Fine Chemicals Manufacture: Technology and Engineering

551 Pages·2001·30.7 MB·English

by  A. Cybulski

Fine Chemicals Manufacture:
Technology and Engineering
by Andrzej Cybulski, M. M. Sharma, J. A. Moulijn, R. A. Sheldon

• ISBN: 044482202X
• Publisher: Elsevier Science & Technology Books
• Pub. Date: December 2001
Preface
The sector of fine chemicals, including pharmaceuticals, agrochemicals, dyes and pigments,
fragrances and flavours, intermediates, and performance chemicals is growing fast. For obvious
reasons chemistry is a key to the success in developing new processes for fine chemicals. However, as
a rule, chemists formulate results of their work as recipes, which usually lack important information
for process development. This book is intended to show what is needed to make the recipe more useful
for process development purposes and to transform the recipe into an industrial process that will be
safe, environmentally friendly, and profitable. The goal of the book is to form a bridge between
chemists and specialists of all other branches involved in the scale-up of new processes or
modification of existing processes with both a minimum effort and risk and maximum profit when
commercializing the process. New techniques for scale-up and optimization of existing processes and
improvements in the utilization of process equipment that have been developed in recent years are
presented in the book. We believe that even experienced process and developmental engineers will
find these interesting and useful in their every day practice.
The book starts with general information on fine chemicals and characteristic features of their
manufacture. Tools that are used in working out new industrial processes and optimization of existing
plants and processes are presented in subsequent chapters. Finally, the target of all laboratory, pilot
and design activities, namely a modern production plant, is described.
Fine chemicals have been produced for tens of years based upon conventional organic chemistry
techniques that generate many wastes, are often insufficiently selective (so less profitable than they
could be), use many hazardous species, and produce problems in scale-up, especially with respect to
safe and economic operation of full-scale reactors. Improving process selectivity is a key factor in
attempts to reduce the consumption of raw materials and minimize the amount of wastes. Therefore,
much attention has been paid to selectivity engineering and catalysis. The use of suitable catalysts for
new processes requires a deep knowledge of catalysis principles. Therefore, in Chapter 3 an extended
course on all kinds of catalysis is given with particular attention to heterogeneous catalysis. Many
important catalytic processes for fine chemicals manufacture are described in Chapter 2 and many
existing and developmental catalytic processes are also summarized in Chapter 3. Engineering tricks
for selectivity manipulation (heterogenization of homogeneous catalysis, manipulation of the 'micro-
environment' and 'macro-environment', the use of an additional liquid phase, and some other
unconventional techniques) are presented extensively in Chapter 4.
In the past, chemical processes for the manufacture of fine chemicals were scaled up gradually,
using many steps between the laboratory and the full-scale plant. This evolutionary way of process
scale-up is still in common use because of a number of requirements imposed by GMP and FDA
regulations. However, this method of process development is not very effective in the elimination of
all risks at a full scale. Therefore, in this book much space is dedicated to process development
(Chapter 5). A variety of tools for safe scale-up of chemical processes are presented, beginning with
evaluation using process profile analysis (see Chapter 2). Scale-up strategies and techniques including
economic evaluations at any stage of process development are described in Chapter 5. Chemical
reactors, being the heart of chemical plants, are discussed in more detail in this chapter. Classification
of reactors, the most common industrial reactors, and reactor design, scale-up, and operation problems
are presented in brief. Basic thermodynamics and kinetics and mathematical modelling of chemical
reactions and reactors are the rational basis for reactor scale-up and as such they are extensively
discussed. The use of empirical mathematical models (tendency modelling) for design, analysis, and
optimization of chemical reactors has been found to be a very useful tool for solving problems
associated with fine chemicals manufacture. As such they are presented in more detail. Examples
illustrating what sort of laboratory data are needed for these modern scale-up techniques are given. A
number of reactions in fine chemicals manufacture are carried out in a semibatch mode by adding one
of the reactants to the other components of the reaction mixture. Mixing then is often crucial for yield
and, especially, selectivity. Both a theoretical approach to that problem and practical guidelines for
laboratory chemists are given in Chapter 5 to help in the identification and solution of problems
associated with mixing and chemical reactions. In the past, safety was a problem that was not tackled
carefully enough, as illustrated by the disastrous Seveso incident and many other accidents in industry.
