Co4 2016

Chimica Oggi - Chemistry Today is a peer-reviewed journal
devoted to fine chemistry, pharmaceuticals and Chimica Oggi - Chemistry Today

biotechnology addressed to a readership belonging to the
industry. An impact factor of 0.538 is listed in the 2015 vol. 34(4) July/August 2016
Journal Citation Reports (ISI Web of Knowledge).
EDITORIAL
2 Pharma Horizon: a new, reliable source of news on pharma
S. Maini
COMPANY PROFILE
4 ENZYPEP Quality by design
6 NEWS
A WORD WITH...
13 Torsten Derr, Chief Executive Officer, Saltigo GmbH
FLOW CHEMISTRY
14 Flow chemistry: analysis of market trends
Sightseeing by skilled flow chemists
o.com
L. Pichon
yps ofact
18 Continuous flow synthesis of heterocyclic scaffolds
www.
Design principles of multistep systems A review
K. Lvei, P. Bana, R. rknyi, G. I. Trs, J. les, Z. Novk, F. Faigl
SCIENCE HISTORY
22 How chemistry underpinned the First World War
M. Freemantle
FINE CHEMICALS & INTERMEDIATES

26 Nano food modeling: Ab initio and DFT studies on ionization of saccharin in aqueous solution
F. Kiani, S. B. Hosseini, S. A. Shahidi, F. Koohyar
PHARMACEUTICAL CHEMISTRY
32 Tiered testing strategy and assignment of occupational exposure limits
for pharmaceutical intermediates
G. C. Winkler, J. Mirwald, K. Gromek, E. L. Barle
CHEMICAL ENGINEERING/PROCESS DEVELOPMENT

38 From batch to continuous processes: a good answer, but what is the question?
Part I - General considerations and the reaction unit perspective
R. M. Nicoud
DRUG DISCOVERY/DEVELOPMENT
45 Synthesis of alkaloids by a diastereoselective allylation of chiral N-sulfinyl imines
F. Foubelo, M. Yus
REGULATION
51 The Authorisation of Biocidal Products under the BPR
R. Elsmore, S. Wright
SUSTAINABILITY
56 Potential of enzymes (urease and carbonic anhydrase) for a sustainable construction industry
M. J. Castro, C. E. Lpez, R. Narayanasamy, J. E. Marszalek, M. P. Luevanos-Escareo,
G. J. Fajardo, N. Balagurusamy
60 The age of cool biobased materials: a new positioning strategy

P. Willems, B. Tjeerdsma
TEKNO SCIENZE SRL INTERNATIONAL SCIENTIFIC ADVISORY BOARD:

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Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

EDITORIAL
SILVANA MAINI
Editorial Director
Teknoscienze Publisher
Pharma Horizon:
a new, reliable source of news on pharma
Silvana Maini
Recent years, like never before, have

seen the pharma industry extremely
active, with breakthrough research,
mergers, acquisitions, partnerships,
manufacturing diversification.
The USA, Asia and Europe have
reached unprecedented quality in the
research and development yielded
and quality of products and services offered.
In March this year we attended Dcat Week 16 in New York, an internationally-known pharma meeting, where we had the opportunity to
speak to several industry players.
The importance of certain hot topics is also shown in the meetings final press release, which we show below:
Graham Lewis, vice president, global pharma strategy, IMS Health, has provided an overview of the global pharmaceutical market and
the key trends impacting the market in the program.
Led by the US, an overall compound annual growth rate (CAGR) of 4-7% is projected to 2019, when the global pharmaceutical market
is projected to reach $1.3 trillion.
The continued resurgence of the US pharmaceutical market with projected CAGR of 6-9% from 2015 to 2019 will lead CAGR in
developed markets, which is projected at 4-7% CAGR to 2019, only slightly below the CAGR of 5-8% for pharmerging markets, dened by
IMS as the most promising emerging markets, in the forecast period of 2015 to 2019. A slowing of growth in pharmerging markets and the
rise of the US pharmaceutical market will lead the US to account for 45% of global pharmaceutical growth from 2016 to 2020.
On a product basis, one of the high-growth areas in the innovator drug market is oncology, specically the immuno-oncology market ().
As pharmaceutical companies seek to innovate to drive revenue growth, a key issue facing the industry is drug pricing and
reimbursement/payer trends.
Roshawn Blunt, managing director, 1798 Consultants, offered insight on these trends for the US and European markets and the related
impact on drug development and commercialization strategies. A key point raised in her discussion was the potential impact of
manufacturing, drug delivery, or product forms in certain reimbursement criteria, offering several case studies to illustrate.
THE CURRENT CHALLENGE WE FACE
As a natural consequence, all this leads to increasingly stringent regulations and increased inspection activity by the American FDA and
the European EMA regulatory authorities.
The regulations on the manufacturing of APIs show the need to apply increasingly stricter standards to monitor GMP application, defining
closer relationships between API manufacturers and business partners involved in the subsequent production phases of the drug.
Thus, the outsourcing industry is thriving, actually expanding, which is good news for all the players involved.
Not least important, biotechnology is also growing, thanks to increasing financial support provided to start-up companies.
2 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

THE ROLE OF THE PRESS
The many matters underlined in this foreword a bit long if you wish, yet also not comprehensive given the complexity of the matters that
have been mentioned show us a global market with a very high number of players along the so-called drug-value chain that starts in
research labs and ends with the patients.
Human resources, academia, research, analytical technology, research technology, manufacturing technology, new materials, services,
logistics, marketing and market access expertsif we were all to sit around a table for some brainstorming to discuss all aspects of the
pharma industry, we would need a huge board to take note, probably not big enough to include everything.
Pharma industry press obviously has a key role in providing information and the latest news.
Teknoscienze, a publishing company founded in 1983 when the journal Chimica Oggi / Chemistry today came out - a journal on fine and
specialty chemistry, has progressively expanded its editorial scope to other areas, such as functional food with the journal Agro FOOD
Industry hi-tech, and cosmetics and personal care with HP&C Today, Household and Personal Care today.
The common feature shared by the three journals is the scientific approach to the topics they focus on.
Though the journals report on three sectors that might seem very different one from the other, they indeed have always had one
objective: support peoples health. A drug, a functional food and even a sun cream have indeed a direct impact on the human being.
Having this background and editorial vocation, we have become aware that we were missing out on the world of pharma, and that we
wanted to create a new space to report on this rapidly-growing and ever-changing industry.
A NEW PUBLICATION BY TEKNOSCIENZE
With this spirit, weve launched Pharma Horizon, a new quarterly pubblication of our publishing group, devoted to those who work on
drugs right from the very beginning with the identification of the starting molecule, through clinical trials, all the way to drug manufacturing
and sales; in full compliance with the regulations that guarantee access to healthcare to anyone that needs it, the proper therapies and
the need to find the proper balance between the universal right to receive healthcare and the financial sustainability of the healthcare
system, a major issue all political campaigns debate on (for instance, the ones of the candidates running for president in the US) and a
major cost of any countrys financial budget.
We will talk about all aspects of the pharma world and with our distinctive science for the industry approach. We will offer updated
information on the sector, theme-based focus pages on scientific and technological trends, regulatory and market updates, also reporting
on the dynamics that govern this sector both internally and in relation to institutions and players.
Each issue will contain:
a Hot Topic that will provide a deep analysis of the main aspects related to it, with interviews to the players and opinion from the experts;
"Latest news" covering a major fact related to the healthcare world;
"Let's meet" providing a interview to a company or institution that distinguished itself for a particular reason;
"Market Access" a column with insights and tips to be prepared while appraching the marketplace with new products;
"Regulatory and compliance" a section addressing some of the most difficult business aspects that pharma companies have to deal with;
"Intellectual Property", a column with updates and analysis of the upcoming developments on the protection of ideas, products and
trademarks in the healthcare sector;
"Business news" a selection of the most important news on M&A, company deals etc;
"Products & Services" a selection of the most relevant news on product launches, approvals etc;
"In&Out" short news on appointments at the top management of companies and institutions
We are joined in this new and ambitious project by qualified experts whose much valued contribution will allow us to deal with complex
issues through strong expertise. Horizon Pharma will also be showcased to major pharma events worldwide.
We wish to thank all the authors, companies and readers who will support us and follow us in this new publishing venture. New frontiers
are continually being opened by research and the peoples new expectations require that we deal with healthcare challenges
which today seem insurmountable yet, as the history of scientific research has always shown, only need our strong committment and
willingness to face and overcome them.
Hoping that this new project meets your interest, please send your opinions to our editorial staff by writing to [email protected].
Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 3

COMPANY PROFILE Chimica Oggi - Chemistry Today customer's publication
Current state-of-the-art large-scale pharmaceutical peptide sortases, two known groups of naturally occurring ligases,
manufacturing: expensive, time consuming and non- require specific enzyme sequences and leave footprints.
sustainable
Today, the vast majority of peptides are synthesized by EnzyPep has now developed a novel enzyme platform
straight-through solid-phase peptide synthesis (SPPS). During based on peptiligase, a hyperstable enzyme genetically
SPPS side-products accumulate often resulting in challenging engineered for fast peptide fragment ligation without
HPLC purification and low overall yield. Although higher hydrolytic side reactions (see Figure 1). This enzyme
yields can be obtained using a fragment condensation can ligate side-chain unprotected peptide fragments
strategy, an SPPS-LPPS hybrid fragment approach is often very efficiently and tracelessly without the need of
not feasible due to racemization, the poor solubility of the a recognition sequence. Additionally it can tolerate
fully protected fragments and the formation of additional detergents, urea, guanidinium chloride, and organic
by-products due to side-chain reactivities. Native chemical co-solvents such as DMF and DMSO. Using site-directed
ligation, another chemical ligation technique, is sequence- mutagenesis, EnzyPep has further improved peptiligase
dependent and cannot currently be applied at large scale both to broaden the substrate scope and conversely to
due to the instability of the thioester moiety. make it specific for certain peptide recognition sequences.
EnzyPeps chemo-enzymatic
peptide synthesis (CEPS): a
generally applicable and traceless
ligation technology for the
synthesis of longer peptides, cyclic
peptides and peptide-to-protein
conjugates
Chemo-enzymatic peptide
synthesis (CEPS) consists of
the enzymatic condensation
in aqueous solution of side-
chain unprotected fragments
which have been individually
synthesized by SPPS. CEPS is totally
devoid of racemization and (side-
chain) protecting groups are not
required. Although several ligases,
such as subtiligase, are known
from the literature, hydrolytic
side reactions associated with
these ligases are still substantial
and fragment condensations Figure 1. EnzyPeps CEPS technology for the synthesis of long linear or cyclic peptides.
not economical. Butelases and

Currently, over 100.000 unique ligases
can be produced in-house. The ligation
efficiency is usually >90%, using only 1.1
equivalent of one of the fragments. If a
specific enzyme is used, the N-terminal
fragment does not require an N-terminal
protecting group (R = H in Figure 1). The
enzyme with the broadest substrate
scope, designated omniligase-1,
is commercially available via Iris
Biotech (OMNI Kit, code EZK2020) and
can assemble virtually any peptide
sequence.
Besides fragment condensation,
EnzyPeps CEPS technology can
also be used for efficient head-to-
tail cyclisation of peptides of over 12
amino acids length (see Figure 1).
The preference for cyclisation over
oligomerisation is significantly higher
than using chemical cyclisation of side- Figure 2. Example of a stepwise coupling of peptides to a protein (Ser-Tyr-Arg-extended hSA).
Using two different selective peptiligases, N-terminal protection of the peptides is not necessary.
chain protected peptides, so cyclization
can be performed at much higher
concentrations. Additionally, extremely - The greater flexibility to select fragments offers more
long polypeptides can be ligated to peptides yielding products predictable and shorter process development & scale-up
of over 850 amino acids in length. Moreover, pharmaceutical timelines.
peptides have been ligated to proteins such as human Serum - The overall cost-price reduction is 30-70%, depending on
Albumin in nearly quantitative yield (see Figure 2). the peptide length, sequence and production scale.
- Enzymatic cyclisation of side-chain unprotected peptides
EnzyPeps CEPS technology offers a number of clear is preferred over oligomerisation such that higher
advantages over the current state-of-the-art technologies: concentrations can be used, thereby further increasing
the volumetric productivity.
- Significantly higher yields and less purification costs - There seems to be no upper limit on peptide length,
compared to full SPPS of a peptide. since it is possible to couple peptides to the N-terminus or
- Compared to chemical fragment condensation C-terminus of proteins with high efficiency.
strategies, peptiligases offer a wide choice of coupling
positions and thus broader flexibility to select fragments, EnzyPeps CEPS technology will revolutionize the way complex
i.e. several convergent routes may be available. This peptides are synthesized. We would welcome the opportunity
not only significantly increases the overall yields (thus to discuss the application of this groundbreaking technology
reducing costs) and output of existing facilities, but can to your peptide with you.
also reduce synthesis times and operating work capital.
- No racemisation and no side-reactions, such as usually
occur in chemical fragment condensation, no matter
at which position in the peptide the fragments are
coupled.
- This results in significantly easier HPLC purification.
Typically, no additional runs of mixed fractions are
required reducing purification costs and organic
solvent consumption, making the overall process more For more information, please contact:
sustainable than current technologies. Peter van Tilburg, CEO
- A higher purity peptide product can be obtained than EnzyPep B.V., Chemelot R&D Campus,
can be achieved by chemical fragment condensation. 93-3-220, Urmonderbaan 22, 6167 RD
- All couplings are in aqueous solution, enabling Geleen, The Netherlands
higher concentration of fragments and thus a higher [email protected]; tel. +31 6 51997895
volumetric productivity.
NOME COGNOME
Indirizzo in minuscolo

NEWS NEWS NEWS NEWS NEWS NEWS NEWS
Researchers watch crystal structure

change in real time
Washington State University researchers have met the long- Administration, whose national security research mission
standing scientific challenge of watching a material change includes fundamental dynamic compression science.
its crystal structure in real time. The Advanced Photon Source synchrotron, funded by the
While exposing a sample of silicon to intense pressure due Department of Energys Office of Science, provided high-
to the impact of a nearly 12,000 mph plastic projectile they brilliance x-ray beams that pass through the test material
documented the transformation from its common cubic and create diffraction patterns that the researchers use to
diamond structure to a simple hexagonal structure. At one decode a crystal changing its structure in as little as 5 billionths
point, they could see both structures as the shock wave of a second.
traveled through the sample in less than half a millionth of a Were making movies, said Gupta. Were watching them
second. in real time. Were making nanosecond movies.
Their discovery is a dramatic proof of concept for a new way Stefan Turneaure, lead author of the Physical Review
of discerning the makeups of various materials, from impacted Letters paper and a senior scientist at the WSU Institute for
meteors to body armor to iron in the center of the Earth. Shock Physics, said the researchers exposed silicon to 19
Until now, researchers have had to rely on computer gigapascals, nearly 200,000 times atmospheric pressure.
simulations to follow the atomic-level changes of a structural They accomplished this by firing a half-inch plastic projectile
transformation under pressure, said Yogendra Gupta, Regents into a thin piece of silicon on a Lexan backing. While x-rays
professor and director of the WSU Institute of Shock Physics. hit the sample in pulses, a detector captured images of the
The new method provides a way to actually measure the diffracted rays every 153.4 nanoseconds the equivalent of a
physical changes and to see if the simulations are valid. camera shutter speed of a few millionths of a second.
For the first time, we can determine the structure, Gupta People havent used x-rays like this before, said Turneaure.
said. Weve been assuming some things but we had never Getting these multiple snapshots in a single impact
measured it. experiment is new.
Writing in Physical Review Letters, one of the leading physics What Im very excited about is we are showing how the
journals, the researchers say their findings already suggest that crystal lattice, how this diamond structure that silicon starts
several long-standing assumptions about the pathways of out with, is related to this ending structure, this hexagonal
silicons transformation need to be re-examined. structure, said Gupta. We can see which crystal direction
The discovery was made possible by a new facility, the becomes which crystal direction. Stefan has done a great
Dynamic Compression Sector at the Advanced Photon job. He has mastered that. We were able to show how the
Source located at the Argonne National Laboratory. two structures are linked in real time.
Designed and developed by WSU, the sector is sponsored
by the U.S. Department of Energys National Nuclear Security www.wsu.edu
SHOWA DENKO (SDK) (TOKYO: 4004) HAS DECIDED TO EXPAND ITS PRODUCTION CAPACITY
The range of LIBs use is rapidly increasing. These days, more and more LIBs are used not only in small devices such as smartphones
and tablets but also in large equipment, especially in electric vehicles (EVs). In China, the demand for large LIBs for use in EVs and
electric buses has been significantly increasing in recent years due to stricter emission control and subsidies to EVs by governments
and a surge in public awareness of the environment. LIBs for use in EVs have large capacities, thereby requiring a lot of materials. As
EV spreads, the size of the market for LIB materials is expected to continue expanding, and will be about 2 trillion in 2020. SCMGTM
has advantages of low resistance and long life, and demonstrates high performance when used in LIBs for EVs. SCMGTM is also rated
high by car manufacturers as material to be used in LIBs for vehicles with idling-stop function, which is expected to spread further.
This time, SDK decided to expand its capacity for producing SCMGTM in order to respond to a lively demand from our customers.
Commercial operation of the expanded production facility is scheduled to start at the end of 2016. Through this capacity expansion,
Omachi Plants SCMGTM production capacity will be increased by 50%, to 1,500t per year. In addition, SDK started to outsource
a part of its SCMGTM production to a manufacturer in China in this June. In January 2016, SDK also started to outsource a part of
its production of SDXTM carbon-coated aluminum foil, which is used as collector for cathode in LIB, to a Chinese manufacturer.
SDXTM has the advantages of low resistance and close adhesion to cathode materials in LIBs, thereby improving charge/discharge
performance of LIBs and contributing to a reduction in the amount of conduction supportive agents and binders added to cathode
materials in LIBs. The demand for SDXTM has also been increasing especially in the field of LIBs for EVs. To meet this increase in
demand, it became necessary for SDK to expand its SDXTM production capacity. Thus SDK started to produce SDXTM in China.
www.sdk.co.jp

New nontoxic process promises larger

ultrathin sheets of 2-D nanomaterials
A team of scientists led by the Department of Energy's Oak has potential applications in semiconductors, photovoltaics,
Ridge National Laboratory has developed a novel way to electrodes and water purification.
produce two-dimensional nanosheets by separating bulk
materials with nontoxic liquid nitrogen. The environmentally Because of the versatility and commercial potential of one-
friendly process generates a 20-fold increase in surface atom-thick 2D nanomaterials, scientists are seeking more
area per sheet, which could expand the nanomaterials' efficient ways to produce larger sheets. Current exfoliation
commercial applications. procedures use harsh chemicals that produce hazardous
byproducts and reduce the amount of surface area per
"It's actually a very simple procedure," said ORNL chemist nanosheet, Zhu said.
Huiyuan Zhu, who co-authored a study published in
Angewandte Chemie International Edition. "We heated "In this particular case, the surface area of the boron
commercially available boron nitride in a furnace to 800 nitride nanosheets is 278 square meters per gram, and the
degrees Celsius to expand the material's 2D layers. Then, we commercially available boron nitride material has a surface
immediately dipped the material into liquid nitrogen, which area of only 10 square meters per gram," Zhu said. "With 20
penetrates through the interlayers, gasifies into nitrogen, and times more surface area, boron nitride can be used as a
exfoliates, or separates, the material into ultrathin layers." great support for catalysis."
Nanosheets of boron nitride could be used in separation and Further research is planned to expand the surface area
catalysis, such as transforming carbon monoxide to carbon of boron nitride nanosheets and also test their feasibility in
dioxide in gasoline-powered engines. They also may act cleaning up engine exhaust and improving the efficiency of
as an absorbent to mop up hazardous waste. Zhu said the hydrogen fuel cells.
team's controlled gas exfoliation process could be used to
synthesize other 2D nanomaterials such as graphene, which www.ornl.gov
EVAPORATION INSIGHTS LEARNING CENTER

Genevac announces the launch of a new website that provides easily navigable access to the companys comprehensive
portfolio of evaporators and concentrators to suit almost any solvent removal application, purchasing budget or productivity
requirement. Located at www.spscientific.com/genevac - the new site offers visitors ready access to an extensive searchable
library of articles, technical papers, application notes and videos in the Evaporation Insights Learning Centre. Alison Wake,
Genevac Product & Marketing Manager commented: We have adopted the learning centre concept developed by our parent
company SP Scientific who have found this information rich resource to be the most popular feature for both customers and visitors
to the web site. There are many applications for Genevac evaporators and concentrators ranging from environmental analysis
through natural products research to parallel chemistry. Our new Evaporator Insights Learning Centre provides scientists with access
to the largest single evaporator / concentrator
knowledge base on the internet. In addition the
website offers detailed Genevac product information
(key feature/benefits, specifications, application
examples, accessories and literature), information
about service and support around the world and
news of the latest events the company is participating
in. The new site brings Genevac together with
other SP Scientific brands onto one website. SP
Scientific is the synergistic collection of well-known,
well-established and highly regarded scientific
equipment brands including Genevac, VirTis, FTS
Systems, Hotpack, Hull, and most recently PennTech,
joined to create one of the leading manufacturers of
specialty equipment for pharmaceutical, academia,
biotechnology and industry.
www.spscientific.com/genevac

