Hydrolysis acetylsalicylic acid

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... 

The case of intramolecular participation in ester hydrolysis has been extensively studied using acetylsalicylic acid (aspirin) and its derivatives. The kinetic data show that the anion is hydrolyzed more rapidly than the neutral species, indicating that the carboxylate group becomes involved in the reaction in some way. Three mechanisms can be considered ... 

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... 

Fig. 5 (a) The pH versus log hydrolysis rate constant profile of idoxuridine at 60°C (solid line). The dashed lines indicate the individual contributions of each kinetic term, (b) pH versus log hydrolysis rate constant profile of acetylsalicylic acid (solid line). The dashed lines indicate the individual contribution of each kinetic term. Adapted from Refs. 105 and 106. 

Apparently similar flowstream universal buffers have been developed by Alibrandi and others [128,129] for assessing kinetic parameters, such as the pH-dependent hydrolysis of acetylsalicylic acid. The pH-time curves are not as linear as in the SGA system. Other reports of continuous flow pH gradient spectrophotometric data have been described, with application to rank-deficient resolution of solution species, where the number of components detected by rank analysis is lower than the real number of components of the system [130]. The linear pH-time gradient was established in the flowstream containing 25 mM H3PO4 by the continuous addition of 100 mM Na3P04. 

Esterases form a wide family of enzymes that catalyze the hydrolysis of ester bonds. They are ubiquitously expressed in all tissues including the intestine, and are found in both microsomal and cytosolic fractions. Prueksaritonont et al. [6] have studied the metabolism of both p-nitrophenol acetate and acetylsalicylic acid by esterases from human intestinal microsomal and cytosolic systems, and the activity values were 2.76 pmol min-1 mg-1 and 0.96 nmol min-1 mg-1, respectively. Thus, the activity for the hydrolysis of p-nitrophenol acetate in human intestine approaches that in the liver. 

Equations The aspirin is titrated with sodium hydroxide so as to neutralize any free acid formed by hydrolysis of the acetylsalicylic acid as shown by the following equation ... 

The hydrolysis of acetylsalicylic acid (aspirin) has also been described, and it involves the rapid acetylation of Lys199 [123], This reactive site also involves Trp214 and has been called the U-site [124], Drugs that inhibit the hydrolysis of substituted acetylsalicylic acids by HSA and decrease the fluorescence intensity of Trp214 are referred to as U-type drugs (e.g., sulfinpyrazone and warfarin). Because U-type drugs also bind to the site know as site I (which overlaps with subdomain IIA), the U-site and I-site are believed to overlap. Lysine residues also appear to be involved in the /3-lactamase activity of HSA [125],... 

A simple compound to begin our presentation is acetylsalicylic acid (aspirin, 7.44), the well-known analgesic and anti-inflammatory drug whose primary metabolite, salicylic acid (7.45), is also an anti-inflammatory agent but not an analgesic. Extensive kinetic data have been published on the chemical hydrolysis of acetylsalicylic acid as a function of temperature and... 

A variety of hydrolases catalyze the hydrolysis of acetylsalicylic acid. In humans, high activities have been seen with membrane-bound and cytosolic carboxylesterases (EC 3.1.1.1), plasma cholinesterase (EC 3.1.1.8), and red blood cell arylesterases (EC 3.1.1.2), whereas nonenzymatic hydrolysis appears to contribute to a small percentage of the total salicylic acid formed [76a] [82], A solution of serum albumin also displayed weak hydrolytic activity toward the drug, but, under the conditions of the study, binding to serum albumin decreased chemical hydrolysis at 37° and pH 7.4 from tm 12 1 h when unbound to 27 3 h for the fully bound drug [83], In contrast, binding to serum albumin increased by >50% the rate of carboxylesterase-catalyzed hydrolysis, as seen in buffers containing the hydrolase with or without albumin. It has been postulated that either bound acetylsalicylic acid is more susceptible to enzyme hydrolysis, or the protein directly activates the enzyme. 

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... 

