Synthesis of Aspirin

Pornillos, M.W.L.; Qua, A.M.; Ramoran, E.G.; Reyes, C.Z.; Rojo, A.A.
University of Santo Tomas, Faculty of Pharmacy

Abstract
Acetylsalicylic acid, known as Aspirin, is one of the most widely used medications to reduce
fever and is also used as a pain killer. The synthesis of acetylsalicylic acid is derived from
salicylic acid and by allowing it to react with acetic anhydride and a catalyst through the principle
of crystallization.

Background of the Study

Acetylsalicylic acid, also known as aspirin,
is one of the most widely used medications
to reduce fever and is also used as a pain
killer. Much of this is believed to be due to
decreased production of prostaglandins and
thromboxanes. Aspirin's ability to suppress
the production of prostaglandins and
thromboxanes is due to its irreversible
inactivation of the cyclooxygenase (COX)
enzyme. Cyclooxygenase is required for
prostaglandin and thromboxane synthesis.
Aspirin acts as an acetylating agent where
an acetyl group is covalently attached to a
serine residue in the active site of the COX
enzyme. It is an acetyl derivative of salicylic
acid. It is a white, crystalline, weakly acidic
substance which melts at 135°C.
Aspirin is synthesized through an
esterification reaction of salicylic acid with
acetyl anhydride which causes a chemical
reaction that turns salicylic acid's
hydroxyl group into an acetyl group (R—OH
→ R—OCOCH
3
). For the reaction to take
place, an inorganic acid such as sulfuric
acid is used as a catalyst. Formulations
containing high concentrations of aspirin
often smell like vinegar because aspirin can
decompose through hydrolysis in moist
conditions, yielding salicylic and acetic
acids.

Crystallization is one of the most used
purifying methods inorganic experiments. It
is a process of crystal formation in a
solution. Organic compounds that are solid
in room temperature are usually purified by
crystallization. The substance to be purified
is dependent to its solubility in change of
temperature whether in a hot or cold
solvent. It is the main factor that affects
crystallization. The substance to be
crystallized should show the ideal solubility
behavior in solvent. A substance can be
purified when both the desired substance
and the impurity have similar solubility at its
boiling point temperature, and when the
impurity represents only a small fraction of
the substance. The desired substance will
crystallize on cooling, but the impurities will
not.

The ferric chloride test is commonly used to
detect the presence of salicylic acid in
commercial aspirin. Ferric chloride reacts
with phenols to produce a purple color.
Since salicylic acid is a phenol and aspirin is
not, pure aspirin should give a negative
ferric chloride test.

The Starch test is used to test for the
presence of starch. Iodine solution reacts
with the starch, producing a purple-black
color. For Aspirin, it is conducted to be able
to know if the drug contains pure aspirin or
just starch as additive.

Methodology
2 grams of salicylic acid was weighed and 5
mL of acetic anhydride was added then
another 5 drops of concentrated sulfuric
acid was added to the solution. The solution
was placed on a water bath (70 - 80
0
C) for
20 to 30 minutes. After 30 minutes, remove
the solution from the water bath then a drop
of room temperature water was added until
solution becomes cloudy. Then rinse the
solution with ice cold water. The solution
was transferred to a beaker then 20 mL of
ice cold water was added then stirred. To
allow aspirin to crystallize, the solution was
placed on an ice bath for 10 minutes then
the solution was filtered and allowed to dry.
The aspirin was weighed.
To test the purity of the synthesized aspirin,
it was subjected to ferric chloride test for
salicylic acid. 1 mL of water was placed in 6
test tubes. A small amount of each sample
was added in every test tube. Salicylic acid
was placed in the first test tube, powdered
commercial aspirin in the second,
synthesized aspirin in the third, benzoic acid
in the fourth and 1 mL of benzoic acid in the
fifth. The sixth test tube, filled with 1 mL of
water, was the control used. The sample
used was dissolved in 1 mL of water then a
drop of 2% aqueous solution of ferric
chloride was added using a pipette. The
observed color produced was noted.
Another test of purity used was starch test.
2 mL of water was placed in 3 test tubes. A
small amount of each sample was added in
each test tube. The powdered commercial
aspirin was placed in the first test tube and
salicylic acid in the second. The third test
tube with 2 mL of water was the control
used. A drop of iodine solution was added in
each test tube. The observed color
produced was noted.
Boiling point determination was also
conducted for 3 samples (prepared ASA,
commercially available ASA, & a control).
Capillary tubes were used. The pulverized
substance was push to the open end of the
tube then the powder was moved to the
other end which was sealed. The tubes
were attached to a thermometer using
rubber bands aligned to the close end of the
thermometer. After attaching, the tubes
were placed in an oil bath. The temperature
at which the powders melted was taken
note.
Results and Discussion
Weight of Salicylic
Acid
2.03g
Weight of filter paper 119.05g
Weight of filter paper
+ ASA
120.58g
Weight of ASA 1.53g
Table 1.0 Data
2.03 grams of Salicylic Acid has 1.53 grams
of ASA.
Test Tube Color Notes
Salicylic Acid
Violet solution w/
ppt.
Commercially
available ASA
Yellow solution with
ppt.
Prepred ASA
Light purple solution
with ppt.
Benzoic Acid
Clear solution with
white ppt.
Benzyl Alcohol Yellow immiscible
Control Clear solution
Table 2.0 Ferric Chloride Test for
Salicylic Acid

