Aspirin salicylic acid mixture

The key compound m the synthesis of aspirin salicylic acid is prepared from phe nol by a process discovered m the nineteenth century by the German chemist Hermann Kolbe In the Kolbe synthesis also known as the Kolbe—Schmitt reaction, sodium phen oxide IS heated with carbon dioxide under pressure and the reaction mixture is subse quently acidified to yield salicylic acid... 

Acetylation. Boil i g. of salicylic acid with 4 ml. of an acetic anhydride-acetic acid mixture (equal volumes) under reflux for 10 minutes. Pour into water. Filter off the aspirin (p. 111), wash with water and recrystallise from aqueous acetic acid (1 1) m.p. l36 ... 

Add 2.0 g of salicylic acid, 5.0 mL of acetic anhydride, and 5 drops of 85% H3P04 to a 50-mL Erlenmeyer flask. Heat in a water bath at 75°C for 15 minutes. Add cautiously 20 mL of water and transfer to an ice bath at 0°C. Scratch the inside of the flask with a stirring rod to initiate crystallization. Separate aspirin from the solid-liquid mixture by filtering through a Buchner funnel 10 cm in diameter. 

As the solvent mixture also contained 225 mg of tetramethyl ammonium hydroxide pentahydrate per liter at a high water content (75%), the surface of the reverse phase would have been largely covered with the tetramethyl ammonium hydroxide pentahydrate. This would have acted as an adsorbed ion exchange stationary phase. It is clear that the free acids, salicylic acid, acetylsalicylic acid (aspirin) and benzoic acid were retained largely by ionic interactions with adsorbed basic ion exchanger and partly by dispersive interactions with the exposed reversed phase. The acetaminophen and the caffeine, on the other hand, being unionized substances, were retained only by dispersive interactions with the exposed reversed phase. 

However, the driving force in this reaction is not large, so one usually ends up with an equilibrium mixture of water, salicylic acid, ASA and acetic acid. A better approach to produce ASA (aspirin) is to react acetic anhydride with salicylic acid in the presence of phosphoric or sulfuric acid acting as a catalyst ... 

In medical practice, other salicylic acid derivatives are used in the form of salts. Magnesium salicylate and sodium salicylate are less effective than respective doses of aspirin however, they are easier on patients that are sensitive to aspirin. Choline magnesium trisalicylate represents a mixture of choline salicylate and magnesium salicylate, which has the same effect as aspirin however, it is easier on patients in which gastrointestinal effects are observed upon taking aspirin. 

In this process, a 500-gallon glass-lined reactor is needed to heat the salicylic acid and acetic anhydride for 2 to 3 hours. The mixture is transferred to a crystallizing kettle and cooled to 3°C. Centrifuging and drying of the crystals yields the bulk aspirin. The excess solution is stored and the acetic acid is recovered to make more acetic anhydride. 

To form aspirin, the salicylic acid is refluxed with acetic anhydride in toluene at 88 to 92°C for 20 hours. The reaction mixture is then cooled in aluminum cooling tanks, and the acetylsalicylic acid precipitates as large crystals that are separated by filtration or by centrifugation, washed, and dried. 

A flow diagram for the production of aspirin is shown in Fig. 10.6 [9]. A mixture of salicylic acid powder, acetic anhydride, and a small amount of sulfuric acid is charged into a batch reactor. The mixture is stirred for 2 to 3 hours and then transferred to a crystallizing kettle. A portion of the mother liquor is recycled in the next run, and the other part of the slurry is centrifuged. The resulting crystalline material is dried in a rotary drier to yield acetylsalicylic acid (aspirin). Excess mother liquor is distilled and the excess of acetic anhydride is recycled. 

Fig. 24 Effect of humidity on the salicylic acid content in aspirin-disintegrant mixtures at 120 days and 25°C (A, aspirin powder). (Adapted from Ref l)...

No drug is as widely used as aspirin. Observers at least as far back as Hippocrates ( 400 B.C.) have noted the use of extracts from the bark and leaves of the willow tree for pain relief. In 1829, a mixture called salicin was isolated from willow bark. Subsequent analysis identified salicylic acid as the active component of this mixture. Salicylic acid was formerly used to treat pain, but this compound often irritated the stomach. Several investigators... 

Solvents (a) phosphate buffers contain AR Na2HP04 and NaH2P04 (0.025 M), pH adjusted to requirements using NaOH or H3PO4 (b) tetra-butyl ammonium phosphate (0.005 M) buffered to pH 7.6 (c) 1% HOAc. Mixture A acetylsalicylic acid (86 mg) paracetamol (5.1 mg) salicylamide (87.8 mg) caffeine (28.1 mg) phenacetin (11.4 mg) in 50 ml of methanol salicylic acid (6 mg) may be included because of the likelihood of its presence as an impurity in aspirin. 

Figure 9.20 Chromatograms of standard mixture of analgesics, column and conditions detailed in text. Eluant 40% methanol/60% 1 % HOAc. Detection (a) 235 nm (b) 254 nm. Peaks (1) paracetamol (2) caffeine (3) salicylamide (4) aspirin (5) phenacetin (6) salicylic acid.

Acetylation of salicylic acid with acetic anhydride yields aspirin. The crude produet may be recrystallized from benzene, mixture of acetie aeid and water (1 1) or various other non-aqueous solvents. 

The interaction between salicylic acid and acetyl chloride gives rise to the formation of aspirin i.e., the acetylated product with the elimination of one mole of HCl. The liberated mineral acid i.e., HCl, being a strong acid readily reacts with pyridine (a weak base) in the reaction mixture to form the corresponding salt i.e., pyridine hydrochloride. 

One of the most frequently used pain relievers is acetylsalicylic acid, which is commonly called aspirin. An aspirin tablet contains more than aspirin, however. Manufacturers mix aspirin with starch, which keeps the tablets from falling apart and makes them large enough for easy handling. Furthermore, aspirin can break down into salicylic acid and acetic acid over time. Therefore, an aspirin tablet is a mixture of at least four substances aspirin, starch, salicylic acid, and acetic acid. 

Figure 4 Use of derivative spectra to determine salicylic acid in aspirin (A) the zeroth and second derivatives of both materials are shown. (B) The equivalent spectra of the mixture in a 1 2000 ratio are shown. (Reprinted with permission from Kitamura K and Majima R (1983) Analytical Chemistry 55 54. American Chemical Society.)...

Over one-half of the salicylic acid is used to manufacture acetylsalicylic acid, quantitatively one of the most important analgesic pharmaceuticals. Acetylsalicylic acid was first produced in 1853 from acetyl chloride and sodium salicylate. Its introduction as a medicament occurred in Germany in 1899 (Aspirin) and in the USA in 1900. Acetylsalicylic acid is now produced by reaction between salicylic acid and acetic anhydride in stainless steel or enamelled reactors at a temperature below 98 °C (duration of reaction 2 to 3 hours). The reaction mixture is refined by crystallization at 0 °C. 

Assayed by the method given under Compound Tablets of Aspirin using 0 25 g of powdered tablets (p. 12), without extracting for salicylic acid, i.e. hydrolyse the mixture in acid solution, extract the caffeine with chloroform, reconvert the p-phenetidine into phenacetin, extract and weigh. 

---