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Ibuprofen Continuous Manufacturing – Process Modeling and Techno-Economic

Assessment (TEA) using SuperPro Designer.

Preprint · April 2022

DOI: 10.13140/RG.2.2.25129.88164

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 Continuous Manufacturing of
Ibuprofen
Process Modeling and Evaluation using
SuperPro Designer®
by

Amir Mustafa, Nikiforos Misailidis, Rafael da Gama and Demetri Petrides

April 2022

This is the ReadMe file of a SuperPro Designer example that analyzes the manufacturing of ibuprofen
utilizing a green synthesis process that operates in continuous mode. Ibuprofen is an over-the-counter non-
steroidal anti-inflammatory drug which can be used as painkiller and to treat inflammation and fever. The
synthesis process involves Friedel-Crafts acylation, hydrogenation, carbonylation, crystallization and drying
of the ibuprofen API. The simulated plant has an annual production capacity of 5000 metric tons of purified
API, which represents 10% of the world demand. The flowsheet of the process is appended to the bottom
of this document. You may test-drive the model by downloading the functional evaluation edition of
SuperPro Designer from the downloads page of our website (www.intelligen.com). All the files of this
example can be found in the Examples \ Pharmaceuticals \ Ibuprofen folder. The default installation path
of the SuperPro Designer Examples folder follows below.

C:\ Users \ Public \ Public Documents \ Intelligen \ SuperPro Designer \ v12 \ Process Library \ Examples

If you have any questions regarding this example or SuperPro Designer in general, please send an email
message to dpetrides@intelligen.com

INTELLIGEN, INC.
Simulation, Design, and Scheduling Tools
For the Process Manufacturing Industries
www.intelligen.com
Introduction

Ibuprofen is one of the three commonly available over the counter non-steroidal anti-inflammatory drugs
(NSAIDs), namely aspirin, ibuprofen, and acetaminophen. It acts on a group of compounds known as
prostaglandins to reduce pain, inflammation, and fever. Because prostaglandins have a broad spectrum of
effects, not all effects of ibuprofen are beneficial. By taking the recommended ibuprofen dose, you ensure
that the benefits outweigh any side effects [1].

Ibuprofen was discovered in 1960 by Dr. Stewart Adams who identified the anti‐inflammatory properties of
aspirin-related drugs and later screened a series of acidic compounds that were synthesized by Dr John
Nicholson. Dr. Stewart Adams (Figure 1) was a pharmacologist in the Research Department of The Boots
Pure Drug Company Ltd at Nottingham, United Kingdom.

Figure 1 - A photograph of Dr Stewart Adams taken in 1987.

His goal was to find analgesic drugs with improved efficacy over aspirin. At the time Stewart Adams began
his research, aspirin and cortisone were the standard medications used to treat rheumatoid arthritis and
other painful arthritic conditions. However, the limitations of both drugs were becoming strikingly evident
even at that time. Little was known about the mechanisms underlying the development of the rheumatic
diseases for which these drugs were intended.
Drugs available in the 1950s and 1960s to treat pain and inflammation in rheumatic diseases included
aspirin, the other salicylates, aminophenols (phenacetin), and pyrazolones, which dated back to the
beginning of the century; phenylbutazone (which was originally used to solubilize aminopyrine and was
accidentally discovered to be a potent anti-inflammatory drug); and the corticosteroids discovered in the
1950s. Gold salts were also found to have disease-modifying effects in rheumatoid and related
arthropathies in the 1930s, although in the 1950s they were thought to be very toxic.

Since the existing remedies for rheumatic diseases were aspirin, corticosteroids, phenylbutazone, and to a
lesser extent gold salts, there was a need for a more potent drug than aspirin that would not produce the
potentially fatal side effect of agranulocytosis seen with phenylbutazone or the serious side effects of
corticosteroids [2]. In the 1950s, Stewart Adams and John Nicholson at Boots company started their
investigation to identify an analogue of aspirin that might be suitable for long-term use for rheumatoid
arthritis. In 1961, after screening more than 600 candidates, Adams and Nicholson filed a patent for the
compound 2-(4-isobutylphenyl) propionic acid, later named ibuprofen; it was granted in the following year.
Ibuprofen compares well to the gold standard treatment for rheumatoid arthritis, aspirin, but has a better
gastrointestinal side-effect profile. In 1983, ibuprofen was approved in the UK as an over-the-counter (OTC)
medicine with a maximum daily dose of 1,200 mg and launched as Nurofen [3]. Some of the physical and
chemical properties of ibuprofen are listed in Table 1.