Useful information on methods and data needed for safe scale-up of chemical reactors are also given
in Chapter 5. Selection of the most appropriate type of chemical reactor concludes Chapter 5 on
process development.
Separations for removing undesirable by-products and impurities, and making suprapure fine
chemicals constitute a major fraction of the production costs. There is an enormous variety of methods
for product separation and purification and many books on the subject have been published. Here, we
deal with the problem in a very general way and we refer the reader to advanced books for details.
Conventional techniques for product isolation and purification, such as fractional distillation,
extraction, and crystallization, still predominate. Some guidelines for scale-up of these techniques and
producing experimental data for scale-up are given in Chapter 5. More information on specific
separation and purification techniques applied to particular problems of fine chemicals manufacture
the reader can find in Chapter 6.
Chapter 7 on production plants starts with the description of plant types with particular attention
given to multiproduct and multipurpose plants, which dominate in fine chemicals manufacture. This is
intended to bring to life before mind's eyes of laboratory chemists what kind of constraints exists that
must be taken into account when thinking about a new (still laboratory) process to be commercialized
in such plants. Equipment in plants for the manufacture of fine chemicals is very much diversified and
includes all types of chemical apparatuses and machinery. Such equipment is presented in many books
on chemical, mechanical, and process engineering. In a brief presentation of the equipment we intend
to draw the reader's attention to some very typical pieces of equipment and some special equipment
that is particularly useful in fine chemicals manufacture only. Some economic data on chemical
equipment are also given to extend economical thinking of laboratory chemists. In sections on plant
design and production planning and scheduling we have described typical design and planning
procedures that exemplify what kind of information from the laboratory is needed to specify
appropriate equipment for a process under development or to compose optimal production plans and
schedules. We believe that even experienced process engineers are not well acquainted with
techniques used in design and planning/scheduling. Therefore, these are described in more detail in
this chapter.
A book like the present one, which is not intended as a textbook for students, cannot be written by
a single author. In fact, it is a multidisciplinary subject and the authors have not tried to omit all jargon
and the flavour of the various disciplines involved. The consequence, of course, is that parts are not
easy to understand for chemists, while others are difficult for chemical reaction engineers. It is hoped
that this book will strongly contribute to bridging the gap between chemists and chemical engineers in
the field. The authors will be grateful for comments from the readers.
A. Cybulski
J.A. Moulijn
M.M. Sharma
R.A. Sheldon
Table of Contents

Preface
Ch. 1 Introduction
Ch. 2 Fine Chemicals and their Synthesis; a Chemical Point of View
Ch. 3 Catalysis in Fine Chemicals
Ch. 4 Selectivity Engineering
Ch. 5 Process Development
Ch. 6 Separation Methods
Ch. 7 Production Plants
App. A Identification of Stoichiometric Expression
App. B Parameter Estimation and Statistical Analysis of Regression
1. Introduction
1.1. CHARACTERISTIC FEATURES OF FINE CHEMICALS MANUFACTURE
Fine chemicals are products of high and well-defined purity, which are manufactured in
relatively small amounts and sold at relatively high price. Although a question of taste,
reasonable limits would be 10kton/year and $ 10/kg (Stinson, 1998, Section 2.1 of this book).
Fine chemicals can be divided in two basic groups; those that are used as intermediates for other
products, and those that by their nature have a specific activity and are used based on their
perJormance characteristics. Performance chemicals are used as active ingredients or additives
in formulations, and as aids in processing.
Fine chemicals form a group of products of large variety: their number exceeds 10,000. The
size of the global fine chemicals market ni 1993 was estimated at $ 42,000 million. The average
annual growth in the period 1989-95 was about 4.5 % (Polastro et al., 1990). Figure 1.1. shows
the division of fine chemicals production by outlet.
Figure 1.1. Outlets for fine chemicals.
