Lake Como 2|4 October 2011 - CHIMICA Oggi/Chemistry Today

in partnership with 

Organised by 

Lake Como 

2|4 October 2011

AGENDA 

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8:30-9:00 Registration 

9:00-9:15 Welcome 

KEY NOTE LECTURE 

9:15-10:00 Ian Baxendale - University of Cambridge - “Chemical 

synthesis and processing using fl ow reactors” 

CASE STUDIES - SESSION I 

10:00-10:05 Session introduction 

10:05-10:35 Giorgio Borghi - Matric Europa - “The advantages of 

continuous production of specialty chemicals enabled by 

fl ow chemistry” 

10.35-10:55 Franz Amann - Dishman Group - “Ozonolysis in a micro 

reactor system” 

10:55-11:25 COFFEE BREAK + POSTERS + EXHIBITION 

11:25-11:55 Gilda Gasparini - AM Technology - “Scaling up fl ow 

reactors” (Biotech case study) 

11.55-12:25 Oliver Kappe - University of Graz - “Challenges and 

opportunities in large scale microwave fl ow chemistry” 

12:30-13.15 LUNCH BREAK 

13:15 – 14:00 COFFEE BREAK + POSTERS + EXHIBITION 

CASE STUDIES - SESSION II 

14:00-14:30 Wenting Chen - Beijing Laviana Pharmatech Co., Ltd - 

“Continuous fl ow reactor: A platform toward the green 

manufacturing” 

14:30-15.00 Barry Johnson - Alfa Laval Ltd - “Achieving production 

scale fl ow chemistry” 

15:00-15.30 Discussion 

15.30-16:00 COFFEE BREAK + POSTERS + EXHIBITION 

REGULATION SESSION 

16.00-16:05 Session introduction 

16:05-16:35 Peter Poechlauer - DSM Fine Chemicals - “From batch 

to continuous: a ‘quality by design’ approach to handle 

hazardous materials in api manufacture” 

16.:35-17:05 Nigel A. Fletcher - Foster Wheeler Energy Ltd - “Successful 

achievement of regulatory compliance and continuous 

pharmaceutical processing” 

17:05-17:35 Christine Moore - FDA - “Continuous manufacturing - FDA 

perspective on submissions and implementation” 

17:35-18:00 Discussion 

18:00 Conclusion fi rst day 

19:00 Gala dinner 

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AGENDA 

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PLANT ENGINEERING SESSION 


9:05-9:35 David Ager - DSM - “Doing the reaction isn’t everything” 

9:35-10:05 Yi Jiang - Corning SAS - “Continuous fl ow reactors: right 

platforms for CRO/CMO” 

10.05-10:35 Dirk Kirschneck - Microinnova - “Manufacturing solutions 

for microreactors and continuous fl ow chemistry” 

10:35-11.05 COFFEE BREAK + POSTERS + EXHIBITION 

11:05-11:35 Pietro Delogu - Serichim - “Continuous fl ow processes: a 

multiproduct modular approach” 

11.35- 12:05 Mark Roelands - TNO Science & Industry - “How to 

develop continuous intensifi ed separations for fi nechemical 

industry?” 

12:05-12.30 Discussion 

12:30-13.15 LUNCH BREAK 

13:15 – 14:00 COFFEE BREAK + POSTERS + EXHIBITION 

PAT - QbD SESSION 


14:05-14:35 Ayman Allian - Abbott - “In situ FTIR monitoring for 

continuous chemistry” 

14.35-15.05 Steven Ferguson - Solid State Pharmaceutical Cluster 

Ireland, University College Dublin - “PAT based design of 

continuous plug fl ow crystallizations” 

PANEL DISCUSSION 

15.05-15:10 Introduction 

15:10-16:00 Panel discussion 

CONCLUSIONS 

16:00 Conclusions 

Chairman and panel discussion co-moderator: 

Prof. Michele Maggini - Padua University 

Co-chairman and panel discussion moderator: 

Sergio Pissavini - Consultant 

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ABSTRACT 

Doing the reaction isn’t everything 

David J. Ager 

DSM Pharma Chemicals - USA 

BIOGRAPHY 

David J. Ager 

David Ager received a B.Sc. from Imperial College, London, and a Ph.D. from the University 

of Cambridge. 

In 1977 he was awarded a Science Research Council Postdoctoral Fellowship that allowed 

him to collaborate with Professor Richard Cookson FRS at the University of Southampton. 

In 1979 he joined the faculty of the University of Liverpool as a Senior Demonstrator. This was 

followed by an assistant professor position at the University of Toledo in Ohio. 

In 1986, he joined the NutraSweet Company’s Research and Development group as a 

Monsanto Fellow. NSC Technologies came out of NutraSweet R&D. 

In 1999, NSC was sold to Great Lakes Fine Chemicals; Dave was a Fellow with 

GLFC, responsible for the development of new synthetic methodology. 

He then left GLFC and has worked as a consultant on chiral and process 

chemistry. 

He joined DSM at the beginning of 2002 as the competence 

manager for homogeneous catalysis and in January 2006, moved 

into the role of Principal Scientist. 

There are many examples of reactions performed in a fl ow regime, especially when hazardous or high-energy intermediates are 

involved. In many cases, a batch method is used to isolate the desired product and this can be economical as it fi ts into an existing 

plant. An alternative is to isolate the product in a continuous manner and this is the focus of this presentation. In particular the use 

of centrifugal contact separators will be described. In addition to being a method to continuously separate immiscible liquids, the 

equipment can also be used to perform reactions at the same time. 

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ABSTRACT 

BIOGRAPHY 

Ayman D. Allian 

In situ FTIR monitoring for continuous chemistry 

Ayman D. Allian 

Abbott Laboratories - USA 

Ayman D. Allian received his PHD at the National University of Singapore under Prof. Marc V. 

Garland and then joined Professor Enrique Iglesia group at University of California, Berkeley 

as a postdoctoral. The main focus of his research was the development of in-situ IR and 

chemometric tools to study reaction mechanism of homogeneous and heterogeneous 

catalytic reactions. 

In 2008, Ayman joined Abbott Process Safety Lab carrying out calorimetric and thermal 

stability studies. He utilized the calorimetric data in combination with kinetics, PAT, 

chemometric, theoretical chemistry to better understand reaction mechanism 

and hazards prior to scale up. He is also driving the fl ow chemistry effort at 

Abbott Laboratories. 

He gave several scientifi c talks and has been an invited speaker at 

numerous international and national conferences. His research work 

has been published in the form of 11 articles in top tier international 

journals with some of the work featured on the front cover. He was a 

recipient of four awards at Abbott including the Abbott Excellence and 

Abbott Impact award. 

The successful transformation of batch processes to fl ow chemistry relies on two foundations. 

First, good understanding of the reaction rates of the process at hand as it dictates both the choice of the fl ow setup and fl ow rates 

to be used during the continuous process. 

Second, there is a need to detect process upsets to ensure highest degree of product quality and yield during continuous 

processing, which can be performed using robust online PAT tools. 

In this study, the use of in situ FTIR spectroscopy as a powerful tool that allowed seamless adaptation of highly energetic ozonolysis 

chemistry to fl ow will be demonstrated. In situ FTIR provided a wealth of information on ozone mass transfer, the required ozone-tosubstrate 

ratio, and other key factors that are critical for a successful continuous process. During continuous operation, the same 

in situ FTIR was used as PAT tool to monitor the process and eliminated the need for offl ine analysis. This understanding provided by 

FTIR allowed the development of a continuous ozonolysis apparatus utilized to generate 2.5 kg of product with only a two week 

lead time. 

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ABSTRACT 

BIOGRAPHY 

Franz Amann 

Ozonolysis in a micro reactor system 

Franz Amann 

Dishman Group - Switzerland 

Amann’s expertise is built on more than 12 years working within the pharmaceutical industry. 

The majority of them with CARBOGEN AMCIS (part of the Dishman Group) where he started 

as project chemist after completing his doctoral degree. 

Later on he was appointed as Scientifi c Specialist, where he assumed responsibilities working 

in synthesis of APIs under cGMP, process optimization, carbohydrate chemistry and micro 

reactor technology (MRT). 

One of the focuses of Amann’s work on MRT is Dishman Group unique device for 

continuous ozonolysis. 

Dr Amann holds a master’s degree in Chemistry from the University 

of Constance, Germany where he also obtained a PhD degree 

through his thesis on: “Synthesis and investigation of donor-analogue 

glycosyl transferase-inhibitors“. 

Dishman (Innovative Ozone Systems/Carbogen Amcis) is working with a proprietary device for continuous ozonolysis based on a 

micro reactor set-up. 

Although the reactions are run under pressure the fl ow chemistry approach delivers safety advantages due to the prevention of 

accumulation of ozonides. 