Table 1 - Chemical Properties of Ibuprofen [4].

Chemical Properties
Appearance Colorless crystalline solid
Boiling Point 157°C
Brand Name Brufen;Motrin;Nurofen;Advil;Nuprin
Density 1.029 g/cm3
IUPAC Name (RS)-2-(4-(2-Methylpropyl)phenyl)propanoic acid
Melting Point 77-78°C
Molar Mass 206.28 g/mol
Molecular Formula C13H18O2
Solubility Insoluble in water

Ibuprofen has an interesting property that it can exist as a pair of enantiomers or stereoisomers that are
chiral in nature. A chiral molecule and its mirror image are non-superimposable, i.e., they are like a pair of
hands — left and right hands are mirror images but not identical.

This chiral property occurs in molecules that have a carbon atom to which four different groups are
bonded. The two enantiomers of ibuprofen are identified by the prefixes R and S (see Figure 2)
Figure 2 - 3D appearances of R- (Left) and S+ (Right) Isomers of Ibuprofen [5].

Enantiomers are identical in many properties such as solubility, melting point, and boiling point. They can
be distinguished by the fact that they rotate the plane of polarization of polarized light in different directions:
the S enantiomer clockwise as the observer looks at the light, and the R counterclockwise. The symbols R
and S refer to the 3D arrangement of the atoms in space. However, the two enantiomers behave differently
when interacting with other molecules such as the prostaglandins. Of the two enantiomers of ibuprofen, the
S form is the pharmacologically active component that inhibits prostaglandin synthesis, while the R form
has no anti-inflammatory effect.

However, it has been found that there is an enzyme in the body that converts the R form into the S. In fact,
60% of the R form is converted into S. This means that in a typical dose of ibuprofen of 400 mg, 200 mg is
S+ and 200 mg R−. Of the 200 mg of R−, 60% (i.e., 120 mg) is converted into the active R form, giving a
total of active form of 320 mg. Therefore, there is little point in going to the trouble of synthesizing just the
S form, and ibuprofen is sold as a racemic mixture (one initially containing equal amounts of both optical
isomers). However, stereospecific synthesis is also possible [1].

Market Size of Ibuprofen

In 2019, the market size of ibuprofen was estimated at around $573 million. According to a study by Beroe
Inc, the global ibuprofen market size is estimated to grow to $645 million by 2023, at a compound annual
growth rate (CAGR) of 2–3%.[6] Another study by Beroe suggests that the total annual global demand for
the ibuprofen is expected to reach 45,233 MT by 2022 [7].

As an OTC drug, ibuprofen is a popular painkiller that is also used to treat fever. The demand for ibuprofen
is steadily increasing. It has been observed that the developed regions, such as the USA and Europe, have
a higher demand for ibuprofen than the developing side of the world. As the world's largest manufacturer
of API, China supplies 90% of the USA's ibuprofen needs, while India exports around 493 metric tons of
ibuprofen API to UK and Ireland. China and India are the leading supply centers for ibuprofen API. All major
key stakeholders with bulk supplying and manufacturing capabilities are located in these regions, capturing
70% of the global market [6].

Some of the major producers of ibuprofen API are [8]:

• Xinhua Pharmaceutical
• IOLCP
• Granules Biocause
• Strides Shasun
• BASF
• SI Group
• Xinhua-Perrigo Pharmaceutical
• Hisoar

Figure 3 illustrates the ibuprofen market growth by region, clearly showing that the Asian and Australian
markets are experiencing the highest market growth while Africa, the Middle East and South America are
experiencing very little or no market growth [9].

Figure 3 - Global ibuprofen market by region (2018-2026).