UMICORE OPENS CATALYST FACILITY IN POLAND

Supporting Europes aim Cleaner air for all
The materials technology and recycling group Umicore today officially opened its new production plant for emission control
catalysts in Nowa Ruda, Poland (near Wrocaw). The facility allows the company to meet the growing demand for automotive
catalysts from its customers in Europe, a trend that is supported by tightening emission legislation in the European Union. With this
addition to its European footprint, Umicore complements its existing automotive catalysts production facilities in Germany, France
and Sweden. The plant, which is located in the special economic zone of Wabrzych, employs around 80 people and works with
the newest generation of process technologies. Pascal Reymondet, Executive Vice President Catalysis at Umicore, comments:
This investment enables us to supply our customers with technologies to meet the most stringent emission legislation and
support Europes aim for cleaner air for all. It also underscores our ambition to be a clear leader in materials for clean mobility.
Umicores catalysts enable improvements to air quality by transforming harmful vehicle emissions through sophisticated catalytic
processes. Umicore has been researching in the automotive catalysts sector for over half a century and producing them for over
40 years. Since then its technology has prevented hundreds of million tonnes of harmful pollutants from being emitted into the air.
www.umicore.com
SUNCOAST HEALTH BRANDS RELEASES TWO NEW BRAIN HEALTH SUPPLEMENTS WITH COGNIZIN CITICOLINE
Suncoast Health Brands has leveraged the power of Cognizin Citicoline for two new brain-health supplements designed to promote
healthier brain activity.
Cerebral Clarity and Focus are two of four supplements offered by Suncoast Health Brands to fuel the brain. Both use Cognizin as the
foundational ingredient for blends that may help the body combat stress and mental fatigue while improving memory performance,
attention, alertness and antioxidant levels. When we created our brain support line for Suncoast Health supplements, we wanted
to use the best ingredients, which is why we decided to put our best foot forward, do the research and find the best ingredients
on the planet for our Cerebral Clarity and Focus products, said Clay Desjardine, Suncoast Health Brand CEO. We have created
products we can hang our hats on and truly be proud to say are in our line. We know everyone is going to love them once they use
them. One of those key ingredients we sourced is Cognizin. We stand behind the quality and reliability of Cognizin. Citicoline is a
compound that promotes the production of phosphatidylcholine (phospholipids), important for brain function. Phospholipids make
up approximately 30% of brain tissue, aid neural communication and provide essential protection for neurons. Clinical research has
shown that citicoline has multiple applications and is able to improve various aspects of the brains physiological activity. Cognizin
Citicoline is a branded form of citicoline, an essential substance for brain health. Citicoline works to enhance communication
between neurons, maintain normal levels of acetylcholine, protect neural structures, and enhance health brain activity and energy.
www.cognizin.com
Chemical etching method helps transistors

stand tall
Smaller and faster has been the trend for electronic devices can lead to current leakage.
since the inception of the computer chip, but flat transistors have The Illinois technique, called metal-assisted chemical etching or
gotten about as small as physically possible. For researchers MacEtch, is a liquid-based method, which is simpler and lower-
pushing for even faster speeds and higher performance, the cost than using ion beams, Li said. A metal template is applied to
only way to go is up. the surface, then a chemical bath etches away the areas around
University of Illinois researchers have developed a way to etch the template, leaving the sides of the fins vertical and smooth.
very tall, narrow finFETs, a type of transistor that forms a tall We use a MacEtch technique that gives a much higher aspect
semiconductor fin for the current to travel over. The etching ratio, and the sidewalls are nearly 90 degrees, so we can use
technique addresses many problems in trying to create 3-D the whole volume as the conducting channel, said graduate
devices, typically done now by stacking layers or carving out student Yi Song, the first author of the paper. One very tall fin
structures from a thicker semiconductor wafer. channel can achieve the same conduction as several short fin
We are exploring the electronic device roadmap beyond channels, so we save a lot of area by improving the aspect ratio.
silicon, said Xiuling Li, a U. of I. professor of electrical and The smoothness of the sides is important, since the
computer engineering and the leader of the study. With this semiconductor fins must be overlaid with insulators and metals
technology, we are pushing the limit of the vertical space, so we that touch the tiny wires that interconnect the transistors on
can put more transistors on a chip and get faster speeds. We a chip. To have consistently high performance, the interface
are making the structures very tall and smooth, with aspect ratios between the semiconductor and the insulator needs to be
that are impossible for other existing methods to reach, and smooth and even, Song said.
using a material with better performance than silicon. Right now, the researchers use the compound semiconductor
The team published the results in the journal Electron Device indium phosphide with gold as the metal template. However,
Letters. they are working to develop a MacEtch method that does not
An array fin transistors made by the MacEtch method. The fins are use gold, which is incompatible with silicon.
tall and thin, with a higher aspect ratio and smoother sides than Compound semiconductors are the future beyond silicon, but
other methods can produce. silicon is still the industry standard. So it is important to make it
Typically, finFETs are made by bombarding a semiconductor compatible with silicon and existing manufacturing processes,
wafer with beams of high-energy ions. This technique has a Li said.
number of challenges, Li said. For one, the sides of the fins are The researchers said the MacEtch technique could apply
sloped instead of straight up and down, making them look to many types of devices or applications that use 3-D
more like tiny mountain ranges than fins. This shape means semiconductor structures, such as computing memory, batteries,
that only the tops of the fins can perform reliably. But an even solar cells and LEDs.
bigger problem for high-performance applications is how the
ion beam damages the surface of the semiconductor, which www.news.illinois.edu
EVAPORATION INSIGHTS LEARNING CENTER

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performance, versatility, ease-of-use and affordability making it the perfect workhorse system for Contract Research Organisations
(CRO's). The EZ-2 Elite is designed to efficiently concentrate or completely dry samples. It is compatible with a wide selection of sample
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SampleGenie technology combined with a FastLyo programme on the EZ-2 Elite allows HPLC fractions to be concentrated
and freeze dried directly into a submission vial. This innovation produces a weighable solid, eliminating manual
handling, increasing recoveries and removing the chance of cross-contamination. Operating the EZ-2 Elite is highly
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Process could make key biodegradable
polymer stronger and longer-lasting
Polylactic acid, or PLA, is a biodegradable polymer commonly Baker treated PLA samples under a variety of different
used to make a variety of products from disposable cups to temperature and pressure conditions for varying amounts of
medical implants to drug delivery systems. A team of Brown time. Pressures ranged from 2,000 to 20,000 pounds per square
University researchers has shown that by treating PLA at various inch. Temperatures used for treatments were above, below and
temperatures and pressures, they can induce a new polymer nearly equal to the glass transition temperature for PLA the
phase in the material one that could possibly decrease the temperature at which the amorphous parts of the material
rate at which it degrades. transition from solid to rubbery.
Its an exciting finding from the standpoint of basic science, Baker showed that the treatments increased the amount of
in that weve found a new polymer phase and have identified crystalline area in the material, but there was another more
a method for inducing it, said Edith Mathiowitz, a professor surprising finding. At higher temperatures and pressures, the
of medical science and engineering at Brown. In terms of amorphous parts of the material became birefringent, meaning
applications, the polymer we worked with in this study has many that they bend light differently depending upon how the light is
uses, and we believe the properties we have discovered now will polarized. That is an indicator of a substantial structural change
allow us to make it better. in the amorphous portions of the material.
The findings are published in the journal Polymer. Generally speaking, birefringence is a property found in crystalline
PLA is a semi-crystalline material, meaning parts of the materials materials, so seeing it in the amorphous regions of PLA was a
molecular structure are ordered into crystals while the rest is surprise. We didnt expect it to have such properties, Mathiowitz
disordered, or amorphous, like glass. Work by previous researchers said. So to see it in the amorphous phase was really amazing.
had shown that treating PLA with heat could increase the Baker then used several methods to further characterize how
materials crystalline makeup, which could help to increase the amorphous regions had changed. Using a technique called
its strength. Researchers in Mathiowitzs lab, led by doctoral X-ray diffraction, he showed that polymer strands in some of the
candidate and U.S. Navy veteran Christopher Baker, wanted amorphous sections had become dramatically more ordered.
to see if adding pressure to the treatment process would further The polymer strands are normally a tangled mess, Baker
influence the materials structure. said. But we found when we processed the material that the
amorphous region became less entangled and much more
oriented in a particular direction.
Further thermal analysis showed that the more ordered sections
had a higher glass transition temperature. In general, amorphous
materials with higher glass transition temperatures degrade at
significantly slower rates.
The new amorphous phase combined with the overall increase
in crystallinity in the treated samples could have significant
implications for the materials mechanical properties, the
researchers said. The higher crystallinity could make it stronger,
while the more ordered amorphous sections could make it last
longer. That slower rate of degradation could be particularly
useful in medical applications, an area in which Mathiowitzs lab
specializes.
For example, PLA is used as a coating for time-release pills and
implantable drug delivery systems. If the rate at which PLA
degrades can be controlled, the rate at which it delivers a drug
can be altered. There is also interest in using PLA for plates and
screws used to stabilize broken bones. The advantage to PLA
implants is that they degrade over time, so a patient would not
need a second surgery to remove them. PLA may degrade too
quickly for some of these applications, but if this new polymer
phase slows degradation, it may become a better option.
Now that weve shown that we can intentionally induce this
phase, we think it could be very useful in many different ways,
Mathiowitz said.
The researchers plan more research aimed at quantifying
changes in material properties as well as investigating whether
this phase can be induced in other semi-crystalline materials.
www.brown.edu
Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

INTERVIEW
A word with...
Torsten Derr
Chief Executive Officer
Saltigo Gmbh
Dr. Derr, first of all let me congratulate you on your recent At the present time, players in the chemical industry have
new appointment as CEO of Saltigo. You were handed over to struggle more and more to remain competitive in the
the reins of the company after the retirement of Mr. Wolfgang marketplace. Which is the trump card you can count on to
Schmitz: what will be the hallmark of your era? differentiate Saltigo from competitors?
Saltigo will continue to play a leading role in the exclusive Competitive costs, quality and compliance are enablers in the
synthesis of agrochemicals and fine chemicals. The custom manufacturing industry. This is the minimum you need
company is in very good shape: highly qualified staff and to be considered for exclusive synthesis. The differentiators to
a world scale technology platform helps us to satisfy the meet our customers requirements are technical capability,
needs of our customers. I will increase the pace of Saltigo flexibility and innovation.
by expanding our capacities and growing our business in Twenty percent of our 1,250 employees are working in R&D
regions outside of Europe. or engineering. This brings our products faster from the lab to
the production plant. From phosgenation over high pressure
Saltigo announced early this year a 60 million investments hydration to low temperature synthesis our people use this
by 2017 for the expansion of the Leverkusen site. Can you portfolio of technologies like playing with toy blocks. Saltigo has
provide our readers with some details of this operation? what it takes to generate profitability: innovation capability, a
Our growth was limited by our manufacturing capacities. 10-plant network in Germany and access to all major customers.
This is why we are significantly expanding our multi-purpose
plants on our site in Leverkusen. We will use a large share of Finally, a word on the economic scenario after the Brexit.
the investment to add further reactors to existing multi-purpose What is your view regarding the actions that the EU companies
facilities and to construct two new solids isolation and drying should undertake to front this new challenge.
lines. Existing equipment will be further automized. In addition, We regret the United Kingdom vote to leave the E.U., as we at
we will invest in an even more efficient raw material and solvent Saltigo are convinced that a strong Europe as a community
supply of our production facilities through the installation of a can best capitalize on the global opportunities presented to
new bulk storage unit. The complete facility will be equipped us including economically. Nevertheless, we will maintain
with a modern process control system to combine the highest the good relationship to our industry partners in the UK and
possible qualitative requirements with maximum productivity. support them wherever possible.
The construction has already started, while commercial
production is planned for the end of 2017. The majority of
these future capacities is already contractually secured with By Carlo M. Buonamico
our customers. Chimica Oggi - Chemistry Today

FLOW CHEMISTRY
LAURENT PICHON
MEPI, Plateforme SAFRAN HERAKLES - Chemin de la Loge
CS27813 F-31078 Toulouse Cedex 4, France
Laurent Pichon
Flow chemistry:
analysis of market trends
Sightseeing by skilled flow chemists
KEYWORDS: Flow chemistry, market and regulatory trends, offer width.
Abstract The recent flow chemistry market, offer, and regulatory trends are displayed in the light of experts
comments. Moving demand is pushing the equipment makers to adapt themselves quickly and
efficiently leading to an innovative and interactive Innovation
A MARKET/PERCOLATION MATRIX This was not so visible until recently, due to internal maturation
processes and, as early stage drug development is always
The concept of flow chemistry has been promoted for more surrounded by strict confidentiality. Vijay Kirpalani, Ceo at Pi
than one decade now, not only through the organization of - Process Intensification Experts LLP, adds: Key drivers for
specific scientific symposiums, but with an increasing and self- Pharma have been cost savings, robust steady-state
adapting offer of innovative equipments available on the manufacture and access to non-infringing routes via hitherto
market at various scales. A need for an up-dated picture of considered forbidden-chemistries. Fine, Speciality and Agro
where this technology breakthrough stands, naturally emerged. chemicals are driven by cost, safety and the stricter
environmental laws.
To more accurately figure out the current flow chemistry
scene, a questionnaire was sent out to both chemical This was confirmed at the last CHEMSPEC Europe in Basel,
companies and equipment manufacturers. All the by Jrg Schrickel, who explained the benefits of flow vs
participants, with no exception, mentioned a positive trend in batch approaches for chlorinations and sulfonations.
the adoption of continuous intensified processes. This trend is Sebastian Rieth from Roche adds: The pharma production
more visible since a couple of years. is under an increasing pressure of costs, so the industry looks
for more economic ways of production. In chemistry, where
All markets do not respond the same way. The first segment to more and more dangerous chemicals are used, it is a big
taste the flow chemistry was obviously the pharmaceutical advantage if I can synthesize them in a small flow-device,
industry. The commissioning by GSK at the beginning of this year and do not have to store or transport them.
of a fully continuous process for API manufacturing is the result Charlotte Wiles of Chemtrix said: Whilst the recent
of a decade of human and technical investments said Andrew publicity cases relating to the use of continuous
Rutter. Most of the big pharmaceutical companies have manufacturing are largely related to the technologies use
reached a well advanced point in the knowledge of flow. within the pharmaceutical industry, the trend of the past
Vijay Kirpalani
Sebastian Rieth Charlotte Wiles Robert Tinder Jeffrey C. Raber
Pi - Process
Intensification Experts Roche Chemtrix Proteaf Technologies KinetiChem

two years is that uptake is fastest We see a rather small
within the fine chemical and percentage of processes in
specialty sectors. flow today but that is certainly
Indeed, the speciality chemical increasing states Jeffrey C.
sector remains a good target, Raber, President of
especially in Europe where a KinetiChem, Inc.
need for new investments is In Fierce Pharma
more pregnant to accompany Manufacturing, Feb. 19, 2013,
continuous market growth. CEO of GlaxoSmithKline
Andrew Witty said: []
This is one of the reasons why Between a third and a half of
equipments providers are the company`s current portfolio
launching larger capacity of drugs could be made using
continuous reactors. These continuous processing..
bigger tools are used for
dedicated productions on the speciality chemicals segment, In reality, the answer is a sophisticated mixture of
while the fine chemicals sector is using those as multi- chemistries trends, application segments and
purpose continuous productions tools. The introduction of geographical zones.
new materials like the silicon carbide, first developed on flow Gareth Jenkins from AM Technology says: For new
chemistry by MEPI in 2008, are rending possible, a large products which need new plants to be built, starting out
variety of chemistries in the same equipment, due to designing with continuous processing in mind will mean
exceptional heat exchange and corrosion proof that all of the potential benefits can be applied. For
performances. Robert Tinder of Proteaf Technologies existing products, however, it is a much more complex
confirms: With new technologies emerging every day, it is picture and depends on many factors. There will be
hard to imagine flow chemistry not gaining greater examples where continuous processing could be used
acceptance as a tool for accomplishing chemical tactically to debottleneck an operation or part of a
transformations. plant.
SIGNS OF HOPE STRATEGIES ARE SELF-DESIGNING
More recently, new investments where disclosed in Europe in In fact we see three emerging strategies for flow chemistry
the fine chemical sector (PCAS in Couterne, Dottikon ES in industrial implementations:
Aargau). These are building encouraging signals for the 1. The "container factory" which consists in building your
flow chemistry in Europe after nearly two decades of a really intensified plant within a mobile box, that can move
quiet period on the investments side. from one workshop to another, or one site to another.
This strategy has been pushed by companies like
These first signs of changes could be propelled by a higher Ehrfeld Mikrotechnik BTS within the INVITE programs.
desire of China & India to improve the eco impacts of their
local chemical industries, and associated closures of out of 2. The "hood factory" consisting of placing the reactive
international standards factories. parts of the milli-plant in a hood, as innovation
platforms do, but also industrial actors like Merck,
At the same time, and logically, the adoption of flow confirmed John Naber at the last RSC Symposium in
chemistry in Asia has been by far the quickest since few years, Cambridge.
while cash flow, quick decision processes, need for up-grade
& innovation are common. The recent growth in Europe is 3. The "squatter factory" is a hybrid solution consisting of
adding on the world demand. placing flow chemistry mobile components (reactors,
pumps, thermal exchange device, data acquisition) in an
When it comes to predict the future market share of continuous existing batch workshop. The former batch reactors are
over batch processes, the answers are all leading to a double temporarily connected to the flow unit and used as
digit figure, but it is harsh to predict it in a more accurate way. feeding or receiving stations. This remains an excellent
option at reasonable cost for some flow eligible chemistry
candidates. MEDICHEM revealed the implementation of
such a strategy on their Girona site with a Corning
reactor at the last Chemistry Today Symposium in Delft,
on September 2015.
The availability of flow chemistry equipment with improved

cost and performance are a boosting factor. Innovative
manufacturing techniques for industrial flow reactors, like 3D
metal printing (selective laser melting) recently developed
Gareth Jenkins Andr H. M. de Vries
and launched by DSM, says Andr H.M. de Vries Business
AM Technology Innosyn
Manager Innosyn, will certainly reinforce the attraction to
the flow offer.

Andrea Adamo Nuno Matos Dirk Kirschneck Alessandra Vizza
Zaiput Flow Technologies Hovione Microinnova Engineering Corning
FUTURE TRENDS
Few barriers are however regularly mentioned.

When it comes to regulatory affairs, and especially for the
pharmaceuticals sector, flow is certainly challenging a batch
minded community.
However, the learning curve is now playing in favor of
continuous processes. In April this year, the continuous
production of Janssen HIV drug Prezista at their Porto Rico
Gurabo site was greenlighted by the FDA, which is
encouraging other pharmaceutical companies to engage
similar moves.
Pharmaceutical companies, or CMO working for the

pharmaceutical sector, like Novartis, Ely Lilly, AstraZeneca, SK
Chemicals... are more and more presenting achievements on
continuous processes at various Flow Chemistry Symposiums.
By courtesy of MEPI
Another concern is the switch to continuous for the

downstream steps.
Andrea Adamo from Zaiput Flow Technologies says: We think several technologies that will allow us to isolate our products
the landscape of equipment offer is quite populated, in a continuous fashion, outputting particles with chemical
especially in terms of reactor units. We hope our in line work- and physical attributes tightly controlled.
up technology will experience wider adoption and lead to
higher level of process integrations. Probably more solutions Dirk Kirschneck, Managing Director of Microinnova
are needed in some aspects of downstream processing. Engineering is adding: In the last two years we have
done more and more activities in downstream processing
But here again, the technology is evolving quickly to fill the like crystallization and extraction as well as in continuous
existing gaps. liquid formulation. Furthermore we realized a high
demand of modular flow systems which can deal with
Nuno Matos, Head of Continuous Manufacturing at Hovione, different types of technologies including one for high
said: We are optimistic that in the next 5 years important viscosities and for continuous processing of solids.
technology developments will occur allowing to extend to
other unit operations what was already achieved with flow However the market is still working in a conservative way
reaction. For instance, at Hovione, besides Spray-Drying, we and breaking the pattern is possible only with the
are currently testing and increase of successful number of installations
developing in continuous and time, as any disruptive technology
adoption in conservative market confirms Alessandra
Vizza Abrial, Regional Commercial Manager EMEA & NSA
Corning Reactor Technologies, at Corning SAS.
The percolation of continuous processes on the

traditionally batch set industrial grounds remains
challenging, but positive signs are now definitively on.
Cultural changes, growing demand, regulatory pushes,
need for more eco-efficient processes, and offer agility
are now paving the way to a bright flow chemistry
spread out.

FLOW CHEMISTRY
KLRA LVEI1,2*, PTER BANA3, RBERT RKNYI3, GYRGY I. TRS1,

JNOS LES1, ZOLTN NOVK2, FERENC FAIGL3,4
*Corresponding author
1. Gedeon Richter Plc., Gymri t 19-21., Budapest, H 1103, Hungary
2. MTA-ELTE Lendlet Catalysis and Organic Synthesis Research Group, Institute of Chemistry,
Etvs University, Pzmny Pter stny. 1/a., Budapest, H 1117, Hungary
3. Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
Budafoki t 8., Budapest, H-1111, Hungary
4. MTA-BME Organic Chemical Technology Research Group, Budafoki t 8., Budapest, H-1111, Hungary Klra Lvei
Continuous flow synthesis

of heterocyclic scaffolds
Design principles of multistep systems A review
KEYWORDS: Continuous flow synthesis, condensed heterocycles, scaffold, multistep flow synthesis, telescoping.
Abstract The synthesis of novel heterocycles is an essential task in small-molecule drug discovery. Continuous flow
processing opens the way for a new paradigm in laboratory-scale synthesis as well as pharmaceutical
manufacturing. Based on our experiences with the multistep synthesis of condensed benzothiazoles, we gathered some of the key
design features in light of literature examples.
INTRODUCTION we faced during our research on the multistep synthesis

of condensed benzothiazoles (14) (Figure 1), in the light of
The design and preparation of new heterocycles as recent references within the flow chemistry literature.
scaffolds or building blocks for active pharmaceutical
ingredients (APIs) is a challenging area in todays small-
molecule drug discovery. Chemists seek new approaches HETEROCYCLIC SCAFFOLDS IN DRUG DISCOVERY
and technologies that can be applied to produce novel
structures, while keeping an eye on the improvement of the The development of new leads for APIs is largely based on
efficiency and productivity of the chemical processes. The the design and synthesis of new heterocycles. Applying them
new enabling technologies (1, 2), like flow chemistry (3, 4), as building blocks, biological activity and physicochemical
provide practical solutions for the synthesis of heterocyclic properties (like solubility, polarity and lipophilicity) of a given
compounds. The emerging trends and recent synthetic molecule can be modulated. In medicinal chemistry, the term
results indicate the growing importance of continuous flow scaffold is used for the core structure of a molecule, which is
manufacturing in academia as well as in pharmaceutical often a heterocyclic ring or ring system. Synthesis of molecules
industry (59). These efforts are also pointing towards the with similar biological profile but replaced central moiety
realization of continuous technologies for API synthesis (10, 11) may become necessary (scaffold hopping), when certain
in accordance with FDAs recommendations (12, 13). properties or novelty of the compound series are problematic.
However, the application of The different chemical structure
flow methods demands a can lead to new patentable
paradigm shift in synthetic libraries (1517).
mentality and a new Although a wide range of
knowledge base, which can heterocycles is theoretically
mean a barrier for those, available (18, 19), the
who are unfamiliar with it. obtainable number and variety
Our experience during the are limited by the parameter
introduction of this technology window, and convenience
to laboratory practice inspired of the synthesis (2022). In the
us to compile this mini-review, preparation of such compounds
to make flow chemistry more with increasing complexity,
Figure 1. Considerations for the proposed multistep continuous flow
accessible. Here we discuss the synthesis of condensed benzothiazoles.
the classical laboratory-scale
problems and their solutions methods are often difficult.