Only l0 firms account for 75% of agrochemicals sales, while the 51 largest drug companies
have a market share of only 33% (Stinson, 1995). About 85% of fine chemicals are
manufactured by companies of the 'triad': the United States (28%), Western Europe (39%), and
Japan (17%). Italy, with 4.0 million litres reactor capacity and 17 manufacturers, topped the
European fine chemicals industry (Layman, 1993). Recently India, China, and Eastern-Central
European countries have gained a significant proportion of the market, as a result of the lower
direct labour costs and the more relaxed environmental and safety standards. It is fair to state that
the high quality of chemists in these countries has also contributed to this development. In 1993,
the cost of producing fine chemicals in India was 12% below that in Europe (Layman, 1993).
Production of pharmaceuticals is heavily concentrated in four countries, namely the USA, UK,
Switzerland, and Germany (Pollak, 1998). Many companies active in fine chemicals business
are rather small. Of course, there is no general role for an optimal size. According to Stinson
(1995) sales of companies producing fine chemicals should be at least $ 50 million per year to be
able to afford the costs of quality control, environmental efforts and to run the plant profitably.
This translates as follows: The minimum long-term economic size of a European fine chemicals
producer would be about 85 to 90 people total, who would support a reactor capacity of about
120,000 litres (Layman, 1993). However, when these firms expand to, say, more than 500
people and annual sales of over $ 100 million, they might become too inflexible to respond to
changes in customer and market needs, so it is not surprising that most compounds have sales
below $10 million per year and form a network with several competing companies.
In recent years two trends have become visible in the manufacture of fine chemicals: (1)
custom synthesis, and (2) specialization in groups of processes or products that are derived from
specific raw materials (chemical trees).
Custom synthesis can be defined as the dedicated production for a single client, often using
technology provided by the customers themselves. Custom chemicals world-wide are a $ 6000
million-per-year-business (Stinson, 1997). According to Illman's estimate about 40% of the
world fine chemicals market is produced through contract manufacturing (Illman, 1995), half of
which goes to the drugs industry. Custom manufacturing develops, among others, due to
inflexibility of the bigger companies. However, experts are divided in their opinions about
contract manufacturing: many of them see large companies with years of experience to be
winners in contract manufacturing, while others insist that room for small specialists,
particularly in the life sciences market, still exists. Mullin (1999) indicates that some of the
fastest-growing contract manufacturers are large firms. For example, fine chemicals at DSM
grew from 2% in 1987 to 25% of the company business in 1998. As is the trend in the Chemical
Industry, this growth was achieved mainly through acquisitions: Andeno, Gist-Brocades, and
businesses from Bristol Meyers Squibb and Chemie Linz.
Many companies specialize in the production of chemicals grouped in 'chemical trees'
characterized by the same chemical roots (compounds) or the same/similar method of
manufacturing. Examples are the Lonza trees based upon: (1) hydrogen cyanide, (2) ketene
(H2C=C=O) and diketene (4-methyleneoxetan-2-one), and (3) nitrogen heterocycles. A different
type of tree is that of DSM Chemie Linz, which branches out from ozonolysis as the core
technology (Stinson, 1996). Wacker Chemie has developed its chemical tree leading to
acetoacetates, other acylacetates, and 2-ketones (Stinson, 1997). Table 1.1 shows examples of
fine chemicals.
Processes in fine chemicals manufacture differ from processes for the manufacture of
commodity chemicals in many respects (see also Chapter 2).
(1) A significant proportion of the fine chemicals are complex, multifunctional large
molecules. These molecules are labile, unstable at elevated temperature, and sensitive towards
(occasionally even minor) changes in their environment (e.g. pH). Therefore, processes are
needed with inherent protective measures (e.g. chemical or physical quenching) or a precise
control system to operate exactly within the allowable range. Otherwise the yield of the desired
product can drop to nearly zero.
