Hydrolysis of aspirin

Hydrolysis of Aspirin. Gently boil a mixture of i g. of aspirin and 15 ml. of 10% sodium hydroxide solution in a 50 ml. conical flask under reflux for 20 minutes. Then cool the solution thoroughly and add dilute sulphuric acid until the precipitation of the... 

Hydrolysis of aspirin in H2 0 leads to no incorporation of into the product salicylic acid, ruling out the anhydride as an intermediate and thereby excluding mechanism 1. The general acid catalysis of mechanism III can be ruled out on the basis of failure of other nucleophiles to show evidence for general acid catalysis by the neighboring carboxylic acid group. Because there is no reason to believe hydroxide should be special in this way, mechanism III is eliminated. Thus, mechanism II, general base catalysis of hydroxide-ion attack, is believed to be the correct description of the hydrolysis of aspirin. 

The hydrolysis of aspirin [Eq. (6-70), R = CH3] is a classic example demonstrating a sigmoid pH-rate effect. Figure 6-13 shows this curve for trimethyl-... 

To conclude this section, we shall consider a more complex example, the pH effects on the hydrolysis of aspirin, acetylsalicylic acid.14,16 The pH profile is given in Fig. 6-4 for the reaction and rate law... 

The pH profile for the hydrolysis of aspirin. The numbers designate four regions for the respective terms in the rate law, Eq. (6-104). 

Since reproducibility of the flow system is critical to obtaining reproducibility, one approach has been to substitute lower-performance columns (50-to 100-p packings) operated at higher temperatures.1 Often, improvements in detection and data reduction can substitute for resolution. Chemometric principles are a way to sacrifice chromatographic efficiency but still obtain the desired chemical information. An example of how meaningful information can be derived indirectly from chromatographic separation is the use of system or vacancy peaks to monitor chemical reactions such as the titration of aniline and the hydrolysis of aspirin to salicylic acid.18... 

PK Banerjee, GL Amidon. Physicochemical Property modification strategies based on enzyme substrate specificities II Alpha-chymotrypsin hydrolysis of aspirin derivatives. J Pharm Sci 70 1304, 1981. 

He also observed that aspirin was easily split in weakly alkaline medium which had consequences for the metabolism (see Section 7). One could say that he established the first profile for the pH dependence of hydrolysis of aspirin. Of course, the definition of pH was unknown at the time. 

The next systematic study of the hydrolysis of aspirin in water, albeit at 100° C., was undertaken by Rath172 who determined a hydrolysis constant of about 0.17 depending on experimental conditions. 

Much work has been done since, and it is quite evident that this seemingly simple hydrolysis to acetic and salicylic acids is both complex and controversial. I am fortunate that I can refer the reader to the excellent and detailed review by Clark A. Kelly151 already mentioned in Section 5.61. The most complete and thorough kinetic studies of the factors involved in the hydrolysis of aspirin are undoubtedly those by Edwards17 3, which were further elaborated by Garrett.174... 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

G. Ahbrandi, N. Micab, S. Trusso, A. Villari, Hydrolysis of Aspirin Studied by Spec-trophotometric and Fluorometric Variable-Temperature Kinetics , J. Pharm. Sci. 1996, 85, 1105-1108. 

A sample of aspirin of accurately known mass is reacted with a known excess amount of sodium hydroxide solution. The alkali first catalyses the hydrolysis of aspirin to ethanoic acid and salicylic acid (2-hydroxybenzoic acid) and then neutralises these acids. The overall balanced equation for the reaction is ... 

Many examples are present in the scientific Uterature underlining the effort in producing kinetic data [9—11]. The Edwards historical study that started the investigation on the mechanism of the hydrolysis of aspirin required hundreds of kinetic experiments [12,13]. Several examples are reported by Carstensen [1] in his review on the subject where, beside the large space dedicated to the determination of the pH-rate profile, the effect of temperature, ionic strength, buffer concentration, and dielectic constant on the stability of drugs was treated. 