Multiple steps, use of hazardous reagents, high pressure successfully applied in our procedure for the synthesis of
and/or temperature are usually required. These circumstances benzofurans and benzothiophenes, in order to replace
can hinder the production of the desired structures. Flow potassium carbonate, which was used in the batch
chemistry, as an enabling technology provides new synthesis (14). While this change did not affect the synthesis
opportunities to broaden the chemical space. of benzothiophenes negatively, we found that this way the
alkylation reaction yielded the intermediate in the case of
benzofurans. To obtain the bicyclic products, we had to
DESIGN OF THE FLOW REACTIONS use the stronger Verkades base (P(CH3NCH2CH2)3N),
which proved to be suitable in terms of the flow conditions
In our recent article (14) we have developed a multistep (28) (Figure 3).
continuous flow approach for the synthesis of various tricyclic
benzothiazoles (compounds I-V, Figure 2).
Figure 2. The prepared tricyclic compounds.
We intended to obtain them in three steps: (1) the

preparation of the corresponding bicyclic compounds
bearing a nitro-group, (2) the reduction of the nitro-group
and (3) the formation of thiazole ring. Possible issues
concerning the selection of the solvent, handling of the
Figure 3. The synthesis of benzofurans and benzothiophenes
insoluble or hazardous reagents, and the implementation mediated by different bases.
of hydrogenation were taken into account during the Reaction conditions: (a) DMF, 100 C, 25 min, 5 bar; (b) ethanol,
synthesis. 100 C, 5 min, 5 bar; (c) DMF, 100 C, 25 min, 5 bar.
The choice of the appropriate solvent is a primary
concern when designing continuous flow reactions. In
the simplest case, a single solvent can be used which Several examples are reported, in which
sufficiently dissolves all reagents and products, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is used as a
tolerates all reaction conditions. Even in this case, soluble strong base (2931). Solid supported alternatives
unexpected precipitation of transient species can occur, of DBU (31), as well as other strong bases such as
because the solubility of these compounds cannot be phosphazenes (29, 32), were used in heterocyclic flow
explored beforehand. However, slight clogging can be synthesis.
flushed out if the system is carefully monitored. During In our view, the most successful approaches employ careful
our work, we found that N,N-dimethylformamide (DMF) screening: polar solvents and soluble organic reagents are
could be applied in every step of the multistep protocol. suitable in the majority of cases.
The final step specifically required DMF to dissolve the The safe handling of explosive or toxic reagents and the
products completely. This motivated us to use this solvent precise control of the process conditions are two of the
in the hydrogenation step in order to simplify the whole main benefits of flow chemistry that are getting more
sequence (14). and more important both in laboratory environment
This solvent also proved to be the best option for the two- and on industrial scale (11, 33, 34). Due to the size of the
step syntheses of 5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)- microreactors, the actual reaction occurs only in a small
one derivatives (23) and imidazo[1,2-a] heterocycles (24). volume at a given time, which minimizes safety issues.
The high solubility of the compounds and their compatibility The handling of bromine in the continuous flow ring-closure
with the integrated purification necessitated the use of N,N- reaction leading to tricycles (14) was safer than in case
dimethylacetamide in the synthesis of 1,2,4-oxadiazole and of batch conditions, since the flow equipment can be
1,2,4-triazole libraries (25). considered as a closed system, which prevents the escape
Dichloroethane was used in the telescoped synthesis of of harmful vapours.
quinoxalines (26). Hazardous reagents were generated in-situ in the
The replacement of the insoluble reagents, most often microreactor during the syntheses of other heterocycles.
bases, by soluble alternatives is a common method to Toxic alkyl nitrite and TMS azide reagents were safely
avoid clogging. N,N-diisopropylethylamine (DIPEA) is often used and the resulting explosive azides were transformed
used under flow conditions (24, 25, 27). This base was to stable triazole products in a two-step sequence (35).

Unstable diazoketones were synthesized and used decomposition products during purification. At this point, we
without isolation for the preparation of a wide range of realized that the initially envisioned telescoped approach
quinoxalines (26). (Figure 4) would show its benefits in this particular problem.
This way, the outcome of the multistep system was better than
Flow processes are also advantageous for hydrogenations. the overall yield of the single steps.
The benchtop hydrogenation modules enable the safe
handling of both hydrogen and the heterogeneous However, during the investigation of the connected system
catalysts, most commonly loaded into packed bed we found, that utilization of the stream from the first step led to
reactors (36). The separation of the catalyst from the poorer results in the formation of the thiazole ring, compared to
reaction mixture is trivial with this setup, since it does the same reaction conducted as an isolated step. We assumed
not require additional filtration. In our work, we utilized that in this case the lack of the premixing of the amines with
commercially available continuous flow hydrogenation ammonium thiocyanate, which happens in the storage flask
equipment with preloaded Pd/C cartridges for nitro- in the single step procedure, hindered the following reaction
reduction in the first step of our sequence. Due to careful with bromine. Increasing the mixing time by adding a coil
optimization (37), sufficiently clean product (without reactor before the introduction of bromine, we could obtain
leaching of the catalyst) was obtainable in every case, higher overall yields. Although, this modification increased the
which helped to avoid the otherwise problematic number of steps (which contributes to complexity adversely),
purification of the sensitive amines (14). it was advantageous in context of the whole process. Similar
Several examples of selective ring saturation, late-stage observations on the importance of the mixing time, in terms of
modification and protecting group removal can be the overall yield and kinetics of the reaction were made in the
mentioned in this context, using flow hydrogenation (3840). continuous flow synthesis of 4,5-disubstituted oxazoles (32).
During the three step synthesis leading to the intermediate
of the API Atazanavir (41), a similar approach was applied When connecting the separately optimised steps in our study,
for the hydrogenation of hydrazone. we had to remove the hydrogen used in the nitro-reduction,
In summary, the ability to conduct reactions that are prior to the thiazole formation. The addition of a buffer vessel
otherwise unsafe is a real advantage of continuous flow to the reaction stream was sufficient for degassing.
processes, which can also be exploited on industrial scale. The same solution was employed in the multistep flow
synthesis of Rolipram (42), while other researchers tended
to avoid the problem of gas separation and conduct
INCORPORATION OF THE REACTIONS INTO A CONTINUOUS hydrogenation as the last step (40, 41).
FLOW SYSTEM
These examples highlight the importance of flexibility when
One of the main goals of continuous flow processes is to designing and implementing highly integrated systems, which
perform multistep reactions in a telescoped way, without are suitable for the synthesis of heterocyclic compounds.
purification and isolation of the intermediates at the end
of each step. Consequently, all reaction steps have to be
designed to be compatible with the whole sequence. FURTHER IMPLICATIONS
To achieve this, every single reaction parameter, chemical
transformation and flow equipment should be taken into Besides the above mentioned advantages, the application of
account. flow chemistry enables the rapid optimization of reactions and
synthesis of compound libraries together with automatization
In the course of our synthesis (14), the aromatic amines (43, 44). In our study, the quick automated optimization
prepared in the first steps proved to be unstable leading to (45, 46) of conditions for each reactions was possible (14).
With the appropriate setup, small volume reaction
mixtures can be handled rapidly and safely, which
lowers the reagent consumption of the optimization
process. New reactions can be discovered this way,
for example, novel route to the core heterocycle
of Efavirenz was enabled by extensive screening of
conditions (47).
Several analogues and larger compound libraries

can be prepared, thankfully to the variability of
such systems. Numerous examples show that this
concept is viable using specific, carefully designed
and optimised fluidic setups (23, 29, 32, 35, 48, 49).
CONCLUSIONS
The application of flow chemistry has great

Figure 4. The multistep continuous flow synthesis of compound V. perspectives in drug discovery. In order to take
Reaction conditions: (a) DMF, 60 C, atmospheric pressure; (b) DMF, 25 C, 30
min, 1 bar; (c) methanol/DMF, 25 C, 30 min, 1 bar. advantage of its benefits, chemists need to learn how
to design and build complex continuous flow systems.

In this mini-review we have focused on the everyday (last checked on May 23rd 2016).
challenges of laboratory-scale multistep flow synthesis. We 14. Lvei K., Greiner I., les J., et al., J. Flow Chem., 5, 7481 (2015).
aimed to present some of the design principles through our 15. Gomtsyan A., Chem. Heterocycl. Compd., 48, 710 (2012).
16. Bhm H.-J., Flohr A., Stahl M., Drug Discov. Today Technol., 1,
experience in this field, alongside with literature examples, to
217224 (2004).
help others with their own experiments.
17. Brown N., Jacoby E., Mini-Reviews Med. Chem., 6, 12171229
(2006).
18. Pitt W. R., Parry D. M., Perry B. G., et al., J. Med. Chem., 52,
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SCIENCE HISTORY
MICHAEL FREEMANTLE
Science writer
Basingstoke, United Kingdom
Michael Freemantle
How chemistry underpinned

the First World War
KEYWORDS: First World War, explosives, propellants, chemical warfare, disinfectants, antiseptics, anaesthetics, analgesics.
Abstract The industrial-scale death and destruction of the First World War could not have occurred without the
industrial-scale production of a vast variety of chemicals. They included the high explosives used to fill
artillery shells, the propellants for firing the shells, and highly toxic chemical warfare agents such as chlorine, phosgene and mustard
gas. Chemicals, however, were used not just to kill, maim and destroy, they were also used to prevent the spread of infection and
help care for the sick and wounded.
INTRODUCTION each other with chemicals in the form of explosives and toxic
gases. Paradoxically, chemistry also underpinned the war in
The First World War was fought from late July 1914 to exactly the opposite way. It helped to save lives through the
November 1918. It pitted the armies and industrial might of use of disinfectants, antiseptics, anaesthetics and a variety of
the Central Powers, notably Germany, against the armies pharmaceutical preparations, not least pain killers.
and industrial might of Britain, France, Italy, Serbia, Russia and
other Allied Powers.
The war relied extensively on the mass production of artillery EXPLOSIVES
weapons, machine guns, rifles, ammunition, and other military
supplies. Over the four years of the war, some ten million High explosives, such as 2,4,6-trinitrotoluene (TNT) and picric
soldiers, sailors, airmen, medical officers and nurses died on acid (2,4,6-trinitrophenol), are materials that, when detonated,
the battlefields, in the trenches, in the tunnelling operations, decompose and release the energy in their chemical bonds
in the air, at sea, and in the casualty virtually instantaneously. The shock
clearing stations and military wave of the explosion travels faster
hospitals. Millions of civilians also than the speed of sound. Armies on
died as a result of the war. both sides of the conflict fired millions
In addition, more than eight million of shells packed with high explosives.
horses died in the war. Some 7,000 For example, during the Battle of the
horses were reported to have been Somme, which was fought from 1
killed on one day alone during the July to 18 November 1916, the British
Battle of the Verdun. The battle and German armies fired a total of
between the French and German 30 million shells. That is equivalent to
armies was fought at Verdun-sur- some 150 shells every minute, day
Meuse in north-eastern France from and night.
21 February to 18 December 1916. The shells were propelled through
Chemistry played a major role in the air by firing propellants, typically
this carnage. When engaged in Shells from the Battle of the Somme, 1916, on display at mixtures of nitrocellulose and
the Ulster Tower Memorial, Thiepval, France.
battle, the opposing armies spent (Photo by Michael Freemantle) nitroglycerine. Propellants are low
much of the time bombarding explosives.

Postcard showing civilians tending two horses, one dead and
Postcard showing a convent in Arras, France, on fire following a the other injured, in a street in Soissons, France, following a
bombardment in 1914. (Postcard courtesy Michael Freemantle) bombardment in 1914. (Postcard courtesy Michael Freemantle)
When ignited by a spark or flame, they burn extremely for its war effort. The country would soon have run out of
rapidly forming carbon monoxide, carbon dioxide, explosives and might possibly have lost the war some time
nitrogen, and other gases. The rate of combustion, and in 1915.
therefore the rate of explosion, although fast, is slower than
the speed of sound. The gases formed by the explosion Britain similarly had a problem in obtaining the raw
generate intense pressures inside the firing chambers of the materials to make explosives. The standard propellant
guns. The pressures are sufficiently high to propel the shells used by the British army and navy in the war was cordite,
out of the barrel of the gun at high velocity. a mixture of nitrocellulose and nitroglycerine in petroleum
Production of explosives and munitions throughout the war jelly. Explosives factories in the country employed acetone
was immense. One factory in North Wales produced 500 as a solvent to manufacture the propellant. The solvent
tons of TNT and 250 tons of nitrocellulose each week at was traditionally produced by the destructive distillation of
the height of the war. And there were many such factories wood, much of which was imported from other countries.
producing explosives in Britain during the war. Other British stocks of acetone and cordite began to run low as
factories filled shells, mines and bombs with explosives. One early as 1915. Britain was in crisis.
such factory in England is reported to have filled 19 million Chemist Chaim Weizmann, a naturalised British subject,
shells, 25,000 sea mines, and 2,500 bombs during the war. came to the rescue. In 1912, he had discovered a way of
producing acetone by the fermentation of maize. Three
At the beginning the war, Germany had a problem years later, he started to work with the British Admiralty to
manufacturing explosives on such a scale. The country scale up the process and by 1917 the country was using
anticipated that the war would last only a few months his process to produce acetone at the rate of almost 3,000
and be over by the end of 1914. But as the war continued tons annually, enough to make all the cordite required
into 1915, its stockpiles of munitions and explosives rapidly by Britains armed forces. Following the war, Weizmann
diminished. Most importantly, nitric acid became scarce. became president of the World Zionist Organisation which
The acid was required for the production of explosives aimed to establish a homeland for the Jews in Palestine. In
such as TNT, picric acid, nitroglycerine, and nitrocellulose. 1949, he became the first president of the State of Israel.
Much of the acid was traditionally produced from Chile
saltpetre, a potassium nitrate mineral imported from South
America. The British naval blockade of Germany, however,
prevented supplies of the acid from reaching Germany.
The chemical industry in Germany therefore had to turn
to other methods of making the acid. Before the war,
German chemist Fritz Haber had discovered a way of
making ammonia from the nitrogen in air. A team at the
German chemical company BASF led by industrial chemist
Carl Bosch subsequently developed the process for
producing ammonia on a large scale. The ammonia was
initially used to make ammonium sulfate, a nitrogenous
fertiliser. Soon after the outbreak of the war, the German
chemical industry adapted its plants to produce nitric acid
from ammonia using a process developed by German
chemist Friedrich Wilhelm Ostwald. The process employs
atmospheric oxygen to convert ammonia into nitrogen
dioxide which in turn is dissolved in water to form nitric acid.
It can be argued that, had it not been for the Haber-Bosch 11,962 First World War servicemen are buried or commemorated
at the Tyne Cot Cemetery, near Passchendaele in Belgium. 8,374
and Ostwald processes, Germany would not have been of the burials are unidentified. (Photo by Michael Freemantle)
able to manufacture nitric acid in sufficient quantities

CHEMICAL WARFARE Allies and the snout-like
canister gas masks developed
The first use of lethal gases by the Germans had become
occurred on 22 April 1915 fairly sophisticated. Both types
when the German army worked on similar principles.
discharged 168 tons of The troops breathed in air
chlorine gas from cylinders through a box or canister
against the Allied troops containing three types of
at Langemarck near Ypres chemical materials. Activated
in Belgium. The so-called charcoal, a highly porous
cloud-gas operation killed form of carbon, trapped
some 800 French, Algerian some of the gases. Strongly
and Canadian soldiers and alkaline materials, such
wounded or gassed a further as soda lime (granules of
2,000. It was the first time in calcium hydroxide containing
history that a weapon of mass a small amount of sodium
destruction had been used. hydroxide) neutralised
The attack and the British Preserved Western Front trenches at the Sanctuary Wood chlorine and other acidic
Museum Hill 62, Belgium. (Photo by Michael Freemantle)
use of chlorine at the Battle gases. Oxidising agents like
of Loos in northern France in potassium permanganate
September 1915 sparked a race to develop more potent destroyed both toxic and tear gases.
chemical weapons. The Germans introduced phosgene The chemical warfare of World War I, although notorious,
in a cloud-gas operation against the British in Flanders in should be placed in context. Statistics reveal that chemical
December 1915. By the end of the war, a wide variety of warfare accounted for a relatively low percentage of the
chemical warfare agents were being used by both sides. battlefield casualties and fatalities on both sides during the
Cloud-gas operations were only successful if the wind war. The vast majority of injuries and deaths were caused
was blowing towards the enemy. Wind was not a factor, by artillery shelling and machine-gun and rifle fire. It is
however, when it came to firing artillery shells filled with doubtful whether chemical warfare had much impact on
toxic gases. The French began firing shells filled with the final outcome of the war.
phosgene against the Germans at the start of the Battle
of Verdun in February 1916. The phosgene had to be
refrigerated before it could be poured into shells.
Later that year, the Germans began to fill artillery shells
with disphosgene, a lethally toxic oily liquid with a much
higher boiling point. It could therefore be readily poured
into shells.
By 1917, both sides in the war had developed gas masks
that protected the eyes, nose and mouth against a range
of lethal gases. The Germans therefore came up with the
idea of employing a chemical warfare agent that attacked
not just the face but the whole body. They decided to
employ a vesicant, or blister agent, that not only blinded
troops and injured their lungs but also blistered and burnt
their skin. The chemical was mustard gas, also known as
sulfur mustard or dichloroethyl sulfide. The gas, actually a
liquid, has little odour, and is able to penetrate clothing.
The Germans first used mustard gas in July 1917 when they
bombarded the British lines east of Ypres in Flanders with
some 50,000 shells filled with the liquid.
The French were the first of the Allied forces to employ the Injured soldier: an exhibit at Muse Somme 1916, Albert, France.
(Photo by Michael Freemantle)
gas as a chemical weapon. They began firing mustard gas
shells on the Western Front in June 1918. The British followed
suit three months later, firing their first mustard gas shells at
the Battle of St Quentin Canal, France, on 29 September, COMBATING DISEASE AND RELIEVING PAIN
the opening day of the battle.
Chemists, chemistry and chemicals played not only an Soldiers fighting at the front were not only at risk of death and
offensive role in chemical warfare, but also a defensive injury from shells, bullets and lethal gases, they also had to
role. Soon after the first deployment of chlorine as a face the threat of various infectious diseases. The troops often
chemical warfare agent in April 1915, the Allies began to lived for days in fly- and rat-infested dugouts and trenches
develop gas masks to protect against the gas. Then, when where they were bitten by fleas and clothed in lice-ridden
the Allies began to use the gas as a weapon, the Germans uniforms. Injured troops sometimes had to lie on the battlefield
developed their own masks. for hours if not days in filthy clothing, mud, and soil teeming
By 1917, the so-called box respirators produced by the with dangerously infectious microorganisms.

Chemical compounds also provided pain relief for wounded
soldiers in another way. Surgeons often used chloroform as
a general anaesthetic to carry out amputations and other
operations in military hospitals and casualty clearing stations.
Diethyl ether, generally known simply as ether, and ethyl
chloride were also employed as general anaesthetics.
CONCLUSION
The First World War was, for the most part, a static war of
attrition of both men and materials. The side that could keep
going longest without exhausting its supplies of both was sure
to win. And that depended to a large extent on chemistry
and chemists. Their ingenuity and efforts ensured that the
factories in their countries could continue making explosives,
The inoculation department at St Marys Hospital, London,
chemical warfare agents, and other essential materials
produced ten million doses of typhoid vaccine during the war. required by their armies, navies, and air forces.
(Photo by Michael Freemantle) Chemists were needed to control the manufacture of
munitions, explosives, metals, leather, rubber, oil, gases, food,
drugs noted British chemist Richard Pilcher in 1917. He called
Dysentery, typhoid, typhus and other infectious diseases were the First World War the chemists war.
rampant in the war, killing hundreds of thousands of troops.
A broad range of disinfectants and antiseptics were employed In the end, Germany found it impossible to supply sufficient
to combat pathogenic microorganisms. Troops disinfected men and materials to sustain its war effort. Despite the best
their trenches and latrines with chloride of lime, also known as efforts of its chemists, the country could not produce fertilisers
calcium hypochlorite or bleaching powder. They also used and pesticides in sufficient quantities to provide all the food
the disinfectant to sterilise drinking water. In addition, medical needed by its civilian population and armed forces and at
officers in casualty clearing stations and military hospitals the same time make the munitions, explosives, and other
treated the wounded with antiseptic preparations consisting items required by its armed forces.
of aqueous solutions of the hypochlorite and other antiseptic In a lecture to German Army officers after the war Haber
chemicals such as boric acid. concluded that the uncompromising alternative was to
Soldiers often carried first-aid kits containing a variety of starve or to shoot. He referred specifically to the nitric acid
items including a phial of tincture of iodine. The tincture is needed to make both explosives and nitrogenous fertilisers.
a weakly antiseptic solution prepared by dissolving iodine Demand outstripped supply. Almost 80 years later, Australian
in a solution of potassium iodide in ethanol and water. The historian Roy MacLeod put it another way. German industry
tincture was applied to the skin around superficial flesh could not deliver both guns and butter he said.
wounds to prevent the wounds from becoming infected Germany chose guns rather than butter, a choice that led to
Carbolic acid, a compound also known as phenol, was malnutrition, starvation, loss of morale, and loss of life on the
also commonly used as an antiseptic and disinfectant. home front. As a result, it lost the war.
Mild disinfectant soaps, known as carbolic soaps,
contained the acid.
Many soldiers injured on the battlefields and in the trenches
received horrendous injuries and had to endure terrible pain.
Surgeons and medical officers used a range of analgesics
to relieve the pain. Preparations containing various forms
of morphine, a potent painkiller, were commonly used.
Morphine is
extracted from
the opium
Cover of The Chemists War:
poppy. It is 1914 1918, Royal Society of
one of eighty Chemistry, 2015
or so alkaloids
found in the
poppy. Alkaloids
are nitrogen-
containing
organic
compounds
with complex MICHAEL FREEMANTLE is a science writer. He is the
Opium poppies: morphine and codeine molecular author of: The Chemists War: 1914-1918 (RSC Publishing,
extracted from poppy pods were
commonly used as analgesics in the war. structures that 2015) and Gas! GAS! Quick, boys! How Chemistry
(Photo by Michael Freemantle) occur widely in Changed the First World War (The History Press, 2012).
nature.

