Table Of ContentA Unique Handbook for the
Chemical Process Industry
Francis X. McConville
F XM E N G I N E E R I NG A ND D E S I GN
W O R C E S T ER M A S S A C H U S E T TS
The Pilot Plant Real Book
A Unique Handbook for the Chemical Process Industry
by Francis X. McConville
Published by:
FXM Engineering and Design
6 Intervale Road
Worcester MA 01602
www.fxmtech.com
All rights reserved. No part of this book may be reproduced or transmitted in any form or by any electronic or
mechanical means, including photocopying, without written permission of the author.
© Copyright 2002 by Francis X. McConville
ISBN Printed First Edition
First Printing 2002
Publisher's Cataloging-in-Publication
(Provided by Quality Books, Inc.)
McConville, Francis X.
The pilot plant real book : a unique handbook for the
chemical process industry / Francis X. McConville.—
1st. ed.
p. cm.
Includes bibliographical references and index.
LCCN 2002108236
ISBN 0-9721769-1-8
1. Chemical plants—Pilot plants—Handbooks, manuals,
etc. 2. Chemical processes—Handbooks, manuals, etc.
3. Chemistry, Technical—Handbooks, manuals, etc.
I. Title
V
TP155.5.M33 2002 660'.28072
QBI02-200782
Disclaimer
The information presented in this book has been collected from sources believed to be reliable, and
while every reasonable effort has been made to verify its accuracy, no guarantee is stated or implied.
Advice and recommendations contained herein are not a substitute for sound engineering design or the
specific instructions provided by the manufacturers or suppliers of the various equipment or materials
discussed. The publisher assumes no responsibility in this regard. The end user is solely responsible for
determining the suitability of the information provided for his or her intended purpose and is strongly
urged to seek qualified professional advice as necessary.
ii
Author's Preface
Is it more efficient to operate a distillation at atmospheric pressure or under vacuum?
What's the difference between a single-phase and a three-phase motor?
What's a Haz-Op?
What's a Class 1, Div. 1 solvent?
What's the difference between a thermocouple and an RTD?
What's an intrinsically safe circuit?
What are the best solvents for azeotropic removal of water?
What happens to an azeotrope under vacuum?
What's a Friedel-Crafts reaction?
These are typical of the questions I often faced as a process engineer fresh from graduate school - questions easily
answered by someone experienced in the field, but which frequently sent me digging into a veritable library of books
and articles on wide-ranging subjects to get a simple answer. So much fundamental information that I thought should be
at my fingertips lay deeply buried in huge handbooks or obscure references.
Thus was the idea for this book born. I have endeavored to collect here, in one convenient place, the information most
often called for by chemists and engineers working in process development. Hence the volume is rich with physical
property data, information on processing equipment, formulas, tips and techniques, and safety recommendations.
Monographs discuss many important aspects of chemical processing and development, and pilot plant operation.
Materials and piping data help ensure that "jury-rigging" temporary pilot setups need never compromise safety.
But this has evolved from a mere handbook to a work that I hope will also help fill a major gap between those who
discover new chemical processes and those whose job it is to scale them up to commercialization. Because of what I see
as a failure of the education system today, graduating chemists and engineers are often ill-prepared for the unique
challenges that are part and parcel of process scale-up. Therefore, I have included detailed suggestions for developing
chemical processes that will be more easily transferred from lab to plant, lists of do's and don'ts in chemical develop
ment, and advice for improving communication across the development organization.
When asked by a colleague who my intended audience was, I had to confess that I wrote the book for myself - and for
technology transfer specialists just like me whose responsibilities straddle the fence between chemistry and engineering.
Process development is a highly interdisciplinary effort and the most successful processes are developed through close
cooperation between various areas of technology. Chemists, for example, need to have an appreciation for phenomena
such as heat transfer and mixing effects to develop scalable processes, whereas some "chemistry" problems can be
solved, and some routes possibly rescued, by creative engineering solutions. The development chemists are intimately
aware of the critical processing steps, and the experienced engineers understand the limitations of plant equipment.
Communication is key to keeping the team working towards a common goal, and the broader a person's perspective is,
the more valuable will be his or her input. There is a definite advantage to being a "jack-of-all-trades" in the field of
process development.