Salicin is an (9-glycoside of a phenol, namely salicyl alcohol. Salicin is a natural antipyretic and analgesic found in willow bark, and is the template from which aspirin (acetylsalicylic acid, see Box 7.13) was developed. Prunasin from cherry laurel is an example of a cyanogenic glycoside, hydrolysis of which leads to release of toxic HCN (see Box 7.7). It is the (9-glucoside of the alcohol mandelonitrile, the trivial name for the cyanohydrin of benzaldehyde. It is the further hydrolysis of mandelonitrile that liberates HCN. 

Ester hydrolysis does not invariably lead to inactive metabolites, as exemplified by acetylsalicylic acid. The cleavage product, salicylic acid, retains pharmacological activity. In certain cases, drugs are administered in the form of esters in order to facilitate absorption (enalapril enalaprilate testosterone undecanoate testosterone) or to reduce irritation of the gastrointestinal Lullmann, Color Atlas of Pharmacology... 

Phenprocoumon Phenprocoumon, 3-(a-ethylbenzyl)-4-hydroxycoumarin (24.1.14), is synthesized by acylating sodium salts of diethyl ester (l-phenylpropyl)butyric acid with acetylsalicylic acid chloride, which forms the compound 24.1.12, which upon reaction with sodium ethoxide cyclizes to 3-(a-ethylbenzyl)-2-carboethoxy-4-hydroxycoumarin (24.1.13). Alkaline hydrolysis of this product and further decarboxylation gives phenprocoumon (24.1.14) [21-28]. 

System suitability is part of method validation. Experience gained during method development will give insights to help determine the system suitability requirements of the final method. An example is the hydrolysis of acetylsalicylic acid to salicylic acid in acidic media. Separation of this degradation peak from the analyte could be one criterion for the system suitability of an acetylsalicylic acid assay. 

Figure 7.57 The metabolism of aspirin (acetylsalicylic acid). Step 1 (hydrolysis) yields the major metabolite, salicyclic acid, which is conjugated with glucuronic acid (pathways 2 and 4) or glycine (pathway 3). All these three pathways (2, 3, and 4) are saturable.

Drugs in solution formulations may be more susceptible to chemical reactions leading to degradation. The most common reactions are hydrolysis, oxidation, and reduction. Usually, the reaction rate or type is inLuenced by pH. For example, the hydrolysis of acetylsalicylic acid (aspirin) is pH dependent, and its pH-rate proLle shows a large and complex variation dfrls to four distinct mechanistic patterns (Alibrandi et al., 2001). Therefore, it is essential to monitor and understand the chemical stability of the drug in pH-adjusted formulations. 

Alkaline hydrolysis rates of a series of thiophenyl 4-X-benzoates (47 X = H, Me, N02) was significantly enhanced in the presence of cyclodextrins (CDs), and this was attributed to strong binding of the benzoyl moiety within the CD cavity and covalent catalysis by secondary hydroxy groups of the CDs (48).63 The effect of MeCN and MeOH on the alkaline hydrolysis of acetylsalicylic acid in aqueous micellar solutions was reported.64 Butylaminolysis of p-nitrophenyl acetate in chlorobenzene in the presence of different kinds of phase-transfer catalysts (crown ethers and gly-mes) supported the existence of a novel reaction pathway exhibiting a first-order dependence on the concentration of the phase-transfer catalyst and a second-order... 

Blood and various organs of humans and other animals contain esterases capable of acetylsalicylic acid hydrolysis. A comparative study has shown that the liver is the most active tissue in all animal species studied except for the guinea pig, in which the kidney is more than twice as active as the liver. Human liver is least active the enzyme in guinea pig liver is the most active. The relatively low toxicity of some of the new synthetic pyrethroid insecticides appears to be related to the ability of mammals to hydrolyze their carboxyester linkages. Thus mouse liver microsomes catalyzing (+)-/runs-resin e 111ri n hydrolysis are more than 30-fold more active than insect microsomal preparations. The relative rates of hydrolysis of this substrate in enzyme preparations from various species are mouse > > milkweed bug > > cockroach > > cabbage looper > housefly. 

Ester hydrolysis R,COOR2 R,COOH + HOR2 Acetylsalicylic acid... 