Figure 1.0 Results for Ferric Chloride
Test
Ferric Chloride test is used to determine the
presence or absence of phenols. It was
used as a confirmatory test for aspirin. It will
not react with aspirin. However, it will react
with salicylic acid, which is used to
synthesize aspirin. Adding an aqueous ferric
chloride solution to a sample of aspirin is a
good way to see if there is any unreacted
salicylic acid. A purple color is an indication
of salicylic acid. In the experiment
performed, salicylic acid and the prepared
ASA produced a positive result. The
commercially available ASA, benzoic acid,
benzyl alcohol and the control all produced
a negative result.
Test Tube Color Noted
Prepared ASA
Clear solution with
ppt.
Commercially
available ASA
Yellow solution with
ppt.
Control Turbid solution
Table 3.0 Starch Test
Starch is a type of binder often used in
medicines, due to the active chemical's
inability to form a pill shape. Formation of
purple-black colored solution indicates
apositive result. None of the samples
rendered a positive result.

Figure 2.0 Results for Starch Test
Substance Melting Point
Salicylic Acid 160-165 ⁰ C
Pure ASA 140-145 ⁰ C
Prepared ASA 155-160 ⁰ C
Table 4.0 Melting Point Determination
Determining the melting point of a
compound is one way to test if the
substance is pure. The theoretical melting
point for salicylic acid is 159 ⁰ C while for
acetylsalicylic acid, it is 136 ⁰ C. From the
experiment that was performed, it can be
inferred that there were impurities present in
the substances. Impurities tend to depress
and broaden the melting range so the
purified sample should have a higher and
smaller melting range than the original,
impure sample.
Conclusion
The Ferric Chloride test is conducted to
determine the purity of a substance. The
results show that salicylic acid and the
prepared ASA showed a positive result
because the test produced a purple color
which indicates that the salicylic acid from
the samples reacted with the aqueous ferric
ion. While the commercially available ASA,
benzoic acid, benzyl alcohol and the control
showed a negative result because the test
produced a clear or yellow color which
indicates that there is no salicylic acid
present in the samples. The starch test
determines the degradation of the drug
since starch is used as an inert binding
material. None of the samples had a
positive result (purple-black solution due to
iodine) which shows that it is still safe to
consume and is far from its expiration date.
The melting point determination is
conducted through an oil bath for the reason
that the aspirin is amorphous leading to a
higher melting point. According to this
experiment, the samples (Salicylic acid,
Pure and prepared ASA) used contains
impurities in their chemical properties as
their melting points are higher than that of
the theoretical.
Related Literatures
Determination of Melting Point. Wired
Chemist. Retrieved from
http://www.wiredchemist.com/chemistry/inst
ructional/laboratory-tutorials/determination-
of-melting-point
Synthesis of Acetylsalicylic Acid and Testing
of Commercial Aspirin for Purity. Retrieved
from:http://users.uma.maine.edu/SusanBak
er/chy%20106%20asa.htm