It's often an educational, and sometimes surprising, experience for a chemist or engineer to bring a carefully tuned
process to the floor of the pilot plant for the first time - to "scale it up" as we say. Things do not always scale up as
expected. Operations are usually much more involved and take much longer than at the lab bench. The potential
hazards are greater, as are the economic consequences of a failed batch. And this works both ways. Technicians who
operate pilot plant equipment may be baffled by the chemistry of the process they are operating. But a broad knowledge
iii
base is the common denominator that can bridge the gap and facilitate what can sometimes be a very involved process.
Although this book is specifically geared to development and scale-up personnel, there is enough material here of
general technical interest to make the book useful to anyone involved in the chemical sciences. In an effort to reach a
broad readership, I have tried to keep the complex mathematics and engineering treatments to a minimum, and provided
references for further study as appropriate.
The Table of Contents on page ν will help familiarize readers with the overall content of the book. Since my guiding
principle has been to make it easy for readers to find what they need, I have also included more detailed tables of
contents for each individual chapter, an exhaustive index, and section tabs as guides. Bibliographic references and
recommended reading list follow Chapter 11. References are indicated by bracketed numerals throughout the text. A list
of common governing agency acronyms is also provided in Chapter 11.
I apologize in advance for the use of English Engineering units, which, unfortunately, are still widely used in many areas
of American technology. I have attempted to provide both metric and English units where space and practicality allowed.
The unique format of the conversion factors provided in Chapter 11 should simplify conversion between unit systems. I
also apologize for any repetition. Some is deliberate, since I feel that certain important concepts bear repeating.
Readers are encouraged to report errata or omissions, fill in holes in the data, download templates, check for updates, or
make suggestions for future editions at our website www.pprbook.com. Please contact me through the site if you feel
you have information that would make a useful addition. Your comments are always welcome.
The name? For decades, aspiring young jazz musicians who wanted to sit in on sessions had to master the "Real Book",
a bootleg, photocopied collection of the great jazz standards - all the songs anyone needed to know in one place. I hope
that, in the same spirit, this book will put at your fingertips the information you need to help you perform your work
more efficiently.
Thanks for reading.
-Francis X. McConville
Acknowledgments
I would like to acknowledge a number of people who guided and advised me along the way: my friend
and colleague, Walter Crockett, for his editorial comments and encouragement; my technical editor, Jon
Thunberg, formerly of Hampshire Chemical Corporation; my proofreader, Janice Morgan Jones; my
former colleagues, Robert Prytko, Kostas Saranteas and Roger Bakale of Sepracor, Inc., for their
suggestions and additions; the many organizations who offered information or granted me permission to
reprint material - MG Industries, Victor Specialty Products, Pfaudler, Inc., Dow Chemical Co., H. S.
Martin Glass Co., Buchi GlasUster, Chemical Transfer Partnership Corp. and Martell Associates; the
folks at Mercantile Press; all the family and friends who offered their support; and especially my wife,
Evelyn, for her infinite patience.
iv
Contents
1 The Pilot Plant
Role of the Plant · Factors in Scale-Up · Some Do's and Don'ts · Tips for Developing Scalable
Reactions · Calorimetry/Safety Screening · Haz-Ops · Flow Diagrams · Batch Records · GMP
2 Equipment and Operations
Equipment Train · Reactors · Agitation · Raw Material Charging · Reaction Control · Sampling
• Workup · Distillation · Crystallization · Isolation/Filtration · Drying · Equipment Cleaning
3 Liquid Handling
Pumps · Pump Sizing, Selection and Troubleshooting · Pipes, Fittings and Valves · Flanges and
Gaskets · Hose · Friction and Viscosity Effects · O-rings · Stoppers · Liquid Storage Vessels
4 Heat Transfer
Heat Transfer in Stirred Vessels · Heat Exchangers · Temperature Control Units · Heat Transfer
Fluid Selection and Properties · Glycols and Brines · Steam · Process Chillers
5 Electricity and Instrumentation
Electrical Safety · Electric Power Basics · Receptacle Types · Electrical Enclosure Data ·
Intrinsic Safety · Motors · Temperature, Pressure and pH Measurement · Process Control Basics
6 Solvents
Safe Handling · Properties and Selection · Solubility Map · Temperature/Vapor Pressure Rela
tionships · Distillation · Binary Azeotropes · Ternary Water-Containing Azeotropes · Water Data
7 Compressed Gases
Safe Handling · Physical Properties · Cryogenic Liquids · Cylinder Specifications · Connection
Data · Pressure Regulators · Gas Metering · Air Data · Air Compressors · Vacuum Systems
8 Chemical Data
Properties of Acids and Bases · Dilutions · pKas · pH Buffers · Color Indicators · Aqueous
