Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.

com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

RESEARCH ARTICLE OPEN ACCESS

Development and Scale Up Of a Chemical Process in

Pharmaceutical Industry: A Case Study
Savita Belwal*, V. Revanth, K.S.V.V. Dinesh, B.V. Reddy, M. Bhagvanth
Rao
*Department Of Chemistry and Department Of Chemical Engineering, CVSR College Of Engineering,
Anurag Group Of Institutions, Hyderabad, India

ABSTRACT
Every process has its own significance and one has to study factors which impact to the process and its
procedure to be followed. This paper is more concerned of how a process is scaled up from lab scale to pilot
plant scale, which is the major step in any industry because moving directly towards manufacturing level
consumes time and money. The report introduces about pharmaceutical industry and how it is different from
the other industries and provides firsthand experience for all the engineers to explore the equipment, process
and unit operations included in it. First aspect of scale up is safety and then comes economy, purity and
optimums. It includes the process and its unit operations such as reactors, distillation, filtration,
crystallization, drying and the equipment involving these operations. Consequently, the scale up rules,
factors influenced strategies and other considerations are observed. To learn and understand the unit process
and operations with their importance, a case study taking one of the stages of production is discussed here.
Keywords: chemical processes, scaling up, reactors, unit operations, equipments, Safety.

I. INTRODUCTION defined as the process of increasing the batch

A chemical engineer is generally size14. Scale-up of a process can also be viewed as
concerned with the industrial implementation of a procedure for applying the same process15 to
processes in which chemical1 or microbiological different output volumes. There is a subtle
conversion2 of material takes place in conjunction difference between these two definitions: batch size
with the transfer of mass, heat, and momentum3-5. enlargement does not always translate into a size
These processes are scale dependent; that is, they increase of the processing volume.
behave differently on a small scale (in laboratories The pharmaceutical industry develops16 produces
or pilot plants) and on a large scale (in production). and markets drugs or pharmaceuticals for use
There is no product that has been manufactured in a as medications. Pharmaceutical companies may
large scale, each and every raw material and the deal in generic or in brand medications and medical
end product is been tested in a lab scale6,7. Then it devices. They are subject to a variety of laws and
followed by a tenfold manufacturing process. Due regulations that govern the patenting, testing,
to this very reason this topic was zeroed in as safety, efficacy and drugs. The reactions which
research project. Lab chemists develop new indulge in pharmaceutical company are hazards,
products by testing it in a lab scale, the end result pyrophoric and sometimes flammable. These types
in proper format is sent to the process engineers. of reactions should be handled carefully as it might
They also develop a chemical reaction process and costs lots of life and property17-19 on over exposure.
pilot engineers try to interpret lab results. Chemists These reactions cannot be directly manufactured in
and Engineers should be very familiar with the a large scale, first these are tested in a lab by the
scale up terminology also should have scale up resource and development department considering
skills and techniques to apply at the plant scale8,9. each factor such as reactivity, flammability and
Chemical production is a result of several chemical safety20, 21.
reactions and purification steps10,11. Purification
steps and processes yield are a direct function of II. METHOD
the level of understanding of the reaction system. 2.1 Major scale up factors:
Reaction quality results have impact in separation Chemical Hygiene: Increased risks and
technology. Production is usually performed on chances for exposure to toxic substances, off-gases
stirred vessels that are operated at batch or semi- must be treated. Expanded Time Scale A reaction
batch configuration12,13. The choice process time differs a lot from the normal lab scale; it takes
configuration is determined at the development about 24 hrs or 2-3 days.
stage of the project. Mixing should be understood
well to get a desired product. Scale-up is generally

