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 ¼ 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 gWeight 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 TestThe 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 Noteda. Salicylic Acid Purpleb. Commercially

available ASA1. Faint Purple tinge2. Yellow

c. Prepared ASA Light Purpled. Benzoic Acid No color reactione. Benzyl Alcohol No color reactionf. Control- H20 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 didn’t undergo color reaction.

Starch TestThe 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 Noteda. Prepared ASA No color reactionb. Commercially

available ASA1. Blue Violet2. Yellow

Greenc. Control- H20 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 determinationTemperature started to melt

Temperature dissolved

Trial 1 120 °C 135 °C

Trial 2 120 °C 125 °C

Average 120 °C 130 °CTable 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 ASA5 mL Acetic Anhydride x 1.082 AA x 1 mol AA x

1 mL 102.09 g AA1 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 fromhttp://reference.medscape.com/drug/zorprin-bayer-buffered-aspirin-343279#showall

[2] Acetylsalicylic acid. Drug Bank. Retrieved August 13, 2014 fromhttp://www.drugbank.ca/drugs/DB00945

[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/Crystallization

[5] Crystallization. Organic Chemistry at CU Boulder. Retrieved August 13, 2014 from http://orgchem.colorado.edu/Technique/Procedures/Crystallization/Crystallization.html

[6] "Ferric Chloride — Pyridine Test Page" . Chemistry.ccsu.edu. Retrieved 2013-09-11. Retrieved August 13, 2014 fromhttp://en.wikipedia.org/wiki/Ferric_chloride_test

[7] Preparation of Acetylsalicylic acid (Aspirin).Retrieved August 13, 2014 from

http://www.chemistry.mtu.edu/~kmsmith/SYP/Student/Tuesday/Aspirin.pdf

[8] Vogel's Textbook of Quantitative Chemical Analysis. Retrieved August 13, 2014 fromhttp://en.wikipedia.org/wiki/Iodine_test

[9] Determination of Melting Points. Gannon University SIM and Auburn University SIM. Retrieved August 13, 2014 from http://www.westminster.edu/acad/sim/documents/SDeterminationofMeltingPoints.pdf

[10] lab manual