Table 1.1 Examples of fine chemicals
No. Product Nature of Industries Catalytic (C) / Scale of Type of
Non-Catalytic Operation Reactor b
(NC):' (tpa)
1 Trimethylhydroquinone; Vitamin C (Homo; Het) 500 - 1000 STR
Isophytol; Vitamin E
2 Methyl heptenone Pharma; Aroma NC & C (Het) 1000 - 2000 CR (nozzle)
3 Vitamin A (Wittig reaction) Vitamin NC 1000 CR (nozzle)
4 lsobutylbenzene Pharma C (Homo; Het) 1000 - 3000 STR
Ibuprofen Nonsteroidal analgestic
5 Fenvalerate Agrochemical C (PTC) 300 - 500 STR
p-Hydroxy benzaldehyde
6 p-Anisic aldehyde Pharma; Aroma and Flavour; C (Homo; Het) 1000 - 3000 STR; EC
Agrochemical
7 Catechol; Hydroquinone Agrochemical; C (Homo) & 1000 - 5000 STR; BCR
Aroma and Flavour; NC
Photography; Additives
(antioxidants)
8 p-Amino phenol Pharma C (Het) & NC 1000 - 5000 STR; EC
9 isocyanates ~ Pharma; Agrochemical; Rubber NC 300 - 2000 STR
I0 Citral Aroma; Pharma C (Het) 1000 - 3000 CR (short
bed)
2,6-di-tert-butylphenol Additives (antioxidants) C (Homo) 1000 - 2000 STR
Phenylglycine/p-hydroxy- Pharma NC & C (Bio) 1500 - 2000 STR; CR
phenyl glycine
31 p-tert-butylbenzaldehyde; Aroma; Pharma C (Homo; Het) 1000 - 5000 STR
Benzaldehyde / Benzyl
alcohol
14 1,4 -dihydroxymethylcyclo- Polyester C (Het) 5000 CR
hexane
51 Phenylethylalcohol Aroma; Pharma C (Homo; Het) I000 - 3000 STR
61 Anthraquinone (AQ) and 2- Dyes; H202; Paper C (Het) 500 - 3000 STR
alkyl AQ's
71 Indigo Dyes C (Het) 300 - 1000 STR
18 Diphenyl ether; m-phenoxy Aroma; Heat Transfer Fluids; C (Het) 1000 - 10000 CR
toluene Agrochemical
91 Benzyl toluenes Heat Transfer Fluids C (Het) 500 - 2000 STR
20 o-, m-, and p-Phenylene- Dyes; Agrochemical; Aromatic C (Het) 1000 - 3000 STR
diamines Polyamide Fibres
21 2,2,6,6- Additive (Light stabiliser) NC & C (Het) 1000 - 2000 CR
tetramethylpiperidinol
22 Gl~coxalic acid Pharma NC 500 - 2000 STR; BCR
" Homogenous (Homo); Heterogeneous (Het); Biocatalytic (Bio); Phase Transfer Catalysis (PTC).
b Stirred Tank Reactor (STR); Bubble Column Reactor (BCR); Continuous Reactor (CR); Electrochemical (EC).
c e.g., n-propyl/n-butyl; cyclohexyl; p-isopropylphenyl i socyanate; i sophorone diisocyanate; 1,5-naphthalene diisocyanate.
(2) Fine chemicals are high-added-value products. In general, expensive raw materials are
processed to obtain fine chemicals, and therefore, the degree of their utilization is very
important. With complex reaction pathways, selectivity is the key problem to make the process
profitable. Selectivity is significant also because of difficulties in isolation and purification of the
desired product from many side products, especially those with physico-chemical properties
similar to those of the desired product (close boiling points, optical isomers, etc.). Furthermore, a
low selectivity results in large streams of pollutants to be treated before they can be disposed of.
Selectivity is even more an issue because in contrast with bulk chemicals production, where a
limited single-pass conversion coupled with separation and recycling of unreacted raw materials
is often applied, usually complete conversion is aimed at. Selectivity can be controlled by
chemical factors such as chemical route, solvent, catalyst and operating conditions, but it is also
strongly dependent on engineering solutions. Catalysis is the key to increasing the selectivity.