www.ijera.com 81|P a g e
Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

Heat Transfer: Laboratory flasks have a relatively distances that materials have to migrate as the
high surface-to-volume ratio, not so in larger dispersion breaks. It is common to extract a
reactors, where heat transfer surface area/volume is mixture with acid to remove acidic by products
greatly diminished, and where heating and cooling with a wash in between. Distillation covers a
must be accomplished by means of a heat transfer number of unit operations involving boiling and
medium pumped through a jacket or heating coil. vaporizing a liquid, and then separating and
Reactor Mixing: Maintaining uniform mixing in condensing vapors. One way is to remove the
proper proportions for the desired reaction condensing vapor so that none return to the boiling
point; another way is to reflux a portion of
Operating Volume: This is usually not possible at condensate is directed back. Then followed by
scale because most reactors have maximum mixing filtration: the unit operation in which impurities,
levels of about 10-20% of their full capacity. turbidity and major separation of liquids and solids
takes place. The major driving force is pressure
Reaction Control: Reaction rate can be regulated drop. A solvent is chosen which dissolves one
by controlled addition of a limiting reagent. component, while not dissolving another.
Drying: Differences in particle size distribution, Crystallization it is an operation which involves
bulk density, flow ability, compressibility, etc., can liquid solid separation, also mass transfer of a
all have a dramatic impact on the character of the solute from the liquid solution to a pure solid
product. crystallize phase occurs. The driving force is super
Raw material Charge: Charging reactants in the saturation which is controlled by cooling. The last
same proportions as in the lab is not possible in a operation is drying: it is mass transfer process
large reactor, ranges of these proportions should be which involves removing of water or another
tested before. solvent by evaporation. This process is often used
as a final production step. Vacuum drying where
Reactor Access: it is not very easy to add or heat is supplied by conduction or radiation mean
remove any compound during the reaction because while the vapor thus is removed by the vacuum
all the reactors are closed. system.

Work Up: concentrating the product by removing 2.3 Scale up strategy

impurities by isolation, distillation and filtration. Scaling a process is not linear, design of
the process has to control by one rate: kinetics,
2.2 Process engineering mass and heat transfer, blending, addition rate. The
Any process includes several unit following factors22,23 are the similarities in a scale
operations form a product from a raw material first up:
unit operation would be a reaction. Reaction is  Dynamic similarity: similar force ratios: Re,
classified by different phases they are involved in. We, Fr
Homogenous: any single phase such as gas, liquid,  Geometric similarities; similar reactor/agitator
solid. Heterogeneous: solid-liquid, liquid-gas, dimensions ratios.
liquid- liquid. Then it is followed by workup which  Kinematic: similar ratios of velocities profile.
refers to series of manipulations required to isolate
and purify products of a chemical reaction. Rate of heat is directly proportional to
Quenching a reaction is to deactivate any unreacted batch size (contact area). We have to maintain
reagents. Quenching neutralizes the reactive dynamic similarity during scale up. Rate of heat
species to stop the reaction to minimize the evolution is directly proportional to batch size.
formation of impurities. Quench solutions are
usually aqueous. 2.3.1 Agitation characteristics:
The next operation is extraction and it is a The choice of impellers depends up on
very common operation carried out to remove process goals, Process scale, and the presence of
impurities from the product stream. A simple other sources of power. Agitator design for
aqueous extraction that works well at the bench can turbulent flow exhibit different mixing
turn into an emulsion at larger scale because of characteristics:
differences in agitation and the greater economic

www.ijera.com 82|P a g e
 Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

Table 1: Types of impellers

Axial impeller Radial impeller

High Pumping and low shear rates Low pumping and high shear rates
Pitched turbine. Propeller Rushton turbine, flat blade turbine
Blending single phase liquids and solids Multiphase fluids

Table 2: advantages and disadvantages of impellers

Agitators Uses Adv/Dis Adv Fluid/solid characteristics
Anchors High viscous flow High power Highly viscous
Speed is proportional to dia consumptions
Propellers - Dead spot 1000cP,
formations Low to medium viscous
FBT Radial flow Not recommended 1000cP
High required applications for gas dispersion
applications
PBT Both radial al and axial Cost effective 1000-100000cP
flow
High shear
Helical Operates under laminar 1000-1000000
screw flow