Large Scale Production of Ibuprofen
The traditional route for ibuprofen synthesis as patented by the Boots company is called Boots Method
(also known as Browns Method). This is a six-step synthesis method and starts with the compound 2-
methylpropylbenzene which can be prepared from compounds separated from crude oil. This compound
has a carbon skeleton similar to that of ibuprofen.

A schematic diagram of the six-step Boots synthesis method is shown in Figure 4. The Boots method of
synthesis has been the method of choice for the industrial manufacture of ibuprofen for several years and
has resulted in the preparation of hundreds of tons of ibuprofen over the last four decades, but it has also
produced hundreds of tons of unwanted, unutilized, and unrecycled waste chemical by-products that must
be disposed of or treated. Much of the waste generated is due to the fact that many of the reactant atoms
are not incorporated into the desired product (ibuprofen) but rather into unwanted by-products (poor atom
economy/atom utilization). In 1981, the BHC company patented a new greener industrial synthesis of
ibuprofen which consists of only three steps. In this process, most of the atoms of the reactants are
incorporated into the desired product (ibuprofen). This results in only small amounts of unwanted by-
products (very good atom economy/atom utilization) thereby reducing the need for disposal and remediation
of waste products.

The percentage atom economy can be calculated by dividing the molecular weight of the desired product
by the molecular weights of all the products generated in a reaction. The calculated percentage atom
economy of the Boots synthesis is 40%, which means that 60% (by weight) of all the reagent atoms in this
synthesis are incorporated into unwanted by-products or waste. On the other hand, the percentage atom
economy for the green synthesis is calculated as 77%, which rises to 99% considering that the acetic acid
generated in step 1 is recovered. Thus, the manufacture of ibuprofen through green synthesis can prevent
the formation of large amounts of chemical waste by-products each year and reduce the quantities of
reactants required.

A schematic diagram of the three-step green synthesis method is shown in Figure 5. The atoms shown in
green in Figures 4 and 5 are the atoms utilized while the atoms shown in red are unutilized atoms or atoms
coming out in waste.
Figure 4 - The Boots Company Synthesis of Ibuprofen (Browns Method) [10].
The development of the BHC Company synthesis of ibuprofen not only won the prestigious Presidential
Green Chemistry Challenge Award in 1997, but also won the coveted Kirpatrick Chemical Engineering
Achievement Award in 1993.

Figure 5 - BHC Company Green Ibuprofen Synthesis [10].

There are other environmental advantages of green synthesis over the Boots synthesis, not the least of
which is the fact that the green synthesis is a three-step catalytic synthesis, while the Boots synthesis
generally requires auxiliary reagents in stoichiometric amounts. In Step 1 of both syntheses, the starting
material, reagent and product are the same in each case, only the catalyst differs. However, the ‘catalyst’
in the Boots’ synthesis (aluminum trichloride, AlCl3) is not a true catalyst. In the process, it is converted into
a hydrated form which usually has to be disposed of in landfills, and fresh material is required for the next
batch. Therefore, it is more of an auxiliary reagent rather than a catalyst. The catalyst in the green synthesis
is a real catalyst; it is recovered and reused so there is no waste generated. It should also be noted that
the Raney nickel and the palladium catalysts in Steps 2 and 3 of the green synthesis are recovered and
reused.

In addition to eliminating large quantities of waste, green synthesis offers the advantage of greater
throughput compared to the six-step Boots synthesis because only three steps are required. This translates
into the ability to produce larger quantities of ibuprofen in less time and with less capital expenditure,
resulting in significant economic benefits for the company. Thus, the green synthesis is a win–win situation
for both the environment and the manufacturer [10] [11]. This example utilizes the green synthesis method
for the production of ibuprofen.

Process Description

A conceptual process for manufacturing ibuprofen was modeled in SuperPro Designer and economically
evaluated to estimate the expected raw material requirements, process equipment capacities, utility
requirements, capital investment and production costs. The process operates in continuous mode using
the BHC green synthesis [12]. Green synthesis has advantages over other methods in terms of energy
requirements, corrosion propensity, co-product disposal, labor, atom economy and processing steps. Most
API plants are operated in batch mode. However, continuous mode is preferable for reducing chemical
waste and increasing overall process efficiency, which would ultimately reduce long term costs. This
example analyzes a process that can manufacture 5000 MT of ibuprofen per year which can satisfy around
10% of the annual global demand.