Solubility Data · Aqueous Solution Density · Organic Functional Groups · Reaction Types
9 Chemical Hygiene and Safety
Safe Handling of Chemicals · MSDSs · Hazards Classifications · Labeling · Fire Safety ·
Personal Protective Equipment · Glove Selection · Respirators · Incompatible Chemicals
10 Materials Selection
Properties of Elastomers, Plastics, Metals and Glass · Metallic Corrosion Data · Glass Corrosion
• Material Compatibility Table
11 Miscellaneous
Unit Conversion Tables · Physical Constants · Mathematical Relationships · Geometric Formu
las · Temperature/Pressure Conversion Charts · Cold Mixtures · Sieve Sizes · Agency Acronyms
Bibliography
Additional Recommended Reading
Index
SEE DETAILED TABLES OF CONTENTS AT EACH CHAPTER
1 The Pilot Plant
Contents
The Role of the Pilot Plant 1-2
Major Factors in Scale-Up 1-3
12 Things to Do During Process Scale-Up 1-5
12 Things to Avoid During Process Scale-Up 1-6
Developing Scalable Reactions 1-7
The Role of Calorimetry and Process Safety Screening 1-9
The Haz-Op 1-10
The Batch Checklist 1-12
The Process Flow Diagram 1-13
The Batch Record 1-14
The Campaign Report 1-15
Notes on GMP 1-16
THE PILOT PLANT REAL BOOK
1 - The Pilot Plant
The Role of the Pilot Plant
A chemical pilot plant can be many things to many people. It can range in scale from a room with a walk-in fume hood
and some 20-liter glassware to an experimental petroleum refinery. This book focuses on the relatively small-scale
development operations found in the pharmaceutical and fine chemical industries. These usually entail manual batch
operation of processes that are often not fully defined, in standard chemical reactors from, say, 20 liters to 200 gallons.
Even with the increasing role of automated bench-scale reactors in process development, most processes will be tested in
the pilot plant before reaching commercial scale. The jump from bench to pilot plant will usually be the single largest
numerical increase in scale (perhaps up to 100 times) which the fledgling process will ever experience, and therefore can
present the greatest challenges.
But "scale-up" is only one of the ways in which a pilot plant can prove itself valuable. It can play a major role in
streamlining what can often be a lengthy development process. Here are some important functions that a pilot plant can
perform in process development:
• Produce raw materials and intermediates to supply further development work.
• Produce developmental quantities of new compounds for evaluation, toxicity testing, safety and stability studies,
clinical trials, and introduction into the market. Often the first few kilograms of a new compound are the most
difficult to make, since an optimized route has not yet been developed.
• Demonstrate that processes can be successfully scaled up and that there are no unexpected ramifications of extended
operating times, slower rates of addition or mixing effects at larger scale.
• Ensure that no important details have been overlooked.
• Test the effects of using commercial-grade raw materials and solvents.
• Identify the best ways to handle and analyze reactants, intermediates, products, waste streams and off-gases.
• Check the effect of the buildup of impurities in recycle streams and other long-term effects.
• Test materials of construction.
• Complete a more detailed mass balance, and obtain better estimates of yield and effluent stream generation.
• Help to better estimate process costs and increase management confidence in investing for full-scale production.
• Obtain design data and optimum operating parameters for specifying larger-scale equipment.
• Train members of the technology transfer team preparing for commercial production.
• Help develop a comprehensive and detailed operating procedure for transfer to manufacturing.
Often, using large-scale glassware is the first scale-up step, but this can be extremely dangerous if mixing is not reliable
and if the glassware must be handled manually. It is not easy to cool such equipment, and a spill can be a disaster
resulting in exposure to flammable solvents or toxic gases. These issues are much more easily controlled using properly
designed glass or stainless reactors in an explosion-proof environment.
Scaling up a chemical process early in its lifetime can be helpful in identifying potential scale issues that may require
engineering assistance or special equipment to handle, in identifying the rate limiting steps, and in giving a feel for the
overall workability of the process. Scaling up too early, of course, risks process changes and wasted time and resources.
Involving team members of various disciplines early reduces the likelihood that process changes will be needed later.
For countless reasons, investment in proper pilot facilities is well worth it. Often, the pilot plant will soon prove itself so
useful that it won't be able to keep up with the demand. Flexibility is one of the keys to success. Priorities shift, projects
are added or dropped and synthetic routes are often altered on the fly. The pilot plant must be able to adapt. The facility
should be able to handle a variety of processes safely with a minimum of special equipment. Equipment should offer
wide corrosion resistance, and should be easy to clean to prevent cross-contamination between batches and products.
