CHAPTER I

INTRODUCTION

1.1 Background
Pharmaceutical industry is a highly innovation driven industry which
throughout its history has contributed to the well-being of the humans by
providing new medicines to address various diseases and have grown into one
of the major sectors in the world. The global pharmaceutical industry is
currently worth US$ 300 billion with few drug companies controlling almost
one third of the market (Raja and Sambandan, 2015).

The name aspirin was agreed by a

committee of those
who had discovered the drug. The
name was derived from a
combination of acetyl and spiraea
(the Latin name for mead-
owsweet). Although the uptake of
aspirin in the medical
community was initially slow, it
soon took off and aspirin
rapidly became known worldwide
as one of the first anal-
gesics
The name aspirin was agreed by a
committee of those
who had discovered the drug. The
name was derived from a
combination of acetyl and spiraea
(the Latin name for mead-
owsweet). Although the uptake of
aspirin in the medical
community was initially slow, it
soon took off and aspirin
rapidly became known worldwide
as one of the first anal-
gesics
Aspirin, known as acetylsalicylic acid (ASA), is a commonly used non-
steroidal anti-inflammatory drug (NSAIDs) for relieving minor aches and pains.
It is also used as an antipyretic to reduce fever, as an anti-inflammatory
medication, and for reduction of death risk due to heart attack. The main
undesirable side effects of aspirin are gastrointestinal ulcers, stomach bleeding,
and tinnitus, especially in higher doses. Aspirin degrades in an aqueous medium
into several toxic intermediates causing environmental pollution, which affects
human health (Mukherjee et al., 2016).
AG synthesized aspirin or medicinal acetylsalicylic acid in 1897
obtained from barks of willow tree. Apart from analgesic, antipyretic and anti-
inflammatory properties, several other therapeutic roles of Aspirin have become
apparent since then. These include its use as an anti-thrombotic agent in the
prevention of cardiovascular diseases (CVD) due to antiplatelet effects and,
more recently, as an agent for cancer prevention and treatment. Aspirin is an O-
acetyl derivative of salicylic acid (ASA—acetylsalicylic acid), and its dominant
mechanism of action is believed to be through the transfer of this acetyl group to
(−OH) and amino (−NH2) functionalities present in biological macromolecules.
The acyl ester group is also unstable under primary conditions, and its
hydrolysis to acetate is believed to proceed by a general base-assisted
mechanism as described previously” (Alegbeleye et al., 2020).
The name aspirin was agreed by a committee of those who had
discovered the drug. The name was derived from a combination of acetyl and
spiraea (the Latin name for mead- owsweet). Although the uptake of aspirin in
the medical community was initially slow, it soon took off and aspirin rapidly
became known worldwide as one of the first analgesics. Within 3 years of its
release onto the market, more than 160 scientific papers had been published
extolling the virtues of aspirin. It went on to become enormously successful
around the world.
Indonesia has carried out development in industrial sector. The chemical
industry has received attention in its development because this industry has
links with other industries. The pharmaceutical industry is one of the industries
that still has to be developed in Indonesia because currently Indonesia is an
export target for foreign drug manufacturers. In Indonesia, hundreds of
pharmaceutical industries have been established, but they are only engaged in
the process of mixing raw materials for drugs, packaging, or marketing.
Acetylsalicylic acid or known in Indonesia as aspirin is one of the
pharmaceutical industries that can be developed in Indonesia. Throughout the
20th century aspirin was known as the "wonder drug" because of its antipyretic,
analgesic, and anti-inflammatory properties. In Indonesia, aspirin is known by
the trademarks "Puyer Bintang Tujuh" (PT Bintang Toedjoe) and "Aspirin
Tablet" (PT Bayer Indonesia).
The increasing demand for aspirin cannot be fully met by domestic
producers, so it still requires imports from abroad. To reduce the number of
imports that continues to increase, it is necessary to build an aspirin plant in the
country. Some national aspirin needs are still fulfilled from other countries, such
as the United States, United Kingdom, Germany, and China. This happens
because domestic production has not been able to meet these needs so it must be
imported from abroad. For this reason, the aspirin industry has good prospects
to be developed in Indonesia. The benefits obtained by Indonesia with the
construction of this plant include:
 1. Save foreign exchange resources by increasing aspirin production in order
to meet domestic needs, thereby reducing import dependence.
2. Assisting factories in Indonesia that use aspirin raw materials because in
addition to being cheaper, continuity of raw materials will also be
maintained.
3. The process of technology transfer, so that there is learning about foreign
science and technology and reducing dependence on foreign workers.
4. Opening new jobs in order to provide employment and economic equality.
5. Also re-enlighten the climate of domestic investors, especially the
pharmaceutical industry.