2.3.2 Material of construction

Table 3: Material of construction
Type of C Mn Ph S Si Mo Cr Ni Uses and application
SS
316 0.08 2 0.045 0.03 01 2.5 17 12 Greater resistance to pitting corrosion.
Poor conductor of heat.
304 0.08 2 0.045 0.03 0.0 18 8 Austenite steel
0.75 Poor conductor
Ease into forming various shapes
Mainly used for cryogenic compounds.
has lower carbon content to minimize
carbide
precipitation and is used in high-
temperature
applications
Hastelloy 0.01 2 0.025 0.01 01 16 15 57 All the acidic reactions that contain
halogens or
metal halides
Glass Steel vessels coated with layer of high temperature Smooth, cleanable and chemical
lined. glass enamel resistance.
Cannot be used for extreme temperatures
and large temperature difference

www.ijera.com 83|P a g e
Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

2.3.3 Impact by reactor dimensions

Table 4: Impact by reactor dimensions
Phenomena Reactor volume L/D ratio S/V ratio
Chemical reaction Significant Weak and indirectly Indirectly
Mass transfer Only directly Significant Indirectly
Heat transfer Weak and indirectly Significant Significant and indirect

2.3.4 Utility: Heating or cooling a reactor is provided by the mentioned utilities:

Table 5: Utilities
S.no Utility (large scale, plant) Temperature range (degrees)
1 Liquid nitrogen -196 to -25
2 Chilled Brine (methanol, water) -25 to 10
3 Chilled water 10 to 20
4 Common water 20 to 35
5 Hot water 35 to 75
6 Steam To 150
7 Viscous Oil Above 150

Compatibility of reactors: each reactor has been grade against each like ,Grade A corresponds to
made up of different allow which makes it useful good compatibility and D is the worst grade and
for particular solvents .each compound is given cannot be used in that particular reactor.

Table 6: compatibility of reactor

Solvents/type of reactor SS 304 SS 316 Hastelloy
Organic halides(RX) A D A
Potassium bromide/chloride A D A
Barium chloride D D B
Al-X D D A

2.3.5 Filtration whereas in closed vessel the nitrogen is applied at

Nutsche filter: Nutsche filter is of two types 1) the top and vacuum at the bottom which give rise
open and 2) closed. These filters are commonly to larger pressure difference .Vacuum filters are not
used for flammable substances. The driving force used for hot solvents. pressure drop is less for
for filtration is pressure difference and is given by vacuum filter. Moisture of filter cake is more for
vacuum and nitrogen .For an open vessel, vacuum vacuum filter than pressure filter.
is placed or applied to the side of the Nutsche

Fig.1: Nutsche filter Fig.2: centrifuge filter

Centrifuge Filter: This type of filter uses the solid is thrown out to the bags. Flammable
centrifugal force to separate the liquid and only if substances are not filtered because heat is produced
solid is product. The filter bags are placed inside during rotation and it might damage the equipment.
the drum, the drum is rotated and mean while the

www.ijera.com 84|P a g e
Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

2.3.6 Drying temperature when the pressure is lowered by

Tray dryer is used for drying sticky creating the vacuum. The evaporation of water
materials, granular mass or crystalline materials, takes place faster. Heat sensitive materials, Dusty
plastic substances, wet mass preparations, materials, and hygroscopic materials, toxic
precipitates and pastes. It can be operated under the materials can be dried in this vacuum dyer. Feed
vacuum often with in direct heating; this is done in materials containing the solvents are also dried by
special vacuum tray dryers for the drying vitamins this vacuum dryer. The solvent material can be
and the other heat sensitive products. recovered by the condensation process. Handling of
In tray dryer hot air is continuously the materials is easy in this drying because of tray
circulated. Forced convection heating takes place to arrangement inside the dryer.It is easy for
remove moister from the solids placed in trays. switching over to the next materials. Hollow
Simultaneously the moist air is removed partially shelves which are electrically heated can be used. It
.In the tray dryers the crude drugs, chemicals, provides large surface area, so the heat can be
powders and tablet granules are also dried and easily transfer throughout the body of the dryer and
shows free flowing of the materials by picking up fast drying action takes place. Hot water can be
the water. Tray dryers require more labor to load supplied throughout the dryer, helps in drying
and unload, process is time consuming, hence process at the desired temperature. Dryer is a batch
increases in the cost. type process. It has low efficiency, expensive; labor
cost is too high for the running of the dryer.
Vacuum Drier Maintaining the dryer is high. There is a danger of
Materials are dried by the principle or overheating due to steam produce. Heat transfer is
applications of vacuum. The water boils at a lower low in vacuum dryer.

