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4-3 - Batch Organic Chemical Synthesis

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Table of Contents
1

Batch Organic Chemical Synthesis ........................................................... 3

1.1

Processes Optimization ..................................................................... 4

1.2

Process Equipment Specifications .................................................... 5

1.3

Reactor Design .................................................................................. 6

1.4

Filter Dryer Design ............................................................................. 7

1.5

Centrifuge Design .............................................................................. 8

1.6

Tray Dryer Design.............................................................................. 9

1.7

P&IDs .............................................................................................. 10

1.8

Unit Operations ................................................................................ 14

References ............................................................................................. 16

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1 Batch Organic Chemical Synthesis

API manufacturing has developed as a large-scale version of the bench-scale
wet-chemistry set-up used to develop processes; typically non-sterile batch
organic chemical synthesis technology.
A typical API process consists of several stages or steps, either chemical
transformations or purifications that may involve isolated or non-isolated
intermediates. Each stage or step comprises numerous unit operations, most
of which are typically operated within certain defined ranges according to a
batch sheet or a manufacturing order.

In-process testing at various points within a stage may be conducted to

confirm that a specific point or condition has been achieved before
progressing to the next step of the process. In addition, isolated intermediates
can be analyzed, and their quality can be determined against specifications.
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API facilities almost universally include process trains comprising of a reactor,

crystallizer, separation device, and dryer to produce bulk quantities of powder.
All of the individual steps, their respective unit operations and associated
ranges, in-process controls, and specifications make up the API process.

1.1 Processes Optimization

API production is driven through safety, quality and costs. Manufacturing
costs are on a continuing downwards pressure. Synthetic API plants (Batch
Organic Chemical Synthesis) normally follow a sequence to produce a solid
product.
1. Reaction (Continuously Stirred Tank Reactor (CSTR))
2. Crystallization
3. Seperation
4. Dry
In broad terms medicinal chemists identify candidate drugs by screening very
many potential molecules (New Chemical Entities (NCE)) against selected
targets. The role of the medicinal chemists is to manufacture the chemicals for
testing.
Only later do synthetic or process chemist and process engineers consider
manufacturing methods. At the same time the face demands for rapid
production of trials material. As pre-clinical and clinical trials progress, the
route and then the process are frozen so as not to invalidate the trial results.
This leaves little time for route optimization. Hence the tendency to stick with
well know unit operations and equipment (CSTR).

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1.2 Process Equipment Specifications

Continuously Stirred Tank Reactors (CSTRs) deliver material reliably through
a series of batch campaigns. In the last 50 years little has changed in the way
of process equipment usage, unit operations and plant layout. There are
however has been major advances in process control systems, containment
and improved design of equipment.
The API industry has focused on improving the design and operation of stirred
tank reactor schemes through advances in equipment detail, standard
arrangement, and plant layouts enabling greater operating efficiency and
batch turnarounds.
Typical CSTR requirements include:

Suitable range of operating conditions:

o -1 to 6 barg
o -30oC to 260oC

Must be able to impart or remove energy at various rates, through

methods as heat transfer and physical agitation

Must be able to charge and discharge or remove material in solid, liquid

and gas form.

Variations in reactor materials of construction include:

Glassed steel

Stainless steel

Hastelloy (specialist steel alloy)

Separation devices are usually pressure filter or centrifuge. The dryer is either
a standalone device or a combined pressure filter or centrifuge.

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1.3 Reactor Design

Chemical process reactor

Reactor vessel

In a continuous-stirred-tank-reactor
(CSTR), one or more fluid reagents
are introduced into a tank reactor
equipped with an impeller. The
impeller stirs the reagents to ensure
proper mixing.
Impeller (agitator) in a CSTR

Reactor vessel in-situ

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1.4 Filter Dryer Design

Integrated Filter Dryer

Horizontal Filter dryer

Comber Filter dryer

Filter plate/sieve/screen

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Discharge Port

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1.5 Centrifuge Design

Inverting-filter centrifuge

The conturbex is the most versatile of

the Siebtechnik centrifuges. It is fitted
with a screen and a scraper worm for
a controlled solid discharge. Typical
applications include separation of
crystalline products, slurries, lactose
and granular products for all
industries.
Conturbex Screen Centrifuge

Centrifuge basket

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Horizontal Inverting Centrifuge

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1.6 Tray Dryer Design

Cabinet tray dryer

Tray Dryer

Tray Dryer

Drum dryer
Drum dryer

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1.7 P&IDs
P&ID is an acronym that means Piping and Instrumentation Diagram - a
diagram showing piping and instrumentation connections between process
units in chemical plants, power plants, water treatment and similar plants. API
facilities almost universally include process trains comprising reactor,
crystallizer, separation device, and dryer to produce bulk quantities of powder.

Reactor and Crystallizer

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Separation Device Centrifuge

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Separation Device and Dryer Filter Dryer

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Hammer Mill and Pack-Off

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1.8 Unit Operations

In chemical engineering and related fields, a unit operation is a basic step in
a process. For example in milk processing, homogenization, pasteurization,
chilling, and packaging are each unit operations which are connected to
create the overall process. A process may have many unit operations to
obtain the desired product.
Chemical engineering unit operations consist of five classes:
1. Fluid flow processes, including fluids transportation, filtration, solids
fluidization, etc.
2. Heat transfer processes, including evaporation, condensation etc.
3. Mass transfer processes, including gas absorption, distillation, extraction,
adsorption, drying etc.
4. Thermodynamic processes, including gas liquefaction, refrigeration etc.
5. Mechanical processes, including solids transportation, crushing and
pulverization, screening and sieving, etc.
Chemical engineering unit operations also fall in the following categories:

Combination (mixing)

Separation (distillation)

Reaction (chemical reaction)

Chemical engineering unit operations and chemical engineering unit

processings form the main principles of all kinds of chemical industries and
are the foundation of designs of chemical plants, factories, and equipment
used.

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Typical vertical processing facility designed for batch production with barrier separation between processing steps

Process
Technical
Services

Process
Technical
Services

Solids
Charging
1

Solids
Charging
2

Liquid
Charging

Solids
Charging
3

Filter
Dryer
Reactor
1

Reactor
2

Reactor
3

Elevator

Laminar Flow Booth

Process
Technical
Services
Solution

Mother
Liquor
Distillate

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Tray
Dryer

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2 References
ISPE Baseline Guide-1
(second edition)
Active Pharmaceutical Ingredients
International Society for
Pharmaceutical Engineering, Tampa,
FL 33607, USA
(2007)

Active Pharmaceutical Ingredients

Development, manufacturing, and
Regulation
Stanley H. Nusim (ed.)
Taylor & Francis Group, Boca Raton,
Florida
(2005)

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