Paracetamol hydrolysis

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

Most of the hemiesters 8.136 underwent no or little enzymatic degradation in human plasma, in agreement with the known inertness of hemiesters toward cholinesterase (see Chapt. 7). In contrast, very rapid hydrolysis was usually seen in pig and rat liver preparations, indicating the involvement of carboxylesterases. The only inert compound was the 3,3-dimethylglutarate hemiester of paracetamol (8.136, X = C(CH3)2CH2, Fig. 8.12). Data on the hydrolysis of such prodrugs by human hepatic enzymes will be welcome. 

The hydrolysis of some amides may be catalyzed by a liver microsomal carboxyl esterase, as is the case with phenacetin (Fig. 4.44). Hydrolysis of the acetylamino group, resulting in deacetylation, is known to be important in the toxicity of a number of compounds. For example, the deacetylated metabolites of phenacetin are thought to be responsible for its toxicity, the oxidation of hemoglobin to methemoglobin. This toxic effect occasionally occurs in subjects taking therapeutic doses of the drug and who have a deficiency in the normal pathway of metabolism of phenacetin to paracetamol. Consequently, more phenacetin is metabolized by deacetylation and subsequent oxidation to toxic metabolites (chap. 5, Fig. 24). 

This manifold has been used for the USALLE of paracetamol from suppositories [17]. Hydrolysis of the analyte prior to reaction with o-cresol in the alkaline extractant medium was also favoured by US (the entire sample plug was irradiated in EC). Hydrolysis and formation of the reaction product displaced the extraction equilibrium, thus favouring extraction into the aqueous phase. The influence of the variables related to the dynamic manifold (namely, flow rate and sample volume), chemical variables (namely, NaOH and o-cresol concentrations) and temperature was studied using the univariate method on account of their independence on the other hand, those related to US (namely, probe position, radiation amplitude and pulse duration) were the subject of a multivariate study in which the latter two exhibited an insignificant but positive effect. Positioning the probe closest to the extraction coil was found to maximize extraction efficiency. The positive effect of US on extraction and analyte hydrolysis provides the overall enhancement shown in Fig. 6.4A, which shows the results obtained in the presence and absence of US. The time required for the development of the method was significantly shorter than that required by the United States Pharmacopoeia (USP) method. In addition, the latter produces emulsions that need about 30 min for phase separation after extraction. 

Although the earliest examples of the use of US as a substitute for phase transfer catalysts in organic addition reactions were reported more than two decades ago and a number of such reactions have since been improved as a result [1-7], the sole analytical application exploiting this potential is a method for the determination of paracetamol where the drug is derivatized by hydrolysis to p-aminophenol, which reacts with o-cresol in an alkaline medium to form the Indophenol Blue dye, according to the following reaction ... 

One of the few recent examples of this reaction is the hydrolysis of paracetamol simultaneously with its LLE into an alkaline medium from suppositories [32]. Separate development of each step showed the yield of the derivatizing reaction to be higher when the hydrolysis step is assisted by US (absorbances were five times higher than with non-sonicated hydrolysis). 

Intramolecular cyclizations are not restricted to attack by a nucleophilic nitrogen (basic amino or acidic amido group). They can also be catalyzed by a nucleophilic oxygen as found in a carboxylate, phenolic, or alcoholic group. Illustration of the catalytic role of a carboxylate group can be found in hemiester prodrugs of phenol (taken as model compound) or paracetamol (Fig. 6 R = H or NHCOCH3, respectively). In addition to enzymatic hydrolysis, three mechanisms of chemical hydrolysis were seen, namely, acid-catalyzed, base-catalyzed, and an intramolecular nucleophilic attack. 

Many examples of the effects of tablet excipients on dmg decompositions are reported in the pharmaceutical literature. Chemical interaction between components in solid dosage forms may lead to increased decomposition. Replacement of the phenacetin in compound codeine and ARC tablets by paracetamol in NHS formulations in Australia in the 1960s (because of the undesirable side-effects of phenacetin), led to an unexpected decreased stability of the tablets. The cause was later attributed to a transacetylation reaction between aspirin and paracetamol and also a possible direct hydrolysis of the paracetamol (Scheme 4.15). 

