Salicylates

Salicylates

Salicylates not only posses antipyretic, analgesic, and anti-inflammatory properties, but also other actions that have been proven to be therapeutically beneficial because salicylates promote the excretion of uric acid and they are useful in the treatment of gouty arthritis. More attention has been given to the ability of salicylates (aspirin) to inhibit platelet aggregation, which may contribute to heart attack and strokes, and hence, aspirin reduces the risk of myocardial infarction. In addition, a recent study suggested that aspirin and other NSAIDs might be protective against colon cancer.

Structural Activity Relationship (SAR) of Salicylates

·The active moiety of salicylates is salicylate anion, side effects of aspirin, particularly GIT effects appear to be associated with the carboxylic acid functional group.

·Reducing the acidity of the carboxy group results in a change in the potency of activity. Example—

the corresponding amide (salicylamide) retain the analgesic action of salicylic acid, but is devoid of anti-inflammatory properties.

·Substitution on either the carboxyl or phenolic hydroxyl group may affect the potency and toxicity.

Benzoic acid itself has only week activity.

·Placement of the phenolic hydroxyl group at meta or para to the carboxyl group abolish the activity.

·Substitution of halogen atom on the aromatic ring enhances potency and toxicity.

·Substitution of aromatic ring at the 5th position of salicylic acid increase anti-inflammatory activity (diflunisal).

Metabolism of salicylic acid derivatives: The initial route of metabolism of these derivatives is their conversion to salicylic acid, which is excreted in urine as free acid (10%) or undergoes conjugation with either glycine to produce the major metabolites of salicylic acid (75%) or with glucuronic acid to form glucuronide (15%). In addition, small amount of metabolites resulting from microsomal aromatic hydroxylation leads to gentisic acid.

i. Aspirin (Emipirin, Bufferin)

Synthesis

Properties and uses: Aspirin is a white crystalline powder, slightly soluble in water and soluble in alcohol, indicated for the relief of minor aches and mild-to-moderate pain in the conditions such as arthritis and related arthritic condition. Also used in myocardial infarction prophylaxis.

Assay: Dissolve the sample in alcohol and add 0.5 M sodium hydroxide. Allow to stand and titrate against 0.5 M hydrochloric acid using phenolphthalein as an indicator. Perform a blank titration.

Dose: Usual adult dose: 300 to 650 mg every 3 or 4 h orally or 650 mg to 1.3 g as the sustained-release tablet every 8 h; rectal, 200 mg to 1.3 g three or four times a day.

Dosage forms: Aspirin tablets I.P., B.P., Dispersible aspirin tablets B.P., Effervescent soluble aspirin tablets B.P., Gastro-resistant aspirin tablets B.P., Aspirin and Caffeine tablets B.P., Co-codaprin tablets B.P., Dispersible co-codaprin tablets B.P.

ii. Sodium salicylate

Synthesis

Properties and uses: Sodium salicylate is a white crystalline powder, soluble in water, sparingly soluble in alcohol. It is used for fever and for the relief of pain. It also possesses anti-inflammatory actions similar to aspirin and symptomatic therapy of gout.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end-point potentiometrically.

iii. Salsalate (Disalacid, Saloxium)

Synthesis

Properties and uses: Salsalate or salicylsalicylic acid is a dimer of salicylic acid. It is insoluble in gastric juice, but is soluble in the small intestine where it is partially hydrolyzed into two molecules of salicylic acid and absorbed. It does not cause GI blood loss. It has antipyretic, analgesic, and anti-inflammatory properties similar to those of aspirin. It is employed in the treatment of rheumatoid arthritis and other rheumatic disorders.

Dose: Usual adult dose is 325–1000 mg 2–3 times a day, orally.

iv. Sulphasalazine (Azultidine, Azaline)

Properties and uses: Sulphasalazine is a bright yellow or brownish-yellow fine powder, practically insoluble in water and methylene chloride, very slightly soluble in alcohol, soluble in dilute solutions of alkali hydroxides. Sulphasalazine is a mutual prodrug. In large intestine, it is activated to liberate 5-amino salicylic acid, which in turn inhibits PG synthesis and the sulphapyridine is useful for the treatment of infection. Hence, sulphasalazine is used in the treatment of ulcerative colitis.

Synthesis

Assay: Dissolve and dilute the sample in 0.1 M sodium hydroxide and add 0.1 M acetic acid and measure the absorbance at the maxima of 359 nm using ultraviolet spectrophotometer. Prepare a standard solution at the same time and in the same manner, using sulphasalazine reference standard.

Dose: Dose orally is initially 3–4 g daily, followed by 500 mg four times a day for maintenance.

Dosage forms: Sulphasalazine tablets B.P.

v. Diflunisal

Synthesis

Properties and uses: Diflunisal is a white crystalline powder, practically insoluble in water, soluble in alcohol, and dilute solutions of alkali hydroxides. It is more potent than aspirin, but produces fewer side effects, and has a biological half-life 3–4 times greater than that of aspirin. It is a nonselective cyclooxygenase inhibitor used as antipyretic, analgesic, and anti-inflammatory.

Assay: Dissolve the sample in methanol, add water, and titrate against 0.1 M sodium hydroxide using phenol red as indicator, until the colour changes from yellow to reddish-violet.