero M. ArmenanteChE70264 Example of Glassed Impellers De Dietrich GlasLock System

Piero M. ArmenanteChE70265 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)

Piero M. ArmenanteChE70266 Flow Generated by an Axial Impeller in a Stirred Tank After Tatterson, 1991

Piero M. ArmenanteChE70267 Close-Clearance Impellers Close-clearance impellers are primarily used with high-viscosity fluids 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.

Piero M. ArmenanteChE70268 Close-Clearance Impellers Common close-clearance impeller types include: anchors helical ribbons gates kneaders Z- and sigma-blade impellers

Piero M. ArmenanteChE70269 Examples of Close Clearance Impellers Anchor Impeller (Source: Chemineer)

Piero M. ArmenanteChE70270 Examples of Close Clearance Impellers After Oldshue, 1984

Piero M. ArmenanteChE70271 Examples of Close Clearance Impellers After Oldshue, 1984

Piero M. ArmenanteChE70272 Examples of Close Clearance Impellers Double Helical Ribbon Impeller (Source: Chemineer)

Piero M. ArmenanteChE70273 Examples of Close Clearance Impellers Auger Impeller (Source: Chemineer)

Piero M. ArmenanteChE70274 Examples of Close Clearance Impellers After Tatterson, 1991

Piero M. ArmenanteChE70275 Examples of Close Clearance Agitation System

Piero M. ArmenanteChE70276 Blending Capabilities of Different Impellers

Piero M. ArmenanteChE70277 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

Piero M. ArmenanteChE70278 Characteristics of Common Radial Impellers 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.

Piero M. ArmenanteChE70279 Characteristics of Common Radial Impellers 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

Piero M. ArmenanteChE70280 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

Piero M. ArmenanteChE70281 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

Piero M. ArmenanteChE70282 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 2510 6 cP) Gates. Used in large squat tanks. Kneaders, Z- and sigma-blade impellers. Used to mix pastes

Piero M. ArmenanteChE70283 D = Impeller diameter C = Impeller clearance off the tank bottom measured from the impeller center C b = Impeller clearance off the tank bottom measured from the bottom of the impeller S ij = distance between i and j impellers Impellers: Nomenclature

Piero M. ArmenanteChE70284 L = Impeller blade length w = Impeller blade width w b = Impeller blade width projected along the vertical axis S ij = distance between impellers i and j = Blade angle of attack (if constant) Pitch Impellers: Nomenclature

Piero M. ArmenanteChE70285 Rushton Turbine L/D=1/4 w/D=1/5 Disk diameter= 3/4D or 2/3 D

Piero M. ArmenanteChE70286 45 Pitched-Blade Turbine

Piero M. ArmenanteChE70287 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

Piero M. ArmenanteChE70288 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

Piero M. ArmenanteChE70289 Jet Mixer External recirculation line Pump

Piero M. ArmenanteChE70290 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.

Piero M. ArmenanteChE70291 Axial Jets in Mixing Tanks Poorly mixed zone

Piero M. ArmenanteChE70292 Angled Jets in Mixing Tanks Poorly mixed zone

Piero M. ArmenanteChE70293 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

Piero M. ArmenanteChE70294 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.

Piero M. ArmenanteChE70295 Example of a Dynamic In-Line Mixer

Piero M. ArmenanteChE70296 Example of In-Line, High Shear, Homogenizing Mixer Greerco (Chemineer)

Piero M. ArmenanteChE70297 Example of a Two-Stage Rotor Stator for In-Line High Shear Mixer Greerco (Chemineer)

Piero M. ArmenanteChE70298 Applications of Dynamic In-Line Mixers After Oldshue, 1984

Piero M. ArmenanteChE70299 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.

Piero M. ArmenanteChE702100 Static Mixers Source: Chemineer

Piero M. ArmenanteChE702101 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

Piero M. ArmenanteChE702102 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.

Piero M. ArmenanteChE702103 Static Helical Mixer for Laminar Flow After Myers et al., Chem. Eng. June 1997

Piero M. ArmenanteChE702104 Static Helical Mixer for Laminar Flow

Piero M. ArmenanteChE702105 Static Helical Mixer for Laminar Flow

Piero M. ArmenanteChE702106 Static Mixers for Turbulent 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

Piero M. ArmenanteChE702107 Static Vortex Mixer for Turbulent Flow

Piero M. ArmenanteChE702108 Static Vortex Mixer for Turbulent Flow Source: Chemineer

Piero M. ArmenanteChE702109 Static Vortex Mixer for Turbulent Flow After Myers et al., Chem. Eng. June 1997

Piero M. ArmenanteChE702110 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.

Piero M. ArmenanteChE702111 High-Shear Equipment High shear equipment include: (high speed) rotor-stator devices valve homogeneizers, such as: valve homogeneizers ultrasonic homogenizers

Piero M. ArmenanteChE702112 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.

Piero M. ArmenanteChE702113 High-Speed, High-Shear Rotor-Stator Mixer

Piero M. ArmenanteChE702114 Example of High-Speed, High- Shear Rotor-Stator Mixer Silverson Machines, Inc.

Piero M. ArmenanteChE702117 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)

Piero M. ArmenanteChE702118 Colloid Mill Greerco (Chemineer)

Piero M. ArmenanteChE702119 Greerco (Chemineer) Colloid Mill

Piero M. ArmenanteChE702120 IKA Colloid Mill

Piero M. ArmenanteChE702121 Greerco (Chemineer) Colloid Mill

Piero M. ArmenanteChE702122 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.

Piero M. ArmenanteChE702123 Valve Homogenizer After Harnby et al., 1985

Piero M. ArmenanteChE702124 Example of Valve Homogenizer Five Star Technologies

Piero M. ArmenanteChE702125 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.

Piero M. ArmenanteChE702126 Ultrasonic Homogenizer After Harnby et al., 1985

Piero M. ArmenanteChE702127 Basic Mechanisms in Laminar Flow Mixing Laminar shear Elongation and extensional flow Distributive mixing Molecular diffusion Stresses in laminar flow

Piero M. ArmenanteChE702128 Mixing Equipment for Highly Viscous Materials Equipment for highly viscous material (such as pastes, dough, plastics) include: kneaders single-screw extruders twin-screw extruders

Piero M. ArmenanteChE702129 Double-Arm Kneader After Perry and Green, 1984

Piero M. ArmenanteChE702130 Single-Screw Extruder Feed Hopper Die

Piero M. ArmenanteChE702131 Twin-Screw Extruder

Piero M. ArmenanteChE702132 Single-Screw Extruder

Piero M. ArmenanteChE702133 Screw Design to Enhance Mixing/Compounding Capability in Single Screw Extruders

Piero M. ArmenanteChE702134 Twin-Screw Extruder with Clam-Shell Barrel Design

Piero M. ArmenanteChE702135 Gear Mixing Elements in a Twin-Screw Extruder

Piero M. ArmenanteChE702136 Kneading Paddles in a Twin- Screw Extruder

Piero M. ArmenanteChE702137 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

Documents

Introduction to Mixing Equipment and Processes in Pharmaceutical Operations Piero M. Armenante 2008 © Special Topics - Modules in Pharmaceutical Engineering