The technical set-up and several chemical examples will be discussed. In most cases, the ozonolysis itself works satisfactory but the 

ozonide processing in semi-batch mode had to be adapted to the requirements of the continuous device. 

Continuous and batch wise production gave comparable results with regard to yield and quality. 

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ABSTRACT 

BIOGRAPHY 

Chemical synthesis and processing using fl ow reactors 

Ian Baxendale 

University of Cambridge - UK 

Ian Baxendale 

Ian R. Baxendale conducted his PhD under the supervision of Prof. Pavel Kocovsky at the 

University of Leicester investigating new Organometallic catalysts based on group VI transition 

metals for stereoselective allylic substitution reactions. He then moved to a postdoctoral 

position with Prof. Steven V. Ley at the University of Cambridge initially conducting Natural 

Product synthesis prior to entering into the fi eld of Solid Supported Reagents and Scavengers. 

In 2005 he co-founded the Innovative Technology Centre (ITC) as a centre of excellence 

for the study and development of advanced chemical synthesis tools and methodologies. 

To this end the centre specialises in the design and implementation of enabling 

technologies such as fl ow chemical synthesis, microwave reactors and 

immobilised reagents and scavengers to expedite complex chemical 

transformations. 

In 2009 Baxendale became a Royal Society University Research Fellow 

working in the Department of Chemistry at Cambridge. 

During the last decade there has been a steady growth in interest within the chemical community for fl ow chemistry 

approaches to synthetic targets due to inherent benefi ts such as automated and telescoped reaction sequences, quick 

reaction optimisations and in-line work-ups and purifi cations. 

Consequently, fl ow chemistry addresses both environmental and economic drivers. 

However, conducting fl ow chemistry requires changes in synthesis planning and execution and so we should be careful to 

determine the true the benefi ts and assess the worth of altering current working practice. 

This talk will focus on some of the benefi ts that can be realised using fl ow chemical processing using examples conducted in 

our laboratories. 

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ABSTRACT 

BIOGRAPHY 

The advantages of continuous production 

of specialty chemicals enabled by fl ow chemistry 

Giorgio Giovanni Borghi 

Matric Europa - Italy 

Giorgio Giovanni Borghi 

A graduate of MIT and Padua University, after several years with Dow-Lepetit at the end of the 

seventies and early eighties, he has worked with many Italian and International engineering 

and contracting companies: Dravo Corporation Chemical Plants Division – Pittsburgh (US), 

GABOR Srl Inveruno (MI), b. e b. ingg. SpA - Milan, DAL Srl - Milan, DEVIN Srl - Milan, b. e b. 

impianti Srl - Milan, LAMCO Land Management Co. - Rome, Symi Progetti Srl - Bari, Intertecno 

S.p.A. - Milan. 

For most of these he has also been a member of the board. 

Since 2010 he is Managing Director of MATRIC Europa Srl, Italian subsidiary of 

MATRIC (Middle Atlantic Technology and Innovation Center) Charleston, WV 

(USA). MATRIC Europa carries out chemical process development and 

optimization with innovative enabling technologies. 

In the last 2 decades the world market share of countries which were leaders in production and export of APIS and specialty chemicals, 

Italy and Spain particularly, has shrunk considerably due to the growth of competitors from the BRIC community, i.e. India and China. 

Manpower accounts for a large share of the production costs, namely about 30% of the production costs for direct manpower and 

over 40% considering other accessory operations QA, QC, logistics, cleaning. Competitiveness of companies operating in this fi eld 

appears to be evermore dependent on their ability to fully exploit the benefi t of new technologies becoming available with an impact 

on the factors which are mostly affected by the difference in cost structure between Europe and its rapidly emerging competitors, 

lowering the incidence of manpower on total production costs. Continuous processes reduce the incidence of manpower on the unit 

product costs, and when linked to on-line real-time analytical platforms enable maintaining the process parameters in an operating 

window which ensures conformity of product quality to the required specifi cation. For this reason particular interest has been devoted 

in the last few years to those enabling technologies which aim at transforming batch processes into continuous processes and take 

advantage of the advances made in the fi eld of PAT and integrated process control for production of API and specialty chemicals. 

Advances in miniaturization technologies have widened the possibilities for development of microanalytical sensing and control 

platforms and PAT applications. The use of microreactors for continuous reactions enable carrying our multivariate studies in the lab 

in short time exploring new process windows, typically utilizing higher temperatures and pressures with respect to industrial processes 

with a very signifi cant impact on reaction times and selectivity, reducing the use of solvents, eliminating the need of costly transports 

and storages, as well as the purifi cation and recovery of the spent solvents. The optimized experimental system can then directly be 

transferred into production by a “numbering up” procedure, greatly reducing the engineering development time and the need of 

additional purifi cation steps to eliminate impurities which generally increase in scaling up chemical processes. Microreactors enable 

production of thousands of tons of product per year and thus virtually any API and most specialty chemicals of commercial interest. 

Other “enabling technologies” are being explored with the aim of linking them and making the complete processes continuous. 

Of particular interest are fi ltrations on selective membranes which are used both for purifi cation of the product and to shift the reaction 

equilibrium by continuously removing the product, and utilization of reactive membranes with immobilized catalysts and enzymes. 

Finally the ability to carry out high throughput experimentations producing large volumes of data have led to the development of 

sophisticated data handling and chemometric techniques and data fusion enabling linking complex raw material composition and 

process parameters to reaction yields. These developments show the potential for important future progress to be made which can 

enable an increase of competitiveness of European industries. 

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ABSTRACT 

BIOGRAPHY 

Wenting Chen 

President, CEO of Beijing Laviana Pharmatech Co., Ltd. and Laviana (Taizhou) Pharmchem 

Co., Ltd. 

A synthetic organic chemist and a chemical engineer by training, turned into a medicinal 

chemist then an entrepreneur (Co-founded Laviana Companies). A US pharmaceutical 

industry veteran with over 10 years working experience as a bench chemist working 

at Smithkline Beecham Pharmaceutical, Dupont-Merck Pharmaceutical, Dupont 

Pharmaceutical and Bristol-Myers Squibb Company. Scientifi c background with 

tracking record of publications and patents. Leadership with proving record in 

leading the CRO and CMO organizations as well as organizing professional 

organization. 

Continuous fl ow reactor: a platform toward the green manufacturing 

Wenting Chen 

Beijing Laviana Pharmatech Co., Ltd. & Laviana (Taizhou) Pharmchem Co., Ltd. - China 

Applying continuous fl ow technology in manufacture process can improve the economic effi ciency of current process by 

improving the reaction yield, minimizing the solvent use, reducing the waste generated, expanding the safety margin as well as 

achieving energy saving and process consistency. 

The process developed in house using micro reactor in Laviana for ongoing CMO projects showed that the purity of crude products 

increased, the solvent use can be reduced or eliminated, and the overall process can be automated to eliminate the chance of 

error. The micro reactor technology provides a unique platform to develop applications in making chemical manufacture greener, 

to access an easy and quick scalable methodology in bulk chemical manufacture, and to make the in-lab manufacturing of bulk 

chemical possible. 

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ABSTRACT 

BIOGRAPHY 

Pietro Delogu 

Pietro Delogu is a chemist who spent his professional life in industrial research. He started 

working in the Research Centre Montedipe, the petrochemical division of Montedison, 

located in Bollate, near Milano. For 15 years his interests were in the fi eld of process 

thermodynamics and kinetics, applied to process modelling, mainly for petrochemical 

processes. 

From 1985 to 1987 he worked at the Donegani Institute of Novara, the Corporate 

Research Centre of Montedison, organising a new Department of Chemical and Process 

Technologies. 

In 1987 his fi eld of activity changed: he was charged at fi rst of the direction 

of the R&D Division of ACNA C.O., and after of the R&D Division in Caffaro. 

In this case the focus was on the dyes and fi ne chemical process 

development, with special attention to agrochemicals. 

Since 2004 he is the CEO of Serichim S.r.l., a Contract Research 

Company operating in Torviscosa. Serichim is one of the fi rst 

chemical research companies based in Italy, involved in 

pharmaceutical and chemical process development. 

His professional skills include process analysis and synthesis exploitation, 

unit operation sizing, experimental team organisation. 

During his activity he has published about 40 paper and patents. Pietro 

Delogu teaches Industrial Chemistry at the Chemical Engineering Faculty of 

Trieste. 

Continuous fl ow processes: a multiproduct modular approach 

Pietro Delogu 

Serichim S.r.l. - Italy 

The use of continuous processes for pharma products and intermediates is going to be more and more popular. Resistances to the 

introduction of this “new” approach in the industrial practice are progressively overcome, as the valuable advantages in terms 

of yields, product quality, safety and production costs become evident. As this technology is leaving the phase of its infancy, 

innovation efforts should be devoted to increase operability and to better defi ne the criteria for qualifi cation of equipments and 

validation of processes. Systems able to afford the continuous operation advantages, at the same time retaining the fl exibility 

typical of the batch plants have to be designed and offered to the pharma industry. 