FINE CHEMICALS &
INTERMEDIATES
FARHOUSH KIANI1, S. BITA HOSSEINI2, S. AHMAD SHAHIDI2, FARDAD KOOHYAR*1
1. Department of Chemistry, Faculty of Science,
Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
2. Department of Agriculture of Food Science Engineering,
Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
Fardad Koohyar
Nano food modeling:

Ab initio and DFT studies on ionization
of saccharin in aqueous solution
KEYWORDS: Saccharin, acidic dissociation constant, nano sweetener modeling.
Abstract The acidic dissociation constant is a particular example of equilibrium constant. The quantitative behavior
of acids and bases in solution can be understood only if their pKa values are known. In this research work,
we calculated the pKa values of saccharin in aqueous solution by an ab initio method. We used the density functional theory (DFT) to
describe the acid dissociation constant. To explain the analyze the formation of intermolecular hydrogen bonds (IHBs) between the
existent species and water molecules, Tomasi,s method (B3LYP/6-31+G(d)) was used. It was shown that anion, and neutral species of
saccharin are solvated with one, two, three, and four molecules of water in alkaline aqueous solutions. We obtained a reasonable
comparison between the experimentally determined pKa values for the acid-base reactions selected by potentiometric and those
reported in the literature demonstrating the theoretically calculated pKa values.
INTRODUCTION deprotonated anion; it can easily form complexes. Saccharin

has a very low solubility but the sodium salt with its
In the modern food industry, food additives are important to deprotonated form is very soluble (6). It is not completely
improve shelf life and quality of food products. Among them, ionized when dissolved in water. It is ubiquitous in biological
artificial sweetener is widely used throughout the world. They systems and play important roles in metabolism and its
are used as sugar substitutes. They dont have the energy and regulation. The behavior of aqueous solutions of saccharin
calories. They are beneficial option for those people who and bases is best understood if we first define some terms.
going to diet and uses products in order to reduce energy or Equilibrium constants for ionization reactions are usually called
sugar intakes for health reasons. The type of sweeteners that ionization constants or acidic dissociation constants (Ka). The
approved as food additives in food stuffs by the European acidity constants are important for the development of new
Union (EU) include: acesulfame (ACE, code of food contents compounds with biological activity. Different experimental
E950), aspartame (ASP, code E951), cyclamate (CYC, code procedures were often used for the determination of acidity
E952), saccharin (SAC, code E954), sucralose (SUC, code constants. These methods include: high-pressure liquid
E955) and neohesperidindi hydrochalcone (NHDC, E959) (1). chromatography (HPLC), liquid-liquid partitioning
Saccharin (O-sulphobenzimide first prepared in 1879 (2). It is chromatography (LLPC), and methods that involve
non-nutritive sweetener. The saccharin can exist in ionic or potentiometric titrations or spectrophotometric
neutral forms. It is about 550 times sweeter than cane sugar. determinations in water or in mixtures of solvents. Some studies
Saccharin is not metabolized in the human organism to detailing with the acid-base properties of compounds in
produce energy, and it is excreted unchanged by the urine. It aqueous solutions and in gas phase are also available (7,8).
is valuable for the diabetic persons and people who need to Therefore, reliable and accurate methods for calculating
control intake of calories (3). High dosage of sodium relative and absolute pKa values are important for
saccharin causes bladder tumors in some male rats. But understanding of the effective pKa values in molecules. The
carcinogenic theory on human populations has been not values of pKa can be calculated using ab initio or DFT
accepted. Studies on more than 30 humans have been methods. In DFT method, the calculations of electronic
completed and support saccharins safety at human level structure were performed with density functional theory and
consumption (4). It is also exhibits bacteriostatic and the electrostatic features were modeled through external
cytostatic properties (5). Saccharin is a weak acid and a charge distributions and continuum dielectrics.

The correlation of theoretical and experimental data can
allow us to the development of predictive models to
calculate the pKa for components which no experimental
data are yet available.
In this study, we aimed to calculate the acidic dissociation
constants of saccharin in aqueous solution by ab initio
method. The theoretically prediction of pKa values using Figure 1. Scheme of deprotonation of saccharin.
quantum chemical methods has attracted a great extent
of interest. So now, pKa values can be predicted by
computational methods on the basis of molecular structure, As it can be seen in Figure 1, the O- atom (from hydroxide
applying various quantum theoretical techniques. The pKa group) attacks to hydrogen atom (in NH group). In this
can be calculated from the energy of the following process, the neutral saccharin changes to anion one.
reaction (9): The solvation free energies (G0sol) for neutral and anionic
species of saccharin have been calculated using the Tomasis
eq.1 method at the B3LYP/6-31+G (d) level of theory at T = 298.15 K.
This data is listed in Table 1.
Using the relation:
eq.2
To explain the obtained acidic dissociation constants, we

investigated the different molecular conformations of
saccharin by the electronic structure theory, density
functional theory (DFT), and self-consistent Reaction Field
(SCRF) model. Finally, through the determination equilibrium
constants, physicochemical properties, IHB and angels of
mentioned molecule, we will be able to prediction the best
model, in nano scale, for solvation of saccharin that can be
useful in food industry.
COMPUTATIONAL METHOD
In this research work, the structures of saccharin were

optimized via the semi empirical PM3 method in program
Hyper chem version 7 for windows. All the geometries of
the initial and solvated molecules in water, considering
intermolecular hydrogen bonds of water with amino group
(Figure 1), were optimized with the Gaussian 09 program Table 1. Calculated total energy using the Tomasi method at the
B3LYP/6-31+G (d) level of theory for neutral and anionic species of
packages. Also, DFT calculations were done using the saccharin at 298.15 K.
hybrid exchangecorrelation functional of Becke (10), Lee,
Yang, and Parr (B3LYP) and the Gaussian 6-31G(d) basis
set (11). The various reactions including neutral and anionic species
To analyze the solvent effects on all species involved in the were tested in excel program, but some of them were not
selected ionization reaction, the polarized continuum studied further because the estimated error in its equilibrium
model (PCM) of Tomasi et al was used. In this method, the constant was unacceptable. The selected model for the
solvent is represented as a structure less polarizable considered system has been shown in Table 2.
medium characterized by its dielectric constant (12).
Ultimately, we selected the solvation of the specimen by
means of intermolecular hydrogen bonds (IHBs) that
involves one molecule of the mentioned specimen and
some molecules of water.
Table 2. Values of pKa for the protonation of saccharin obtained using
the Tomasi method at the B3LYP/6-31+G(d) level of theory, at 298.15 K.
RESULT AND DISCUSSION
The inclination of a molecule to lose its hydrogen atom as Solvent-solute interactions

an acidic proton is quantified as pKa (13). The neutral form
of saccharin has carbonyl and amine groups. As it can be Ionic product of water
seen in Figure 1, the amine group can lose a proton and All aqueous solutions contain hydrogen (H+) and hydroxyl
change to N. Concept of microscopic ionization constant (OH-) ions. From the ionization of the
is shown in the equation 3: water molecules, these ions are derived totally:
eq.3 eq.4

For an ionization reaction in pure water or an aqueous The equilibrium constant Ka that characterizes the above
solution, a water molecule loses the hydrogen atom to reaction can be obtained from the bellow equation:
become a hydroxide ion (OH-). The hydrogen nucleus (H+)
protonates other water molecules to form hydronium ion eq.12
(H3O+), immediately.
The equation 11 was used to theoretically determine the
eq.5 value of the ionization constant of saccharin in water. Table
3 shows the optimized values of molecular properties of the
Since water is only a little dissociated, the concentration of neutral HL(H2O) solvated with one water molecule (Figure 3),
undissociated water molecules, [H2O], can be constant. and L- anion (Figure 3) for saccharin. Obviously, the
Therefore: formation of the saccharin anion implies that the electronic
density of the N9 atom increases notably (in absolute value).
eq.6 It can be observed that the pKa value which was
theoretically calculated (pKa = 2.148410485) is relatively
At 298.15 K, Kw = 1.008 10-14. It shows that only a few of the comparable with the experimentally determined pKa
water molecules are ionized (14). (pKa = 2) (17). Figure 2 and Table 1 show the marked increase
The autoproteolysis reaction of three water molecules is of the total energies of anions when the number of water
shown in equation 7: molecules (in solvation) increase.
eq.7
The above reaction indicates that both H+ and OH- ions are
hydrated with one water molecule.
With consideration equations 5, 6 and 7, we reach to
equation 8 (15, 16):
eq.8 Figure 3.
Calculated
structure for
Since, [H2O] is the molar concentration of water, KN1 saccharin
(at 298.15 K) was calculated as follows: solvated with
water molecules
at the B3LYP/6-
eq.9 31+G(d) level

of theory
and using
the Tomasis
method in water
at 298.15 K.
The data that was listed in Table 3 shows that the water, by
exerting its hydrogen-bond donor (HBD) capability, forms IHBs
with saccharin (18). The water molecules which are originated
Figure 2. Plot of the total energy (KJ. mol-1) of solvated neutral from the acid-base reaction together with the hydration
saccharin per water molecule against the number of solvation water molecule of the saccharin interact with the saccharin
water molecules
molecules by means of IHBs. The hydrogen bonds can be
classified as strong, moderate, and weak, according to their
Ionization constant of saccharin lengths, angles, and energies (19). For saccharin molecule
It was selected that in alkaline solutions, saccharin suffers a which has been solved in water, the distance and angels that
reaction of partial neutralization as follows: characterize these intermolecular hydrogen bonds (Table 3)
indicate that they belong to the class of moderate.
eq.10 According to earlier studies, the moderate hydrogen bonds
have the following characterization: bond length of HB is
In the above reaction, HL (H2O) represents the neutral between 1.5 and 2.2. A0, and the bond angel is 130-180 (19).
saccharin which is solvated with one water molecule. It must be noted that IHBs data can be used in the design of
Also L is the saccharin anion. benefit and economical nano sweetener. Because of the
The reaction 11 was obtained by combining equations 7 important and usable physico-chemical properties of nano
and 10. sweetener, they can be conjugated to biomolecules and
have a widespread application in biologic, food science and
eq.11 medical science (20).

It showed that there is a good agreement between the
theoretically determined acidic dissociation constants and the
experimentally determined ones. This agreement along with the
electronic density, q, structural properties, and IHBs helps us to
design nano sweetener modeling of saccharin.
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that uses pH values to calculate the ionization constants of A., 61, 93-102(2005).
17. Zhao L., Long W., Syringe filter suitability for sample preparation in
saccharin. With this purpose, we selected various acid-base
drug assays. Agilent Technologies, Inc., Publication number 5991-
reactions that include the solvation of the hydrogen, hydroxyl
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ions, and other anions or neutral molecule in protic solvents such 18. Marcus Y., Chem. Soc. Rev., 22, 409-416 (1993).
as water, which possess a high hydrogen-bond-donor capability. 19. Jeffrey G. A., An Introduction to Hydrogen Bonding; Oxford University
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molecules and anions form IHBs with some molecules of water. (1976).
PHARMACEUTICAL
CHEMISTRY
GIAN C. WINKLER*, JENS MIRWALD, KAMILA GROMEK, ESTER LOVSIN BARLE
* Corresponding author
Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland
Gian C. Winkler
Tiered testing strategy and assignment

of occupational exposure limits
for pharmaceutical intermediates
KEYWORDS: Classification labelling and packaging, occupational health, worker safety, pharmaceutical manufacturing, integrated
testing strategy.
Abstract In pharmaceutical manufacturing, occupational exposure limits (OELs) and health hazard label elements
are achieved via appropriate engineering and industrial hygiene concepts to protect workers from the
exposure to chemically reactive intermediates (IMs), compounds with limited or no toxicity information. The testing strategy for hazard
identification of IMs has to be optimized for cost efficiency and reduced use of test animals. In addition to worker safety, results of an
integrated testing strategy have to be acceptable to regulatory authorities for classification, labelling, packaging and transport of
chemicals. This publication describes the presently established Novartis tiered testing strategy and assignment of OEL for IMs. A decision
tree provides a step by step guidance. The rationale for the use of each endpoint and the type of data selected are presented.
INTRODUCTION for transportation and required protective measures in

manufacturing (risk management).
In pharmaceutical manufacturing occupational exposure The integrated testing strategy usually consists of a tiered
limits (OELs) and health hazard label elements are achieved testing approach. Results originate from multiple data sources
via appropriate engineering and industrial hygiene concepts and tests. In a first step for compounds with limited or no toxicity
to protect workers from the exposure to chemically reactive information, results from a literature search, in silico data,
intermediates (IMs) (small molecules < 1000 Da), compounds including (Q)SAR (quantitative structure activity relationship),
for which there is limited or no toxicity information. In Novartis, and if feasible a read-across study of a surrogate compound,
a tiered testing strategy (TTS) is applied for pharmaceutical are assessed. The data is then integrated into a toxicological
intermediates. It serves different purposes related to different assessment applying professional judgement. In a second step,
regulatory settings, e.g. occupational health protection additional laboratory tests are performed to confirm previously
measures as well as labelling according to the Globally ambiguous results or to confirm in silico or in vitro data.
Harmonized System (GHS)/or classification, labelling and The objective of this manuscript is to describe and comment on
packaging of substances (CLP) regulations (1, 4). In addition, the presently established TTS for small molecule intermediates
the acute oral toxicity and skin irritation studies used in (IMs) in Novartis. The decision tree which provides a step by
the TTS are in accordance with the United Nations (UN) step guidance, is presented. For each endpoint, data and
recommendations on the transport of dangerous goods (2). the rational for selecting individual toxicity tests are provided.
In addition to worker safety, results of a practicable integrated Assignment of the OELs is provided based on the available
testing strategy have to be acceptable by regulatory information. Some recommendations for the future use of
authorities for classification, labelling and packaging of alternative non-animal tests are included.
chemicals. The tests have to be compliant with international
regulations applicable in the envisaged markets. The
integrated testing strategy should be designed such that it MATERIAL AND METHODS
contributes to reducing animal use for safety testing (3). Such a
tiered testing approach contributes to reduced animal testing Database searches were initiated in Embase, Medline and
whenever a positive finding in one test makes additional testing Biosis (OvidSP provided by Wolters Kluwer, Alphen aan den
unnecessary. For instance, a positive sensitization study covers Rijn NL), by combinations of the keywords pharmaceutical
protection strategy applied also for skin irritation without further intermediate (191 hits), with tiered banding (0 hits),
testing. The test strategiy should also impact cost effectiveness mutagenicity (2 hits), skin sensitization (2 hits), skin irritation

(0 hits), contact sensitization (0 hits), dermal sensitizer (0 Class Method (8; OECD TG 423), which provides a rough
hits) and ITS (for integrated testing strategy) (31 hits) covering estimate of acute oral toxicity class. Acute oral toxicity is not
the span 1996 to March 2016. Resulting hits were reviewed and part of the tiered decision tree, because only OELs (based on
integrated into this publication. 28-day repeat dose oral toxicity study in rats) are intended for
The company database was used to retrieve, sort and long-term exposure protection of manufacturing employees.
summarize test results and information of individual chemical The use of in silico methods that predict bacterial mutagenicity
intermediates. A total of 162 IMs were assessed between 2014 of IMs has been validated recently (9) and is suitable for
and 2016. Of these, 34 compounds met selection criteria testing IMs early during development of the synthesis scheme.
(including negative genotoxicity test, available in vivo skin The negative predictive value for 188 IMs (158 negative,
irritation, contact sensitization and at least a 28-day repeat 30 positive in the Ames test) was 97% correct versus Ames
dose oral toxicity study in rats). Both, a 28-day repeat dose oral test results. On the other hand, the positive predictive value
toxicity study in rats as well as reproductive and developmental of 57% was considered too low for reliable prediction. In a
toxicity study in rats were performed for 11 IMs. much larger study, a similarly good negative predictive value
was determined using the tool Sarah Nexus version 1.1 (10).
Therefore, all intermediates with positive in silico prediction are
TTS FOR OCCUPATIONAL HEALTH HAZARD ASSESSMENT of IMs subject of a standard bacterial reverse mutation test according
to (8; OECD TG 471) test guidelines, but IMs with negative in
The health hazards endpoints recommended by European silico predictions are accepted as such without further testing.
regulatory agency for classification, labelling and packaging From a preliminarily analyzed subset of 142 intermediates of
of chemicals (including IMs) and protection of human health Novartis, 14% (19) tested positive for mutagenicity, based
are acute oral toxicity, skin and eye irritation, skin sensitization on the reverse mutation (Ames) test. A total of 123 IM were
and mutagenicity (4, 5). negative for mutagenicity, either by in silico analysis or based
This base set is suggested for evaluating the intrinsic health on the reverse mutation (Ames) test.
hazards of chemicals produced at low tonnage per annum Occupational contact dermatitis (OCD) constitutes up to 30%
by the Registration, Evaluation, Authorisation and Restriction of all notified occupational diseases. OCD to intermediates
of Chemicals (REACH) regulation (5). occurs frequently in employees working in drug development
In 2008 the decision not to test eye irritation in vivo for animal and manufacturing plants (11). This is attributed to reactive
welfare reasons was taken by the company. Instead, skin intermediates and drugs (12). Thus, well documented processes
irritants are classified as eye irritants without further testing. for hazard identification are crucial. Following GHS (1) and the
It has to be considered that in pharmaceutical manufacturing European regulation for classification, labeling and packaging
highly effective technical, operational or personal protective of substances and mixtures (4), classification is based on human
equipment is routinely employed. On the other hand, data and results from validated animal testing (13). From a
quantities handled in research labs are much smaller than in preliminarily analyzed subset of 122 intermediates of Novartis,
pharmaceutical manufacturing. Thus, potentially hazardous IMs 44% tested positive for contact sensitization, based on the in
can be processed in fume cupboards to reduce exposure. vivo local lymph node assay (LLNA). In Novartis, skin sensitization
In most cases, the 28-day repeated dose study in a relevant is examined currently with a LLNA (8; OECD TG 429) modified
species is the minimum dataset from which the IMs may be according to Ehling et al. (14, 15), which provides separate
evaluated and an occupational exposure limit (OEL) for human endpoints for lymph node activation, cell count, skin irritation
exposure can be calculated. The regulation for the health and toxicity. Once, global regulatory bodies of industrial key
hazard part requires that a 28-day repeated dose toxicity regions accept replacement of the LLNA with alternative non-
study, in vivo skin and eye irritation studies, in vitro genotoxicity animal tests, the TTS can be modified accordingly.
studies and an in vivo reproductive/developmental toxicity If animal testing for skin irritation needs to be performed, it
screening study be conducted (5). The IMs in scope of this TTS is done according to the standard test in rabbits (8; OECD
for the health hazard part, however, are below the 1 ton per TG 404). An overview of alternative methods for assessing
year threshold and hence not subject to registration under skin irritation/corrosion and their strength, weaknesses and
REACH (5). Consequently, this base set conducted (without the limitations as well as regulatory acceptance in the EU are
28-day repeated dose study in a relevant species) is insufficient provided by ECHA, the European Chemicals Agency (16).
for calculating a substance specific OEL. From a preliminarily analyzed subset of 120 intermediates of
Novartis, 12.5% tested positive, based on the in vivo skin irritation
test in rabbits.
RATIONALE Test results of the TTS are used to classify IMs according to
the Classification, Labelling and Packaging regulation (CLP)
The value of acute oral toxicity testing of drug substances in in the EU as well as for GHS worldwide (1, 4) and to assign
animals for assessing the actual hazard in humans has been an OEL value, a safe exposure level. It serves for measuring
examined recently by comparing the median lethal doses with and controlling actual exposure levels of employees and the
minimal effective therapeutic doses. There is a low correlation implementation of adequate protection measures.
between the median lethal dose and minimal effective In the absence of an available substance specific OEL value,
therapeutic dose (6). Similarly, by data modelling of industrial from authorities, the OEL is calculated internally, when a
chemicals or intermediates, it has been demonstrated that sufficient dataset (as mentioned above) is available. In the
acute oral toxicity testing data are not a reliable endpoint for absence of sufficient data, an OEL based on comprehensive
categorizing into CLP/GHS hazard categories (7). evaluation of all previously tested IMs will be determined.
In vivo acute oral toxicity tests are still required for complying The OEL value is generally based on the most sensitive health
with UN recommendations for the transport of dangerous hazard endpoint and possible consequences expected e.g.
goods (2). It is usually conducted following the Acute Toxic life-threatening, disabling, irreversible or chronic effects (17).

oral toxicity study in rats are
sufficient to protect also for
reproductive hazards.
Remaining endpoints will not
Figure 1. The TTS Decision Tree.
trigger more stringent handling
requirements, since protection
measures for mutagenicity
will cover hazards of all
subsequent endpoints (skin
sensitization and skin irritation).
Mutagenic IMs (tested
positive in the Ames test)
are not tested further for skin
sensitization and irritation
properties, unless required
for registration purposes
under REACH (5). It has to
be noted that a positive
Ames test is subject of an
individual assessment for GHS
classification.
Step 2: Contact Sensitization

(marked red in Figure 1)
Non-mutagenic IMs are
tested by the LLNA next. For
occupational health purposes,
HAZARD IDENTIFICATION BASED ON TTS sensitizers with no systemic effect data are limited to an
OEL value of 100 g/m3 and a hazard notation is applied
IM candidates are assessed as displayed in Figure 1. The which triggers industrial hygiene practices preventing skin
approach follows a stepwise decision tree focusing on three exposure. Sensitizers are not tested further for irritation
different health hazards and their respective endpoints. The properties. In a preliminary analysis of 34 REACH registered
TTS sequence follows the endpoints for mutagenicity in Step intermediates with 28-day oral repeat dose toxicity studies,
1, skin sensitization in Step 2 and skin irritation in Step 3. Acute 95% (32 IMs) had an OEL above 100 g/m3. OELs of the
oral toxicity is not part of the stepwise decision tree, because two remaining IMs were two fold lower than the 100 g/
predictive interpretation of acute toxicity test results for m3 limit. Based on analysis of substance-specific OELs, this
occupational exposure is very limited. On a case by case indicates that the limit of 100 g/m3 is a conservative value
basis, the use of acute toxicity may be considered, as it is for the vast majority of tested IMs and provides sufficient
described in Step 4. protection of the employees.
Following the same principle, non-sensitizers are tested for
Step 1: Mutagenicity (marked blue in Figure 1) skin irritation that triggers an OEL value of 100 g/m3 in case
Based on the combination of literature findings, in silico of a positive result.
evaluation and professional judgment, the reliability of
available data for the classification non-mutagenic Step 3: Skin Irritation (marked white in Figure 1)
for the IM is confirmed. Positively predicted IMs and IM tested negative for mutagenicity and contact
insufficiently documented non-mutagenic IMs are tested in sensitization are tested for skin irritation. There is an
the standard Bacterial Reverse Mutation Assay (Ames test) exception for IMs with extreme pH value of 2 and 11.5.
(8; OECD TG 471). If an IM is positive in the Ames test, the They are classified as corrosives and a hazard notation is
compound is considered mutagenic and limited to a applied without testing, since such IMs are likely to evoke
value of 1 g/m3, because of its assumed carcinogenic serious skin effects. Risk assessment at the workplace is
potential. The rationale for adequacy of 2 g/m3 is conducted to provide an appropriate protection strategy.
based on the acceptable life-time cancer risk rate as Positive testing in the absence of systemic effect data
presented recently in detail (18) and rounded to 1 g/m3 leads to an OEL value of 100 g/m3. Since the company
(precautionary principle applied). Mutagenicity could also decision not to test eye irritation in vivo anymore, skin
be a reproductive toxicity risk, but the OEL of 1 g/m3 is irritant IMs are classified as skin and eye irritants without
sufficient to protect also for reproductive hazards. further testing.
In 11 non-mutagenic IM tested more extensively, OELs
based on 28 or 90-day repeat dose oral toxicity study Step 4: Final OEL Determination
in rats were lower than OELs based on the reproductive IMs tested negative for all endpoints (mutagenicity, contact
and developmental toxicity study in rats. OEL values sensitization and irritation) are assigned an OEL value of
calculated from the reproductive and developmental 1000 g/m3, if there is sufficient evidence that the substance
toxicity study were frequently above the dust level would not cause any systemic effects. In contrast, an OEL
(> 3000 g/m 3). Based on these data, it can be assumed value of 100 g/m3 is applied (see Figure 2) if any systemic
safely that the OELs based on 28 or 90-day repeat dose effects are expected.