Fig 4: Vacuum drier Fig.3: Tray Drier

III. RESULT AND DISCUSSIONS lithium. The importance of addition of n-BuLi is

This case study includes one of stage the that it removes or changes the structure of A to
manufacturing processes. This example shows each form desirable structure B. The change in structure
and every unit operations involved in a process and results in an exothermic reaction. The addition
its work and necessary and also to understand temperature should be -70C, otherwise there are
reagents and raw materials addition in to a reactor. chances of impurities if the temperature increases.
These case studies also explain scaling up from Temperature and time are critical parameters. We
bench to pilot plant and also the important always have to keep dioxoborolane 0.1 to 0.2 equiv
parameters to be noted like the batch time, slightly higher than n-BuLi to avoid formation of
temperature and pressure. Before actually handling des bromo impurity. If addition rate is fast and
any chemicals one must read MSDS (Material exothermic nature was observed to -45 to -40 C and
Safety Data Sheet). Desbromo impurity is 30 to 40%.Temperature is a
In this Stage they are two important critical parameter and additions should be slow.
reagents which have to carefully charge in to the
reactor those are di borolane ester and n-butyl  Process Flow Diagram

www.ijera.com 85|P a g e
Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

www.ijera.com 86|P a g e
Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

Safety: The most important scale up step where Utilities: This stage requires less than -70 to – 80°
parameters such as pressure is maintained in order C and which is not possible with dry ice as they do
to control a runaway reaction. Safety relief valves it in lab. The only alternate is Liquid Nitrogen as
and rupture disc are used either in combination or it has melting point about -196°C and it can easily
individually to maintain only a required pressure. maintain about -90°C in the reactor jacket to
Parameters like these are interpreted by both perform at our desirable temperature. The used
chemical and chemists before performing a volume of nitrogen liquid is measured in water
reaction. column. When temperature about 25 – 30°C. When
temperature about 25 to 30°C is required CT water
Type of Reaction is used as the utility and above temperature Hot
This reaction is highly exothermic Water is been used.
reaction and temperature has be less than -70 C to Addition of raw materials and reagents:
ensure purity of the product. Reagents MSDS have to be studied thoroughly to
handle them, it includes its boiling point, auto
Reactor: The reactor used in this stage is ignition temperature, flame temperature water or
Hastelloy stainless steel reactor, it mainly consists moisture reactive agents. These reagents (n-BuLi)
of nickel and other metals which give a good are kept in low pressure cylinders and a pipe which
chemical resistance and are cryo reactors i.e. can goes till the bottom of the cylinder to transport to a
operate at lower temperatures up to 100°C.The reactor. A three way valve is used to transport these
maximum volume that can be operated is 1000L. reagents in to the reactor. Weight is determined by
The minimum volume for stirring is 30L (MSV), keeping it on the weigh balance while charging in
the minimum volume to note the temperature is to the reactor. Three valve is cleaned and dried by
30L (TTV).Valves used to maintain the pressure nitrogen, then a certain pressure is applied on the
are Rupture disc and safety relief valve. head of the pyrophoric agent(n-BuLi) by nitrogen
These two valves release the excess pressure in the and the liquid has no place to except through the
reactor. Scrubber and vent line are used to pipe already inserted in the cylinder which is
remove gases which evolve during the reaction. connected to a reactor. When shutting down it is
Pressure in the reactor is maintained by nitrogen flushed by the solvent in which it is present so that
as it is inert. not even little amount of it is left in the reactor.

Observation

Figure: Time vs Temperature

IV. CONCLUSION minimize scale up problems is by data gathering

The industrial experience is interesting and detailed process understanding. Having
and with this one can understood that what skills a technical staffs – both chemists and engineers –
chemical engineer requires to fulfill industrial that are well trained with up-to-date knowledge of
needs and also determination and kind of hard current thinking can help with design of better
work one has to do to work in a chemical field. All processes with fewer scale up issues. Using outside
the unit operations in the pharmaceutical industry help in the form of consultants with industry
which includes: how to choose a reactor based on experience can be invaluable for companies
the type of reaction, pH, and utilities required for wishing to design low-cost processes which can be
that particular reaction, charging of pyrophoric easily scaled up24 and in trouble-shooting persistent
reagents and also the pressure maintenances have manufacturing problems.
been covered in this paper. The best way to

www.ijera.com 87|P a g e
Savita Belwal.et al. Int. Journal of Engineering Research and Application www.ijera.com
ISSN : 2248-9622, Vol. 6, Issue 7, ( Part -2) July 2016, pp.81-88