FIGURE 10 Change in fluorescence intensity (solid line 404 nm) during hydrolysis of aspirin (pH 7.00) in variable-temperature kinetic experiment. M T(K) = 323.05 + 1.631 x 10 3f (dashed line). 

FIGURE 14 Change in absorbance (solid line) during a VpHK experiment concerning hydrolysis of aspirin at T = 342.5 , X = 298.5 nm. The dotted line shows the variation of pH. M not known analytically. 

Figure 14 shows the variable-pH kinetic (VpHK) profile obtained spectrophoto-metrically for the reaction of hydrolysis of aspirin with pH varying in the range 2-10 at T = 342.5 K. The variable-concentration conditions were realized by adding a concentrated solution of NaOH (0.6 M) to the thermostatted reaction vessel containing the aqueous solution of acetylsahcylic acid and a buffer composed of acetic acid (0.01 M), fosforic acid (0.01 M), and boric acid (0.01 M). In this way an almost linear increase of pH was generated. The absorbance was read by an optical fiber cell and stored in a computer. The pH was monitored by a pH sensor connected to a computer. 

Edwards, L. J. (1950), The hydrolysis of aspirin. A determination of the thermodynamic dissociation constant and a study of the reaction kinetics by ultraviolet spectrophotometry, Trans. Faraday Soc., 46,723-735. 

Alibrandi, G., Micali, M., Trusso, S., and Villari, A. (1996), Hydrolysis of aspirin studied by spectrophotometric and fluorometric variable-temperature kinetics, I. Pharm. Sci., 85, 1105-1108. 

A typical example of an intramolecularly catalyzed reaction is the hydrolysis of aspirin (equation 2.15).12 The hydrolysis of the ester bond is achieved by intramolecular general-base catalysis. Comparison with the uncatalyzed hydrolysis rate of similar compounds gives a rate enhancement of some 100-fold from the catalysis.13 This may be extrapolated to a figure of 5000-fold if the pKa of the base is 7 rather than the value of 3.7 in aspirin. 

Fig. 11.1 pH profile for the hydrolysis of aspirin at 25°C the line is drawn from Equation 11.1 using experimental kinetic parameters from reference [1 ] the dotted line is the curve calculated without inclusion of the ko term. 

Equation 11.1 relates to the particular case of the catalysed hydrolysis of aspirin. More generally, we may write Equation 11.2 for the catalysed pseudo-first-order reaction (for example) of substrate HS ... 

Figure 2 Hydrolysis of aspirin to acetic and salicylic acid.

Ball MC. Solid-state hydrolysis of aspirin. J Chem Soc Faraday Trans 1994 90 997-1001. 

FIGURE 5.4 Hydrolysis of aspirin in an aqueous suspension at 34°C. [Graph reconstructed from data by K. C. James, J. Pharm. Pharmacol., 2, 363 (1958).]... 

The hydrolysis of aspirin in aqueous suspension is zero-order. Aspirin was suspended in an aqueous solution, which was maintained at pH 2.5. The amount of aspirin suspended initially was 70 g/L. After 2 weeks, a 5 ml aliquot of the suspension was withdrawn and found by analysis to contain 0.3375 g aspirin, (a) What is the rate constant for the hydrolysis of aspirin in suspension, expressed in g/L/day (b) How long will it take for 10% of the aspirin suspended initially to hydrolyze (c) After 50% of the aspirin suspended initially is hydrolyzed, how much additional time is required for 50% of the remaining aspirin to hydrolyze ... 

It is interesting to take notice of the effect of an aromatic carboxylic acid group on hydrolysis. The effects of pH on the hydrolysis of aspirin and aspirin methyl ester have been investigated. 

FIGURE 5.31 pH-rate constant profiles for the hydrolysis of aspirin (dotted line) and aspirin methyl ester (solid line). [Graph reconstructed from data by G. M. Loudon, J. Chem. Ed., 68, 973 (1991).]... 

FIGURE 5.41 pH-rate constant profile for the hydrolysis of aspirin in 0.5% aqueous ethanol solution at four temperatures. [Graph simulated from data by E. R. Garret, J. Am. Chem. Soc., 79, 3401 (1957).]... 

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