SYNTHESIS OF ASPIRIN

Authors: Meneses, Eunice Rae M., Pacheco, Meah G., Palma, Paola Louise R., Perez, Fleur Jeizl, Refuerzo,
Maria Godesa
University of Santo Tomas, Faculty of Pharmacy
Abstract: Acetylsalicylic acid is synthesized through the esterification process of the salicylic acid and the
acetic anhydride, an acid catalyst. Test for impurities such as the Ferric Chloride Test, Starch Test and
Melting Point Determination were performed. It was concluded that impurities were present in the
crude sample of Acetylsalicylic acid.
I. Background of Study
Aspirin, an acetyl derivative of salicylic
acid, is a white, crystalline, weakly acidic
substance, with a melting point of 136 C
(277 F), and a boiling point of 140 C (284 F).
[1]

It is insoluble in cold water.
It is a prototypical analgesic used in the
treatment of mild to moderate pain. It has anti-
inflammatory and antipyretic properties and
acts as an inhibitor of cyclooxygenase which
results in the inhibition of the biosynthesis of
prostaglandins. Acetylsalicylic acid also inhibits
platelet aggregation and is used in the
prevention of arterial and venous thrombosis.
[2]
Aspirin can be made by reacting salicylic
acid with acetic acid in the presence of an acid
catalyst. The phenol group on the salicylic acid
forms an ester with the carboxyl group on the
acetic acid. However, this reaction is slow and
has a relatively low yield. Acetic anhydride is
used instead of acetic acid for its reaction is
much faster and it has a higher yield since acetic
anhydride is much more reactive than acetic
acid.
[3]
Crystallization is the (natural or
artificial) process of formation of solid crystals
precipitating from a solution, melt or more
rarely deposited directly from a gas.
[4]
Crystallization is based on the principles of
solubility: compounds (solutes) tend to be more
soluble in hot liquids (solvents) than they are in
cold liquids. If a saturated hot solution is
allowed to cool, the solute is no longer soluble
in the solvent and forms crystals of pure
compound. Impurities are excluded from the
growing crystals and the pure solid crystals can
be separated from the dissolved impurities by
filtration.
[5]


Figure 1. The Aspirin Synthesis Reaction

II. Materials and Methods:
The materials used in this experiment
are: hard glass test tube, 10-mL graduated
cylinder, dropping pipette, beaker,
thermometer, stirring rod, filter paper, and
funnel. The following reagents were utilized:
salicylic acid, acetic anhydride, concentrated
sulphuric acid.
After the preparation of the indicated
materials and reagents, 2 grams of salicylic acid
was weighed through the use of analytical
balance. The sample weighed was transferred
then into a hard glass test tube. With the aide
of graduated cylinder, an exact amount of 5 mL
acetic anhydride was added to the sample in
the test tube. 5 drops of concentrated sulphuric
was added as well, stirring it until the salicylic
acid was completely dissolved to obtain a
solution. It was placed later on into a water
bath set up which has a temperature of 70 to 80
C for 20-30 minutes with occasional stirring. A
drop wise of water with a room temperature
was added until the solution becomes cloudy.
After which, the solution was removed from the
setup. The inner wall of the test tube was
scratched and it was rinsed with cold water. The
rinsing was transferred into a beaker and was
then placed on an ice bath for 10 minutes to
accumulate crystals. The solution was filter in a
pre-weighed filter paper and was dried. And
lastly, the aspirin was weighed again.
After the accumulation of crystals,
confirmatory tests were performed. First is the
Ferric Chloride Test. 6 test tubes were
prepared, containing 1 mL of water. The
following was added into each corresponding
test tube: salicylic acid, commercially available
aspirin, prepared aspirin, benzoic acid, benzyl
alcohol, and the controlled variable which is the
water. Each solution was shake and 1 drop of
2% aqueous Ferric chloride was added. The
second confirmatory test is the Starch Test. 3
test tubes, each containing 2 mL of water was
prepared and the following were added into a
corresponding test tube: prepared aspirin,
commercially available aspirin, and the
controlled variable- water. 1 drop of Iodine was
then added into each test tube. The melting
point of the aspirin was determined. A 40 mL
beaker with oil was prepared. It was placed on
hot plate and a thermometer was immersed
into the oil to check the temperature of the
water. 2 capillary tubes, each filled with the
aspirin is banded into the thermometer. The
temperature in which it started to melt and
when it was completely dissolved was noted.
III. Results:
Weight of salicylic acid 2.0055 g
Weight of Acetylsalicylic
acid
1.8032 g
Table 1. Weight of Salicylic Acid and Acetylsalicylic Acid
The weight of the salicylic acid is 2.0055 g while
the weight of the Acetylsalicylic acid which was
synthesized by the former is 1.8032 g.
Ferric Chloride Test
The ferric chloride test is used to determine the
presence or absence of phenols in a given
sample.
[6]
It is used as a purity test in the
synthesis of aspirin. The addition of ferric
chloride to salicylic acid produces a specific
color caused by the reaction of salicylic acid
with aqueous ferric (Fe(H2O)6+3) ion. The
oxygen atoms of the acid

group COOH, and of
the -OH group on the salicylic acid together can
form a complex with Fe(H2O)6+3. That complex
has an intense violet color. In aspirin, the OH
group of salicylic acid has been replaced by a O-
COCH3 group which prevents the second bond
from being formed. The resulting complex with
aspirin shows only a slight yellow color, not very
different from that of Fe(H2O)6+3 itself.
[7]