ACKNOWLEDGEMENT [17]. A. Behr, V. A. Brehme, Ch. L. J. Ewers,

The authors are thankful to “Technology H. Grön, T. Kimmel, S. Küppers and I.
Transfer Department, Inogent Laboratory Pvt. Ltd. Symietz , New Developments in Chemical
Nacharam”, Hyderabad, India for support and Engineering for the Production of Drug
assistance. Substances, Engineering in Life Sciences,
4(1), 2004, 15–24.
REFERENCES [18]. H. Weinmann, The EVolution of a
[1]. G. H. Vogel, Verfahrensentwicklung ReVolution: Laboratory automation in
(Weinheim, Wiley-VCH, 2002) Chemical Process R&D, Symposium
[2]. W. Storhas, Bioverfahrensentwicklung presentation at The 3rd International
(Weinheim, Wiley-VCH, 2003) Symposium,; Boston, 2000.
[3]. M. Baerns, Technische Chemie [19]. C. Simms and J. Singh, Rapid Process
(Weinheim, Wiley-VCH, 2006) Development and Scale-Up Using A
[4]. A. Behr, W Ebbers and N. Wiese, Multiple Reactor System, Org. Proc. Res.
Miniplants, Chem.-Ing.-Tech., 72, 2000, Dev, 4 (6), 2000, 554–562.
1157 -1166. [20]. N.G. Anderson, Practical process
[5]. P. Claus and G. H. Vogel, Die Rolle der development (Academic Press, 2000).
Chemokatalyse bei der Etablierung der [21]. J. H. Atherton and K. J. Carpenter,
Technologieplatform Nachwachsende Process development, Physico-chemical
Rohstoffe [work deals with the concepts (Oxford Science, 2000)
development of new chemical processes [22]. I.A. Gargurevich, Foundations of
based on biomass as a sustainable raw Chemical Kinetic Modeling, Reaction
material with the help of chemocatalysis], Models and Reactor Scale-Up ,J Chem
Chem.-Ing.-Techn. 78, 2006, 991-1012. Eng Process Technol, 7(2), 2016, 284-
[6]. Ullmann, Encyclopedia of Industrial 290.
Chemistry (Weinheim, Wiley-VCH 6th [23]. K. Miklia, J. Creek, D. Kucab, G.
edition, 2002). Tatterson, Scale Up, Small-scale
[7]. T. Bieringer, S. Buchholz and N. Feasibility Studies, Tests and Testing, J
Kockmann, Future Production Concepts in Chem Eng Process Technol, 7(2), 2016,
the Chemical Industry: Modular – Small- 293-297.
Scale – Continuous, Chem. Engg. [24]. Dr T. Laird, How to minimize scale up
Tech.,36( 6), 2013, 900–910. difficulties, Chemical Industry Digest,
[8]. R. Dittmeyer, Winnacker-Küchler: 2010, 51-56.
Chemische technik (Weinheim, Wiley-
VCH, 5. Auflage, 9 Bände, 2003).
[9]. W. Ehrfeld, Microreactors (Weinheim,
Wiley-VCH, 2000).
[10]. M. Zlokarnik, Scale-up and Miniplants,
Chem.-Ing.-Tech, 75, 2003, 370-375.
[11]. G. H. Vogel, Process development
(Weinheim, Wiley-VCH, 2005)
[12]. F. P. Helmus, Anlagenplanung
(Weinheim, Wiley-VCH, 2003).
[13]. V. Hessel, Recent developments on new
components for Microplants, Chem.-Ing.-
Tech. 74, 2002, 17-30 and 381-400.
[14]. V. Hessel and H. Löwe Microchemical
Engineering: Components, Plant
Concepts, User Acceptance – Part II,
Chem. Eng. Technol, 26, 2003, 391-408.
[15]. E. L. Paul, Y. A. Atiemo-Obeng and S. M.
Kresta, Handbook of industrial mixing
(Wiley-Interscience, 2004).
[16]. K. J. Carpenter, Chemical reaction
engineering aspects of fine chemicals
manufacture, Chem Eng Sci, 56, 2001,
305-322.

www.ijera.com 88|P a g e