Our communication discusses two topics: fi rst, how scaling up can be carried out in order to guarantee results independent 

of the reactor size for the plant reaction section (when a conventional reaction system, based on plug fl ow reactors, is used); 

second, a typical sequence of unit operations, able to effect the production of several APIs, is presented and proposed as a 

continuous multiproduct unit. The multiproduct plant approach should be considered a very interesting requisite in order to 

allow productions in campaigns based on continuous processes. 

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ABSTRACT 

BIOGRAPHY 

Steven Ferguson 

Steven Ferguson is a researcher in the fi nal year of his PhD at the Solid State Pharmaceutical 

Cluster, University College Dublin. 

He began in this role in 2008 and his research focuses on the application of continuous 

processing to pharmaceutical crystallization. 

His particular expertise lies in crystallization design and in process analytical technology. 

He is currently collaborating on the Solid State Pharmaceutical Cluster, Continuous 

Crystallization Platform Project. 

His background is in chemical and bioprocess engineering with a degree also from 

University College Dublin. 

PAT based design of continuous plug fl ow crystallizations 

Steven Ferguson, Gary Morris, Hongxun Hao, Mark Barrett, Brian Glennon 

Solid State Pharmaceutical Cluster, University College Dublin - Ireland 

This study presents the development of a plug fl ow crystallization (PFC) platform consisting of a vortex mixer combined with a 

tubular reactor. Process analytical technologies (FBRM, PVM, FT-IR) were applied in-situ in order to characterize and optimize 

crystallizations via the use of novel fl ow cells. In addition to this a new calibration free method for concentration monitoring 

was successfully utilized. These techniques permit signifi cant reductions in process development time and could also be 

applied to in situ monitoring and control of continuous industrial crystallizations. 

The results of this characterization indicate that plug fl ow crystallizers provide a robust and impressively productive 

crystallization methodology. Supersaturation was found to be depleted extremely rapidly within the reactor volume allowing 

for the maximum potential system yield to be obtained. This meant that despite the small size of the crystallizer (~40 ml) it was 

capable of producing approximately 50 kg of product per day. In addition to this, vortex type mixers have demonstrated 

the ability to maintain mixing effi ciency at unequal fl ow rate ratios. This presents obvious operational advantages when 

compared to conventional confi ned impinging jet (CIJ) (CIJ) mixers, allowing allowing larger anti-solvent additions relative to product feed. 

This facilitates facilitates the the generation of higher supersaturation and resulted in the the reduction in fi nal product particle size below 10 µm, 

highlighting the potential of such crystallizer confi confi gurations to eliminate the need for milling operations to reduce particle size. 

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ABSTRACT 

BIOGRAPHY 

Successful achievement of regulatory compliance and continuous processing 

Nigel A. Fletcher 

Foster Wheeler Energy Ltd - UK 

Nigel A. Fletcher 

Nigel graduated in 1975 from Imperial College, London with an Honours Degree in Chemical 

Engineering and joined Foster Wheeler. Following training as a process designer he developed 

skills related to high value product plant design and joined the Pharmaceutical Division. He 

then worked in pharmaceutical plant design for over 25 years on batch APIs, sterile APIs, 

biologics, Secondary pharmaceuticals and some specialist chemicals. In 2005 he became 

part of the team developing one of the fi rst continuous pharmaceutical plants and was 

involved throughout the design, construction and commissioning of the plant. Since then he 

has been involved in several other continuous pharmaceutical (and fi ne chemical) 

plants all involving the conversion of batch processes to continuous operation. 

He is now the Manager of the Pharmaceutical group in Foster Wheeler in the 

UK and is also a director of the Britest Organisation. 

The presentation starts by looking at the key regulatory issues facing the designer and the operator of a pharmaceutical continuous 

processing plant. It continues with a short review of the background to continuous processing and some of the recent output of 

the US FDA and other leading regulatory agencies to understand what challenges must be met. The lecture then moves on to a 

case study for a multiproduct continuous plant and reviews how the multiproduct aspect added new challenges to the design. 

The case study describes some of the features of the plant that the project team designed introduced to address instrumentation 

and control, cleaning and other ‘normal’ GMP issues together with all the ‘new’ regulatory concerns. Finally the presentation looks 

at some of the lessons learned, what has happened since the unit came into operation and how the owner is now using the plant. 

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ABSTRACT 

BIOGRAPHY 

Scaling up fl ow reactors (Biotech case study) 

Gilda Gasparini 

AM Technology - UK 

Gilda Gasparini 

Gasparini graduated in Chemical Engineering at Universitá degli Studi di Bologna and took 

her PhD in Chemical Engineering at Loughborough University. Her research was focused on 

particle production by emulsifi cation techniques for controlled release drug administration. 

Since October 2008 she is responsible for AM Technology continuous reactors. She has been 

involved in the design development and she is following a number of projects including FP7 

projects involving the Cofl ore ACR for APIs production and crystallization and a TSB funded 

project on biocatalysis. 

Unlike batch reactors, the output of a fl ow device can be changed without altering the hardware or set-up conditions. This 

fl exibility saves time and cost in development. The improved control capabilities of fl ow systems can also deliver better yield and 

productivity. However, the use of fl ow reactors in bio applications are still limited. Traditionally, fl ow systems have been considered 

unable to handle multiphase systems and long reaction time effi ciently. Three UK technology companies, C-Tech Innovation, 

Ingenza and AM Technology are collaborating to develop new fl ow process techniques for bio manufacturing. The project will 

integrate all aspects of bioprocess development from catalyst discovery and engineering, to process design, through to small 

footprint manufacturing of high value products. 

The objectives of this project is to design a compact fl ow reactor for continuous bio processing and develop improved process 

design techniques to accelerate the introduction of new bio-manufacturing processes for a variety of product types such as 

unnatural amino acids and chiral amines. 

Results will be shown shown based on the biocatalytic oxidase of the D-amino acid giving a mixture of L-amino acid and the a-ketoacid 

using wild-type D-amino acid oxidase. This is a multi-phase multi-phase reaction (G/L/S) with a reaction time in batch of over 24 hours. hours. Tests on 

the optimization optimization from batch to continuous at the lab scale have already shown shown a reduction in reaction time from 24 24 to 3 hours hours and 

the following production scale up study results results will will be shown and discussed. 

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ABSTRACT 

BIOGRAPHY 

Continuous fl ow reactors: right platforms for CRO/CMO 

Yi Jiang 

Corning Reactor Technologies - China 

Yi Jiang 

Yi Jiang currently is the Regional Business Director of Asia Pacifi c located in Shanghai for 

Corning Reactor Technologies. He was the Manager of Global Reactor Engineering and 

Application Engineering at Corning European Technology Center in France. Prior to joining 

Corning Reactor Technologies in 2008, he was a Project Manager and Research Manager 

for Chemical Systems & Integration at Corning Corporate Research in upstate New York. 

Before joining Corning in 2003, Yi worked in chemical & petrochemical industries such as 

Sinopec, DuPont, and ConocoPhillips where he was primarily focusing on industrial reactor 

designs, process development and novel reactor applications. Yi earned his PhD 

in chemical engineering from Washington University in St. Louis, a MS, and BS 

all in chemical engineering from China. Yi hold more than 10 Patents, 25 

publications in top ranking chemical engineering journals. In last 5 years, 

Yi has been serving as chairs/co-chairs for novel reactor technical 

sessions at AIChE Annual Meetings, Asia Pacifi c Chemical Reactor 

Engineering Conferences etc. 

This presentation will highlight some recent technology breakthroughs in continuous fl ow reactors, and how these advancements 

can enhance the fl exibility in process development and the scalability in cost-effective production. 

Searching for better “effi ciency” and “fl exibility in Big Pharma has led to signifi cant growth in CRO/CMO business today. Globally 

CRO has undertaken 1/3 of drug development, with annual market expansion rate of 20-25%. Asia pacifi c becomes a crucial 

region crowed with a signifi cant number of CRO/CMO competing with quality, cost, and service reputation. Besides the nature of 

this cost-conscious business, dedicated CRO/CMO must provide fast response to customer’s need, combined with their fl exible, 

reliable, and competitive specialist approaches. 

This presentation will summarize how module-based advanced fl ow reactors have been applied for effective fl ow-chemistry 

process development of multipurpose, and why they could quickly meet the product demands in competitive and dynamic 

ecosystem. 

As the providers of this new technology platform, how important to help CRO/CMO recognize the potentials of this technology and 

delivery values of this technology applications. 

14 




ABSTRACT 

BIOGRAPHY 

Achieving production scale fl ow chemistry 

Barry Johnson 

Alfa Laval - Sweden 

Barry Johnson 

Barry R. Johnson is Product & Process Development Manager, Alfa Laval Reactor Technology, 

and works out of Alfa Laval’s Tumba site in Sweden. 

