Aspirin impurities

Many pharmaceutical compounds contain chromophores that make them suitable for analysis by UV/Vis absorption. Products that have been analyzed in this fashion include antibiotics, hormones, vitamins, and analgesics. One example of the use of UV absorption is in determining the purity of aspirin tablets, for which the active ingredient is acetylsalicylic acid. Salicylic acid, which is produced by the hydrolysis of acetylsalicylic acid, is an undesirable impurity in aspirin tablets, and should not be present at more than 0.01% w/w. Samples can be screened for unacceptable levels of salicylic acid by monitoring the absorbance at a wavelength of... 

Fig. 4 Effect of acetylsalicylic anhydride impurity on the dissolution rate of aspirin tablets. (From Ref. 34.)...

In addition to salicylic and acetic acids, very small quantities of acetylsalicylanhy-dride (0.0012 to 0.024%) and acetylsalicylsalicylic acid (0.03 to 0.1%) have been found in aspirin preparations. The former has been determined by gas chromatography,1 0 TLC170 and spectrophotometry,171 the latter by gas chromatography. 14 0,1 a controversy is still ongoing (cf. 152) whether the occasionally observed hypersensitivity against aspirin is caused by these two impurities and whether the basis of the adverse reaction is immunological. 

In a synthesis reaction, an impure sample of aspirin was prepared from 2-hydroxybenzoic acid and ethanoic anhydride. The reaction mixture was heated for approximately 10 minutes. 

The impure aspirin sample was then purified by recrystallisation from ethanol. Describe the steps the chemist would need to take to purify the aspirin sample using this technique. 

Add a small volume of hot ethanol to the aspirin and see if it dissolves. If any solid remains, add another small volume of hot ethanol. Place the aspirin-ethanol mixture on a hot-plate for one minute. If any solid remains, add another small volume of ethanol. Repeat until all the solid has dissolved. Carry out a hot filtration to remove any insoluble impurities and leave the filtrate to cool to room temperature. Filter the crystals. 

Ethanol must be capable of dissolving aspirin when the solution is hot and aspirin must be less soluble in ethanol when cold. The impurities should be soluble in ethanol. 

The melting point results suggest that the aspirin obtained is slightly impure. The temperature range is broad and the temperature is below the accepted melting point. 

The source of the raw materials can greatly influence hydrolytic reactions. This is exemplified by Gold and Campbell [54] where talc obtained from different sources impacts markedly on the overall stability of the aspirin tablet formulation. This is possibly attributable to the effect of different types and amounts of surface impurities, which are dissolved in the adsorbed moisture layer, where they subsequently react with the API. It could also influence the pH of the micro-environment. 

That s quite a claim for the little pill that was concocted in 1897 by Felix Hoffmann, a chemist working for the Bayer company in Germany. While Hoffmann did synthesize the first commercial sample of acetylsalicylic acid, as aspirin is known generically, he wasn t the first to produce the substance in the laboratory. That honor goes to Karl Friedrich Gerhardt, who, in 1853 at Montpellier University in France, concocted an impure version with an eye towards improving on the effects of salicylic acid, a commonly used painkiller. At the time salicylic acid was extracted from the leaves of the meadowsweet plant and used for the treatment of fevers and pain, particularly of the arthritic variety. But it had to be taken in... 

Figure 4 Nonsteroidal anti-inflammatory drugs, acetaminophen, and caffeine separated by CEC on a 75-mm-i.d. column packed with 5-mm ODS Nucleosil particles immobilized within a polymer matrix. Mobile phase 70% acetonitrile/30% acetate, 10 mM (pH 3.0). UV detection at 254 and 220 nm 20 kV applied, effective length 17 cm, total length 26 cm. Analytes (1) unknown impurity (2) acetaminophen (3) caffeine (4) aspirin (5) naproxen (6) flurbiprofen (7) ibuprofen. (Reprinted from Ref. 22, with permission.)...