1.2 Design Capacity

The establishment of the Acetylsalicylic acid (ASPIRIN) plant must pay
attention to the import data to meet Acetylsalicylic acid (ASPIRIN) needs in
Indonesia. In the selection of Acetylsalicylic acid (ASPIRIN) plant design
capacity there are several things that need to be considered.

1.2.1 Projected Market Needs in Indonesia

This increase in the need for Acetylsalicylic acid (ASPIRIN) can be
seen from the increase in domestic demand each year, as in Table 1.1.
Table 1.1 Acetylsalicylic acid (ASPIRIN) Import Data

Year Import (Tons/Year)

2016 237.542
2017 228.63
2018 227.826
2019 259.668
2020 229.332
(Source: Badan Pusat Statistik, 2021)
Based on Table 1.1, the demand for Acetylsalicylic acid
(ASPIRIN) in Indonesia in 2033 can be predicted. This prediction is based
on an analysis using linear regression and plotted in the graph in Figure
1.1.
 270
260
250

Needs (ton)
240
230 f(x) = 1.46 x − 2713.31
R² = 0.03
220
210
2016 2017 2018 2019 2020
Years

Figure 1.1 Graph of Import Data for ASPIRIN Needs in Indonesia

Based on the analysis using linear regression by considering the
needs of Acetylsalicylic acid (ASPIRIN) in Indonesia, it can be estimated
the need for Acetylsalicylic acid (ASPIRIN) in Indonesia within the next
ten years, namely in 2033 is 250 Tons/ Year. Based on these factor, the
design capacity of the plant is 1100 Ton/Year. This amount is expected to
fulfill domestic needs and the rest 850 ton can be exported to other
country to increase foreign exchange.

1.2.2 Availability of Raw Materials

The availability of raw material is an important factor for the
survival of factory production, raw materials must receive serious
attention with periodic availability in sufficient quantities. The raw
materials used in the process of producing Acetylsalicylic Acid
(ASPIRIN) are acetic anhydride and salicylic acid. Both raw materials can
be obtained from abroad which located in China. Acetic anhydride will be
met from Changsheng Chemical Co. Ltd with a production of capacity of
50.000 ton per year. Meanwhile, salicylic acid will be met from Yinan
Yunxiang Chemical Co. Ltd with a production capacity 52 ton per year.

1.2.3 Overseas Similar Factory Capacity

From Encyclopedia of Chemical Processing and Design (Mc Ketta,
1982) it is obtained data that the minimum capacity that can still provide
minimum profit when establishing and aspirin plant is 500 ton per year.
Meanwhile, aspirin factory that have been established overseas and still
provide benefits, namely:
Table 1.2 Overseas Plant Capacity
 Factory Country Capacity
Monsanto Chem. Co Brazil 1000
Monsanto Chem. Co Thailand 1500
OSG New York 1814
Monsanto Chem. Co India 2000
Dow Chemical USA 5500
Rhon Phulene’s Sh. Fons France 8000
Rhodia Thailand 9072
Source: http://www.competition-commission.org.uk

1.3 Location of Plant Establishment

The location of the plant establishment plays an important role in the
sustainability of the plant. Availability of adequate land and other infrastructure
is vital in running the plant. In determining the location of plant, it is necessary
o consider e supporting factor that are interrelated. The factor that are need to be
considered are as follows:
1. Raw Material Supply
The source of materials is an important factor in choosing the location of the
plant. The location should be close the source of raw materials to reduce
transportations and storage costs
2. Marketing
Marketing location will greatly affect the cost of transportation. The location
close to the market is an important consideration to save distribution costs
and reachable for the consumers.
3. Transportation
The availability of adequate transportation facilities such as roads, ports, or
trains will facilitate the transportation both the raw material and product.
Aside from transportation sector, telecommunication sector is also needed to
considered
4. Labor
Most of the labor obtained from the community around the plant and experts
obtained from graduates from nearby colleges or universities from outside
the area where the factory is established.
5. Utility
 Utilities includes the need of adequate electricity and the sufficient amount of
water to be used in the production process, needs of employees, and needs of
fuel.

By considering several factors mentioned above, the location of this

acetylsalicylic acid (ASPIRIN) plant is determined in the Cilegon - Banten area
for the following reasons:
1. Second Indonesian Port (PELINDO) is located in Cilegon to facilitate the
transportation of raw materials that imported from China.
2. Cilegon area provides an adequate land transportation to facilitate the
distribution process of raw materials and products to other regions (both
Java and outside Java).
3. Increasing the market value of the product (aspirin) because there are quite a
lot of pharmaceutical industries in West Java.
4. Cilegon is a large industrial area so the utility needs can be provided easily.