Johnson joined Alfa Laval in 2002, working with the commercial investigation and development of 

various technologies and products for process intensifi cation. As the Reactor Technology Product 

Manager he is currently engaged in the worldwide launch and early implementation phases of 

Plate Reactor technology for the company. On a daily basis he is involved in approaching and 

supporting customers, developing chemical case studies for the Plate Reactor technology and 

in the design, development and characterization of Plate Reactor units. 

Prior to joining Alfa Laval, Johnson was at a chemical engineering consulting fi rm in 

the United Kingdom, where he was fi rst introduced to the concepts of process 

intensifi cation and continuous reactor technology. He also managed Mixing 

research consortia during his tenure. 

Johnson holds a Bachelor’s degree in Chemistry and a PhD in Physical 

Chemistry - “Oscillations and Chaos in Combustion Chemistry”- both 

from the University of Leeds, Leeds, England. He has completed 

post doctorate studies in Analytical Science and Chemical Chaos. 

Johnson has also authored educational software and books for teaching and 

assessment in undergraduate Chemistry courses. 

Alfa Laval is a leading global provider of specialized products and engineered 

solutions, dedicated to helping its customers to optimize the performance of their 

processes, time and time again. Alfa Laval helps its customers to heat, cool, separate 

and transport products such as oil, water, chemicals, beverages, foodstuffs, starch and 

pharmaceuticals through its worldwide organization in almost 100 countries. 

Alfa Laval has embarked upon a demonstration programme for Plate Reactors at large scale in order to contribute to the case for 

continuous process plants in the Fine and Pharmaceutical Industry. Reactions which utilize reagents and chemistries common in 

the industry are chosen to address the issues of operating with real materials. The study is aimed primarily at developing scale up 

guidelines, but will also, inevitably, give lessons on process startup and shutdown, economics and equipment (both reactor and 

ancillaries) performance. 

In this presentation we will present our experience from 2 reactions, a TEMPO catalysed oxidation and an organometallic synthesis 

/ reduction. These reactions introduce different and common processing challenges including immiscible phases, competing 

byproduct reactions, sensitive reagents and highly energetic materials. 

Studies are performed at a number of different reactor sizes and throughputs culminating with operation in a ART ® Plate Reactor 

PR49 at the 50 to 100 L / hr range. At each scale the reaction yield is assessed with regard to the reactor operation and performance. 

Adaptions to the operating scenario and to the reactor for operation at the next larger scale are determined and implemented. 

15 




ABSTRACT 

BIOGRAPHY 

Challenges and opportunities in large scale microwave fl ow chemistry 

C. Oliver Kappe a 

, Toma N. Glasnov a 

, Roman Morschhäuser b 

, Matthias Krullb b 

, Christoph Kayser b 

, Jochen Stock b 

a) Christian Doppler Laboratory for Microwave Chemistry and Institute of Chemistry - Austria 

b) Clariant Produkte Deutschland GmbH - Germany 

High-speed microwave synthesis has attracted a considerable amount of attention in recent years. Since the fi rst reports on the 

use of microwave heating to accelerate organic chemical transformations by the groups of Gedye and Giguere/Majetich in 

1986, more than 5000 articles have been published in the area of microwave-assisted organic synthesis (MAOS). Not only is direct 

microwave heating able to reduce chemical reaction times from hours to minutes, but it is also known to reduce side reactions, 

increase yields and improve reproducibility. 

For many years it has been attempted to transfer MAOS into a commercially relevant scale. Apart from missing technological 

concepts, the relatively low effi ciency in terms of energy conversion from microwave radiation into heat is a major hurdle which 

has so far prevented up-scaling of this promising technology. Well known but undesired up-scaling effects like thermal runaways, 

corrosion of pipe work and the reliability of continuous fl ow systems causes severe problems for any engineer dealing with highly 

pressurized systems at temperatures of 250°C and above. Nevertheless, the possibility of performing chemical reactions close to 

“borderline” conditions for most transformations can open up interesting novel process windows. 

Even in the absence of a “specifi c microwave effects”, the potential of volumetric heating can be signifi cant and should become 

even more visible with increasing scale. By using several model transformations (e.g. Scheme) we will demonstrate the good 

scalability of various synthetic organic transformations under microwave conditions on a multi kg/hour scale. 

NH 2 

NH 2 

+ 

C. Oliver Kappe 

C. Oliver Kappe is Professor of Organic Chemistry and Director of the Christian Doppler Laboratory 

for Microwave Chemistry (CDLMC) at the University of Graz, Austria. He received his diploma- (1989) 

and his doctoral (1992) degrees in organic chemistry from the University of Graz where he worked 

with Professor Gert Kollenz on cycloaddition and rearrangement reactions of acylketenes. After 

periods of postdoctoral research work on reactive intermediates and matrix isolation spectroscopy 

with Professor Curt Wentrup at the University of Queensland in Brisbane, Australia (1993-1994) and on 

synthetic methodology/alkaloid synthesis with Professor Albert Padwa at Emory University in Atlanta, 

USA (1994-1996), he moved back to the University of Graz in 1996 to start his independent 

academic career. He obtained his “Habilitation” in 1998 in organic chemistry and was 

appointed Associate Professor in 1999. Since 2011 he holds the position of Professor 

of “Technology of Organic Synthesis” (Organische Synthesetechnologie) at the 

University of Graz. He has spent time as visiting scientist/professor at e.g. the 

Scripps Research Institute (La Jolla, USA, Professor K. Barry Sharpless, 2003), 

the Toyko Institute of Technology (Toyko, Japan, Professor T. Takahashi, 

2008), the University of Sassari (Sassari, Italy, 2008), and the Sanford-Burnham 

Institute for Medical Research (Orlando, USA, 2010). 

C. Oliver Kappe is currently Editor-in-Chief of the Journal of Flow Chemistry 

(Akadémiai Kiadó) and a member of the Flow Chemistry Society. He is also a 

board member of the International Society of Heterocyclic Chemistry and The 

Society of Combinatorial Sciences. In addition he has been an Editor of the Journal 

QSAR and Combinatorial Sciences (Wiley-VCH, 2003-2007) and has served/serves on the 

Editorial/Advisory Boards of the Journal of Combinatorial Chemistry (ACS), Molecular Diversity 

(Springer), ChemMedChem and ChemSusChem (Wiley-VCH), Journal of Heterocyclic 

Chemistry (Wiley-VCH) and a number of other journals. 

O 

neat (5 M) 

N 

OH 

(excess) 

MW, 260 °C (25 bar) 

5 L/h (42 s residence time) 

N 

H 

25 mol/h 

(3.65 kg/h = 86 kg/day) 

Data of energy effi ciency will be presented for some standard reaction types including amidations and esterifi cations. An outlook 

on the technological potential of continuous microwave-heated fl ow systems and future targets for further development will be 

given. 

16 




ABSTRACT 

BIOGRAPHY 

Manufacturing solutions for microreactors and continuous fl ow chemistry 

Dirk Kirschneck 

Microinnova - Austria 

Dirk Kirschneck 

Dirk Kirschneck founded Microinnova in 2003 (Managing Director, Majority owner). 

He established Microinnova as key player for process design and manufacturing applications of 

microreactors, process intensifi cation as well as fl ow chemistry. 

Dirk Kirschneck has given 23 presentations and 9 invited lectures on scientifi c conferences and 

seminars in the fi eld of micro process engineering. 

He has written 3 book chapters as author and co-author and 1 review article. 

He is key researcher in 2 European Union FP7 research projects. 

The Austrian Chemistry Federation has nominated Kirschneck as Austrian 

Industry delegate for the working party “Process Intensifi cation” of the 

EFCE. 

Flow chemistry in combination with process intensifi cation tools as microreactors offers a lot of new possibilities in development 

and manufacturing of chemicals. Advantages as reactions in novel process windows, higher safety or better product quality 

are important drivers to switch from batch to continuous processing and to integrate intensifi cation technology. With this new 

approach also plant technology has to be reconsidered. Highly automated continuous microfl uidic systems displace fl asks in 

laboratory, fl ow mini-plants replace the conventional pilot plant systems and high effi cient and fl exible manufacturing systems are 

doing the manufacturing process instead of batch vessels. This change brings a lot of challenging tasks for plant technology and 

devices, as required pressure and temperature ranges are much higher and dimensions of the equipment often need to be much 

smaller. Flexibility is a key of successful design and the need of GMP-compliant design makes the topic even more diffi cult. 

Microinnova has worked out plant solutions which fi t in this new approach of development and manufacturing and meet perfectly 

the demand of effi ciency and fl exibility. 