Test Tube Color Noted
a. Salicylic Acid Purple
b. Commercially
available ASA
1. Faint Purple tinge
2. Yellow
c. Prepared ASA Light Purple
d. Benzoic Acid No color reaction
e. Benzyl Alcohol No color reaction
f. Control- H
2
0 No color reaction
Table 2. Ferric Chloride Test Results
Result shows that salicylic acid has a
color reaction in the Ferric Chloride test. A
purple solution was noted. Two commercially
available ASA were tested. The first obtained a
lavender solution while the second had a yellow
solution. The prepared ASA had a color reaction
as well in which it had obtained a lavender
solution. On the other hand, Benzoic acid,
Benzyl alcohol and the controlled variable
which is water didnt undergo color reaction.
Starch Test
The Iodine test is used to test for the presence
of starch. Iodine solution iodine dissolved in
an aqueous solution of potassium iodide
reacts with the starch, producing a purple-black
colour. However, the intensity of the colour
decreases with increasing temperature and with
the presence of water-miscible organic solvents,
such as ethanol.

Test Tube Color Noted
a. Prepared ASA No color reaction
b. Commercially
available ASA
1. Blue Violet
2. Yellow
Green
c. Control- H
2
0 No color reaction
Table 3. Starch Test Results
Result shows that only the commercially
available ASA undergo color reaction. The first
ASA tested had a violet solution while the
second had a yellow one.
Melting point determination
Temperature
started to melt
Temperature
dissolved
Trial 1 120 C 135 C
Trial 2 120 C 125 C
Average 120 C 130 C
Table 4. Melting Point Range of Trial 1 and Trial 2
Experimentally, melting point is actually
recorded as the range of temperatures in which
the first crystal starts to melt until the
temperature at which the last crystal just
disappears. It indicates the level of purity of a
sample. An impure compound melts over a
wider range of temperatures, usually greater
than 2 degrees.
[9]

Two capillary tubes containing sample which is
the prepared ASA were tested to determine the
melting point of ASA. Based from the result, the
average temperature where in the sample
started to melt was at 120 C, while the
temperature where in it was completely
dissolved was at 130 C.
Percentage Yield:
Acetylsalicylic acid:





Percentage Yield:


IV. Conclusion
Salicylic acid is positive in Ferric
Chloride Test, meaning it has a presence of
phenol group. A pure acetylsalicylic acid would
obtain a yellow color or a faint purple tinge. The
prepared sample was proven to be impure
because of its light purple color. The impurity
of the prepared acetylsalicylic acid is because of
the presence of salicylic acid that was not
completely dissolved during the water bath
heating process.
Starch is used as a binder in drug
products. Manufacturers usually use it and in
the experiment, only the first sample of
commercially available acetylsalicylic acid had a
positive result.
2.0055g Salicylic Acid x 1 mol SA x 1 mol ASA x
138.12g SA 1 mol SA
180.157 g ASA = 2.6159 g ASA (Limiting Reactant)
1 mol ASA
5 mL Acetic Anhydride x 1.082 AA x 1 mol AA x
1 mL 102.09 g AA
1 mol ASA x 180.157 g ASA = 9.5470 g ASA
1 mol AA 1 mol ASA (Excess Reactant)
Percentage Yield = 1.8032 g x 100 = 68.932%
2.6195 g
The melting point range of a pure
aspirin is from 138 C to 140 C.
[6]
The gathered
result is lower (120 C to 140 C), which means
impurities are present in the sample.
V. References:
[1] Zorprin, Bayer Buffered Aspirin
(aspirin) dosing, indications,
interactions, adverse effects, and
more". Medscape Reference. WebMD.
Retrieved August 13, 2014 from
http://reference.medscape.com/drug/z
orprin-bayer-buffered-aspirin-
343279#showall
[2] Acetylsalicylic acid. Drug Bank.
Retrieved August 13, 2014 from
http://www.drugbank.ca/drugs/DB009
45
[3] Synthesis of Aspirin. Retrieved August
13, 2014 from
http://www.laney.edu/wp/cheli-
fossum/files/2012/01/8-Synthesis-of-
Aspirin.pdf
[4] Tavare, N.S. (1995). Industrial
Crystallization. Plenum Press, New York.
Retrieved August 13, 2014 from
http://en.wikipedia.org/wiki/Crystallizat
ion
[5] Crystallization. Organic Chemistry at CU
Boulder. Retrieved August 13, 2014
from
http://orgchem.colorado.edu/Techniqu
e/Procedures/Crystallization/Crystalliza
tion.html
[6] "Ferric Chloride Pyridine Test Page".
Chemistry.ccsu.edu. Retrieved 2013-09-
11. Retrieved August 13, 2014 from
http://en.wikipedia.org/wiki/Ferric_chl
oride_test
[7] Preparation of Acetylsalicylic acid
(Aspirin).Retrieved August 13, 2014
from
http://www.chemistry.mtu.edu/~kmsm
ith/SYP/Student/Tuesday/Aspirin.pdf
[8] Vogel's Textbook of Quantitative
Chemical Analysis. Retrieved August 13,
2014 from
http://en.wikipedia.org/wiki/Iodine_tes
t
[9] Determination of Melting Points.
Gannon University SIM and Auburn
University SIM. Retrieved August 13,
2014 from
http://www.westminster.edu/acad/sim
/documents/SDeterminationofMeltingP
oints.pdf
[10] lab manual