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

AbstractAcetylsalicylic 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 135C. Aspirin is synthesized through an esterification reaction of salicylic acid with acetyl anhydride which causes achemical reactionthat turns salicylic acid's hydroxylgroup into anacetylgroup (ROH ROCOCH3). 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 likevinegar because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic andacetic 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.

Methodology2 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 - 800C) 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 DiscussionWeight of Salicylic Acid2.03g

Weight of filter paper119.05g

Weight of filter paper + ASA120.58g

Weight of ASA1.53g

Table 1.0 Data2.03 grams of Salicylic Acid has 1.53 grams of ASA. Test TubeColor Notes

Salicylic AcidViolet solution w/ ppt.

Commercially available ASAYellow solution with ppt.

Prepred ASALight purple solution with ppt.

Benzoic AcidClear solution with white ppt.

Benzyl AlcoholYellow immiscible

ControlClear solution

Table 2.0 Ferric Chloride Test for Salicylic Acid

Figure 1.0 Results for Ferric Chloride TestFerric 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 TubeColor Noted

Prepared ASAClear solution with ppt.

Commercially available ASAYellow solution with ppt.

ControlTurbid solution

Table 3.0 Starch TestStarch 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 TestSubstanceMelting Point

Salicylic Acid160-165 C

Pure ASA140-145 C

Prepared ASA155-160 C

Table 4.0 Melting Point DeterminationDetermining 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 C while for acetylsalicylic acid, it is 136 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.ConclusionThe 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 LiteraturesDetermination of Melting Point. Wired Chemist. Retrieved from http://www.wiredchemist.com/chemistry/instructional/laboratory-tutorials/determination-of-melting-pointSynthesis of Acetylsalicylic Acid and Testing of Commercial Aspirin for Purity. Retrieved from:http://users.uma.maine.edu/SusanBaker/chy%20106%20asa.htm