For development and small scale production, Microinnova has developed a system called “fl ow mini-plant”. In contrast to the 

classic batch-technology-development, where a strict separation between the lab and pilot plant and respectively the lab and 

pilot phase is given, a certain merger of these two development phases during the development of continuous fl ow processes has 

been detected. This results in enormous time and cost savings by signifi cant shortening of the pilot phase. Some of the lab and pilot 

phases of a process development can even be operated on one and the same plant only with small modifi cations. 

Consequent the solutions for manufacturing: The “modular multipurpose plant’” platform designed by Microinnova delivers a 

performance of a continuous plant mixed with the fl exibility of a batch vessel. The “unit operation solution’” substitutes a specifi c 

process step, in a chain of most batchwise run operations, with an intensifi ed continuous plant, whereby the change in the total 

procedure is minimal, but the increase of performance of the overall process is high. Finally also a “dedicated plant” can be 

equipped with intensifi cation technologies which is interesting for all long-term production where no fl exibility for product change 

is needed. 

17 




ABSTRACT 

BIOGRAPHY 

Continuous manufacturing 

FDA perspective on submissions and implementation 

Christine Moore 

FDA - USA 

Christine Moore 

Christine Moore is the Deputy Director for Science and Policy of FDA’s Offi ce of New Drug 

Quality Assessment. 

She started at the agency in 2004 as the Branch Chief of the newly created Manufacturing 

Science group. 

Christine has been actively involved in FDA’s Quality by Design initiatives and was a member 

of the expert working group for ICH Q8(R). 

Prior to joining the FDA, she worked for 10 years in API process development and 

scale-up at Pfi zer and Searle/Pharmacia. 

Her background is in chemical and biochemical engineering, with 

degrees from Northwestern University and Massachusetts Institute of 

Technology. 

Continuous manufacturing is a technology actively being explored for pharmaceutical manufacturing, both by academia and 

industry. With its lower equipment size and higher throughput, continuous manufacturing has the potential to provide economic 

and safety benefi ts. From a quality perspective, the online monitoring and control used in continuous manufacturing can lead 

to increased product quality assurance and implementation of real-time real testing (RTRT) approaches. This presentation 

will discuss the regulatory implications of continuous manufacturing from a US FDA viewpoint. Both scientifi c and regulatory 

considerations will be provided for developing and implementing a continuous manufacturing process. 

18 




ABSTRACT 

BIOGRAPHY 

From batch to continuous: a ‘quality by design’ approach to handle hazardous materials in 

API manufacture 

Peter Poechlauer 

DSM Fine Chemicals - Austria 

Peter Poechlauer 

Peter Poechlauer received a PhD in organic chemistry from Innsbruck University in 1986. 

2 years of post-doc studies at Munich University in the Laboratories of Prof. Rolf Huisgen 

followed. Both activities were dedicated to the elucidation of organic reaction pathways. 

In 1990 he joined Chemie Linz, later OMV, as a synthetic chemist. 

Since 1996 he has worked with DSM as scientist, project leader and competence manager. 

2003 – 2007 he headed a department of process technology. 

Since 2007 he has worked as principal scientist with a focus on process intensifi cation and 

micro reactor technology. 

After some reluctance the pharmaceutical industry has started to embrace concepts of continuous manufacturing and in the 

meantime various pharmaceutical intermediates and API s are manufactured using partially or fully continuous synthetic routes. 

This has opened further options in the way manufacturers of pharmaceuticals secure the quality of their products: Authorities are 

supportive of these new developments, as they both streamline production processes, and allow a better process understanding. 

DSM focuses on new methods of pharmaceutical fi ne chemicals production and uses systematic approaches to analyze 

processes for improvement options based on continuous manufacturing. We have implemented several continuous processes 

for API manufacture. 

The presentation will exemplify the translation of “batch” recipes into continuous fl ow recipes following “quality-by-design” 

principles. 

19 




ABSTRACT 

BIOGRAPHY 

How to develop continuous intensifi ed separations for fi ne-chemical industry? 

Mark Roelands, Ikenna Ngene 

TNO - The Netherlands 

Mark Roelands 

Mark Roelands works as Senior Research Scientist in the Process Intensifi cation team of TNO, 

the Dutch contract research organization, located at Delft in the Netherlands. His work 

focuses on Continuous Intensifi ed Separations for Flow Chemistry. 

Mark was educated as a Chemical Engineer at the Delft University of Technology and he 

holds a PhD from the same university, where he worked on continuous crystallization at the 

Laboratory for Process Equipment in the group of prof. Peter Jansens. 

For several years Mark worked in industry as a researcher at Akzo Nobel in a 

process technology support role with specialization on separations. In 2005 

he joined TNO’s separation technology department. 

In the Process Intensifi cation team Mark develops innovative 

equipment for (fi ne)chemical processes for the classical 

separations: evaporation, extraction and crystallization. Mark’s 

ambition is to bring the Volumetric Productivity of these separations 

to the same level as achieved in continuous reactors. 

The conventional way to carry out processes in fi ne-chemical industries is in batch operation in stirred tank reactors. These are 

not only used for chemical reactions but also for subsequent separations like evaporation, extraction, stripping and crystallization. 

However, stirred tank reactors are not effi cient for these tasks because of mass and heat transfer limitations. 

“Intensifi cation” of reactors and separations is an opportunity for fi ne-chemical industries to improve product quality, to lower 

processing cost and to achieve more sustainable processes. Over the last decade major steps forward were made in the 

development of continuous micro-structured reactors. 

The next step is the introduction of continuous micro-structured separation equipment that has a similar performance on 

separation effi ciency. For separation the major challenge is to scale down the volume of the equipment while maintaining 

productivity by controlling mass and heat transfer over interfaces (droplets, bubbles, particles and fi lms). It is not expected that 

existing large-scale separation equipment can be simply scaled down. 

The key performance indicator for intensifi ed processes is the Volumetric Productivity (VP) expressed as mass fl ow per unit volume 

of the equipment in [kg/m 3 /hr]. The volumetric productivity can be expressed as the product of the fl ux in the equipment and the 

specifi c surface area of the device: VP = J.e, with J = fl ux expressed in [kg/m 2 /hr] and e = specifi c surface area expressed in [m 2 /m 3 ]. 

At TNO we developed two technologies for widely applied separations: extraction using intensifi ed contactor technology and fl ash 

distillation using micro-evaporator technology. We achieved proof-of-principles for: 

- solvent switch: transferring a compound from one solvent to another by evaporation; 

- aqueous work-up: removal of spent acid or base by extraction with water; 

- dehydration: extraction of reaction water. 

Our objective is to accelerate the development of these technologies by showing that the desired Volumetric Productivity is 

achievable for real industrial cases. Additional challenges to bring this promising technology into reality are: multi-purpose 

applicability, chemically resistant materials, modular construction for fl exible capacity and cost-effectiveness. 

20 



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co co co co co co co------chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman chairman 

BIOGRAPHY 

Michele Maggini – University of Padova - Italy 

Michele Maggini (b. 1959) obtained a Laurea in Chemistry from the University of Padova 

in 1984. From 1986 through 1988 he was Research Associate at The University of Chicago. 

After one year in the industry and eight years as a scientist of the Italian Council of Research 

(CNR), in 2000 Maggini became Full Professor of Organic Chemistry at the University of 

Padova. 

Michele Maggini started his scientifi c activity at the University of Padova. 

In 1986 he moved to The University of Chicago where he carried out an extensive 

work on the systematic functionalization of the cubane hydrocarbon. Before 

moving back to Padova, he spent one year at Lepetit Research Center 

working on glicopeptide antibiotics. 

In 1993 he began to study the chemical reactivity of fullerenes 

through cycloaddition reactions. 

Presently, his main research interests are in the fi eld of organic solar 

cells, of solid-state materials with special wettability characteristics 

induced by organic modifi cation, and in the fi eld of organic synthesis 

in microfl uidic systems. 

Maggini is a member of the Italian Chemical Society and of the American 

Chemical Society. 

He teaches organic chemistry and chemistry of organic materials. 132 papers 

published from 1986; h-index (WOS) = 39. 

BIOGRAPHY 

Sergio Pissavini – Process Intensifi cation Consultant 

Dr. Sergio Pissavini presently is operating as consultant in the Process Intensification area. 

He will join the GEA Refrigeration group on mid October 2011 as President Oil&Gas 

Technology center with worldwide responsibility. 

He has been Business Director of the Corning Reaction Technology Business Unit with 

Worldwide responsibility until September 2011. In this position he was responsible 

to create a new business structure from sales to manufacturing operation, the 

related business processes and launching commercially the new product; 

long term business strategy, technology strategy were as well part of his 

responsibility. 

Prior Sergio Pissavini was vice president of Sulzer Chemtech, a 

Swiss corporation active in mass transfer equipment, falling film 

crystallization. While there he held P&L responsibility of the 

Europe and Middle East division. 