Space should be available for experimental setups. And pharmaceutical pilot plants need to accomplish all this within the
added constraints of GMP operation (see page 1-16). The following pages explore some important thoughts and con
cepts that will help you maximize the utility of your pilot plant and take full advantage of its tremendous value.
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1 - The Pilot Plant
Major Factors in Scale-Up
Scaling up chemistry from laboratory glassware to larger reactor vessels is by no means a simple linear process. A
number of things that may not be immediately evident to the inexperienced scientist are very different at larger scale,
and many of these can have a tremendous impact on process performance. The biggest problem areas faced by the scale-
up team are listed below, along with a brief explanation of how they can affect the success of the project. It might seem
that by maintaining dynamic similarity during scale-up (keeping the same mixing velocities, temperatures, concentra
tions, etc.) performance would be equivalent, but this is far from the case. The advantages of getting process engineers
involved early in the development effort may become obvious reading through the following items. More detailed
discussions of techniques to circumvent these difficulties can be found on page 1-7 and throughout Chapter 2.
Expanded Time Scale - Perhaps the biggest surprise to the chemist or engineer bringing a process to the plant for the
first time is how long everything takes. Charging the raw materials and solvents can take hours. A heating or cooling
step accomplished in minutes at the bench can take 8 hours or longer. A simple distillation can take 12 hours. Isolation
of a product in a centrifuge can take more than 24 hours at large scale. A laboratory synthetic step that a chemist could
complete in a workday and have the product in the drying oven by dinnertime can take 2-3 days of round-the-clock
operation to complete. Such extended processing can cause decomposition, polymorphic shifts or other problems.
Stream stability is an important aspect of scale-up that should be borne in mind throughout the development process.
Chemical Hygiene - Handling chemicals at the large scale poses greatly increased risks and chances for exposure to
toxic substances. Laboratory fume hoods can cover many sins, but at the pilot scale, electrostatic hazards of handling dry
powders, flammable solvents and wet filter cakes are greatly increased. Dusting is a huge problem when transferring
bulk solids. Off-gases must be treated using a scrubber to prevent escape into the atmosphere. All of this means that
various personal protective equipment must be used, and safety devices and interlock systems must be installed.
Heat Transfer - Laboratory flasks have a relatively high surface-to-volume ratio. This, and their small size, makes it
easy to heat or cool them quickly (think ice baths) and to easily hold the reaction temperature constant. Not so in larger
reactors, where heat transfer surface area/volume is greatly diminished, and where heating and cooling must be accom
plished by means of a heat transfer medium pumped through a jacket or heating coil. Heat removal rates can be 10 times
slower per unit volume at the pilot scale, and as much as 30 times slower at commercial scale. This approaches adiabatic
operation, which should hint at the value of reaction calorimetry in process safety screening, especially for exothermic
reactions (see page 1-9). The heat generated per unit volume in an exothermic reaction remains constant as scale
increases. However, the total amount of heat to be removed increases as the cube of the reactor size, whereas, for
jacketed reactors, the area available for heat transfer increases only as the square of the reactor size (see page 4-4). Other
factors can also affect heat transfer, namely characteristics of the heat transfer fluid, the thickness and thermal conduc
tivity of the reactor walls, and mixing effects. Low temperature reactions also necessarily take much longer because of
these limitations.
In order to accomplish heating in a reasonable time frame, process operators must try to maximize the temperature
difference between the vessel jacket and the vessel contents. Wall temperatures might exceed temperatures experienced
by the reaction mixture at the bench, raising concerns about stability, e.g., decomposition on dry reactor walls. For
cooling, jacket temperatures may be far lower than at the bench, which can lead to reagent freezing, crash crystallization
and other effects not seen at smaller scale.
Temperature Control - Maintaining constant temperature is also much more difficult at larger scale. Constant tempera
ture baths are not available. The temperature control system for a chemical reactor consists of a dynamic feedback loop
to control the circulation of heat transfer fluid or some other medium. Heat generated in the reactor must be removed at a
rate matching its production. Even an operation as simple as solvent addition while maintaining temperature can become
a lengthy operation if, for example, the solvent is much colder than the batch or if there is a significant heat of dilution.
Also, if the role of mixing is not well understood, blend-times may be longer, and temperature gradients may exist from
the center to the edge of reactor, possibly increasing the rate of side reactions and the formation of by-products.