The development of the model was based on data available in the technical and patent literature supported
by our engineering judgment and experience with related processes.

For reporting and analysis purposes, the process flowsheet has been divided into four sections:

• Friedel-Crafts Acylation Section (black icons)

• Hydrogenation Section (purple icons)
• Carbonylation Section (blue icons)
• Crystallization and Purification Section (green icons)
Flowsheet sections in SuperPro are simply sets of related unit procedures (processing steps). For
information on how to specify flowsheet sections and edit their properties, please use the Help tool (Help
Index Section) or refer to Chapter 8.1 of the SuperPro manual provided in PDF format with the SuperPro
installation. The contents of each process section are described in greater detail next. The flowsheet of the
model is appended to the bottom of this document.

Friedel-Crafts Acylation

The raw materials acetic anhydride and isobutyl benzene (IBB) and the recycled hydrofluoric acid (HF) are
first mixed in a mixture preparation procedure (P-1 / MX-101) and then pressurized using a centrifugal pump
(P-2 / PM-101) to 7 bar. The pressurized mixture is then heated to 80 ⁰C using a heating procedure (P-3 /
HX-101). The heated mixture is then fed to a plug flow reactor (P-4 / PFR-101); the reaction mixture is
maintained at 80 ⁰C with a residence time of 3 hour. Table 2 shows the Friedel-Crafts acylation and acetyl
fluoride by-product formation reactions in the plug flow reactor [12].

Table 2: Friedel-Craft Acylation.

Acylation - Molar Stoichiometry Conversion

Friedel-Crafts Acylation:

1 C4H6O3 + 1 C10H14 → 1C12H16O + 1CH3CO2H 85.07%

Acetic Anhydride + Isobutyl Benzene (IBB) →

4-isobutylphenylacetophenone (4-IBTP) + Acetic Acid

Formation of Acetyl Fluoride

1 HF + 1 C4H6O3 → 1 CH3CO2H + C2H3FO 5%

Hydrogen Fluoride + Acetic Anhydride → Acetic Acid + Acetyl Fluoride

The output stream from the PFR is first sent to a mixer-settler (P-5 / MSX-101) for liquid-liquid extraction
with HF. Most of the unreacted IBB is removed in the heavy phase and then recycled back to P-1 / MX-101
through a custom flow splitting procedure (P-7 / FSP-101) where a portion of the recycled stream is purged
based on the amount set by the process. The light phase from the mixer-settler (P-5 / MSX-101) is flashed
with a flash drum (P-6 / V-101) to vaporize 98% of the HF in the feed stream at 0.8 bar. The vapor phase
is then condensed using a condenser (P-8 / HX-102) and pumped with a pressure increase of 2 bar using
a centrifugal pump (P-9 / PM-102) to recycle this stream using a flow adjusting procedure (P-10 / FAD-101)
where a certain portion of the stream is purged based on the process requirements. The liquid phase from
the flash drum (P-6 / V-101) is sent to a rigorous distillation column (P-11 / C-101), and its distillate, which
contains the majority of the acetic acid, is sent to waste treatment. The bottom phase from this column is
sent for further purification of the intermediate 4-isobutylphenylacetophenone (4-IBTP) to a second rigorous
distillation column (P-12 / C-102), where the majority of the unreacted reactants and HF solvent are
removed in the distillate and sent for waste treatment, while almost all of the 4-IBTP is removed in the
bottom phase and sent for hydrogenation [13].

Hydrogenation Section

The bottom stream from P-12 / C-102 is first cooled down to 90 ⁰C using a cooling procedure (P-13 / HX-
103) and then stored in a storage vessel (P-14 / V-102). Next, it is pumped out from the storage vessel
using a centrifugal pump (P-15 / PM-103) with a pressure increase of 6.1 bar, and then mixed with
compressed hydrogen gas coming from a gas compression procedure (P-16 / G-101) at 7.1 bar using a
custom mixing procedure (P-17 / MX-102). After that, the solution is cooled to 25 ⁰C in cooler P-18 / HX-
104 before feeding it to a fixed bed reactor (P-19 / FBR-101), modeled by a plug flow reaction procedure.
Raney Nickel is used as catalyst inside this fixed bed reactor. Table 3 shows the Hydrogenation reaction
inside the fixed bed reactor [10] [14].