SYSTEMIC EFFECTS classification and labelling
according to current regulations
As discussed above, IMs tested and the current stage of
negative for all endpoints, but toxicological knowledge
suspected to potentially cause regarding our own IMs. With
systemic effects, are limited to an OEL the expected growth of the
value of 100 g/m3. Some information toxicological knowledge of IMs,
on the possible systemic toxicity may the TTS and OEL setting can be
be identified from structural similarity to adjusted. In addition, the base
the drug substance, mode of action, set of studies for IMs used in the
results of QSAR studies, read-across TTS is in accordance with the
from similar chemical structures UN recommendations on the
or other sources. In a preliminary transport of dangerous goods (2).
assessment of 34 internal IM data The concept has been optimized
of Novartis with repeat dose toxicity for cost efficiency and reduced
studies, it was demonstrated that up use of animal testing, while
to 50% of IMs, which tested negative maintaining an efficient hazard
in the base set studies, may cause assessment for worker protection.
systemic effects at doses between 100 The staging of literature
- 1000 g/m3. review and in silico assessment
For classification according to GHS predetermines the need and
and CLP regulations (1, 4) results of extent for further laboratory tests
the TTS have to be aligned separately and animal experiments.
using professional judgment and taking In the analyzed subset of
into account all endpoints tested intermediates, we retrieved data
(mutagenicity, contact sensitization for Novartis IMs. We compared
and irritation and acute oral toxicity). incidence rates analyzed in
For transport classification according Novartis with those published
to the UN recommendations on the recently for 9,801 substances
transport of dangerous goods, only registered under REACH from
results of the acute oral toxicity and Figure 2. IMs Tested Negative for All Endpoints Decision 2008-2014 (22). The incidence
Tree.
the skin irritation/corrosion studies are *The internal definition of mutagenicity is incongruent rate for skin irritants (12.5%) was
considered with regards to health (2). from an occupational health perspective as compared comparable to that published. On
to CLP/GHS(1, 4). A positive in silico mutagenicity the other hand, the prevalence
prediction or an Ames test are not sufficient for a CLP/
GHS classification. However, the ultimate decision is rates for mutagenicity and
PHARMACODYNAMIC AND always taken by consulting an expert. genotoxicity (14% versus 5% in (22))
**The hazard categories will be assigned based on test
CYTOTOXIC ACTIVITY OF IMs results
and for contact sensitization (44%
versus 20% (22)) were much higher
As a general rule, IMs with structures in our own subset of IMs. This can
that correspond closely with the active pharmaceutical be attributed to a sample bias in the subset analyzed, since
ingredient (API) in the synthesis are assessed equally to the many IMs were structurally related to each other. Several
final API. So the OEL is based on the minimal therapeutic dose. originate from the same synthesis scheme. Many of the
Occasionally, there are IMs with limited structural similarity pharmaceutical intermediates are also reactive by design.
to the API, which exhibit pharmacological activity (19). For From an economical and animal welfare standpoint it
example, intermediates are known, which resemble the makes sense to integrate occupational health, CLP and
chemical structure of atropine. They are psychotomimetic and transport of dangerous goods classification and labeling
may elicit hallucinogenic effects (including delusions and/or requirements and to use the presented TTS as a standard.
delirium) in manufacturing employees at low exposure levels. The fact that the OEL assigned to mutagenic IMs also
Another example of a pharmacologically active IM is covers contact sensitization and skin irritation hazards, such
Staurosporine. It is an intermediate for several oncology drugs. that specific tests for these endpoints are not required,
It has been developed initially as possible cancer therapeutic reduces the number of animals used Pharmaceutical IMs
itself. Therefore, the drug testing includes preclinical studies are shipped internationally as dangerous goods and the
and clinical trials as well (20). Staurosporine is a potent transportation costs, due to labeling, packaging, trained
inhibitor of the ubiquitous protein kinase C, an apoptosis personnel etc., represent the major part of the logistic
inducer and it arrests mitosis in healthy and neoplastic cells expenses.
(cytotoxicity) (21). Staurosporine was not mutagenic in the Different approaches have been published on setting
Ames test and an OEL can be calculated, which may be occupational exposure limits for pharmaceutical IMs with
based on the minimal therapeutic dose. limited or no toxicity data. On the one hand, an acceptable
daily intake can be based on the threshold of toxicological
concern (TTC) principle (23), on the other hand exposure
CONCLUSIONS limits have been established based on in vitro data, only
(19). However, these publications address only occupational
The presented TTS for pharmaceutical intermediates exposure limits. They do not include the classification and
considers occupational exposure hazards as well as labelling topics.

Future developments in validation and regulatory http://www.oecd-ilibrary.org/environment/test-no-423-acute-oral-
acceptance of non-animal test methods, probably in the toxicity-acute-toxic-class-method_9789264071001-en
area of irritation/corrosion studies, are expected and can 9. Araya S.H., Lovin Barle E., Glowienke S., Mutagenicity assessment
strategy for pharmaceutical intermediates to aid limit setting for
be integrated easily, once global regulatory bodies of key
occupational exposure. Regul. Toxicol. Pharmacol. 73(2), 515-520
regions accept the replacement. The tiered procedure
(2015).
supports consideration of the actual TTS value assessed at
10. Barber C., Cayley A., Hanser T., et al. Evaluation of a statistics-
each decision point before additional studies are requested. based Ames mutagenicity QSAR model and interpretation of the
For the time being, the presented TTS provides a ready to results obtained. Regul. Toxicol. Pharmacol. 76, 7-20 (2016).
use decision tree that is already applied in pharmaceutical 11. Bircher A.J., 2012. Drug allergens. In: Rustemeyer, T., Elsner, P.,
manufacturing, successfully. John, S.M., Maibach, H.I. (Eds.), Kanervas Occupational
Dermatology, 2nd ed. Springer Verlag, Berlin Heidelberg (G).
12. Goossens A., Vander Hulst K., 2012. The pharmaceutical and
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Maibach, H.I. (Eds.), Kanervas Occupational Dermatology, 2nd
ed. Springer Verlag, Berlin Heidelberg (G).
We are grateful for support on this topic by Stephane
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Kervennic and the manuscript review by Philip Bentley.
Barle E., Workshop report: Classification of dermal sensitizers in
pharmaceutical manufacturing. Regul. Toxicol. Pharmacol. 72(3):
501-505 (2015).
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CHEMICAL ENGINEERING/
Industry perspective
PROCESS DEVELOPMENT
ROGER-MARC NICOUD
Ypso-Facto, 10 Viaduc Kennedy, 54000 Nancy, France
Roger-Marc Nicoud
From batch to continuous processes:

a good answer, but what is the question?
Part I - General considerations and
the reaction unit perspective
KEYWORDS: continuous processes, batch processes, Batch Stirred Tank Reactor (BSTR), Continuous Stirred Tank Reactor (CSTR),
Continuous Plug Flow Reactor (CPFR).
Abstract The switch from batch to continuous process is a major topical question in the fine chemical,
pharmaceutical and biopharmaceutical industries. In spite of a genuine interest, as shown by the
profusion of recent literature and symposia on the topic, batch remains the widely accepted standard in these industries and the
steps taken toward continuous remain somewhat shy. A paradox? Here, we propose a fresh look at the question through the
chemists eyes but with process engineer glasses. In this first part, general considerations and simple reaction unit operations are
investigated. The second part of the article (1) will propose general considerations on the purification unit operations, less simple
reaction unit operations, and the overall process perspective.
INTRODUCTION fine chemical and pharmaceutical processes as opposed

to continuous manufacturing in the commodity industry.
Many recent articles, symposia and initiatives show that One can see a sign that fine chemical and pharmaceutical
moving processes from batch to continuous is a topic raising industries are less advanced process-wise than others.
serious considerations in fine chemical, pharmaceutical and Although probably partly true, this view is certainly too
biopharmaceutical industries. restrictive. As an example, operating distillation continuously
As a matter of fact, many industries implemented for refining oil but batch-wise for producing Cognacs certainly
continuous processes decades ago, but the fine chemical, has serious arguments!
pharmaceutical and biopharmaceutical processes are still An important reason may be that, in contrast with fine
largely operated in a batch mode. chemistry, in commodity chemistry, the demand is
Nowadays, several leading companies (Novartis, GSK, predictable, sales are based on (process) performance and
AstraZeneca, Pfizer, Eli Lilly, Genzyme, Sanofi, Lonza, etc.) the agility to change is not a key driver.
have disclosed their interest and activities in the field and the However, considering that continuous processes are a
FDA is clearly pushing in that direction. priori less agile than batch processes or that continuous
In addition, major successes have also been achieved, processes are a priori more efficient than batch processes is
like Novasep installing their first large scale continuous for a large part a matter of faith.
chromatographic processes (including solvent recycling) Unfortunately, I do not have any expertise to address faith
almost 20 years ago (2). issues, but chemical engineering skills, even basically used,
Nevertheless, despite genuine interests and significant can help rationally assess the pros and cons of batch and
achievements, examples of continuous processes in the fine continuous processes.
chemical, pharmaceutical industries are still rather limited. An important barrier for developing continuous processes
Historically the priority has been set to the ability to produce is that chemists are almost entirely trained with batch
and characterize high quality molecules, much less to systems and thus switching to continuous requires to speak
production process performances. with chemical engineers and then with mechanical and
In addition to historical and psychological barriers, there are automation engineers, etc. Such a language barrier is often
many reasons that can account for the batch operation of huge and probably at the origin of many fears.

In addition translating a typical chemical recipe like heat A, able to turn, you could therefore propose a formula one. They
then add gently B until first precipitates are obtained, then finally realize that they also require a car able to accommodate
add C and stir vigorously.. in terms of chemical engineering bumpy roads. You can then propose a rally car.
is not a trivial task! The same applies to process design. Deciding whether
This article offers a birds eye view of how basic and moving from batch to continuous operation makes sense or
understandable chemical engineering can bring arguments not first requires to define the objectives. Considering that, in
and highlight the competitive edges when comparing batch the end, the aim is to minimize costs is certainly too coarse an
and continuous processes. approach to the problem. Costs may take many forms: opex,
capex, safety, regulatory, etc. all of which are somehow
related to technical performances.
GENERAL CONSIDERATIONS The selection of the best process is a multi-faceted issue and
a matter of compromise. For example, in addition to product
To begin with, we experienced a lot of confusion among quality or safety, one could be willing to:
many professionals with the concept of being continuous or Maximize the yield, normally expressed in kg (or mol) of
not. product per kg (or mol) of reactant, for obvious
The following example from the chromatography area economic and environmental reasons;
will show how this concept may be largely a matter of Increase the robustness, the ability to cope with varying
perception: constraints like production needs, some feed stream
1. In a Batch Chromatography column, periodic injections evolutions, etc.;
are performed at the inlet and a purified fraction is Maximize the productivity, often expressed in kg of
periodically recovered at the outlet. In some systems, this product per system volume per hour: this is certainly an
purified fraction is sent to a falling film evaporator (FFE) important factor, but the connection with economy is
equipped with a recycling loop. By adjusting the complicated. For instance a large chromatography unit
concentration rate in the FFE and the volume of the operated at low pressure (thus less productive) can be
recycling loop, this batch labelled system is able to cheaper than a small unit operated at high pressure;
deliver a continuous stream of purified solute at a nearly Minimize solvent consumption often expressed in litres per
constant concentration. kg of product: this can be a major contributor, and in
2. In Multicolumn Continuous Chromatography systems, by many applications, developing a process must integrate
connecting several columns in series with astute inlet/ the ability to recycle solvent as early as possible. For
outlet stream connections, one can design efficient instance, unless a real advantage is obtained, using a
systems allowing to process a continuous stream of feed single solvent instead of multicomponent mixtures is a
material (2). However, this continuous labelled system good option.
delivers a target solute in the recovered outlet stream In general, industrials want everything, but they definitely
that exhibits very strong concentration variations over cannot get everything. For instance, maximizing productivity,
time, and these streams can even be stopped at some yield and robustness at the same time are, in general, not
intervals. compatible.
This tends to show that, for chromatography, the batch or In order to assess the possible impacts of moving from a
continuous label is given according to the way the feed batch mode to a continuous mode, one needs first to
stream is processed, not according to the way the purified understand how this change is going to impact the technical
streams are delivered. Similar non-evident accepted performances of unit operations (productivity, kinetics, solvent
definitions can apply to non-chromatographic processes. consumption, yield, etc.).
In addition, a possible confusion arises with the concept of In addition to impacting unit operations, moving from a batch
being continuous (streams are processed without interruption) mode to a continuous mode also impacts the connection
and being steady state (all variables are constant with respect between the unit operations, control, process stability, down
to time): whereas a batch process can definitely not be times (e.g. heating, cooling, cleaning), etc.
steady state, a continuous process can be steady state or not. By a better interconnection between unit operations, one
The concept of being continuous may also be a matter of may be able to get rid of unnecessary tanks, thus minimizing
scale of observation or a matter of objectives: a dual head footprint, a significant cost factor in biopharmaceutical
pump operates in a batch mode if you are interested in one processing. This full process perspective will be developed in
specific inlet stream but continuously if you are interested in part II of this article (1).
the outlet stream.
I learnt a very simple way to summarize things during a lecture
given by Dr Poechlauer from DPx Fine chemicals: In a batch A UNIT OPERATION PERSPECTIVE
process the different tasks are separated by then. I do task A,
and then task B and then task C In a continuous process, the To begin with, let us compare batch and continuous
different tasks are separated by here. I do task A here, and operations in simple and idealized situations.
task B here and task C here Consider a Batch Stirred Tank Reactor (BSTR) as schematically
It is now time to speak about objectives. Optimizing or simply represented in figure 1 a), and let us try to use it to cook soft
defining a process requires the definition and selection of an boiled eggs.
objective function. One must know what one needs to identify Producing soft boiled eggs requires the eggs to be contacted
the best solution. This basic consideration is often forgotten! with water at 100 C during 3 minutes. This is easily performed
Assume that your customer is asking you to deliver them the with the BSTR described in figure 1 by bringing the eggs into
fastest car. You would probably propose them a dragster. the reactor with a basket and removing them after exactly
However, they come back to you because they need a car three minutes (the BSTR is a complex name for a casserole ).

Let us assume that a few identical chromatography
columns are operated in parallel, in such a way that the
feed injection in column n starts when feed injection ends in
column n-1. All columns do exactly the same job, they are
simply operated in shifted cycles. Overall, using a manifold,
one can inject feed and collect fractions more or less
continuously, and we have transformed our batch system
into a continuous one.
By assumption, all the columns are identical and perform the
same work. This means that no productivity, yield or eluent
consumption improvement can be expected compared to
a single batch column process.
Figure 1. a) Batch Stirred Tank Reactor (BSTR), b) Continuous Stirred We moved from batch to continuous, without improving
Tank Reactor (CSTR) and c) Continuous Plug Flow Reactor (CPFR). performance, but by adding a significant degree of
complexity
We know however that continuous multicolumn systems
This BSTR can be transformed into a Continuous Stirred Tank are often claimed to be more efficient than batch
Reactor (CSTR, often called CHEMOSTAT in bioprocessing) by systems. The reason must consequently be found
feeding the vessel with a continuous flow of eggs and collecting elsewhere than in the simple move from batch to
the same flow of eggs at the outlet (Figure 1 b)). The flow of eggs continuous. We will see in part II (1) that the improvement
can be determined such as the eggs spend three minutes inside comes from residence time distribution properties (in that
the system and are thus adequately cooked, in principle case a counter-current contact).
If we add progressively eggs in boiling water and withdraw them With two very simple illustrations (eggs cooking and
at the same rate, we obtain the continuous casserole. chromatography) we have shown how important it is to
We all know that when adding some food in the boiling water of keep in mind that:
a casserole, a few minutes later, we dont remember when this Moving from batch to continuous is certainly not a
or that ingredient has been added especially when they are guarantee for process improvement,
identical like our eggs! This means that after 3 minutes you may A batch stirred reactor and a continuous plug flow
withdraw an egg which has just been added (extremely soft reactor can have identical performances (there are
boiled), or an egg that is (very) hard boiled. Chemical engineers exceptions however!),
speak of Residence Time Distribution (RTD): when a pulse of The way of contacting the reactants (stirred, plug flow,
tracer is injected at the inlet of a CSTR, the outlet signal (the RTD) counter-current) plays a key role.
is given by a decreasing exponential function. In other words, To get further insight, the use of basic chemical engineering
while the average residence time in the system is 3 minutes, considerations will be of great help.
different eggs may have spent very different times in the reactor.
Our attempt to transform our batch process with the BSTR into
a continuous process with the CSTR to cook soft boiled eggs is DESIGNING REACTORS: BASIC CONSIDERATIONS
thus unlikely to be efficient if we think that transposing batch to
continuous comes down to adding an inlet and an outlet stream. The object of this section is to show how very basic concepts
We must thus define our objective: the critical feature to ensure of chemical engineering can help rationalizing the thought
perfect cooking of the eggs is to make sure that all eggs spend process. There is absolutely nothing new, everything can be
exactly the same time at the prescribed temperature in the found in classical reaction engineering textbooks (3-4-5) so
device. This can be achieved continuously with a conveyer that references will be limited to the minimum.
able to transport the eggs in an oven as described in figure 1 We first consider the conversion of a molecule R (reactant)
c). Such a system, imposing the same retention time for all the into a molecule P (product). Our objective is to compare the
particles (eggs), has the characteristics of a Continuous Plug performance of three ideal reactors BSTR, CSTR and CPFR,
Flow Reactor (CPFR). already presented, for performing the conversion.
It is relatively intuitive that the eggs will be cooked similarly in
systems a) and c), the influence of time and abscissa being R1
simply interchanged.
We will see later that this similarity between the performances of The kinetics are first supposed to obey a first order law so that
the CPFR and the BSTR is quite general. the reaction rate, r, is represented by:
With this trivial example we learn that unit operation
performances are not really impacted by the batch or (mol.m-3.s-1) eq. 1
continuous character (CPFR and BSTR are similar), but rather
by residence time distribution considerations. In addition, if no where k is the rate constant (s-1) and CR the reactant
care is taken, transforming a batch mode into a continuous concentration (mol.m-3).
mode can make things worse (CSTR is less efficient than BSTR in Compressibility of the reacting medium, thermal exchange,
that example). equilibria (liquid-vapour, reaction) or non-ideal effects as well
Let us now go back to preparative chromatography. as secondary reactions are neglected in this section.
Chromatography is a batch process by nature: an eluent at The systems are thus fully described by the knowledge of the
constant composition is fed onto a column, periodic injections concentrations CR and CP at any time or any location.
are performed at the inlet, and purified fractions are periodically A chemical engineering secret for calculating systems consists
collected at the outlet. in writing mass balances.

A mass balance written over a time interval dt in a BSTR of The first line of table 1 shows that the conversion increases
volume V gives: versus residence time in a continuous system in the same way
as it increases versus time in a batch system. Furthermore,
eq. 2 one can see that conversions obtained in BSTR and CPFR are
identical provided that = t.
which leads to: One can further notice that, for a given time t or mean
residence time , the conversion is always lower in a CSTR
eq. 3 compared to a BSTR or a CPFR. This is further extending the
intuition gathered with the eggs example: setting a reaction
where is the initial reactant concentration. time in a BSTR identical to the residence time in a CSTR does
Similarly, a mass balance written between the inlet and the not imply identical performances.
outlet of a CSTR of volume V fed by a constant flowrate Q gives: We can further analyse our systems by defining the intrinsic
reactor productivity (mol.s-1.m-3) as the number of mole of R
eq. 4 converted per unit of time and per volume of reactor.
By definition, one obtains for our simple reaction system:
which leads immediately to:
eq. 9
with , the mean residence time (s). eq. 5
It is important to realize that these productivities are
Finally, a mass balance written over a slice of thickness dz associated with the reaction step only and do not take into
(m) of a CPFR of volume V = L (where L is the length (m) account turnaround times, hence the name intrinsic reactor
and the section (m2) of the reactor) fed by a constant productivity.
flowrate Q gives: One can then easily express intrinsic reactor productivities as
a function of conversion rate. Results are given in table 1 and
eq. 6 graphically represented in figure 2.
where u = Q/ is the fluid velocity (m.s-1)

After integration over the entire bed length one obtains:

with , the mean residence time (s). eq. 7
We immediately notice that the reactant concentration

exiting a CPFR with a residence time t is exactly identical
to the one obtained in a BSTR after time t if one takes = t.
This confirms our intuition built for eggs cooking, at least for
simple first order reactions. In fact, the CPFR and BSTR have
similar performances in a very wide range of situations, owing
to the structure of the mass balances. Considerations about
fluid compressibility could, for instance, be a reason for
differences.
The solution obtained for a CSTR has a different structure and Figure 2. Relation between the intrinsic productivity and the
conversion rate for BSTR, CSTR and CPFR. One single first order
the three reactors will be compared in the next paragraphs. reaction is considered. mol.m-3.s-1.
For this simple example, we can easily define the
conversion X as:
The intrinsic productivity obtained for the different reactors
thus eq. 8 has an intriguing property: it is maximum when the conversion
equals zero (thus at zero reaction time) and decreases after.
Where is a reference concentration that can represent The explanation is simple: the instantaneous productivity (in
the initial reactant concentration (BSTR) or the inlet reactant mol.s-1.m-3) is given by the chemical reaction rate (in mol.s-1.m-3)
concentration (CSTR or CPFR). and the reaction rate is maximal when reactant concentration
Equations 3, 5, 7 and 8 immediately give the conversion is maximal thus at low conversions prevailing initially.
reported in table 1. As a consequence, to obtain a high reactor productivity, one
has to work at very low conversion rates (thus yields).
Life is always a matter of compromise
In this example, it appears clearly that, irrespective
of the desired conversion, the least efficient reactor
is the CSTR and that BSTR and CPFR are much better
(Figure 2). Again, being continuous is certainly not a
guaranty for success!
As already mentioned, our calculated intrinsic reactor
productivities are only associated with the reaction
step. Estimating the practical productivity of a batch
Table 1. Comparison of key performance indicators for BSTR, CSTR and CPFR.
One single first order reaction is considered. reactor requires taking into account the time required
to move from one batch to the next (turnaround time).

