PROCESS CHEMISTRY
INTRODUCTION
Petr Beňovský
My experience has been that process chemistry is a
roller-coaster ride, with tremendous highs and lows,
where you learn theory and concepts, as needed, on
the fly, from your colleagues and from those
reference books (while meeting seemingly
unattainable milestones and timelines)
Peter J.Harrington
Pharmaceutical Process Chemistry for Synthesis
Rethinking the Routes to Scale-up, Wiley, 2011
DIFFERENCES BETWEEN ACADEMIC AND PROCESS
CHEMISTRIES
Academic – Discovers, reveals, disputes, confirms, brings new
knowledge.
Small amount of material.
Process – Selects, optimizes, seeks for efficiency, defines control
points, considers efficiency and environment (also
safety).
Role of chemical engineers.
Relatively large amount of material.
Outline of the class
• History of fine process chemistry, recent trends, future;
• Differences between laboratory and larger scale experiments;
• Scale-up/downscale considerations;
• Safety;
• Crystallization (solubility, metastable zone, nucleation, crystal
growth, optical resolution, Viedma ripening, attrition enhanced
deracemization, seeding, Ostwald ripening, new trends in
crystallization);
• Polymorphism;
• Typical process operations (mixing, heat transfer, agglomeration,
product isolation, distillation, drying, purification, work up,
reactors);
Outline of the class (cont.)
• Continuous manufacturing, flow chemistry;
• Synthetic route selection;
• Analytical methods, Process Analytical Technology (PAT), Design
of Experiments (DoE), Quality by Design (QbD), Purge Analyses;
• Environmental Aspects;
• Economy, Cost of Goods (CoG);
• Regulatory issues, patents.
Examples from recent literature about various topics within the
whole lecture.
Recommended reading:
• Anderson, N.G. Practical Process Research & Development, A
Guide for Organic Chemists, 2nd Edition, Elsevier Inc. 2012;
ISBN 978-0-12-386537-3
• Hulshof, L.A. Right First Time in Fine-Chemical Process Scaleup,
Scientific Update LLP 2013; ISBN 978-0-9533994-1-3
• Blacker, A.J.; Williams, M.T. Pharmaceutical Process
Development, Current Chemical and Engineering Challenges,
RSC Publishing 2011; ISBN 978-1-84973-146-1
Examination:
Written test (total 50 points)
45 – 50 points ….. A
39 – 44 points ….. B
33 – 38 points ….. C
27 – 32 points ….. D
21 – 26 points ….. E
HISTORY, RECENT
DEVELOPMENT AND FUTURE
OF PROCESS
(PHARMACEUTICAL)
CHEMISTRY
Petr Beňovský
HISTORY OF PROCESS (PHARMACEUTICAL)
CHEMISTRY
Gesner’s treatise – 1599 – bath of Marie
From Alchemy to Chemistry
1668 – Merck founded in Germany, nowadays one of the largest chemical and
pharmaceutical companies all over the world;
1891 – Merck US subsidiary founded (Merck & Co.), in 1917 (after WW I) expropriated
and became independent American company;
1856 – William Henry Perkin assigned by his teacher (August Wilhelm von Hofmann) to
attempt the synthesis of quinine from aniline. Instead, he prepared mauveine;
1876 – Eli Lilly company founded by colonel Eli Lilly in US (1923 first
commercially available insulin; 1940 first mass production
penicillin); first written instructions to process workers; quality
controls;
1899 – Bayer – blockbuster aspirin (still manufactured – about
40 000 tons per year);
1903 – Merck – diethylbarbituric acid
HISTORY OF PROCESS (PHARMACEUTICAL)
CHEMISTRY
Early 1950s – Merck the synthesis of cortisone acetate from
desoxycholic acid
(Org.Process Res.Dev. 8, 708 (2004))
CORTISONE ACETATE
CORTISONE ACETATE
CORTISONE ACETATE
CORTISONE ACETATE
DNBS = 3,5-dinitrobenzenesulfonic
acid
MPPA = monoperoxophthalic
acid
DDH = dibromodimethyl
hydantoin
CORTISONE ACETATE
1960s – Upjohn and ICI companies developed synthetic routes to
prostaglandins
1960s to 1980s – the advent of asymmetric synthesis (Sharpless,
Jacobsen, the Monsanto process – asymmetric
hydrogenation, Takasago – asymmetric
isomerisation)
HISTORY OF PROCESS (PHARMACEUTICAL) CHEMISTRY
1990s - Merck - Indinavir
Treatment of HIV – AIDS related diseases;
Very large dose – 2.4 g per day, i.e. cca 1 kg per year per
person;
Challenge to design a synthesis that could be executed on a
scale approaching that of commodity chemicals.
HISTORY OF PROCESS (PHARMACEUTICAL) CHEMISTRY
Hudlický, T.; Reed J.W. The Way of Synthesis; Wiley 2007
INDINAVIR (cont.)
Senanayake, C.H. et al Tetrahedron Lett. 36, 3993 (1995)
Hudlický, T.; Reed J.W. The Way of Synthesis; Wiley 2007
INDINAVIR (cont.)
Rossen, K. et al Tetrahedron Lett. 36, 6419 (1995)
Hudlický, T.; Reed J.W. The Way of Synthesis; Wiley 2007
INDINAVIR (cont.)
INDINAVIR (cont.)
2004 – Novartis – Discodermolide – large scale production (60 g)
– 39 steps – 17 chromatographic purifications – 43 chemists
participation – over 20 months (!!)
A polyketide natural product;
One of the most potent promoters of tubulin assembly;
A potent inhibitor of tumor cell growth in several MDR (multidrug
resistence) cancer cell lines;
Attempts to do semi-synthesis by a fermentation process failed;
HISTORY OF PROCESS (PHARMACEUTICAL) CHEMISTRY
MATERIAL – limitation in materials, equipment and commercial suppliers;
METHODOLOGY – relatively good portfolio of various reactions, but often
harsh reaction conditions;
CHEMICALS – difficult to get broad range of commercially available
starting material;
ANALYTICAL SUPPORT – degradation methods, tedious
INSTRUMENTS – very limited, later spectroscopy (UV/VIS, IR, optical
rotation)
FINANCIAL SUPPORT – money from science enthusiasts, maybe some
societies or companies (focused on particular field of interest)
SAFETY – significant improvement and systematic evaluation of possible
risks over last 40 years
HISTORY OF PROCESS (PHARMACEUTICAL) CHEMISTRY
RECENT DEVELOPMENT
• Increased regulatory expectations – even more focused
on the patient’s safety – more controls and deeper
process understanding;
• Automated platforms and robotics – high throughput
methods;
• Cooperation of process chemists with academics;
• Green chemistry, sustainability;
• Continuous production (finally !!), flow chemistry;
• Powerful software enables better modeling;
• Biotechnologies
THE FUTURE
• Intensification of the research and development work;
• Automation; continuous manufacturing;
• Real-time measurement – Process Analytical Technology (PAT);
• Shift from the Quality by Certificate (QbC) to Quality by Design (QbD)
• Outsourcing;
• University spin-offs – contract synthesis and cooperation;
• More environmental oriented
THE FUTURE
Drug Discovery Today 18, 795 (2013)
THE FUTURE
Drug Discovery Today 18, 795 (2013)