(3) In the manufacture of fine chemicals many hazardous chemicals are used, such as highly
flammable solvents, cyanides, phosgene, halogens, volatile amines, isocyanates and
phosphorous compounds. The use of hazardous and toxic chemicals produces severe problems
associated with safety and effluent disposal. Moreover, fine chemistry reactions are
predominantly carried out in batch stirred-tank reactors characterized by (i) a large inventory of
dangerous chemicals, and (ii) a limited possibility to transfer the generated heat to the
surroundings. Therefore, the risk of thermal runaways, explosions, and emissions of pollutants to
the surroundings is greater than in bulk (usually continuous) production. That is why much
attention must be paid to safety, health hazards, and waste disposal during development, scale-
up, and operation of the process.
Fine chemicals are often manufactured in multistep conventional syntheses, which results in a
high consumption of raw materials and, consequently, large amounts of by-products and wastes.
On average, the consumption of raw materials in the bulk chemicals business is about 1 kg/kg of
product. This figure in fine chemistry is much greater, and can reach up to 100 kg/kg for
pharmaceuticals (Sheldon, 1994; Section 2.1). The high raw materials-to-product ratio in fine
chemistry justifies extensive search for selective catalysts. Use of effective catalysts would result
in a decrease of reactant consumption and waste production, and the simultaneous reduction of
the number of steps in the synthesis.
(4) One of the most important features of fine chemicals manufacture is the great variety of
products, with new products permanently emerging. Therefore, significant fluctuations in the
demand exist for a variety of chemicals. If each product would be manufactured using a plant
dedicated to the particular process, the investment and labour costs would be enormous. In
combination with the ever changing demand and given the fact that plants are usually run below
their design capacity, this would make the manufacturing costs very high. Therefore, only larger
volume fine chemicals or compounds obtained in a specific way or of extremely high purity are
produced in dedicated plants. Most of the fine chemicals, however, are manufactured in
multipurpose or multiproduct plants (MPPs). They consist of versatile equipment for reaction,
separation and purification, storage, effluent treatment, solvent recovery, and equipment for
utilities. By changing the connections between the units and careful cleaning of the equipment to
be used in the next campaign, one can adapt the plant to the intended process. The investment
and labour costs are significantly lower for MPPs than for dedicated plants, while the flexibility
necessary to meet changing demands is provided. The need for versatility of equipment
originates from the great number of products in rather limited quantities to be manufactured in
the plant every year. Such versatile equipment is suitable for all the processes, although it is
certainly not optimal. The most versatile reactors are stirred-tank reactors operated in batch or
semibatch mode, so such reactors are mainly used in muitiproduct plants. Continuous plants
with reactors of small volume are sometimes used despite the small capacity required. This is the
case when the residence time of reactants in the reaction zone must be short or when too much
hazardous compounds could accumulate in the reaction zone.
From the foregoing it will be clear that in fine chemicals process development the strategy
differs profoundly from that in the bulk chemical industry. The major steps are (i) adaptation of
procedures to constraints imposed by the existing facilities with some necessary equipment
additions, or (ii) choice of appropriate equipment and determination of procedures for a newly
built plant, in such a way that procedures in both cases guarantee the profitable, competitive, and
safe operation of a plant.
(5) The accuracy of analytical methods has increased enormously in the past decades and this
has enabled detection of even almost negligible traces of impurities. The consequence is that
both regulations and specifications for intermediates and final fine chemicals have become
stricter. Therefore, very pure compounds must often be produced with impurities at ppm or ppb
level. The production of complex molecules in many cases results in mixtures containing
isomers, including optical isomers. The demand for enantiomeric materials is growing at the
expense of their racemic counterparts, driven primarily by the pharmaceutical industry.
Therefore, both stereoselective synthesis and effective, often non-conventional methods of
pur~/'ication (e.g. High Performance Liquid Chromatography (HPLC) and treatment under
supercritical conditions) are in a wider use to meet the stricter requirements. The increasing need
for optical purity, with complex and often not very effective methods of racemate resolution,
stimulates the development of new stereoselective catalysts, including biocatalysts. In this
respect, biotechnology si becoming a competitor to classical chemical technology.