The turnaround time, the time required to empty, fill, If n = 0 so that r = k irrespective of concentration (except
clean, equilibrate temperatures between batches can be zero), the reaction kinetics become independent of
everything between a few hours or a few days for bio- concentrations and thus independent of the history or
fermenters. profiles of concentrations in the reactor. This occurs for some
If t (s) is the turnaround time, the expression for the BSTR rearrangement reactions or some reactant-inhibited catalytic
productivity given in eq. 9 must be modified into: reactions, for instance. Under these conditions, all three
reactors considered lead to the same conversion and same
eq. 10 productivity.
The results obtained for n = 1 and for n = 0 can be extended
This turnaround time can have a major impact on and similar calculations show that, as far as conversion rate or
productivity as shown in figure 3. Even a turnaround time specific reactor productivity are concerned:
about 10 percent of the time required to complete the 1. For n > 0, the BSTR = CPFR are better than the CSTR
reaction (thus kt 0.1) impacts significantly the BSTR 2. For n = 0, BSTR = CPFR = CSTR
productivity. This favours continuous reactors, not because 3. For n < 0, the CSTR is better than the BSTR = CPFR
they are intrinsically better (CSTR and BSTR have the same These rules hold in an isothermal and incompressible medium.
intrinsic productivity) but because the batch reactor is They may fail (not necessarily) otherwise.
poorly operated. Situation 1 being more frequent than the others, in a vast
Under these conditions, and under many industrial conditions, majority of situations, the CSTR is the least efficient system.
the point is less to optimize the intrinsic reactor productivity
than to take care of what is done with the reactor outside Autocatalytic and auto-inhibited reactions
production hours. Different chemical reactions or bio-reactions can be inhibited
or catalysed by the product.
In an autocatalytic reaction, the product of the reaction acts
as a catalyst, and this can be symbolized as:
R2
This situation is not very frequent but exists. A simple example

is the preparation of soap: reaction of triglycerides with
caustic soda contained in water is limited by the non-
miscibility of oil and water. As the reaction progresses,
sodium carboxylate (soap) is formed which increases
miscibility and thus reaction rate (6).
For illustration purposes, we can assume a reaction of rate law:
eq. 11
Figure 3. Relation between productivity and conversion rate for
BSTR, CSTR and CPFR. Influence of the turnaround time. One single
first order reaction is considered. = 1 mol.m-3.s-1. Introducing the conversion, one obtains:

eq. 12
The conclusion of this simple study is that CPFR and BSTR are
identical in principle, that CSTR is less performant, but that the The reaction rate equals zero in the absence of reactant or
existence of turnaround times can drastically decrease the product and thus reaches a maximum with the conversion.
BSTR performances. Let us note Xmax the conversion maximizing the reaction rate
What has been found above has been demonstrated (Xmax = 0,5 in our case).
for a first-order reaction in an incompressible medium, with It can be shown that the best reactor choice for maximizing
no thermal effects and no phase change. However, even the productivity consists in using a CSTR for raising conversion
though egg cooking is not first-order, water is boiling (phase up to Xmax and then a CPFR to raise the conversion from Xmax
change), the casserole is heated (thermal exchange), and to the target. Definitely not intuitive
water vapour is a gas (compressible medium), the rules and
results demonstrated above still hold! This suggests that they Influence of undesired reactions
are of some general applicability that may help the engineer If only the desired reaction would occur, the life of the
even though the theoreticians will claim and demonstrate engineers would certainly be too easy! In general, undesired
that there are exceptions . reactions leading to by- or co-products U (U for undesired)
We will shortly illustrate how orders of reaction different from take place, according to consecutive or parallel schemes:
one or the presence of side reactions can impact our findings.
Consecutive, like and ; R3
Reaction kinetics of reaction order different from one Parallel, like and . R4
Let us now assume that the reaction rate can be expressed
with an equation having the structure: Under these circumstances, conversion must be considered in
connection with selectivity or yield. In other words, converting
eq. 10 the reactant is not enough: one needs to make sure that it is
converted into the desired product and that the production
where n is the reaction order. of undesired products is minimized.

The choice of the reactor is not eggs we have shown how pretty basic
only impacting conversion but also chemical engineering considerations
selectivity and yield. allow brushing simple rules for
Let us consider the case of parallel selecting appropriate reactors (eg
reactions first. It can be shown that: BSTR, CSTR or CFPR) under relatively
If the reaction orders are identical, idealized situations.
the yield is independent from the This teaches us that, from a chemical
reactor choice: CSTR = BSTR = engineering point of view, at the
CPFR. reaction level, the problem is less
If the order of the desired reaction moving from batch to continuous
is greater than the order of the than selecting a stirred or a plug flow
undesired reaction: BSTR or CPFR mode. Under many circumstances,
are to be preferred for maximizing BSTR and CPFR can have similar
the yield of the targeted product. performances, BSTR is more efficient
If the order of the desired reaction than CSTR. The choice of the adapted
Continuous QVFphoto reactor.
is lower than the order of the Courtesy of Peschl-UV
reactor (for Instance a CSTR versus
undesired reaction: CSTR is to be a BSTR) is largely dependent on
preferred for maximizing the yield the stoichiometric structure of the
of the desired molecule. reactions. In addition, in many situations,
the problem is less optimizing the reactor
In many situations, the reaction orders are not itself than minimizing the down times
known. Often the chemist however knows (or associated with periods during which the
feels at least) whether increasing the reactor is not producing..
reactant (or main reactant) concentration Saying that "taking into account reaction
favours one reaction at the expense of the schemes and kinetic laws is an important
other reaction(s). step for proper reactor design" seems trivial,
Then the three bullet points listed above can but how often is that done in practice?
be written in a more qualitative form: So far, we have limited our discussion to
If the observed rates of production of P simple reaction conditions. Extending
and U are equally sensitive to the the thought process to purification steps,
reactant concentration, reactors operated in more complex
CSTR = BSTR = CPFR. situations and considering entire processes
If the observed rate of production of P is instead of simple unit operations are the
favoured by an increase of the reactant tasks of part II.
concentration, then BSTR or CPFR must Stirred QVF tank reactor can
be preferred. be used in batch or
continuous mode.
If the observed rate of production of U is Courtesy of De Dietrich Process ACKNOWLEDGMENTS
favoured by an increase of the reactant Systems
concentration, then the CSTR must be The author is grateful to Daniel Schweich,
preferred. Jean-Marie Basset and Ypso-Facto co-workers,
From a theoretical point of view these rules result from Aline Devoille, Margit Holzer, Kilian Kobl, Stefano Lange, Marc-
the apparent reaction orders. But these orders need not Olivier Simon for fruitful discussions and comments.
to be known: only tendency behaviours of the reactions
observed at the lab are sufficient!
For consecutive reactions, the rule is simple: BSTR and NOTATIONS
CPFR are more efficient than the CSTR, all other things
being equal. BSTR: Batch Stirred Tank Reactor
CSTR: Continuous Stirred Tank Reactor
These three examples show that choosing a continuous stirred CPFR: Continuous Plug Flow Reactor
vessel or a plug flow reactor should depend on the reaction
(and side reaction) structure.
REFERENCES AND NOTES
CONCLUSION 1. Nicoud R.-M., Chemistry Today, publication pending (2016).

2. Nicoud R.M., The Amazing Ability of Continuous Chromatography
Moving a process from batch to continuous is certainly an To Adapt to a Moving Environment, Ind. Eng. Chem. Res. 2014, 53,
interesting possibility but not a guaranty for improving fine 37553765
3. Elements of Chemical Reaction Engineering (4th Edition), Fogler
chemical or biochemical operations.
H.S. edited by Prentice Hall, Laflin (2005);
Before even speaking of improvement, one should precisely
4. Chemical Reaction Engineering (3rd Edition), Levenspiel O.,
define the objective: maximizing productivity, maximizing edited by John Wiley & Sons, Hoboken (1999)
yield, decreasing solvent consumption are different 5. Gnie de la Raction Chimique, Schweich D. Edited by Tec &
requirements that cannot, in general, be satisfied with a Doc Lavoisier, Paris (2001).
single technical answer. 6. Gnie de la Raction Chimique, Villermaux J. Edited by Tec &
Starting from the intuitive day-to-day process of boiling Doc Lavoisier, Paris (1985).

DRUG DISCOVERY/
DEVELOPMENT
FRANCISCO FOUBELO, MIGUEL YUS*
Departamento de Qumica Orgnica, Facultad de Ciencias
and Centro de Innovacin en Qumica Avanzada (ORFEO-CINQA),
Universidad de Alicante, Apdo, 99, E-03080 Alicante, Spain
Francisco Foubelo Miguel Yus
Synthesis of alkaloids
by a diastereoselective allylation of chiral N-sulfinyl imines
KEYWORDS: Diastereoselective allylation, chiral N-sulfinyl imines, alkaloids, desulfinylation, indium metal.
Abstract The indium-promoted allylation of chiral N-sulfinyl imines represents a useful and versatile procedure to
prepare chiral protected homoallyl amines in a diastereoselective manner. Desulfinylation under acidic
conditions liberates easily the corresponding enantioenriched homoallyl amines. This type of compounds can be easily manipulated
synthetically in order to prepare a series of natural alkaloids in an enantiopure form, using simple transformations.
INTRODUCTION An interesting version of the reaction shown in Scheme 1

consists in a three-component reaction (6), which allows the
Among the reactions involving the addition of an in situ generation of the imine (from the aldehyde 4 and the
organometallic reagent to carbonyl compounds or imines, sulfinamide ent-5) in the presence of the allylation mixture,
the corresponding allylation offers the advantage of making so the corresponding protected N-tert-butylsulfinyl homoallyl
possible the further manipulation of the allylic moiety. In amine is prepared with similar results that those obtained
general, the allylation of imines has been far less studied than starting from the isolated imine (Scheme 1). Scheme 2
the corresponding reaction with carbonyl compounds (1, 2). illustrates the one-pot method using the enantiomerically pure
On the other hand, the asymmetric version of this reaction commercially available sulfinamide, to yield the enantiomeric
would afford chiral homoallylic amines, able to be products ent-3 (7).
transformed into interesting chiral nitrogen-containing
compounds (3, 4). Some years ago (5), we found out that
indium metal can promote the allylation of chiral N-tert-
butylsulfinyl imines 1 with allyl bromides 2 under mild reaction
conditions, giving the expected protected homoallyl amines
3 with good yields and diastereoselectivities (Scheme 1).
The observed stereochemistry could be easily explained

considering a chair-like transition state I in which the
Scheme 2. Reagents and conditions: i, Ti(OEt)4, In, THF, 60 C.
indium atom is coordinated to both the nitrogen and the
oxygen atoms, and the group R1 is located in a pseudo-
antiperiplanar It is worthy to note that the desulfinylation of compounds 3 is
position with a very simple process, taking place by simple treatment with
respect to the hydrochloric acid in an organic solvent.
sulfinyl group.
SYNTHESIS OF ALKALOIDS
The allylation of (S)-N-tert-butylsulfinyl imines 1 with allyl

Scheme 1. Reagents and conditions: i, In, THF, bromide 2 in the presence of indium metal gave the expected
60 C.
products 3 with high yields and diastereoselectivities.

Treatment of these compounds with methyl vinyl of the corresponding chiral imine and allylated to give the non-
ketone (MVK) and the ruthenium catalyst 6 yielded isolated protected homoallyl amine 14, which by treatment
the corresponding unsaturated ketones 7. Successive with potassium hexamethyldisilazide (KHMDS) gave the sulfinyl
hydrogenation of the carbon-carbon double bond using derivative 15, easily deprotected under acidic conditions to
the Wilkinson catalyst followed by desulfinylation and final afford compound 12 as its hydrochloride (Scheme 6) (16).
reduction afforded spontaneously the corresponding cis-
piperidines 8, isolated as their hydrochlorides (Scheme 3) (8).
Scheme 6. Reagents and conditions: i, Ti(OEt)4, THF; ii, CH2=CHCH2Br,

In, 60 C; iii, KHMDS, THF, 0 C; iv, HCl, MeOH, dioxane.
Scheme 3. Reagents and conditions: i, In, THF, 60 C; ii, MVK, 6 cat.,

CH2Cl2, 45 C; iii, H2 (1 atm), (Ph3P)3RhCl cat., EtOH, rt; iv, 4 M HCl,
The simple hydrogenation of compound 12 yielded (+)-coniine
dioxane, MeOH, 0 C; v, NaBH3CN, buffer pH 5, rt; vi, HCl, Et2O.
(16), the major alkaloid extracted from poison hemlock and
responsible of its toxicity, as its hydrochloride (Scheme 7) (16).
Among compounds 8 prepared, it is dihydropinidine (8a),
a defense alkaloid of the Mexican bean beetle Epilachna The same starting
varivestis (9, 10), as well as isosolenopsins 8c,d, venom material was
alkaloids of fire ants (Solenopsis) (11). Structurally related treated with acryloyl
cis-6-methylpipecolic acid 9 is an interesting key constituent chloride under
of several bioactive basic conditions to
molecules (12-14). Scheme 7. Reagents and conditions: i, give compound 17,
H2 (1 atm), Pd/C cat., MeOH.
It can be easily ready to get a ring-
prepared by closing metathesis
oxidation of the in the presence of the catalyst 6 giving the bicyclic system
Scheme 4. Reagents and conditions: i, precursor 8d under 18. Final methylation at the conjugate position using a lithium
TFAA, Et3N; ii, RuCl3H2O cat., NaIO3; iii, standard conditions cuprate (17) afforded compound 19 in a stereoselective
K2CO3, MeOH, then 1M HCl.
(Scheme 4). manner (16). This bicyclic derivative has been reported (18, 19)
to be the precursor of the alkaloid (-)-cermizine C (20), so this
The corresponding trans-derivatives of the type 8 could method represents a formal synthesis of this alkaloid (Scheme 8).
be prepared changing the final reduction step shown in
Scheme 3. One example is the preparation of (+)-solenopsine
10, another natural alkaloid isolated from the fire ants (11)
(Scheme 5). After preparing the intermediate 7, it was
hydrogenated and cyclized under acidic conditions to
yield the tetrahydropyridine 11, which was submitted
finally to a reduction using the mixture of AlMe3/LiAlH4 at
low temperature to yield the expected trans-configurated
alkaloid 10 (15).
Scheme 8. Reagents and conditions: i, CH2=CHCOCl, CH2Cl2,

NaOH; ii, 6 cat., CH2Cl2 reflux; iii, Me2CuLi, BF3OEt2.
Another application of compound 12 was the synthesis of

Scheme 5. Reagents and conditions: i, H2 (1 atm), (Ph3P)3RhCl cat.,
EtOH; ii, HCl, dioxane, 0 C; iii, AlMe3/LiAlH4, -78 to 0 C; iv, HCl, Et2O.
(-)-pelleterine 21 (20) a key intermediate in the biomimetic
synthesis of natural alkaloids. Thus, once compound 12
was protected as its Boc derivative 22 (the corresponding
One interesting molecule that can be further elaborated sulfinyl derivative failed in the oxidation), it was submitted to
to give alkaloids in a chiral form is 2-allylpiperidine 12. the Wacker oxidation to give the ketone 23 that after final
5-Bromopentanal (13) was submitted to the tandem formation deprotection gave the expected alkaloid 21 (Scheme 9) (16).

Oxidative carbon-carbon double bond cleavage afforded
the aldehyde 32, which was submitted to an iterative process
using the sulfinamide 5 and allyl bromide (2). The obtained
sulfinyl derivative 33 was deprotected and hydrogenated to
Scheme 9. Reagents and conditions: i, Boc2O, CH2Cl2, NaOH; ii, O2, give the diamine 34, that without isolation was condensed
PdCl2 cat., Cu(OAC)2, DMF; iii, HCl. with 4-bromobutanal under basic conditions yielding finally the
expected alkaloid (+)-tetraporenine T3 (30) (Scheme 11) (24).
In addition, stereoselective reduction of (-)-pelleterine (21)
allowed the preparation of (+)-allosedridine (24) (21), as well When the aldehyde 32 was treated
as the two-step transformation into (+)-lasubine (25) (22). with ent-5 under the same reaction
conditions the final product was
Another its epimer (+)-tetraponerine T4 (35)
application of (24). A DFT study could explain the
(-)-pelletrine obtained stereochemistry. In addition,
(21) is the other members of the family, namely
preparation tetraponerines T1, T2 and T5-T8 were also synthesized following
of 5-epi-(+)- the methodology shown in Scheme 11, and studied their
cermizine C antiproliferative activity (25).
(26). Condensation of compound 21 with the Meldrum acid
(27) in the presence of acetic acid afforded the bicyclic (-)-Aphanorphine (36), that was isolated from the fresh-
compound 28, which was hydrogenated easily to give 29 with water blue-green alga Aphanizomenon flos-aquae (26),
high diastereoselectivity (13:1 dr). Final transformation into the incorporates a 3-benzazepine scaffold that resembles
desired alkaloid, isolated as its trifluoroacetate, was achieved benzomorphane analgesics. For its synthesis the protected
in a one-pot process by addition of methylmagnesium homomethallyl amine 38 was prepared starting from
bromide followed by in situ reduction and final treatment with 4-methoxyphenylacetaldehyde (37) and the sulfinamide
trifluoroacetic acid (Scheme 10) (16). 5 under the standard conditions shown above, but using
methallyl bromide (39) as the allylation component. Oxidation
of compound 38 with m-chloroperbenzoic acid (mCPBA)
Scheme 10. under basic conditions afforded an epoxide with concomitant
Reagents and
conditions: i, oxidation of the sulfur atom, which by treatment with
AcOH, EtOH, potassium iodide gave the alcohol 40 as a 1:1 diastereomeric
60 C; ii, H2 (4
mixture at the newly created stereocenter. The Friedel-Crafts
atm), PtO2 cat.,
EtOH; iii, MeMgBr, cyclization of this alcohol was not possible under different
THF, 65 C; iv, acidic conditions. Therefore, it was transformed into the
NaBH3CN, AcOH;
v, TFA, MeOH. corresponding N-benzoyl derivative 41, which then was
cyclized and deprotected to yield the bicyclic compound
42. Final N-methylation to give compound 43 followed by
O-demethylation, in both cases under standard conditions,
afforded the expected alkaloid 36 (Scheme 12) (27).
Scheme 11.
Reagents and
conditions: i, HCl,
THF; ii, CbzCl,
CH2Cl2, NaOH;
iii, OsO4 cat.;
NaIO4, lutidine;
iv, 5, Ti(OEt)4, 2, In
THF, 60 C; v, HCl,
THF; vi, H2 (4 atm),
Pd/C, MeOH; vii,
Br(CH2)3CHO,
K2CO3, CH2Cl2.
It is worth noting that starting from ent-21, easily available

from ent-12, the corresponding alkaloid ent-26 could be easily
obtained. In addition, protonation of compound 26 should
render a stereogenic nitrogen via equilibration to the most
stable trans-quinolizidine conformation of the free amine. As a
consequence, all four diastereomers of cermizine C could be
prepared following the methodology shown in Scheme 10.
A little bit more sophisticated structurally is the alkaloid
(+)-tetraporenine T3 (30), one of the components of a family
of alkaloids that Pseudomyrmecine ants (of the genus Scheme 12. Reagents and conditions: i, In, Ti(OEt)4, THF; ii,
Tetraponera) segregate against their enemies (23). The CH2=CMeCH2Br (39), 60 C; iii, mCPBA, NaHCO3, CH2Cl2, 0 C; iv, KI,
K2CO3, DMF, 100 C; v, TfOH, PhOMe; vi, PhCOCl, NaOH: vii, AlCl3,
starting material was compound 15, which after protection CH2Cl2; viii, NaOH, 80 C; ix, CH2O, NaBH4CN; x, BBr3, CH2Cl2.
exchange gave the benzoxycarbonyl (Cbz) derivative 31.

The same set of reactions shown in Scheme 12, applied to the The indium-promoted diastereoselective allylation was the
starting ent-5 allowed the preparation of (+)-aphanorphine. key step in the preparation of the alkaloid (-)-tylophorine (44),
This chemistry is important in order to assign unequivocally the isolated from the plant Tylophora indica, used in traditional
structure of both enantiomers (28). medicine due to its antibacterial, antiasthmatic, antiviral and
anti-inflamatory properties (29, 30). This chemistry was applied
to the aldehyde 45 to yield the corresponding homoallylic
amine 46 with high diastereoselectivity (95:5 dr). Tandem
hydroboration/oxidation under standard conditions gave
the alcohol 47 that was cyclized under Mitsunobu conditions
to yield the pyrrolidine 48, which without purification was
transformed into the alkaloid 44 (Scheme 13) (31).
7-Methoxycryptopleurine (49), an analogue of compound 44

could be prepared as it is depicted in Scheme 14. Starting from
the aldehyde 45 and using 5 as the sulfinamide component
the homoallyl amine 46 was prepared. After Boc exchange as
protecting group (to give 50), formylation of this material under
rhodium and nickel-catalyzed conditions afforded compound
51, which after a tandem hydrogenation/deprotection gave
the piperidine 52. Final treatment of this compound with
aqueous formaldehyde under acidic conditions gave the
expected alkaloid (S)-49 (Scheme 14) (32).
The synthesis of the enantiomer (R)-49 involved allylation of ent-

46 to give compound 53, ready to suffer ring-closing metathesis
with the Grubs-II catalyst to afford the corresponding piperidine
54 after hydrogenation. Final deprotection and cyclization
with formaldehyde (as shows Scheme 14) gave the expected
product (R)-49 (32). Citotoxicity studied for both enantiomers
demonstrated that the (R)-enantiomer is much more potent
Scheme 13. Reagents and conditions: i, 5, Ti(OEt)4, In, THF, rt; ii, 2, than its enantiomer against four cancer lines examined.
THF, 65 C; iii, 9-BBN, THF, 0 C to rt; iv, H2O2, NaOH; v, Ph3P, DIAD,
THF; vi, HCl, MeOH, 0 C to rt; vii, CH2O, H2O, 90 C.
N-Sulfinyl imines
derived from
3-(2-bromophenyl)
propanal have
been used in the
reaction with two
Grignard reagents
as the key step for
the straightforward synthesis of the alkaloids (-)-angustureine
(55) or (-)-cusparein (56) (33). In the case of the alkaloid 55,
the above mentioned indium-promoted allylation of the same
sulfinyl imine was also used as the key step for its synthesis:
after allylation and intramolecular N-arylation, a cross-
metathesis with (Z)-3-hexene and final hydrogenation led to
the desired molecule (34).
Apart from the

application of the
indium-promoted
diastereoselective
allylation of chiral
N-sulfinyl imines
to the synthesis
of alkaloids, this technology has been successfully used in the
asymmetric synthesis of substituted azetidines and pyrrolidines
(35, 36), -methylene--lactams (37, 38), bicyclic benzolactams
(34, 39), -methylenebenzocycloalkenes (40), and functionalized
homoallyl amines (41). In addition, recently the indium-promoted
allylation of chiral ketimines generating quaternary stereocenters
Scheme 14. Reagents and conditions: i, HCl, MeOH; ii, Boc2O, NaOH; (42), and the same process applied to the propargylation (43)
iii, [RhCl(cod)]2 cat., CH2O, H2O, BIPHEP, Ni-Xantphos, PhMe, 90 C; and allenylation (44) of chiral aldimines, as well as the reaction
iv, H2 (1 atm), Pd(OH)2/C; v, TFA; vi, CH2O, H2O, HCl, EtOH, 90 C.
with other electrophiles (45-47) has been reported.