Previously, he held a variety of positions in the Chemical Process 

Industry in process engineering, troubleshooting engineering, 

and sales and marketing in companies such as Exxon Chemicals, 

Agip Petroli and Foster Wheeler Group. 

Sergio Pissavini received his Ph.D. in organic chemistry from the Pavia 

University in Italy. 

He is also part of the IMD alumni group. 

21 




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22

Scalable in situ diazomethane generation in continuous-fl ow reactors 

Emiliano Rossi a , Pierre Woehl b , Michele Maggini a 

a Dipartimento di Scienze Chimiche dell’Università degli Studi di Padova, Via Marzolo 1, 35131, Padova, Italy 

b Corning European Technology Center, 7-bis Avenue de Valvins, 77210, Avon, France 

Diazomethane is a highly reactive and selective reagent for the synthesis of pharmaceuticals and fine chemicals (1). 

However, its acute toxicity and explosive characteristics strongly discourage a large-scale use in synthesis. 

In this communication we report an optimized continuous generation of diazomethane through the base-induced 

decomposition of the precursor N-methyl-N-nitrosourea which is safer to store than other diazomethane precursors. Process 

scale-up was quickly and efficiently achieved on a modular continuous-flow platform that allowed the production and use 

of diazomethane up to 19 mol d -1 at a total flow rate of 53 ml min -1 , while maintaining the amount of diazomethane itself in 

the reactor limited to 6.5 mmol. 

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1 

Microstructured glass reactors and LED illumination: photochemistry as good as it can get 

Simone Silvestrini, Christian Corrado De Filippo, Tommaso Carofi glio, Michele Maggini 

Dipartimento di Scienze Chimiche, Università di Padova, via Marzolo 1, 35131 Padova (PD) Italy 

Light emitting diodes (LEDs) are interesting cold light sources with very high power conversion (80-90%) and narrow 

emission bands. They find application in consumer electronic devices and lighting. LED light has only found limited use in 

photochemistry because of the difficulty to obtain low-cost diodes that emit in the deep UV region. However, since new 

materials for LED applications is rapidly filling this gap, LED-driven photochemistry has the potential to become an important 

tool to access selective and efficient chemical syntheses. 

In this presentation we show how organic photochemists and material scientists can benefit from LEDs through the use of 

microstructured glass reactors. To this end, we present two examples that best encompass the most interesting features of 

LED illumination: (i) low power consumption, resulting in economical and environmental friendly processes and (ii) narrow 

emission bands, resulting in highly selective reaction paths. 

(i) Low-power commercial white LED arrays can be used for the quantitative conversion 

of reagents in photocycloadditions thanks to their high efficiency and the optimal 

geometry of glass microreactors. The reduced thickness of the microfluidic channel, 

ensures a uniform illumination of the reaction mixture, reduced reaction times and high 

space time yields. 

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2 

This process productivity could, at least in principle, fulfill the needs of small pharma or 

fine chemical companies. Best reaction parameters were first developed on a smallvolume 

flow reactor (0.9-1.35 ml) for minimal reagents consumption. 

Then a 10-folds production improvement was achieved by increasing the flow reactor 

dimensions (15-25 ml) with a very limited optimization effort. 

(1) G. Maas, Angew. Chem. Int. Ed., 48, 2009, 8186. 

(ii) Illumination of small (3 nm) silver nanoparticles (AgNPs) results in a growth along 

preferential directions, depending on the wavelength of the radiation. This effect can 

be used to produce AgNPs with specific shapes and plasmonic properties that depend 

on the excitation wavelength used. In this case, microfluidic reactors allow to quickly 

produce AgNPs that can be functionalized with thiols or used immediately for surface 

enhanced raman spectroscopy (SERS) analysis. 

23 



Process intensifi cation under high-temperature/pressure conditions using microwave 

technology 

Doris Dallinger a , Hans-Jörg Lehmann b , Jonathan D. Moseley c , Alexander Stadler d , C. Oliver Kappe a 

a 

Christian Doppler Lab. for Microwave Chemistry and Inst. of Chemistry, Karl-Franzens-Univ. of Graz, Heinrichstrasse 28, A-8010 Graz, Austria 

b 

Preparation Laboratories, Global Discovery Chemistry, Novartis Institute for BioMedical Research, Basel, Switzerland 

c 

AstraZeneca, Process Research and Development, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK 

d 

Anton Paar GmbH, Anton-Paar Strasse 20, A-8054 Graz, Austria 

The direct scalability of microwave-assisted organic synthesis (MAOS) in a new 

bench-top microwave reactor (Masterwave, Anton Paar) is investigated. 

Several different organic reactions have been scaled-up typically from 

1 mmol up to the 2.5 mol scale. The transformations include the Biginelli 

multicomponent reaction, transition metal-catalyzed carbon-carbon crosscoupling 

protocols (Heck and Suzuki reactions), a Diels-Alder cycloaddition, 

the Newman-Kwart reaction, the 

synthesis of 2-methylbenzimidazole 

and 3-acetylcoumarin, the 

Knoevenagel and a S Ar reaction. A 

N 

range of different solvents (high and 

low microwave absorbing), and varying reaction times and temperatures have been explored. In 

all cases, it was possible to achieve similar isolated product yields on going from a small scale (2 mL 

processing volume) via medium scale (20 mL) to large scale (max 750 mL volume) without changing 

the previously optimized reaction conditions (direct scalability). Up to 300 g in a single run could be 

accomplished, allowing a daily output in the kg range. The multimode microwave instrument used in 

the present study currently allows batch processing in a 1 L PTFE vessel with maximum operating limits 

of 250 °C and 30 bar of pressure and potentially could be adopted to continuous fl ow processing. 


3 

Highly selective pressure driven etching of femtosecond laser irradiated silica 

Walter Navarrini a , Francesco Venturini a , Maurizio Sansotera a , Roberto Osellame b , Giulio Cerullo b 

a Politecnico di Milano, Dipartimento di Chimica, Materiali e Ingegneria Chimica ”Giulio Natta”, Via Luigi Mancinelli, 7, 20133 Milan, Italy 

b Istituto di Fotonica e Nanotecnologie - CNR, Dipartimento di Fisica - Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milan, Italy 

Micro-machining a device onto glass using standard photo-lithographic techniques is troublesome since glass is isotropically 

etched. This absence of a preferential etching direction doesn’t allow the production of complex micro-devices. However, 

when compared to silicon, glass is characterized by good transparency, good corrosion resistance and it is also much 

cheaper. Therefore glass may be an excellent candidate to be used as a bulk material for micro-fluidic devices if it could be 

possible to find an efficient way to control the aspect ratio of the etched trenches. To overcome the glass isotropic etching 

limitations and locally modify the glass structure by making it more reactive against etching agents, a femtosecond laser 

irradiation methodology has been developed. With this technique it is theoretically possible to produce three dimensional 

micro-channels, chambers and complex structures inside transparent solid materials. Femtosecond laser irradiation followed 

by chemical etching (FLICE) with Hydrogen Fluoride (HF) is an emerging technique for the fabrication of directly buried, threedimensional 

micro-fluidic channels in silica. The procedure described in literature consists 

in irradiating a silica slab followed by a chemical etching step using an HF solution. With 

aqueous HF the etching process is self-terminating due to diffusion resistances, leading to 

a maximum micro-channel depth of about 1.5 mm while the use of low-pressure gaseous 

HF can quickly produce 3 mm long channels with an aspect ratio (Depth / Diameter) 

higher than 25. Unfortunately the high aspect ratio is not constant but depends on the 

depth of the channel. When the micro-channel is short the aspect ratio increases rapidly 

until it reaches its maximum value at lengths of around 1400um. Thereafter the aspect ratio 

starts to decrease slowly. In this poster we present a variation of the etching methodology 

that is based on the dynamic displacement of the etchant. This method resulted in a slight 

increase of the aspect ratio compared to the standard low-pressure gaseous HF method. 

By adopting the appropriate experimental conditions, we’ve obtained an aspect ratio 

(Depth/Diameter) value of 29, and an etching speed of 4 μm/min. 


4444444444444444444444 

24 



Segmented fl ow reactor: effi ciently develop chemical reactions using fl ow systems 

Jan K. Hughes a , Werner Zinsser b 

a Accendo Corporation, 3762 S. Carson Avenue, Tucson, AZ 85730-2544, USA 

b Zinsser Analytic GmbH, Eschborner Landstrasse 135, 60489 Frankfurt, Germany 

Over the past three years, the use of continuous flow reactors for organic chemical reactions has been on the rise as these 

systems enable extreme reaction conditions (300 °C and 150 Bar), which are not easily obtained using traditional laboratory 

equipment. 

Although continuous flow systems broaden the types of chemistries one can pursue, they have three major limitations when 

used for chemical development (screening and optimization) and library production: the minimum amount of reagent for 

each experiment/compound is very high, experimental throughput is very low and accurate reaction kinetic information 

is difficult to obtain. 