Reactor Mixing - Simply because of the increased geometry at large scale, blend times or turnover times can be signifi
cantly longer than at the bench. Blend times on the order of 1-2 seconds are typical in a laboratory flask, but may be
THE PILOT PLANT REAL BOOK 1-3
1 - The Pilot Plant
many times longer at larger scale. Local areas of excess reagents may exist, which can cause formation of by-products.
In this way, reaction selectivity or yield can be affected. pH control is a perfect example of this phenomenon. Local high
concentrations of acid or base at the point of addition can induce hydrolysis or other degradation reactions.
The impact of mixing effects is even more pronounced for two-phase reactions where interfacial surface area limits
mass-transfer and can thus determine the reaction rate. Phase transfer reactions and extractions are good examples.
Generating the same interfacial area per unit volume at larger scales is not trivial. Heterogeneous catalytic reactions face
the same difficulties. Good suspension and distribution of the catalyst and high fluid velocities can have a significant
impact on rate. If the rate drops too far, dangerous accumulations of unreacted reagents can occur. Viscosity, which is a
strong function of temperature, also plays a role. This is why, in general, it is easier to scale up homogeneous reactions
than heterogeneous ones. However, even some homogeneous reactions can be agitation-limited if reactants are not well
mixed at the molecular level.
Mixing cannot be scaled up by simply using geometrically similar, but larger, mixers. Many other factors must be
considered. For example, consider the case of a reaction catalyzed by a shear-sensitive enzyme. Operating a mixing
impeller which is say, 5 times greater in diameter, at the same rpm as its bench-scale counterpart will result in an agitator
tip speed, and thus a shear rate, which is also 5 times greater. But operating at 1/5 the rpm to obtain the same tip speed
will not generate the same degree of turbulence. For a more detailed discussion of mixing scale-up, see Chapter 2.
Operating Volume - Evaporating to dryness, or very low volumes, is a convenient laboratory technique. This is usually
not possible at scale because most reactors have maximum mixing levels of about 10-20% of their full capacity.
Reaction Control - Very often, because of the heat-removal limitations discussed above, processes are designed so that
reaction rate can be regulated by controlled addition of a limiting reagent. But here, again, a greatly expanded time-scale
must be expected at the pilot scale as compared to the bench. As mentioned above, for very low-temperature reactions
the sensible heat of the reagent solution alone can approach the heat of reaction. Addition may require several hours,
which can affect reaction equilibrium, yield and impurity formation.
Drying - Drying is often accomplished using vacuum ovens in the lab. Similar units (vacuum tray dryers) are also used
in pilot and commercial plants, but the drying cycles will be much longer. Dynamic units such as rotary cone dryers,
tumble dryers, paddle dryers and the like are also common but these types of equipment produce materials with very
different physical characteristics than those obtained from tray driers. Differences in particle size distribution, bulk
density, flowability, compressibility, etc., can all have a dramatic impact on the character of the product.
Raw Material Charges - Because of handling difficulties, it may not always be possible to be as accurate in charging raw
materials at large scale as at the bench. Scale-up will require that acceptable charge ranges be determined, and the limits
of these ranges must eventually be tested. Remember that pilot plant water and solvents may also be much colder.
Visibility - Chemists who rely on visual indication of reaction milestones, such as initiation of crystallization, may be
disappointed to find that the best they can do at scale is to peer into a pitch-black reactor through a small sight window.
Batch progress needs to be marked by quantifiable properties that can be measured using dependable analytical methods.
Reactor Access - Opening a reactor to add seed crystals or to collect samples is often not possible at large scale, because
it may compromise batch integrity or operator safety. Often, it is necessary to use closed sampling systems (see page
2-15), solids addition chambers, or to add seeds in a slurry.
Work-Up - Often, pilot extractions and phase separations leave much more water behind than on the bench because of
the greater tank surface area and longer settling times. Water removal can become more of a headache, and azeotropic
drying or the addition of drying agents may become necessary. Waste minimization becomes an important concern
during this sometimes volume-intensive stage of a process.
In general, liquid-phase batch processes are the easiest to scale up. It is simpler to control batch processes than continu
ous reactors, and the residence time is better-defined. Of course, continuous processing is sometimes necessary, espe
cially for unstable products or highly exothermic reactions. The disadvantages of operating in the batch mode are the
long downtimes between batches, the high labor requirements, and possible batch-to-batch variation in product quality.
To minimize downtime and obtain consistent results, it is important to plan carefully and to understand, as well as
possible, those process parameters that affect yield and quality.
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