ACKNOWLEDGEMENTS 14. Troin, Y.; Carbonnel, S, Heterocycles 2002, 57, 1807.
We thank the continued financial support from our Ministerio 15. Medjahdi, M.; Gonzlez-Gmez, J. C.; Foubelo, F.; Yus, M.
de Ciencia e Innovacin (MCINN; projects CONSOLIDER Heterocycles 2012, 86, 727.
16. Bosque I.; Gonzlez-Gmez, J. C.; Foubelo, F.; Yus, M. J. Org.
INGENIO 2010-CDS2007-00006, CTQ2011-24151, CTQ2011-
Chem. 2012, 77, 780: Corrigendum: Bosque I.; Gonzlez-Gmez, J.
24165), the Ministerio de Economa y Competitividad
C.; Foubelo, F.; Yus, M. J. Org. Chem. 2012, 77, 4190.
(MINECO; projects CTQ2013-43446-P, CTQ2014-51912-REDC,
17. Snider, B. B.; Graboski, J. F. J. Org. Chem. 2007, 72, 1039.
CTQ2014-53695-P), FEDER, the Generalitat Valenciana 18. Morita, H.; Hirisawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron
(PROMETEO 2009/039, PROMETEOII/2014/017) and the 2004, 60, 7015.
University of Alicante. 19. Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron
2009, 65, 1608.
20. Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752.
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REGULATION
RICHARD ELSMORE*, SAMANTHA WRIGHT

JSC International Limited, The Exchange,
Station Parade, Harrogate HG1 1TS, United Kingdom
Richard Elsmore Samantha Wright
The Authorisation of Biocidal Products

under the BPR
KEYWORDS: Biocides, Biocidal Products Regulation, BPR, Regulation (EU) 528/2012, Biocidal Products Directive, BPD, 98/8/EC,
biocidal products, biocidal product authorisation, national biocide authorisation, Union authorisation, mutual recognition,
simplified authorisation.
Abstract Over recent years the legislation concerning the placing of biocidal products on the market within the EU
has changed significantly. We are seeing the gradual transition from national requirements to a
harmonised European system of regulation. While the new EU wide system is based on a two phase approach, initially focussing on
active substances, the second phase of this process is now impacting many companies who place formulated biocidal products,
such as disinfectants, on the market. The change over from the diverse national approval systems to the BPR product authorisation
process is triggered by the approval of the active substances that a product contains and product authorisation will now become
essential if existing products are to remain on the market or before new products can be launched.
While certain biocidal products have traditionally been regulated under the old national rules in some Member States, the BPR
requirement for product authorisation will impact all biocidal products that fall within scope of the BPR and represents a major change
particularly for some products that may only have been lightly regulated in the past. As such, the requirements for BPR product
authorisation can represent a significant challenge for companies who market these types of products. This article examines the
process of product authorisation and some important considerations when planning to place a biocidal product on the market.
INTRODUCTION assessment of active substances. This process was originally

expected to be completed over a 10 year period with
Historically the regulation of biocidal products has varied completion in 2010, but this timeline was extended initially to
considerably within the various Member States of the EU. 2014 and, more recently, under the BPR to the end of 2024.
Nationally some groups of product such as rodenticides and While active substances remain under evaluation the existing
insecticides have been regulated in most Member States, other national rules for biocidal products remain in Member States
types of biocide such as disinfectants and preservatives have with only certain aspects of the BPD/BPR having effect.
been regulated in some Member States but not in others. Even The second phase of the European biocide legislation
where different Member States have had systems in place for impacts biocidal products directly. Once an active substance
biocidal products, the requirements have not been consistent successfully completes its evaluation and a positive decision is
and have varied considerably from country to country. made regarding its safe use in biocidal products, a deadline
is set for product dossiers to be submitted for all biocidal
Because of this lack of a level playing field within the EU a products that are based on that active substance. Under the
harmonised system of control was proposed in the early BPR this deadline is referred to as the Approval date for the
1990s along the same lines as the harmonised system for active substance and this is published in the Official Journal
agricultural pesticides (1). This draft non-agricultural legislation of the EU as an Approval Regulation. For products that are
was introduced as the Biocidal Products Directive (2), or BPD, based on more than one active substance, it is the Approval
which was published in 1998 and implemented in Member date for the last active substance in the formulation to be
States on 14 May 2000. The BPD was subsequently repealed approved that triggers the deadline for product authorisation.
and replaced by the Biocidal Products Regulation, or BPR (3), A phased active substance submission timetable was used
in 2012. The BPD and the BPR are both based on a two based on the product type in which the active substance is
phase process. The first phase involves the evaluation and used (starting in 2004 and running through to 2008).

The timing of active substance approval has been reflected applicable sell through time. This Article states that in the case
in the timings for product authorisation, with active substances of a decision not to approve an active substance, a Member
that were submitted earliest (e.g. wood preservatives and State may continue to apply its current system or practice of
rodenticides) tending to gain approval first. Other factors have making biocidal products available on the market for up to
impacted when an active substance was approved such 12 months after the date of the decision not to approve an
as the resources available to the evaluating member state active substance in accordance with the third subparagraph
and where additional data have needed to be generated. of paragraph 1, and may continue to apply its current system
Because of this, active substance approvals have been or practice of using biocidal products for up to 18 months after
staggered. Under the BPR the Biocidal Product Committee that decision. This means that products can continue being
(BPC) of ECHA must come to an opinion on an active placed on the market for 12 months with a further 6 months to
substance. The likely timing of this can be determined from allow products to be used up.
the BPC working programme which is published on the ECHA
website; the website also includes the opinions once they are ECHA also published a list of upcoming deadlines relating
made. Without going into the legislative details of the process, to the ability to notify active substances which, for example,
in principle the Approval Regulation is published approximately had been redefined or were not considered to be active
6months after the BPC opinion (although this can be later) and substances under the BPD (4).
the approval date is 24 months after the BPC opinion.
A target has been set for at least 50 active substance / PT APPROVED SUPPLIER LIST (ARTICLE 95)
ECHA opinions and Commission decisions to be made per
year to allow the 2024 completion deadline to be met. In addition to containing an active substance that is being
supported through the Review programme it is also a
Some of the active substance approval dates in 2016/17 are requirement of the BPR that, after 01 September 2015, only
listed below (not exhaustive): biocidal products consisting of, containing, or generating a
relevant substance, can only be made available on
the EU market if the substance supplier or product
supplier is included in the approved supplier list
(Article 95 list) for the product type to which the
product belongs. This list is regularly updated by
ECHA and can be found on the ECHA website.
PRODUCT AUTHORISATION OPTIONS
Under the BPR there are a number of options

available for product authorisation. These include:
National authorisation and mutual recognition

Companies planning to sell their products in
one EU Member State must apply for product
authorisation in that country. The Member State
competent authority evaluates the application
and makes a decision on the authorisation within
3 years of the date of approval.
If a company wishes to extend the national

product authorisation to other markets, it can ask
other Member States to recognise it. Companies
can apply for mutual recognition (MR) either
in sequence or in parallel. To apply for MR in
sequence, a company will first need to get their
Active substance approvals that are expected to trigger product authorised in one Member State. After this, they can
product authorisations in 2017, but where the Approval request other Member States to recognise this authorisation.
Regulation has not been published at the time of writing, include
Biphenyl-2-ol (PT 3), Formaldehyde (PT3), L(+) Lactic acid (PT1). For MR in parallel, the company can submit an application
for product authorisation in one Member State (called the
Equally important is when active substances are not approved reference Member State) and simultaneously ask other
for particular product types as this will mean that products will countries to recognise the authorisation as soon as it is
need to exit the EU market. Recent examples include Triclosan granted. If the concerned Member States do not agree
in PT1, 2, 7 & 9 (Decision (EU) 2016/110 & 2014/227/EU), PHMB to MR, the case will be referred to the coordination group,
in PT 1, 6 & 9 ((EU) 2016/109), Glutaral (Glutaraldehyde) in PT which has 60 days to seek agreement. If the coordination
1 & 13 (Decision 2014/227/EU). Once a decision has been group cannot reach an agreement, the matter is referred to
published Member States will follow Article 89(2) of the BPR the Commission which may ask ECHA for an opinion on the
regarding any products that are on the market and the scientific or technical aspects of the case.

Union authorisation (UA) If a new product has a variation in the active or non-
Certain biocidal products can be authorised at Union level. active components, already in the biocidal product family
This will allow companies to place their biocidal products on composition, there is a 30 day notification period before
the market throughout the entire Union, EEA and Switzerland, placing new products in the family on the market.
without the need to obtain specific national authorisations.
Union authorisation can be granted to biocidal products R&D Permits
with similar conditions of use across the Union, except those Any tests and experiments carried out for research and
containing active substances meeting the exclusion criteria. development purposes using unauthorised biocidal products
The timeframe for initiating the authorisation process differs and their (not approved) active substances must be recorded
depending on whether the product contains new or existing and may require notifications if a release in the environment
active substances. is possible.
For existing active substances UA will be possible in three Parallel Trade Permits
different stages, depending on the product-type: This type of application allows a company to import, and
For product-types 1, 3, 4, 5, 18 and 19 - from 1 September 2013 place on the market in a second member state, a product
For product-types 2, 6 and 13 - from 1 January 2017 already authorised in another Member State under the BPR,
For the remaining product-types (7, 8, 9, 10, 11, 12, 16 and 22) when an identical product is already authorised under the EU
from 01 January 2020 BPR in the second member state.
UA is not applicable to products in PT 14, 15, 17, 20 and 21.
Simplified authorisation IMPACT OF THE BPR ON PRODUCT AVAILABILITY

The simplified authorisation procedure aims to encourage
the use of biocidal products that are less harmful for It has long been recognised that the BPR will result in a
the environment, human and animal health. Simplified reduction in the number and diversity of biocidal products
authorisation applies only to products that contain active on the EU market as companies continue to rationalise
substances that appear in Annex I of the BPR (and comply their product ranges. This is primarily driven by the cost and
with the specified restrictions listed in Annex I). There are also resources required. A recent AISE/CEFIC survey published in
specific requirements that the product does not contain December 2015 (6) indicated that, overall, about 26% of the
any substance of concern or any nanomaterials and that its products currently on the market (covered by the survey) were
intended use does not require personal protective equipment. expected to be withdrawn in the future. The same withdrawal
In addition the biocidal product must be sufficiently effective. rate was observed across the different biocidal product
main groups with the trend equally affecting SMEs and large
Same Biocidal Product Authorisation companies.
The Same Biocidal Product Regulation is a similar system to the
back-to-back process under the BPD or national requirements. In addition the survey indicated that 74% of biocidal products
This procedure can be utilised when a biocidal product or expected to be supported in the future would be grouped into
product family has been authorised or has been submitted families which reconfirms the high interest of industry for the BPF
via R4BP, and authorisation is sought for an identical product. concept, as it enables a considerable reduction of the total
The application of the Same Biocidal Product, once submitted number of dossiers to be evaluated in the future, thus reducing
will be validated within 30 days. This includes a check of the workload for both industry and authorities.
the LoA to the related reference product and review of the Of concern for smaller national organisations was that the survey
specified differences and evidence of being identical on all indicated that less than 10% of the products currently on the EU
other aspects between the Same Biocidal Product and the market are sold at local level, i.e. only in one or two Member
related reference product. The application will be granted or States. Around half of the products are sold in more than 10
refused within 60 days after the validation of the application, countries, i.e. 30% in 11 to 15 Member States, and another 25%
or, where applicable, from the subsequent date of adoption of in more than 15 Member States. This would tend to suggest the
the corresponding decision concerning the related reference dominance of products sold in many Member States.
product. The Same Biocidal Product will be independent of the
reference dossier with the authorisation number being held by The intention to use UA seems to have decreased slightly since
the applicant. The procedure is provided in the Commission the last survey (undertaken in 2011), as in this survey around
implementing Regulation (EC) 413/2013 (5). 44% of the future dossiers (58% individual products and 42%
families) were thought to be submitted for UA, versus 56% in
Biocidal Product Families (BPF) 2011. This reduction is thought to be due to the perceived UA
Biocidal Product Families build on the Frame formulation costs which are seen as too high by a majority of companies,
concept under the Biocidal Products Directive (BPD). BPF regardless of their size.
allow for the replacement of a non-active substance with
another of the same or lower risk. All products within the
biocidal product family are covered by the one authorisation DOSSIER PREPARATION
for the family as a whole; each individual product does not
have a separate authorisation. There is no limit to the number The BPR product dossier will include specific data on individual
of products within each family, and no notification is required products or on product families. This data will include phys chem
if a new product is placed on the market as a result of a studies, storage stability data and efficacy studies to support
change in the pigment, perfume or dye, as long as these are any claims made. These studies must be conducted to strict
incorporated into the biocidal product family composition. guidelines and may need to be done under GLP.

The product dossier will also include details on the use of stage which involves product authorisation. While many of
the product in the form of specific risk assessments looking the first active substances that were approved triggered
at how the product is used and the routes of exposure; this the authorisation of products that have traditionally been
must show that the product use is safe for both humans heavily regulated throughout the EU (such as rodenticides,
and the environment before it can be authorised. Typically wood preservatives and insecticides), more recent
no data is required with the product dossier on the active approvals are affecting products that may have been only
substance as this is usually captured in a letter of access lightly regulated in many Member States. It is important
from the active substance supplier. It should be noted, that companies which formulate and supply biocidal
however, that the available active substance data may products such as disinfectants, water treatment biocides
not necessarily be sufficient to cover a specific products and slimicides track the status of the active substances
use and additional studies may be required. Because of that they use and plan for how they will approach product
this, it is advisable to start discussing letters of access and authorisation. While the BPR provides a number of options
what they cover with suppliers at an early stage. to reduce costs, such as same product authorisations, the
use of product families and union authorisation, the costs
It is important to realise that generating the required data associated with regulatory compliance are significant and
and risk assessments does take time and should be planned rationalisation of product lines can provide a good starting
well in advance of the dossier submission date to allow point for companies with extended portfolios of products.
for refinement of risk assessments and reporting of studies.
Storage stability tests (depending on the claimed shelf It is also important to realise that until the time for BPR
life) can take several years to complete. In addition the product authorisation for a particular product, national
importance of efficacy testing should not be overlooked rules continue to apply in Member States and these must
as only products that are sufficiently effective will be be complied with. Companies should develop strategies
authorised. As new efficacy test methods and efficacy for their product authorisations well in advance of the
guidance are developed it should not necessarily be deadline for BPR product submission and determine which
assumed that products that have been on the market for is the best regulatory route towards product authorisation
many years and may have been tested under different for their company and their product ranges.
methods, will pass the new standards required by the
BPR. In some cases this may only result in changes being
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MARIA J. CASTRO1, CARLOS E. LPEZ1, RAJESWARI NARAYANASAMY2, JOLANTA E. MARSZALEK1,

MIRIAM P. LUEVANOS-ESCAREO1, GERARDO J. FAJARDO3, NAGAMANI BALAGURUSAMY1*
1. Laboratorio de Bioremediacin, Facultad de Ciencias Biolgicas, Universidad Autnoma de Coahuila,
Carretera Torren-Matamoros km 7.5 Torren Coahuila, Mxico
2. Facultad de Ingeniera, Ciencias y Arquitectura de la Universidad Jurez del Estado de Durango
3. Facultad de Ingeniera Civil de la Universidad Autnoma de Nuevo Len
Nagamani Balagurusamy
Potential of enzymes
(urease and carbonic anhydrase)
for a sustainable construction industry
KEYWORDS: Urease, carbonic anhydrase, biomineralization, bioconcrete, biocement, biodeposition.
Abstract Concrete is the most commonly used material of numerous structures around the world due to resistance,
durability and low cost compared with other construction materials. However, traditional construction
materials are susceptible to suffer deterioration by physical, chemical and biological factors that produce irreversible damage to their
structure, which requires a high-cost of repair and maintenance. Additionally, during production process cement industry emits about 0.73
0.99 t CO2/ t of cement produced. Bioconcrete is emerging as an ecological, economical and sustainable alternative for construction
industry. Biomineralization by bacteria facilitates the development of bioconcrete, wherein calcium carbonate is formed by the metabolic
activity of microorganisms, which involves a series of complex reactions directed mainly by urease and carbonic anhydrase enzymes. In
this review, biomineralization processes involved in bioconcrete formation and their potential use for the construction industry is discussed.
INTRODUCTION As a consequence of their self-repair character, CO2

emission could also be minimised. Bioconcrete production
Concrete is widely used as construction material around includes biomineralization process, which involves the
the world due to its resistance, durability and low cost formation of calcium carbonate by metabolic activity of
in comparison with other construction materials (1,2). microorganisms, where two enzymes; urease and carbonic
However, it is susceptible to undergo deteriorations due anhydrase play a vital role (8,9). Role of urease enzyme in
to diverse physico-chemical and biological factors (3,4). the biomineralization process is reviewed here.
These factors induce formation of cracks in internal
structure of concrete causing irreversible damage. It has
been estimated that the cost of repair and maintenance BIOMINERALIZATION
is around $147/m3 of concrete, despite the fact that cost
of concrete production ranges between $65 and $80/ Biomineralization is a complex process involving metabolic
m3 (5). Cement is the most important component of the activity of diverse organisms in the formation of minerals,
concrete since it provides properties of compaction, which are termed as Biominerals. Metabolic activity of
and with growth of modernization and industrialization microorganisms has been responsible in large part for the
demand for cement has been increasing. The demand for deposition of minerals throughout the history of the Earth
cement in 2006 was about 2540 million tons (Mt), which is (10, 11). At the end of the precambrian era and at the base
predicted to increase between 3680 (low estimate) and of the Cambrian era, about 540 million years ago, various
4380 Mt (high estimate) in 2050. This increase in activity microorganisms evolved with ability to generate most of the
of the construction industry has generated a negative 64 known minerals, and the composition of biominerals varied
impact on the environment. Concrete industry emits 0.73 according to the metabolic diversity of microorganisms (12).
0.99 t CO2/ t of cement produced (6), which accounts Carbonates, phosphates, silicates, sulphates, sulphides,
for about 5-7% of global CO2 emission (2, 7). Recently, civil oxides or hydroxides form biominerals along with variety of
and environmental engineering researchers are working cations such as calcium, iron, magnesium, and manganese.
on the development of sustainable building materials with Biominerals can also be formed by organic macromolecules;
extended useful life. Bioconcrete is being reported as such as proteins, polysaccharides, glycoproteins and
one of the novel materials showing increased resistance, proteoglycans, which also aid in structural formation,
durability, apart from self-repair properties. protection and sensory detection (13, 14).

Biomineralization of CO2 into magnesium- and/or calcium- UREASE (UE)
carbonate (15) is one of the most abundant biominerals in our
earth (16), and this is because calcium intervenes in various Urease (EC 3.5.1.5) is a metalloenzyme containing nickel
bacterial metabolic activities (12). Calcium biominerals belonging to the group of hydrolases classified as urea
group comprises 50% of the known calcite biominerals amidohydrolase. Urease plays an important role in nitrogen
(CaCO3), and constitute 4% of the earth crust (12, 17). requirements of various organisms including bacteria, fungi,
Biomineralization can be divided into two main algae and plants (23). Urease catalyses the hydrolysis of
mechanisms; biologically controlled mineralization (BCM) urea into ammonia and CO2. As a consequence, there
and biologically induced mineralization (BIM) (8). Another is considerable increase in pH and CO2 concentration in
mechanism, biologically influenced mineralization (BIFM) the microenvironment of the bacteria. One mole of urea is
was suggested in 2009 (18). BCM can occur by extracellular hydrolysed to 1 mole of carbamate and 1 mole of ammonia
(BCMe), intercellular (BCMi) and intracellular (BCMin) (eq.1) carbamate is spontaneously hydrolysed to form one
means, where microorganisms have control on grade of additional mole of ammonium and carbonic acid (eq.2),
nucleation, growth and deposition site of biominerals (8, 19). which are balanced in solution to form bicarbonate (eq.3),
Bacterial cells with BCMe mechanism produce a molecular 2 moles each of ammonia and hydroxide (eq.4) which
matrix of macromolecules such as proteins, glycoproteins, increases pH, and shifts the balance of bicarbonate into
proteoglycans and polysaccharides, which facilitates carbonate (eq.5). As a consequence, there is high influx
nucleation and deposition of biominerals (8, 11). In BCMi, of calcium ions and excessive expulsion of protons, which
the microorganisms coexist in biofilms, and the epithelial obligates the bacteria to export calcium outside the cell
surfaces of cells are used as the organic substrate leading and compensate for loss of protons for their survival. In this
to nucleation and formation of biominerals. On large areas process, there is availability of dissolved inorganic carbon
of cell surface exoskeleton is formed to protect structures. and calcium ions in the microenvironment, which results
BCMin occurs within specialized vesicles or vacuoles that in the precipitation of calcium carbonate outside the cell
lead directly to the nucleation of biominerals intracellularly. (eq.6 and 7) (Figure 1) (11).
In this mechanism, the microorganisms have a high degree
control over concentration of cations and anions that eq.1
constitute biominerals in a microenvironment in which
organic matrix is used as a site of nucleation. Mineralized eq.2
structures by this mechanism present intrinsic morphologies,
specific for each species (12). An example is formation of eq.3

nano-crystals ferromagnetic such as magnetite or greigite,
resultant product of interaction between biopolymers and eq.4
proteins. These minerals are connected to intracellular
structures known as magnetosomes that are synthesized eq.5
by a diverse group of bacteria involved in the iron cycle
called magnetotactic bacteria (19, 20). BIM occurs only eq.6
by extracellular means as a result of interaction between
metabolic activity of organisms and the environment. eq.7
In this process, microorganisms have limited control on
nucleation, growth and deposition of biominerals. These
biominerals are characterized by their wide range in size of
particulates, poor crystallinity and morphology (21).
This mechanism of biomineralization is favoured by
different biological surfaces such as membrane, cell walls,
exopolymers, biofilms and even inactive spores, which
function as a site of nucleation and growth of crystals
through ions adsorption (21, 22). Moreover, precipitation
of biominerals induced in some cases is dependent on
the chemistry of exterior environment of the cell (16, 22).
Microbially induced calcium-carbonate precipitation
(MICP) is widely present in bacteria and takes place in
different environments such as soil, fresh water, water and
marine sediments. Calcite, aragonite and vaterite are
some of the most representative biomineral polymorphs
with different types of crystallization such as rhombohedral,
orthorhombic and hexagonal (16). Urea hydrolysis,
photosynthesis, denitrification, sulphate reduction, Figure 1. Schematic illustration of MICP by urease activity.
oxidation of organic acids and methane oxidation are
the major metabolic pathways involved in MICP, and they
occur in interaction with calcium (5). Of these pathways, Among soil bacteria, urease activity is widely reported in
urea hydrolysis is less complex, where the precipitation of Sporosarcina pasteurii, previously known as Bacillus pasteurii
calcite occurs by production of carbonate ions in presence (11), Bacillus sphaericus and Bacillus cereus (24, 25). Apart
of ammonia through a series of complex biochemical from urease, carbonic anhydrase also plays a role in MICP,
reactions that are directed by the enzyme urease (17). although their role has not yet been studied in detail.