5555555555555555555555555555 

Meso scale fl ow reactions for reaction screening and optimization 

Kristin Price a , Joel Hawkins a , Neal Sach b , Terry D. Long c 

a Pfi zer Global Research and Development, Pfi zer Inc., Central Research Division, Eastern Point Road, Groton, CT 06340, USA 

b Pfi zer Global Research and Development, La Jolla site, Pfi zer Inc.,10777 Science Center Drive (CB6/2243), San Diego, CA 92121, 

USA 

c Accendo Corporation, 3762 S. Carson Avenue, Tucson, AZ 85730-2544, USA 

Flow reactors have proven to be a useful tool for organic chemistry as they enable the pursuit of extreme reaction conditions 

(300 °C and 150 Bar). There are a variety of commercially available continuous flow systems, which are primarily used for 

the synthesis of large scale quantities of starting material (gram) or product (kilogram). 

Until recently, flow systems were not generally used to explore new reaction conditions as in chemical screening and 

optimization or to make compound libraries as they require more reactant than needed for analysis or biochemical 

screening and they generally have low (poor) experimental throughput. 


6666666666666666666666666 

For flow systems to become more widely used as a tool for organic chemistry these 

limitations must be removed and one solution is the adoption of segmented flow systems. 

We explain how segmented flow works and how as little as 20 µL of reactant can be used 

per experiment, experimental throughput can be as high as ten times faster than that 

continuous flow systems and how extremely accurate reaction kinetic data is obtained. 

We review a meso-scale segmented flow reactor, commercialized by Accendo 

Corporation, for reaction screening and optimization where we were able to screen 

new conditions with small microliter amounts of reactant in high temperature conditions 

and compared these results with those performed in a microwave system. In addition, 

we describe chemical optimizations using design of experimentation (DOE) protocols 

and then using the optimized conditions and the segmented flow automated system 

for the synthesis of a 36 compound matrix library, which was done three times at three 

temperatures in order to dramatically increase the number of successfully synthesized 

compounds. 

25 



Continuous fl ow chemistry in multi-phase systems 

Dieter Most, Ian Grayson, Marco Lerm, Heidi Grön, Klaus Stadtmüller 

Evonik Degussa GmbH, Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang, Germany 

The application of continuous processing in the manufacture of fine chemicals can lead to problems where there are 

multiple phases in the process, or when a phase has to be removed from the process in order to ensure complete reaction 

or the suppression of side reactions. Two examples are given where this problem has been solved on laboratory and pilot 

scale. In the first example (gas/liquid/gas removal) a photochlorination was performed in a loop reactor. This process had 

been operated on a production scale for several years for the manufacture of a product for the electronics industry. Impurity 

formation during the chlorination meant that an extensive purification of the downstream product was required, involving 

multiple distillation and recrystallisation steps. Key to a purer downstream product was found to be the continuous removal 

of the HCl by-product from the photochlorination step by a nitrogen purge, while maintaining a continuous chlorination 

(1). The improved quality of the intermediate allowed a subsequent 4-step continuous distillation process to be employed 

for the isolation of the downstream product. In the second example (gas/liquid/solid) an air oxidation of a pharmaceutical 

intermediate was followed by acidification and isolation of the crystallised product. 

A spiral wound oscillating flow reactor was used, with three sequential sections (air 

oxidation, cooling and acidification) (2). In comparison with the batch process, where 

variable amounts of polymeric impurities were formed due to the long residence times, a 

purer crystalline product was isolated directly from the reactor. 


7 (1) 

Performance of modular SiC-ceramic microreactors for severe environments 

R. Aicher, A. Grimm, A. Krecker, F. Meschke 

ESK Ceramics GmbH & Co. KG, Max-Schaidhauf Str. 25, D-87437 Kempten, Germany 

Ceramic Microreactors represent the latest achievement in the development of tools for continuous flow process technology. 

The material Silicon Carbide is new in the field of reactor equipment. It offers several advantages over conventional 

materials as it boosts the performance and the efficiency of reactors. 

Especially the ability to weld plates out of EKasic ® Silicon carbide gives the advantage to manufacture hermetic gas tight 

microreactor modules. Two family systems are available with 2 types of fully welded mixer modules, 2 types of residence 

time modules and 1 type of quench module. 

The EKasic ® ceramic modular systems are ideal to treat or to let react highly corrosive media like in fine chemical synthesis 

and high exothermic reaction processes. 


888888888888888888888888888 

M. Lerm, J. Lotz, K. Stadtmüller, EP 2045249 

(2) H. Grön, R. Schütte, K. Drauz, K. Stadtmüller, J. I. Grayson, EP 1855788. 

The advantages on performance are outlined by detailed examples. 

26 



Novel process windows 

Boosted organic chemistry under harsh reaction conditions in microreactor 

Qi Wang, Volker Hessel 

Eindhoven Univ. of Technology (TU/e), Dept. of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology 

Den Dolech 2, 5600 MB Eindhoven, The Netherlands 

Microreactors possess high mass/heat transfer capability which provides a transport intensifi cation fi eld (1). For many organic 

reactions, however, this on its own is not enough to ensure productivity (and sometimes selectivity) high enough to be competitive, 

especially for an industrial application. A second chemical intensifi cation fi eld rather has to be added. Novel Process Windows 

(NPW) stand for the use of highly intensifi ed, unusual and typically harsh process conditions to boost micro process technology and 

fl ow chemistry for the fi ne chemical production (2-3). In extension, NPW give emphasis to a third process-design-intensifi cation 

fi eld through process simplifi cation and integration. Five projects under the umbrella of the ERC Advanced Grant on Novel Process 

Windows (NPW) are in the process of making fundamental investigations here (started April 2011). The ERC research aims to 

be comprehensive and holistic: starting from a molecular-mechanistic (New Chemical Transformations) and kinetic scale (High- 

Temperature/pressure Processing) (4-5) via the scale of reaction environment (Solvent-free 

Operation and Tuneable/ eactive Solvents) (6-7) up to a process scale (Process Integration 

and Simplifi cation). 


9 

The 1,3-Huisgen cycloaddition-based triazole Click Chemistry is explored in a micro-capillary 

fl ow reactor with two objectives: 

1) high-p, T processing using two-step fl ow synthesis starting from inorganic azide; aim - 

process simplifi cation to catalyst-free route 

2) copper-catalyzed processing using one-step fl ow synthesis starting from hazardous 

organic azide; aim - process simplifi cation to one elemental path by using smart catalyst. 

Simplifi cation is also the motif for process design analysis of the oxidation of cyclohexane/ 

cylcohexene: 

1) multiple chemically advanced routes with the classical air oxidant of cyclohexane (or by 

photo and even ozone) to cyclohexanone (even further to ε-caprolactam) or formation 

of oxime from cyclohexane by using nitrosyl chloride; 

2) one-step direct oxidation of cyclohexene to adipic acid with hydrogen peroxide (or even 

ozone) as oxidant; 

3) double-direct route starting from H 2 and O 2 . 

The known chemical rate acceleration of the Claisen rearrangement through high-p, T 

processing will be used for subtle mechanistic analysis on: 

1) selectivity and stereoselectivity issues at ring intermediate; 

2) increasing space-time yield under the correspondingly short residence times, all 

accompanied by theoretical considerations. 

Selectivity and conversion effects through tunable solvents and process integration (reactionseparation) 

are studied for the n-octene hydroformylation: 

1) supercritical CO2 to decrease phase number; 

2) nanoporous membranes for homogeneous catalyst separation; 

3) possibly fl uorous solvents for catalyst separation; 

4) possibly heterogeneous catalyst. Such new process chemistry will provide new conceptions 

for system (multi-scaled multi-integrated microreactors) and process design at a pilot and 

production level. 

Through cost- and life-cycle analysis in a generic way it shall be ensured that the fi ndings are 

mutually exploited and then can be transferred to a large number of reactions. 

(1) Wirth T., Microreactors in organic synthesis and catalysis, Wiley-VCH, 2008. 

(2) Hessel V., Renken A., et al., Handbook of micro-reactor engineering and micro-reactor 

chemistry, three-volume edition, Wiley-VCH, Weinheim, 2009. 

(3) Hessel V., Chem. Eng. Technol. 32 (2009) 1655-1681. 

(4) Razzaq T., Glasnov T. N., et al., European J. Org. Chem. (2010) 1321-1325. 

(5) Murphy E. R., Martinelli J. R., et al., Angew. Chem. Int. Ed. 119 (2007) 1764. 

(6) Bourne R. A., Han X., et al., Angew. Chem. 121 (2009) 5426 –5429. 