All specialists involved in the business of fine chemistry should be aware of the characteristic
features of fine chemicals and their manufacture. Obviously, the most important for the
development of new products si chemistry, i.e. the choice of the most appropriate route to the
desired product. The role of molecular modelling si growing, particularly in the field of
performance chemicals. Chemistry is also crucial in developing or improving processes for the
manufacture of fine chemicals. The chemistry of fine chemicals has been dealt with in many
books and review papers. Therefore, only those chemical problems arising during process
development will be emphasized that can contribute to solving problems of selectivity,
environmental protection, safety, and optimization when commercializing the process, especially
in existing multi-product plants.
The implications of the features of fine chemicals manufacture mentioned above, are,
however, not that obvious to all parties taking part in process development. On the one hand,
chemical and process engineers are dedicated mainly to the engineering part in process
development, often neglecting process chemistry, as this might be erroneously considered less
important for a full-scale plant. On the other hand, synthetic chemists often finish their work
with laboratory recipes neglecting needs of procedures for process development. The reasons for
this approach have been listed by Laird (1989):'
(l) research chemists are interested ni the properties of the product, and how ti si made on a
small scale si of less importance,
)2( the synthetic route may be long (and therefore expensive),
)3( the raw materials and reagents may not be available ni bulk quantities,
)4( the routes may not be stereospecific - ni research the required isomer will often be isolated
by using a chromatographic step at the end,
(5)the reaction conditions may involve processes which are difficult to operate in standard
plants - e.g. high pressure, very low temperatures,
(6) toxic reagents and intermediates, which are easy to handle on a gram scale, may prohibit
working on a kilogram scale,
)7( exothermic reactions, which can be handled safely ni the laboratory, are more difficult to
control in a full-scale plant,
(8)effluents - easy to dispose of ni the laboratory - are a serious consideration in process
development. Heavy metal reagents, chlorinated solvents, toxic intermediates, etc. may
have to be eliminated from the process before effluents can be safely treated. This subject is
becoming very sensitive ni Europe.'
This book deals with the problems neglected by laboratory chemists, having in mind needs of
the process to be performed on a full scale. It is intended to form a bridge between specialists of
various branches in the scale-up or modification of existing processes in fine chemistry, with
both a minimum effort and risk and maximum profit when commercializing the process. The
objective is to establish a good basis for the mutual understanding between chemists and
engineers involved in R&D, design, and production planning in the fine chemistry business. To
reach this objective, the following key ideas and technical issues associated with profitable,
environmentally friendly, and intrinsically safe processes for the manufacture of fine chemicals
will be discussed, i.e.
(cid:12)9 catalysis and selectivity engineering as a means to increase selectivity and reduce production
and/or emission of pollutants to the environment,
(cid:12)9 process development with emphasis put on safe scale-up of chemical reactors with as high
selectivity as possible,
(cid:12)9 techniques for product isolation and purification yielding a product that will meet high
quality requirements characteristic for fine chemicals, including combi-processes: reactor-
separator systems (e.g. the reactor-distillation column) that have lower capital costs and
lower separation costs, and
(cid:12)9 implementation of new chemical processes and improvement of existing processes that will
be realized in multipurpose plants typical for the fine chemicals manufacture.
1.2. CATALYSIS IN FINE CHEMISTRY
General aspects of catalysis are discussed in Chapter .3 Catalysis has been proven to be very
effective in making processes faster, with a reduced number of synthetic steps, more selective,
and characterized by simpler waste disposal and improved safety. Apart from increasing
selectivity, the use of catalysts results in easier isolation and purification. Catalysts can be
divided in homogeneous and heterogeneous catalysts or, depending on taste, in chemo- and
biocatalysts. In terms of chemical performance, homogeneous catalysts are often quite
satisfactory but they must be removed from process streams before disposing them to the
surroundings. Heterogeneous catalysts can be separated from the product more easily, or even
require no separation at all (fixed-bed reactors are very convenient reactors). When aged, the
heterogeneous catalyst should be withdrawn from the reaction zone and replaced with a fresh or
regenerated catalyst. Moreover, heterogeneous catalysts perform bifunctional functions better,
which is advantageous in many applications. Therefore, heterogeneous catalysis simplifies