Table 3 - Hydrogenation Reaction.

Hydrogenation- Molar Stoichiometry Conversion

Hydrogenation Reaction:

1 C12H16O + 1 H2 → 1 C12H18O 99.11 %

4-isobutylphenylacetophenone (4-IBTP) + Hydrogen → 1-(4-isobutylphenyl) ethanol

(1-4IBTE)

Carbonylation Section

The output stream from the fixed bed reactor (P-19 / FBR-101) is then flashed adiabatically using a flash
drum (P-20 / V-103), and the unreacted hydrogen is vented through the vapor stream. The liquid phase
containing 1-(4-isobutylphenyl) ethanol (1-4IBTE) is first stored in P-21 / V-104 and then pumped out using
a centrifugal pump (P-22 / PM-104) at 7.3 bar. This stream is mixed with compressed carbon monoxide at
7.3 bar coming from a gas compressor procedure (P-23 / G-102) via a custom mixing procedure (P-24 /
MX-103). The mixture is heated to 120 ⁰C using a heating procedure (P-25 / HX-105) and fed to a plug flow
reactor (P-26 / PFR-102), where the carbonylation reaction takes place. The reaction is carried out at 120
⁰C with a residence time of 1 hour, and it is modeled using the first equation shown in Table 4 [10]. Palladium
chloride is used as catalyst for this reaction.
Table 4 - Carbonylation and Decomposition Reaction.

Carbonylation- Molar Stoichiometry Conversion

Carbonylation Reaction:

1 C12H18O + 1 CO → 1 C13H18O2 96%

1-(4-isobutylphenyl) ethanol (1-4IBTE) + Carbon Monoxide →

Ibuprofen

Decomposition

1 C12H18O → 1 C12H16 + H2O 100%

1-(4-isobutylphenyl) ethanol (1-4IBTE) → 4-Isobutyl Styrene(4-IBS) + Water

A small portion of the intermediate 1-4IBTE is decomposed to isobutyl styrene (IBS). The decomposition
reaction is modeled by the second equation in Table 4, where unreacted 1-4IBTE is decomposed to IBS
with a conversion rate of 100%.

The output stream from the plug flow reactor (P-26 / PFR-102) is first cooled to 90 ⁰C using a cooling
procedure (P-27 / HX-106) and then flashed (P-28 / V-105). The unreacted carbon monoxide is vented in
the vapor phase.

Crystallization and Drying Section

The liquid phase containing ibuprofen is mixed with an ethanol solution via a custom mixing procedure (P-
29 / MX-104) and then sent for crystallization (P-30 / CR-101). Ibuprofen is crystallized with a crystallization
yield of 95%.

The output stream from the crystallization procedure (P-30 / CR-101) is sent to a basket centrifuge (P-31 /
BCFBD-101) to recover the crystals. The basket centrifuge operates in batch mode and includes the
following operations:

- Filter. The mother liquor is separated from the crystals, up to a final loss-on-drying (LOD) of 20%.
- Cake Wash. The crystals are washed with 2 volumes of ethanol per volume of cake
- Transfer Out. The crystals are transferred out to tank P-32 / V-106

The cycle time of the centrifuge is about 0.83 hours. There are two basket centrifuges operating in
staggered mode so that there is always one centrifuge filtering the inlet slurry coming from the continuous
crystallizer. The storage tank (P-32 / V-106) feeds a drum dryer (P-33 / DDR-101). The output of the drum
dryer contains almost 99.99% of ibuprofen crystals. The filtrate stream from the basket centrifuge (stream
S-135), which contains a large portion of ethanol, and the vapor stream evaporated in the drum dryer are
first collected in P-34 / V-107 and then fed to a rigorous distillation column (P-35 / C-103) where most of
the ethanol along with a small amount of water are recovered in the distillate stream. The distillate is cooled
down to 30 ⁰C in a cooler (P-36 / HX-107), stored in P-37 / V-108, and then recycled via a flow adjusting
procedure (P-38 / FAD-102) and a flow distribution procedure (P-39 / FDIS-101), which supplies ethanol to
the basket centrifuge (P-31 / BCFBD-101) and to the crystallizer (P-30 / CR-101). Ethanol make-up is added
to the flow adjusting procedure. Lastly, the bottom stream from the rigorous distillation column (P-35 / C-
103) is sent for waste disposal.