(7) Mehnert C. P., Cook R. A., et al., J. Am. Chem. Soc., 124 (2002) 12932-12933 

27 



Huisgen cycloaddition to rufi namide: pressure impact on reaction environment and 

kinetics 

Svetlana Borukhova a , Alvaro C. Varas a , Volker Hessel a , Qi Wang a , Paul Watts b , Charlotte Wiles c 

a Eindhoven University of Technology, Department of Chemical Engineering & Chemistry, The Netherlands 

b Department of Chemistry, University of Hull, United Kingdom 

c Chemtrix BV, Geleen, The Netherlands 

Click Chemistry is a multi-step synthetic concept recently introduced by Sharpless (1). 

The variant of the Huisgen 1,3-dipolar cycloaddition paves new routes into the discovery and production of drugs. 

This work will follow the fi rst fl ow route for Click chemistry, most recently developed (2). 

We aim at high-temperature operation to speed up the reaction to industrial productivity and high-pressure operation with 

extended (dielectric constant ε, viscosity η, and reaction constant k) material and kinetic parameter space - with hope for a 

catalyst-free process while maintaining stereoselectivity. 

Then, a commercial drug, Rufi namide, which was reported to be in the top-200 best selling 

drugs of recent years (3), would be synthesized under intensifi cation of its fl ow synthesis. 


10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

Using commercial equipment (Labtrix ® S1 system from Chemtrix BV) a safe and effi cient way 

of organic azide preparation under continuous fl ow at decreasing the reaction time was 

demonstrated, to get acquainted with the fi rst step in Click Chemistry. 

3-Phenylpropyl methanesulfonate and 1-bromo-3-phenylpropane were converted to the 

respective azides ((3-azidopropyl)benzene) at 100% conversion in 30 s. 

Chemical intensifi cation was needed and achieved via a high-T route (195˚C) for 1-chloro-3phenylpropane 

2, which is only a fair leaving group; achieving then complete conversion 

in 20 min for a 1:1 reactant ratio. 

Using high-c conditions in addition (doubling the azide salt) reduced the time for complete 

conversion further to 60 s. 

In new research, the synthetic plan is to start with 2,6-difl uorobenzylchloride and sodium azide 

salt to produce alkyl azide, which will then react according to a procedure proposed (4) 

with methyl 3-methoxyacrylate to yield a [3+2] cycloaddition product, that when treated with 

ammonia in methanol will result in a precipitated product, Rufi namide. 

Massive speed-up of the Rufi namide synthesis is expected to achieve under superheated 

conditions, through the exponential dependence of the reaction rate on temperature as 

described by Arrhenius equation. 

The same can be achieved by pressure only - chemical equilibria and rates as well as the 

Gibbs’ enthalpies of reaction and activation volumes are strongly infl uenced by pressure – 

caused by the pressure-induced changes of physical properties of matter such as density, 

viscosity, dielectric constant, or conductivity. 

The model reaction is to be studied under the pressures up to 2000 bars in this research. 

Normally, a copper catalyst is used to block one of the addition sites of the alkynes (enes) in 

Click Chemistry. 

Instead and to simplify the process, we propose to use steric hindrance, normally seen as an 

obstacle in reactions, to reach similar stereoselectivity by virtue of the pressure effect, resulting 

in a catalyst-free process. 

(1) Kolb H.C., Sharpless, K.B. Drug Discov.Today, 2003, 8, 1128. 

(2) Smith C.D. , Org. Biomol. Chem., 2007, 5, 1559. 

(3) Baumann M., Baxendale I.R., J. Org. Chem.,2011, 7, 442. 

(4) Mudd W.H., Stevens E.P., Tetrahedron Letters, 2010, 51, 3229. 

28 



On-line NIR spectroscopy to control a seeded API crystallization step 

Cédric Schaefer, Clémence Lecomte, David Clicq, Alain Merschaert, Edith Norrant 

Biopharma Process Sciences, UCB Pharma S.A., Braine-l’Alleud, Belgium 

Process Analytical Technologies (PAT) has emerged as a prominent and powerful tool in the development and manufacture 

of pharmaceutical products. Numerous examples have been reported on the use of PAT in recent years but fairly limited 

on the use of quantitative on-line NIR methods in chemical processes. 

We have recently developed an on-line quantitative NIR method for the seeded crystallization of an API that required a tight 

control of solvent composition and concentration. Feasibility of the method was initially demonstrated on laboratory and 

technical pilot plant batches with a lab scale spectrometer and probe. In a second phase, the manufacturing equipment 

was purchased and implemented in c-GMP environment following ICH qualification requirements. 

The presentation will focus on the methodology used for the development of the calibration model which encompasses 

experimental design with statistical analysis (DoE), Principal Component Analysis (PCA) 

and Partial Least Square (PLS) regression methods. 


11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 

Flow-type multi-tubular reactor modeling: the effect of non-uniform radial 

E.V. Ovchinnikova, V.A. Chumachenko 

Boreskov Institute of Catalysis SB RAS (BIC), pr. Akademika Lavrentieva, 5, Novosibirsk, 630090, Russia 

Production of industrial chemicals is infl uenced by fl uctuations in the market demand. At a chemical plant, the production capacity and 

consumption of raw materials may change a lot depending on the market situation. For widely used fl ow-type multi-tubular reactors, 

variations in raw gas feed can provoke critical regimes, and for highly exothermic processes - even runaways. 

In the present work, we study reasons of occurrence of critical reactor regimes on the example of a large-scale process of formaldehyde 

production at one of the Russian industrial enterprises and propose possible preventing measures. 

The production of formaldehyde in this study is carried out in a multi-tubular fi xed bed reactor by means of oxidizing the methanol to 

formaldehyde over metal oxide catalyst. This reaction is exothermic; heat withdrawal is done by the DOWTHERM-type high boiling 

organic heat transfer fl uid circulating between the tubes. 


12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 

Our QbD approach for model and method validation will also be discussed as well as the 

results of the risk analysis performed to define the potentially influential noise as well as 

controlled and experimental parameters to include in the calibration. The robustness of 

the analysis has thus been constructed into the model development. 

Finally, some key learning points from the implementation of an on-line analysis in a 

c-GMP environment will be presented. 

The performance analysis of the fl ow-type multi-tubular reactor is based on an extended continuous 

2D model of heat and mass transfer. The model considers the variation of the gas linear velocity 

along the tube’s radius and the dependence of the radial and the axial thermal conductivity on 

the gas linear velocity in the tubes and on the parameters of the dispersion medium. 

It is established that a decrease in production capacity accompanied with decrease in gas fl ow 

feed in the reactor leads to a decrease in the gas linear velocity, which in its turn, decelerates 

the heat transfer. The study of the reactor’s mathematical model considering non-uniform radial 

heat transfer has exhibited the dependence between the decrease in gas fl ow feed and the 

elevation of maximal temperature in the hot spot of the catalyst layer. On a real-world multitubular 

reactor, we observe that these changes and irregularities of stream distribution can lead 

to critical operating regimes. 

29 



Production of Semiconductor Nanoparticles in a Continuous Flow Reactor 

Daniel Ness a , Jan Niehaus a , Van-Huong Tran b , Horst Weller a,b 

a CAN (Center for Applied Nanotechnology) GmbH 

b Institute of Physical Chemistry, University of Hamburg, Grindelallee 117, 20146 Hamburg, Germany 

Over the time nanoparticles (NPs) became omnipresent not only in research specialized schools, but also in a commercial way for 

companies from different kind of areas. Their unique and size-dependent characteristics as well as their great variety in composition 

and features have shown to be valuable in a range of different applications (1). 

Especially Cd-based fl uorescent NPs – Quantum Dots (QDs) - found a great acceptance in processes for monitoring and targeting, 

e.g. in light emitting devices or lasers (2) as well as marker for biological systems like proteins or DNA (3). The wide-spreaded strategy for 

the synthesis of QDs is based on a batch process called hot-injection method (4). Up-scaling the synthesis is diffi cult in this manner and 

leads to slightly different properties each time the reaction has been performed. Combining the utilization needs with the features of 

a continuous fl ow reactor for the production of NPs gives some crucial advantages over the common batch synthesis (5): 

- reaction conditions can simply be modifi ed and adjusted 

- easy optimization of particle systems by rapid screening of parameters 

- avoiding wastage of expensive materials and time 

- high reproducibility of NP properties 

- online quality control by integrated spectroscopic units 

- enhancement of production even to the kg-scale possible 

Herein we report the development of a continuous fl ow reactor system for the production of 

fl uorescent NPs. 


13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 

(1) A. P. Alivisatos, Science 1996, 271, 933. 

(2) R. Xie et al., J. Am. Chem. Soc. 2005, 127, 7480. 

(3) R. Jin, Angew. Chem. 2008, 180, 6852. 

(4) H. Weller et al., J. Phys. Chem. B 2003, 107, 7454. 

(5) B. K. H. Yen et al., Adv. Mater. 2003, 15, 1858. 

30

Lake Como 2|4 October 2011 - CHIMICA Oggi/Chemistry Today

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