NPC is ideally suited for the analysis of compounds prone to hydrolysis because it employs nonaqueous solvents for the modulation of retention. An example of the use of NPC in the analysis of a hydrolysable analyte was demonstrated by Chevalier et al. [28] for quality control of the production of benorylate, an ester of aspirin. A major issue in benorylate production is the potential formation of impurities suspected of causing allergic side effects therefore monitoring of this step is critical to quality control. The presence of acetylsalicylic anhydride prohibited the use of RPLC since it can be easily hydrolyzed in the water-containing mobile phase. However, an analytical method based on the use of normal-phase chromatography with alkylnitrile-bonded silica as the stationary phase provided an ideal solution to the analysis. Optimal selectivity was achieved with a ternary solvent system hexane-dichloromethane-methanol, containing 0.2 v/v% of acetic acid to prevent the ionization of acidic function and to deactivate the residual silanols. The method was validated and determined to be reproducible based on precision, selectivity, and repeatability. 

Test the solubility of your sample in toluene and in hot water and note the peculiar character of the aqueous solution when it is cooled and when it is then rubbed against the tube with a stirring rod. Note also that the substance dissolves in cold sodium bicarbonate solution and is precipitated by addition of an acid. Compare a tablet of commercial aspirin with your sample. Test the solubility of the tablet in water and in toluene and observe if it dissolves completely. Compare its behavior when heated in a melting point capillary with the behavior of your sample. If an impurity is found, it is probably some substance used as binder for the tablets. Is it organic or inorganic To interpret your results, consider the mechanism whereby salicylic acid is acetylated. 

Salicylic acid as an impurity was investigated in 12 different brands of aspirin formulations readily available in Lagos (Nigeria). The HPLC method adopted for the investigation involved a mobile phase of methanoi/water (20/80, v/v) adjusted to pH 2.5 with phosphoric acid and was run on a 50 mm column monitored at 240 nm. The limit of detection for salicylic acid was 5 ng. Only three of the formulations showed the presence of salicylic acid impurity and all these contained salicylic acid in excess of the USP 1980, limit of 0.3% salicylic acid per tablet (52). 

Talc is chemically unreactive in general. For aspirin formulations, it was found that talc impurities, such as calcium carbonate and calcium silicate, were responsible for the aspirin degradation observed [42], Impurities such as iron oxide and aluminum silicate did not affect the stability of the aspirin. 

A typical example of a limit test is the test for salicylic acid in a sample of Aspirin BP. Salicylic acid is formed by hydrolysis of aspirin (or may be an impurity from the synthesis). The test involves comparing the violet colour produced when the sample is reacted with ferric chloride with that obtained from a standard salicylic acid solution. 

Lurie, I.S. McGuiness, K. The quantitation of heroin and selected basic impur-ties via reversed phase HPLC. II. The analysis of adulterated samples. J.Liq.Chromatogr., 1987, 10, 2189—2204 [also impurities, acetaminophen, acetylcodeine, acetylmorphine, acetylprocaine, aminopyrene, amitriptyline, antipyrene, aspirin, barbital, benztropine, caffeine, cocaine, codeine, diamorphine, diazepam, diphenhydramine, dipyrone, ephedrine, ethylmorphine, lidocaine, meconin, methamphetamine, meth-ap Tilene, methaqualone, monoacetylmorphine, morphine, nalorphine, niacinamide, nicotinamide, noscapine, papaverine, phenacetin, phenmetrazine, phenobarbital, phenolphthalein, procaine, pro-panophenone, propoxyphene, P5rilamine, quinidine, quinine, salic lamide, saUsalicylic acid, secobarbital, strychnine, tetracaine, thebaine, tripelennamine, tropacocaine, vitamin B3, vitamin B5 electrochemical detection]... 

Noninterfering adenosine, albuterol, alphenal, aspirin, caffeine, carbamazepine, cefazo-lin, cephalexin, cephalothin, cimetidine, ciprofloxacin, claforan, desipramine, enoxacin, fleroxacin, furosemide, hydralazine, hydrochlorothiazide, minoxidil, norfloxacin, pheny-toin, propafenone, sulindac, teicoplanin, theophylline, vancomycin Interfering some indocyanine green impurities... 

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. 

Explain why a melting point below 137°C is indicative of an impure sample of aspirin. 

Reactive chemical impurities as byproducts of synthesis acetylsalicylsalicylic acid and acetylsalicylic anhydride in aspirin... 

Impurities contaminating commercial aspirin preparations could be responsible for appearance of urticaria and angioedema in some patients (de Weck 1971 Bundgaard and de Weck 1975). These contaminants include acetylsalicylic anhydride, acetylsalicylic salicylic acid and cw-disalicylide. A rapid and convenient colorimetric method has been described recently for the quantitative determination of these immunogenic impurities in aspirin (Bundgaard 1976). 

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