Modeling Tip - In this example, the thermodynamic physical state (PS) calculation option for the entire
flowsheet was set to Raoult’s Law while for the rigorous distillation column P-35 / C-103 it was set to
"Modified Raoult’s Law” with Wilson coefficients. To set the PS calculation method for the entire flowsheet,
right click on an empty area of the flowsheet and select PS Calculation Options  Default PS Calc.
Toolbox ... That will pop out the dialog box below, where you can change the K-value calculation model to
Raoult’s Law (Figure 6):

Figure 6 - PS Calculation Options Dialog.

After modifying the K-value calculation method, make sure to change the default PS calculation method to
the rigorous method by right-clicking and selecting PS Calculation Options  Shortcut vs Rigorous ...
and then selecting the rigorous calculation method (see Figure 7 below).
Figure 7 - Shortcut vs Rigorous PS Calculation Selection Dialog.

To change the PS Calculation method in the rigorous distillation column, right-click on the rigorous
distillation procedure and select Operation Data, which opens the distillation operation data dialog box,
and switch to the Rig. Toolbox tab (see Figure 8 below).

Figure 8 - Rig Toolbox tab in a Continuous Rigorous Distillation Procedure.

Material Balances

Table 5 displays the overall process data such as the annual operating time, unit production reference rate
and Operating days per year. This table was extracted from the RTF version of the Materials & Streams
report, which can be generated by selecting Reports Materials & Streams in the main menu bar of
SuperPro. The format of the report can be set using the dialog that appears when you select Reports
Options in the main menu bar. The annual throughput of the modeled manufacturing facility is 5,000 MT
of purified ibuprofen.

Table 5 - Overall Process Data.

OVERALL PROCESS DATA

Annual Operating Time 7,920.00 h

Unit Production Ref. Rate 5,000,035.59 kg MP/yr
Operating Days per Year 330.00
MP = Flow of Component 'Ibuprofen-Cr' in Stream 'Ibuprofen'

Table 6, which was also taken from the Materials & Streams Report, displays the raw material requirements
in kg/yr, kg/h, and kg/kg of MP (“MP” stands for main product, the purified ibuprofen in this case). It clearly
shows that Isobutyl Benzene (IBB), Acetic Anhydride and Ethyl Alcohol used in the Crystallization and
Drying section of the process are the dominant raw materials in terms of quantity.

Table 6 - Material Requirements.

BULK MATERIALS (Entire Process)

Material kg/yr kg/h kg/kg MP

Acetic Anhydride 3,605,909 455.29 0.72
Carbon Monoxide 887,845 112.10 0.18
Ethyl Alcohol 3,161,717 399.21 0.63
HF(aq) 809,166 102.17 0.16
Hydrogen 75,764 9.57 0.02
IBB 4,156,241 524.78 0.83
Water 161,009 20.33 0.03
TOTAL 12,857,650 1,623.44 2.57
 Cost Analysis

SuperPro Designer performs thorough cost analysis calculations, estimating the capital expenditure
(CAPEX) as well as operating costs (OPEX) of a project. It generates the following three pertinent reports
(via the Reports menu): the Economic Evaluation Report (EER), the Cash Flow Analysis Report (CFR),
and the Itemized Cost Report (ICR). Table 7 displays the Executive Summary of the Economic Evaluation
Report.

For a plant that produces approximately 5,000 MT of ibuprofen API per year, the total capital investment
was estimated to be around $36 million, while the annual operating cost was calculated to be $57 million.
The resulting unit production cost is 11 $/kg of product. Assuming a selling price of 15 $/kg of API, the gross
margin would be 62%, the return on investment 200%, and the payback time around 6 months. These
metrics suggest that this process for ibuprofen production is economically feasible.

Table 7 - Executive Summary.