Acetylsalicylic acid (aspirin) (pKa= 3.62) undergoes acid-base catalyzed hydrolysis. The pseudo-first-order rate constants were determined at four different temperatures (25, 35, 50.3, and 60.3°C) as shown in Figure 5.41. The hydrolysis of aspirin follows Equation (5.167) with k0o = 0 and k0 = 0. Each rate constant is given by ... 

Anionic micellar systems were found to increase the rate of the acid catalyzed hydrolysis of acetylsalicylic acid (Nogami et al., 1962), methantheline bromide (Nogami and Awazu, 1962), n-butyl acetate, t-butyl acetate, ethyl p-aminobenzoate, and ethyl o-aminobenzoate (Sakurada et al., 1967), but decreased that of methyl benzoate slightly (Sakurada et al., 1967). The acid catalyzed hydrolysis of anionic amphi-philes also generally tend to be accelerated by micellization (Table 5). The rates of the acid catalyzed hydrolyses of sodium sulfoethyl do-decanoate, sodium undecanoate, and sodium sulfobutyl caprylate are significantly greater in micellar than in non-micellar solutions while that of sodium dodecyl sulfoacetate is unaffected by micelle formation (Meguro and Hikota, 1968). 

The reaction you have just executed is an organic reaction known as an acid-catalyzed hydrolysis. The suffix -lysis means to cut, and hydrolysis means to cut with water. In this reaction, acetylsalicylic acid is cut with water to form salicylic acid and acetic acid, as shown in figure 2.1.1. 

Dmgs that contain ester linkages include acetylsalicylic acid (aspirin), physostigmine, methyldopate, tetracaine and procaine. Ester hydrolysis is usually a bimolecular reaction involving acyl-oxygen cleavage. For example, the hydrolysis of procaine is shown in Scheme 4.2. 

Hydrolysis is a major biotransformation pathway for drugs containing an ester functionality. This is because of the relative case of hydrolyzing the ester linkage. A classic example of ester hydrolysis is the metabolic conversion of aspirin (acetylsalicylic acid) to salicylic acid. " Of the two aslcr moieties present in cocaine, it appears that, in general, the methyl group is hydrolyzed preferentially to yield ben-roylecgoninc os the major human urinary metabolite. The... 

Figure 8 Hydrolysis of acetylsalicylic acid (aspirin) to acetic acid and salicylic acid (a phenolic acid) by carboxylesterase activity.

Acetylsalicylic acid Tablets Microwave-assisted analyte hydrolysis UV-Vis 4.0 pg mL-1 Flow injection system merging zones in-line microwave-assisted alkaline hydrolysis of acetylsalicylic acid to salicylic acid that reacts with Fe(III) to form a coloured complex [414]... 

A.V. Pereira, C. Aniceto, O. Fatibello-Filho, Flow injection spectrophotometric determination of acetylsalicylic acid in tablets after on-line microwave-assisted alkaline hydrolysis, Analyst 123 (1998) 1011. 

In other reactions of starch esters, for example, 2,3-di-O-acetylamylose reacted with A-iodosuccinimide in the presence of triphenylphosphine to give 2,3-di-0-acetyl-6-deoxy-6-iodoamylose.2019 The ester bonds are fairly stable to acid-catalyzed hydrolysis. Starch esterified with acetylsalicylic acid administered to dogs did not increase the acetylsalicylic acid level to any significant extent in the animal s blood serum.2020 The slow release of herbicides from their esters with starch was analyzed.2021,2022 Alkaline hydrolysis of starch esters is easier than acid hydrolysis.2023 The enthalpy of starch acetate formation was 143.5kJ/mole, and acetylation decreased the susceptibility of the starch backbone to enzymatic hydrolysis and iodine uptake.2024 The hydrolysis of starch and starch acetate in alkaline solutions obeys second-order kinetics.1988... 

Ancient peoples used salicin to reduce fevers. Write an equation for the acid-catalyzed hydrolysis of the O-glycosidic bond of salicin. Compare the aromatic product with the structure of acetylsalicylic acid (aspirin). Use this information to develop a hypothesis explaining why ancient peoples used salicin to reduce fevers. 

M. J. Habib and J. A. Rogers, Hydrolysis and stability of acetylsalicylic acid in stearylamine-containing liposomes, J. Pharm. Pharmacol. 45,496-499 (1992). 

---