1.4 Process Review

1.4.1 Kinds of Acetylsalicylic Acid (ASPIRIN) Manufacturing Process
There are several methods of producing aspirin:
a) Synthesis of Aspirin according to Kolbe
The preparation of acetylsalicylic acid was carried out by using the
Kolbe Synthesis, a method invented by a German chemist named
Hermann Kolbe. In this synthesis, sodium phenoxide is heated with CO 2
at high pressure, then acid is added to produce acetylsalicylic acid. The
resulting acetylsalicylic acid is then reacted with acetic anhydrous with
the help of salicylic acid to produce acetylsalicylic acid (George Austin,
1984).

b) Aspirin Synthesis Method After Modification of Kolbe Synthesis by

Schmitt
Sodium phenoxide solution goes into a revolving heated ball mill
which has a vacuum and heat pressure (130oC). Sodium phenoxide is
turned into a dry fine powder, then it is contacted with CO 2 at a pressure
of 700 kPa and a temperature of 100oC to form sodium salicylate.
 Sodium salicylate is dissolved out of the mill and then decolored using
activated carbon. Sulfuric acid then added to precipitate acetylsalicylic
acid, purified acetylsalicylic acid by sublimation.
To form aspirin, salicylic acid was refluxed with acetic anhydrous
in toluene solvent for 20 hours. The reaction mixture is then cooled in an
aluminum cooling tank, the acetyl salicylic acid settles as large crystals.
The crystals are separated by filtration or centrifugation, rinsed, and then
dried. Based on this process, to produce 1 ton of salicylic acid, 800 kg of
phenol, 350 kg of NaOH, 500 kg of CO2, 10 kg of zinc, 20 kg of zinc
sulfate and 20 kg of activated carbon are required (George Austin,
1984).

c) Aspirin Synthesis Method by Esterification

The process of making acetylsalicylic acid used is esterification
salicylic acid with acetic anhydrous. In this reaction what takes place is an
esterification reaction, which is the formation of an ester from the reaction
between salicylic acid and anhydrous acetate. This reaction is a type of
nucleophilic substitution reaction.
The nucleophilic reaction involves releasing H+ (hydrogen) ions
from salicylic acid which is nucleophilic (nucleophile) that attack the
acetate anhydrous thereby the acyl group CH 3-C(O)- release as the leaving
group (Le). This acyl group combines with the acetyl group to form acetic
acid as a byproduct (J.J Mc. Ketta, 1981).

1.4.2 Process Selection

Table 1.1 Kinds of Acetylsalicylic Acid (ASPIRIN) Production Process
Aspirin Synthesis Aspirin Synthesis
Aspirin Synthesis
Method by Method by
Method by Kolbe
Schmitt Esterification
Pressure 6 atm 7 atm 1 atm
Temperatur
100oC 100oC 90oC
e
Conversion 90% 90% 90%
Time 11 jam 20 jam 2 jam
 From the comparison of the three processes above, the preparation of
Aspirin is planned using the esterification process between Salicylic Acid
and Acetic Anhydrous with the following considerations:
a. The operation used low temperature and pressure so there will be less
energy required.
b. The level of purity of the aspirin product obtained is higher.

1.5 Product Usability

Aspirin is a common drug for relieving minor aches, pains, and fevers.
People also use it as an anti-inflammatory or a blood thinner. The uses of Aspirin
includes:
1. Pain and swelling
Aspirin can relieve mild to moderate pain, swelling, or both associated with
many health issues, such as:
 Headaches
 A cold or flu
 Sprains and strains
 Menstrual cramps
 Long-term conditions, such as arthritis and migraine

2. Preventing cardiovascular events

The daily use of low-dose aspirin can lower the risk of cardiovascular events
in some people — it is not safe for everyone. The Food and Drug
Administration (FDA) recommend only using aspirin in this way under the
supervision of a doctor. In people with a high risk of cardiovascular events,
low-dose aspirin can reduce the risk by preventing blood clots from
forming.

3. Treating coronary events

 Doctors may administer aspirin immediately after a heart attack, stroke, or
another cardiovascular event to prevent further clot formation and cardiac
tissue death.

4. Aspirin can also be part of a treatment plan for people who have recently
had:
 revascularization surgery, such as an angioplasty or coronary bypass
surgery
 a mini-stroke, or transient ischemic attack
 an ischemic stroke, which is caused by a blood clot