CARBONIC ANHYDRASE (CA) 1.125 and 1.018 mM min-1.mg-1 respectively (30).
CA and urease activity of B. megaterium was 115 U.ml-1
Carbonic anhydrase (EC.4.2.1.1) is a metalloenzyme, with zinc and 690 U.ml-1 respectively (31). These data clearly
content that catalyses the inter-conversion of CO2 and HCO3 demonstrates the wide range in the metabolic activity
(eq.8). In this process, H+ ions are generated, which promotes of different bacteria, which depends on environmental
the precipitation of carbonate as calcium carbonate (eq.9) conditions and thus their potential use will have that
by the presence of calcium ions. dependency too.
eq.8 In general, the process of biocementation depends on six

fundamental concepts; (a) activity of urease, (b) activity
eq.9 of carbonic anhydrase, (c) concentration of calcium,
(d) concentration of dissolved inorganic carbon (DIC),
CA is also produced by prokaryotes and eukaryotes as it is (e) pH and (f) the availability of nucleation sites. Calcium
essential in many biological processes such as respiration, carbonate particles adhere to the cement, creating a
CO2 acquisition, ions transport, acid-base balance, solid mass, and in this process the biominerals can be
mineralization and photosynthesis. Activity of CA promotes deposited evenly in inter-granular spaces, reinforcing
the formation calcium carbonate (26). Role of carbonic properties of compaction (8). It is observed that the
anhydrase in biomineralization was reported by Hwang and cells tend to encapsulate as a means of protection
coworkers (27) and they observed that the morphology under unfavourable conditions due to increase in pH
of calcium carbonate due to microbial precipitation generated by concrete matrix. The encapsulation limits
is dependent on two parameters; constant pressure of the transfer of nutrients and therefore leads to inactivity
CO2 and addition of polymers involved in growth and and even death of bacteria (32, 33). Nonetheless, it is
nucleation (Figure 2). possible that cells can wake up from their vegetative
state and regain their metabolic and urease and CA
activities, as and when favourable conditions return in the
microenvironment. Bacterial spores were encapsulated
and their potential activity in self-healing of fractures
was studied (32). It was observed that self-healing was
48-80% higher than specimens without encapsulated
spores. They further observed that with adequate physico-
chemical conditions, bacterial spores germinated and
recorded urease activity. However the cell encapsulation
can also passively influence the biomineralization, as
microorganisms can serve as a nucleation site for the
deposition of calcite (9, 33). This passive process is known
as biologically influenced mineralization (18). Although,
this mechanism is similar to MICP, live bacteria is not
necessary for the formation and deposition of these
biominerals (18).
Figure 2. Schematic illustration of CaCO3 biomineralization by

carbonic anhydrase (27). BIODEPOSITION
The precipitation and biodeposition of calcium

BIOCEMENT carbonate has been applied as a novel technique for
the remediation of construction materials and is known as
MICP favors the formation of biocement, which is dependent Calcite Bioconcept (34). Calcite Bioconcept is based
on the activities of urease and carbonic anhydrase (eq.10). mainly on the ability of a bacterial cell to precipitate
Interdependence of both enzymes in this process can be calcium carbonate minerals on its cell surface and
explained by the fact that urease activity is dependent thereby heal the fractures formed in the structure of the
on the incorporation of nickel in their active site, which is costructions materials. This concept was first applied in
regulated by the interconversion of CO2/HCO3 catalyzed by 1990 for the protection of ornamental stones. However,
carbonic anhydrase (11, 28). the efficiency of this technique is widely being studied
under laboratory conditions in the last decade by way of
eq.10 incorporating different microorganisms (34, 35).
This technique was applied for the remediation and
It has been observed that different soil bacteria protection of Euville limestone material obtained from the
showed different kinetic values of urease and carbonic mixture of fossilized crinoids and equinoides, joined by
anhydrase activity. Km and Vmax of urease in free cells of crystals of calcium carbonate (36). Two ureolytic bacteria,
Sporosarcina pasteurii was 17.30 mM and 1.57 mM min1. Bacillus sphaericus and Bacillus lentus were incorporated
mg1 respectively and the immobilized cells recorded a into limestone cubes of various dimensions and were
Km of 22.3 mM with a Vmax of 0.73 mM min1.mg1 (29). studied for deposition of calcite on agar plates, capacity
Whereas, Km of free and immobilized, purified CA enzyme for urea hydrolysis, production of extracellular polymeric
from Bacillus pumilus was 1.211 and 4.547 mM with Vmax of substances, biofilm formation and - potential.

They reported that bacterial colonies of both tested strains 5. Seifan M., Samani A. K., & Berenjian A. Appl Microbiol
showed crystal aggregates in the range of 75 to 95% of Biotechnol, 100(6), 2591-2602 (2016).
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Rev, 16(8), 6220-6238. (2012).
to 4.07 0.15 g NH4- N l-1, production of extracellular
7. Ivanov V., Chu J., & Stabnikov V. Bacteria for concrete
polymeric substances in the range of 0.08 0.01 to 0.12
surface treatment, Chapter 15, in Handbook of Basics of
0.02, biofilm formation in the range of 1.4 1.0. 102 to 3.2
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and was recorded that the incorporation of ureolytic
Rev,148,117 (2015).
bacteria B.sphaericus in sol-gel with calcium (Cl 2Ca or
11. Jimenez-Lopez C., Jroundi F., Rodrguez-Gallego M., Arias J.
Ca (NO3) 2) showed effective results in the remediation
M., & Gonzalez-Muoz M. T., Biomineralization Induced by
of cracks of 0.1 to 0.6 mm size and further reduced the Myxobacteria, in Communicating Current Research and
permeability (37). The effect of different temperatures Educational Topics and Trends in Applied Microbiology,
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activity at 37 C and S. psychrophila recorded high
Biomacromolecules, 6(3), 1289-1298 (2005)
activity at 10 and 20 C. These authors concluded that
15. Kim I. G., Jo B. H., Kang D. G., Kim C. S., Choi Y. S., & Cha H. J.
B.sphaericus is the most suitable ureolytic bacteria for
Chemosphere, 87(10), 1091-1096 (2012).
biodeposition applications under different temperature 16. Perito B. & Mastromei G. Molecular basis of bacterial calcium
conditions. It has been shown that biodeposition is carbonate precipitation, Chapter 5, in Molecular
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permeability of water and aggressive gases, and thereby 17. Achal V., & Pan X. Curr Microbiol, 62(3), 894-902 (2011).
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In 1st WTA International PhD Symposium: Building materials
damages, these novel technologies apart from promoting
and building technology to preserve the built heritage
self-healing, can offer other benefits such as reducing
International Association for Science and Technology of
the permeability of substances and aggressive gases, Building Maintenance and the Preservation of Monuments
increasing resistance and thereby extending the utility life (WTA), 33, 439-457 (2009).
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SUSTAINABILITY
PHILIPPE WILLEMS*, B. TJEERDSMA

Orineo bvba, Acaciastraat 14, B-3071 Erps-Kwerps, Belgium
Philippe Willems
The age of cool biobased materials:

a new positioning strategy
KEYWORDS: Biobased materials, positioning, up cycling, agro side-streams, aesthetic.
Abstract Bioplastics just celebrated their 25th jubilee. A rather sad celebration, as current market share does only
represent 0,2% of the European thermoplastic and thermosetting market, despite large multinational
involvement and consumer support. Own research on the reasons for this limited commercial success concluded on a failing
positioning. Most bio-based materials are promoted on their properties, vegetable origin, end-of-life options and benefits for the
environment. So far so good, except that suppliers always benchmark against conventional synthetic plastics. And when positioned
as such, bio-based materials tend to fall short on price/performance ratio.
A new positioning strategy, based on a balanced What could be the reason for such a
communication between rational (addressing limited success? Most research on this
objective facts), emotional (addressing aesthetic concludes on price and performance.
aspects) and intuitive (addressing personal values) Current bioplastics are still 2-3 times more
properties offers new opportunities. expensive then conventional plastics and
This is illustrated by the recent launch of a new as long as price parity is not obtained, large
bio-based material for interior decoration. acceptance of bioplastics is limited (3, 7).
Other sources claim a 15% price premium for
Bioplastics (8) but even this premium does not
INTRODUCTION cover the price gap.
The first mention of man-made plastic material goes back Isnt there some positive perspective for bioplastics?
to 1862 (1, 3). A mouldable cellulose nitrate material, called Many studies and articles anticipate double digit growth
Parkesine created great interest at the Great International for bioplastics in the coming years (9, 10, 11). Are we
Exhibition in London. This was well before the worlds first at the end of the lag-time, to use a biotechnological
synthetic plastic, Bakelite, back in 1907, the start of the terminology? First observation is that most anticipated
plastic era(2). Only in 1990, when ICI brought Biopol on the growth goes towards drop-in bio-polyethylene and bio-PET,
market, the Bioplastic Revolution started (1). supported amongst others by Coca-Colas PlantBottle
and TetraPaks Tetra Rex Bio-based packaging (8, 11).
25 years later, with the accumulated knowledge of a century A more positive evolution in this field is the support given by
of organic chemistry and progress in biotechnology and Coca-Cola, Danone and ALPLA to polyethylenefuranoate,
fermentation processes, bioplastics barely represent 0,2% a fully biobased alternative to PET (12). Secondly, and
of the European thermoplastic and thermosetting polymer more worryingly, similar growth rates were forecasted in
consumption (4, 5) and 0,5% of plastics consumed in bags and articles back in the 90s and 00s (13, 14, 15, 16, 17). And
packaging. It is not because of a lack of interest from large these projections felt considerably short.
corporation, as most major chemical and agro companies in
the world are (or have been) actively involved in developing So, there must be another limiting factor in the emergence
biobased plastics and polymers. It is also not because of a of bio-based materials. One such factor could be a failing
lack of consumer acceptance. Increasing public concern positioning strategy.
about the environment, climate change and long-term limited
global fossil fuel resources are indeed important drivers to find The aim of this paper is to present a novel positioning
alternatives to petroleum-based plastic materials (6), drivers strategy for biobased materials, a strategy that balances
already present at the start of the Bioplastic Revolution. both objective and subjective aspects.

CURRENT BIO-BASED MATERIAL POSITIONING Many companies, especially technology-driven companies,
are tempted to overstress these rational messages in their
How are bio-based materials or bioplastics now positioned? communication. This is definitely a good strategy when
We also looked at different actors in the value chain: communicating towards peers, but peers are nor customers
polymer suppliers, compounders, end-users and identified or consumers of the product. Customers and consumers are
the positioning of their products. Not surprisingly, all bio- not always technically skilled. In their quest for properties and
based materials are positioned as the better alternative to functionality they are expecting some reassurance on the
the environment. All actors stress on the same arguments: performance, rather then complicated data sets. Thats why
greenhouse gas reduction, carbon mobilisation, end-of-life in the 360 positioning, rational messages are translated in a
options (biodegradation, recycling, incineration), no use of simple and clear message to customers and consumers, with
genetically modified crops and limited impact of biomaterials the possibility to access to hard scientific data upon request.
on land use. There is barely a differentiation between the
different biomaterials proposed. Technical arguments Rational messages are essential, but should never be overstressed.
and certification also have a determining place in the
communication strategies. A third striking element is that all Emotional messages
polymer suppliers systematically benchmark their products to In the 360 positioning, emotional messages are those
synthetic polymers (18, 19, 20). stimulating the senses. Consumers are buying products they
The problem of this communication strategy is that leaves price like. Products that are looking good, feeling good, tasting
and performance playing a prominent role in the purchase good, smelling well. Aesthetic and haptic properties of bio-
decision-making process: environmental arguments are nice based materials are rarely mentioned in the communication of
to have but not determining enough to justify a less attractive bio-based material suppliers. Strange. Especially because this
price/performance ratio. is the battlefield where you win the hearth of the consumers.
What is missing in the communication? Passion for the product, Emotional messages are upgraded from non existent to
aesthetics, a nice story to tell consumers. Items included in the prominent in the 360 positioning strategy.
communication made by Veuve Clicquot about their new
champagne packaging, Naturally Clicquot (21). Intuitive messages
Intuitive messages are sent towards the personal values of the
customers and consumers. This is where the environmental
360 POSITIONING benefits of a product will come forward. Where social benefits
will be mentioned. Where products are serving the personal
A new way to position bio-based materials, called a 360 image of consumers. Where GMO and end-of-life issues are
positioning can be an alternative. This is especially valid for addressed. Where LCA comes in.
innovative bio-based materials that should be promoted on
their own merits and not in comparison to synthetic polymers. Those intuitive arguments are well described in the bio-
It is somewhat less relevant to bio-based drop-in products. based literature, unfortunately highly factual and diluted
with rational arguments. A better option is to combine these
The 360 positioning is based on a balanced value proposition, intuitive messages into a nice story that customers can further
addressing both objective product properties and subjective tell to the consumers. And again, the story needs to be simple
arguments. Centrally in all communication stands the consumer and visual for the consumer.
benefit, the one stakeholder who finally decides to buy a
product, who drives the whole value chain (22, 23). The 360 Balance and honesty
positioning principle stresses on simple, clear and balanced The 360 positioning covers the rational, emotional and intuitive
messages: rational, emotional and intuitive messages (Figure 1). messages in a balanced way. Customers and consumers first
need to want the product (the emotional part), then need to
Rational messages be convinced that the product matches their personal set of
Each product has objective properties: mechanical properties, values (the intuitive part) and finally need to be reassured that
composition, processing the product will deliver
conditions, functional according to expectations
properties, purity, etc. (the rational part). Only
Whatever positioning when the 3 elements
strategy a company are well balanced, price
chooses, each product becomes less of an issue
must perform according in the purchase decision
to the expectations and bio-based products
of the application. may carry a substantial
To substantiate these premium.
properties, companies
may decide to have their With the easy access to
products certified against information nowadays
standards by independent through internet, social
institute. In certain media, etc., it is essential
applications, this is even that the intuitive messages
Figure 1. Visualisation of the 360 positioneing.
mandatory. are true and honest.

Hiding information for customers and consumers or green- 360 POSITIONING
washing your story will inevitably be sanctioned by customers
and consumers. The occurred image destruction will be Touch of Nature addresses peoples expectation
difficult if not impossible to regain (24). comprehensively: the 360 positioning. The intuition is triggered
by the sincere and credible feedstock story. The relationship
between fond memories and the Touch of Nature materials
TOUCH OF NATURE, THE THEORY APPLIED creates an emotional response. The personalised look, texture,
pattern further mobilizes our senses. The functionality and
The new bio-based material introduced by Orineo fully rely properties of the materials reassures the ratio. This balanced
on the 360 positioning strategy described above. It is a liquid positioning between rational, emotional and intuitive properties
formulation that can be used for seamless floors, desktops, are the true innovation of Touch of Nature biomaterials.
countertops, interior decorative panels, etc. The end consumers
are typically private residents, shop owners, theatre managers, Independent institutes have evaluated Touch of Nature
etc. with a building or renovation biomaterials in flooring
project. Quite often architects applications. The materials are well
and interior designers are suited for heavy-duty residential
influencing them in their material and commercial applications and
Figure 2. Symbolic representation of material properties.
choice. Therefor architects, obtained a Cfl, S1 fire certification.
interior designers, end consumers
form the audience. This community needs to be convinced; Using well-known symbols (Figure 2) rather then naked data for
its their language that is needed in all communication. The the different material properties makes it much more visual and
same logic applies for all other bio-based products: define understandable for the customers/consumers of the material.
the right audience and tune the message according to their
expectations based on the 360 positioning principles. The pitch
Finally, Orineo edited a short pitch (Figure 3) that can be used
What follows illustrates how Orineo communicates successfully to introduce the novel bio-based product in a concise way. Its
with its audience. In support, it requires a website and home the elevator pitch to intrigue the customers and consumers.
style that reflects the strength of the material. In this case,
warmth, beauty of nature, a sense of luxury and comfort. Its now commercial: liquid biobased formulations for seamless
floors, tabletops and furniture based on these side-streams.
PRODUCT
CONCLUSION
Based on market research, we identified an opportunity for a
bio-based material for interior decoration. This market offers As for many other developers and suppliers of bio-based
opportunities for premium-priced products in rather large materials, Orineo initially also focused its resources on
volumes. The challenge was to design a bio-based material the technical aspects of its novel product. This included
that looks natural and has an undisputable aesthetic value. internal development work, external material testing and
The solution is based on a cold-curing 2-component bio- certification and optimisation of application procedure. The
based binder derived from a vegetable oil with a history real differentiating factor came later and appeared essential
such as linseed oil. This binder system is the body of the when starting to introduce the product in the market.
product. It determines the resilient structure and
soft touch. Combined to the binder, a bio-
based filler based on residues of the food and Figure 3. The Pitch, a short easy-
agro-industry. Fillers with a story, such as coffee reading text with complementary
visual element.
grounds, berry seeds, used cork stoppers, etc.
These fillers determine the aesthetic properties Imagine the work and people
involved in bringing coffee beans
of the material: its matte appearance, its
from their exotic plantation into
colour, its texture. The fillers are the hearth and your morning mug. Consider now
the soul of the material. the tiny fraction of the bean being
brewed and the few minutes
to empty your espresso. Well,
Orineo developed a new range
BRAND of biomaterials based on the
80% waste of your cup of coffee,
coffee grounds. Biomaterials
To support the product launch, a brand was designed for a 20 years lifetime.
Plenty of time for nature to
created. The Touch of Nature brand is based on
replenish the feedstock!
3 principles:
1. Credibility: The materials are biobased and And it does not stop here. Branded
as Touch of Nature, these
look natural materials look good, feel good
2. Sincerity: The ingredients are chosen and perform well. One more
carefully to ensure a sustainable resource step? Same story with used cork
stoppers, berry seeds, olive leaves,
management to obtain a range of colours and
3. Stimulation: The material mobilizes the senses: patterns based on nature.
it looks good, feels good and smells good

Its all about identifying the real audience for the product, 9. Smithers-Rapra, The Future of Global Bioplastics to 2021; full report
in this case architects, interior designers and building project publication June 2016
owners and position the product as an aesthetic solution, with 10. Future Market Insights: http://www.futuremarketinsights.com/
press-release/biobased-biodegradable-plastics-market (last
a great story associated with its raw materials and an easy-to-
checked In May 2016)
understand technical message. This balanced combination
11. European Bioplastics e.V.: http://www.european-bioplastics.org/
of rational, emotional and intuitive messages is summarized in
market/ (last checked In May 2016)
the 360 positioning strategy used now for every development 12. E. de Jong, M.A. Dam, L. Sipos, G.J.M.Gruter, ACS Symp. Ser. 2012,
of bio-based materials by Orineo. 1105, 1
13. NRLO: Biodegradable plastics, future trends in Western Europe
and the USA; 1989
REFERENCES 14. European Commission: Production of thermo-bioplastics and
fibres based mainly on biological material: 1994
1. The History of Bioplastics: https://www.timetoast.com/ 15. SOFRES: Lutilisation non-alimentaire des produits agricoles. Taylor-
timelines/65909 (last checked In May 2016) Nelson-Sofres Consulting, 1998
2. ACS: http://www.acs.org/content/acs/en/education/ 16. Proceedings of EC Synmposium on Renewable Bioproducts,
whatischemistry/landmarks/bakelite.html (last checked In May 24&25 June 1997 Wageningen
2016) 17. Freedonia Group: http://www.freedoniagroup.com/
3. Plastic News: http://www.plasticsnews.com/ brochure/23xx/2387smwe.pdf (last checked In May 2016)
article/20140806/25TH/140809964/despite-its-history-bioplastics- 18. Natureworks: http://www.natureworksllc.com/The-Ingeo-Journey
remains-a-niche-industry (last checked In May 2016) (last checked In May 2016)
4. Harald Kaeb, Narocon InnovationConsulting, 9th International 19. Rodenburg Biopolymers: http://www.biopolymers.nl/rodenburg_
Conference on Biobased Materials, Cologne 5 April 2016 biopolymers (last checked In May 2016)
5. PlasticEurope, the facts 2014, published November 2015 20. Braskem:http://www.braskem.com/Portal/Principal/Arquivos/
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October 06, 2014 http://exclusive.multibriefs.com/content/ Verde_2014_ING_site.pdf (last checked In May 2016)
bioplastics-trends-and-drivers-for-greener-plastics/engineering 21. Veuve Clicquot: http://naturally.veuve-clicquot.com/naturally.
7. Packaging World, September 27, 2015: http://www.packworld. php (last checked In May 2016)
com/sustainability/bioplastics/biopolymers-packaging-some- 22. H. Toch, Happy Profit, Uitgeverij Lannoo, Amsterdam 2014
hurdles-strong-signs-growth 23. Orineo: http://touchofnature.eu/the-brand/ (last checked In May
8. Biofuels Digest, December 16, 2015: http://www.biofuelsdigest. 2016)
com/bdigest/2015/12/16/consumers-go-green-are-we- 24. Two marketing buddies walk into Buddha, edited by Susan
leveraging-this-trend-enough/ Verhagen, Kindle edition, Antwerp, Belgium (2014)

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Chimica Oggi - Chemistry Today is a peer-reviewed journal

devoted to fine chemistry, pharmaceuticals and Chimica Oggi - Chemistry Today

FINE CHEMICALS & INTERMEDIATES

CHEMICAL ENGINEERING/PROCESS DEVELOPMENT

60 The age of cool biobased materials: a new positioning strategy

TEKNO SCIENZE SRL INTERNATIONAL SCIENTIFIC ADVISORY BOARD:

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

Recent years, like never before, have

THE CURRENT CHALLENGE WE FACE

2 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

A NEW PUBLICATION BY TEKNOSCIENZE

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 3

4 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 5

Researchers watch crystal structure

6 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

New nontoxic process promises larger

EVAPORATION INSIGHTS LEARNING CENTER

8 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

UMICORE OPENS CATALYST FACILITY IN POLAND

Chemical etching method helps transistors

EVAPORATION INSIGHTS LEARNING CENTER

10 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 13

KEYWORDS: Flow chemistry, market and regulatory trends, offer width.

14 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

SIGNS OF HOPE STRATEGIES ARE SELF-DESIGNING

The availability of flow chemistry equipment with improved

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 15

Few barriers are however regularly mentioned.

Pharmaceutical companies, or CMO working for the

Another concern is the switch to continuous for the

The percolation of continuous processes on the

16 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

KLRA LVEI1,2*, PTER BANA3, RBERT RKNYI3, GYRGY I. TRS1,

Continuous flow synthesis

INTRODUCTION we faced during our research on the multistep synthesis

18 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

Figure 2. The prepared tricyclic compounds.

We intended to obtain them in three steps: (1) the

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 19

Several analogues and larger compound libraries

The application of flow chemistry has great

20 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

How chemistry underpinned

22 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 23

24 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 25

Nano food modeling:

KEYWORDS: Saccharin, acidic dissociation constant, nano sweetener modeling.

INTRODUCTION deprotonated anion; it can easily form complexes. Saccharin

26 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016

To explain the obtained acidic dissociation constants, we

In this research work, the structures of saccharin were

The inclination of a molecule to lose its hydrogen atom as Solvent-solute interactions

Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016 27

28 Chimica Oggi - Chemistry Today - vol. 34(4) July/August 2016