EXECUTIVE SUMMARY (2022 prices)

Total Capital Investment 36,401,000 $

Capital Investment Charged to This Project 36,401,000 $
Operating Cost 56,628,000 $/yr
Revenues 150,001,000 $/yr
Cost Basis Annual Rate 5,000,036 kg MP/yr
Unit Production Cost 11.33 $/kg MP
Net Unit Production Cost 11.33 $/kg MP
Unit Production Revenue 15.00 $/kg MP
Gross Margin 24.52 %
Return On Investment 45.81 %
Payback Time 2.18 years
IRR (After Taxes) 33.14 %
NPV (at 7.0% Interest) 82,317,000 $
MP = Flow of Component 'Ibuprofen-Cr' in Stream 'Ibuprofen'

Figure 9 displays the annual operating cost breakdown, which is also a part of EER. This type of chart can
be included in the report by selecting Reports Options and activating the Include Charts option on the
lower right corner of the dialog. The chart shows that the raw materials cost is the most important accounting
for 74% of the overall operating cost, followed by facility-dependent (10%) and labor-dependent (8%) costs.
Figure 9 - Annual Operating Cost Breakdown.

Sensitivity Analysis
Table 8 and Figure 10 below display a sensitivity analysis for the production of ibuprofen to estimate the
unit production cost and capital investment for different plant capacities ranging from 500 MT to 10,000 MT
of ibuprofen per year.

Table 8 - Unit production cost and capital investment for different plant throughputs.

Throughput (MT) Unit Production Cost ($/kg) Capital Investment ($)

500 24.34 13 M
1000 17.11 15 M
2500 12.81 24 M
5000 11.33 36 M
7500 10.82 48 M
10000 10.57 60 M
Figure 10 - Sensitivity Analysis of Unit Production Cost and Capital Investment for a range of plant
throughputs between 500 and 10,000 MT/year.

It is evident from the above chart that there is a significant reduction (~ 50%) in unit production cost when
the scale of the production plant is increased from 500 MT to 5000 MT/year. A plant capacity of 5,000
MT/year was chosen as the base case because the reduction in the unit production cost for plant capacities
larger than 5,000 MT/year is marginal.
Summary
Ibuprofen is an over-the-counter non-steroidal anti-inflammatory drug which can be used as painkiller and
to treat inflammation and fever. Our objective with this example was to present a continuous ibuprofen
production model in SuperPro Designer using green synthesis that is easy to understand and follow. As
indicated in the preceding analysis, a plant with a capacity of 5,000 metric tons of ibuprofen per year
requires a total CAPEX of around $36 million and annual operating expenditures (including depreciation)
of around $57 million, leading to a unit manufacturing cost of $11.3/kg of purified ibuprofen. The
predominant cost is the cost of raw materials, especially isobutyl benzene, followed by the facility-
dependent costs.

References
[1] Reckitt Benckiser, “Chemistry in your cupboard: Nurofen.” The Royal Society of Chemistry, 2013.

[2] K. D. (Editor) Rainsford, “Ibuprofen : Discovery, Development and Therapeutics,” p. 623.

[3] D. Connelly, “A brief history of ibuprofen,” The Pharmaceutical Journal. https://pharmaceutical-

journal.com/article/infographics/a-brief-history-of-ibuprofen (accessed Feb. 15, 2022).

[4] “Ibuprofen Properties, Molecular Formula, Applications - WorldOfChemicals.”

https://www.worldofchemicals.com/chemicals/chemical-properties/ibuprofen.html (accessed Feb. 15,
2022).

[5] “Dexibuprofen,” Wikipedia. Feb. 19, 2022. Accessed: Mar. 24, 2022. [Online]. Available:
https://en.wikipedia.org/w/index.php?title=Dexibuprofen&oldid=1072767293

[6] B. Inc, “Global Ibuprofen Market Size to Grow at 2-3 Percent CAGR by 2023, Says Beroe Inc.”
https://www.prnewswire.com/news-releases/global-ibuprofen-market-size-to-grow-at-2-3-percent-cagr-by-
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[7] B. Inc, “Global Ibuprofen Market Size to Reach 45,233 MT by 2022, Says Beroe Inc.”
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