Scheme 4.15 Reactions showing the postulated transacetylation between aspirin and paracetamol and the direct hydrolysis of paracetamol.

Aspirin is a carboxylic acid derivative, while paracetamol is a substituted phenol. Addition of a strong base (e.g. sodium hydroxide) would result in ionisation of both acids (and some hydrolysis of the aspirin). To separate the acids successfully, a discriminating base must therefore be used, which is formed from an acid intermediate in strength between carboxylic acids and phenols. Such an acid is carbonic acid (H2COs) and addition of sodium bicarbonate solution will result in ionisation of the aspirin as the sodium salt. This salt will be water soluble and may be removed in the lower phase. Addition of fresh organic solvent and dilute hydrochloric acid solution will yield aspirin as free acid. 

Paracetamol Pharmaceutical formulations Microwave-assisted alkaline hydrolysis yielding p-aminophenol UV—Vis 0.2 pg ml. 1 Flow injection system reaction of [436] p-aminophenol with 8-hydroxyquinoline in the presence of KIO4 yielding a blue indophenol dye de-bubbler prior to the flow cell... 

Paracetamol Suppositories Ultrasound-assisted LLE and alkaline hydrolysis UV—Vis 0.38 pg ml. 1 Flow injection system LLE without [149] phase separation iterative change of the flow direction to improve extraction/ hydrolysis organic phase inserted as a plug before detection... 

Paracetamol Pharmaceutical formulations Microwave-assisted alkaline hydrolysis yielding p-aminophenol UV-Vis 0.2 pg mL 1 Flow injection system sample stopping [437] inside the microwave oven reaction of p-aminophenol with o-cresol in alkaline medium yielding a blue compound the solution leaving the oven flows through a coil inside an ice-bath gas-phase removed prior to the colour-forming reaction... 

Liquid—liquid extraction, as exemplified by the spectrophotometric determination of paracetamol in suppositories [149] without phase separation (8.5.1.3). A pronounced speeding up of analyte extraction and hydrolysis was attained with several iterative flow reversals. 

F. Priego-Capote, M.D. Luque de Castro, Ultrasound-assisted continuous liquid—liquid extraction without phase separation and hydrolysis of paracetamol in suppositories, Anal. Chim. Acta 489 (2003) 223. 

Z. Bouhsain, S. Garrigues, A. Morales-Rubio, M. de la Guardia, Flow injection spectrophotometric determination of paracetamol in pharmaceuticals by means of on-line microwave-assisted hydrolysis and reaction with 8-hydroxyquinoline (8-quinolinol), Anal. Chim. Acta 330 (1996) 59. 

A. Criado, S. Cardenas, M. Gallego, M. Valcarcel, Continuous flow spectrophotometric determination of paracetamol in pharmaceuticals following continuous microwave assisted alkaline hydrolysis, Talanta 53 (2000) 417. 

Para-nitrophenol (PNP) is an essential starting material for existing technologies used in the production of analgesics such as N-acetylpara-aminophenol (APAP) (paracetamol). It is usually obtained either by direct nitration of phenol (eq.l) or by the sequence involving the nitration of chlorobenzene and the subsequent hydrolysis of para-nitrochlorobenzene (PNCB)(eq.2)[ 1 ]. 

EC oxidation is commonly employed in the analysis of some basic drugs, especially morphine and related opioids (Chapter 6, Section 1). Even if a compound is not amenable to EC oxidation, its metabolites may be. Phase I metabolism of aromatic xenobiotics often proceeds with aromatic hydroxylation. Hydrolysis of phenolic esters, reduction of diazo double bonds to primary amines and other reactions also occur. EC detection is not widely used to measure acidic or neutral compounds, such as salicylate or paracetamol after overdosage, since these compounds, although easily oxidised, are normally present at relatively high concentrations and UV detection is adequate. However, EC methods may be useful in measuring the plasma concentrations of these compounds attained after a single oral dose. ... 

Examples of substances that are prone to hydrolysis are acetylsalicylic acid, ampicillin, barbiturates, chloramphenicol, chlordiazepoxide, cocaine, corticosteroid phosphate or succinate esters, proteins, folinic acid, indomethacin, local anaesthetics, paracetamol (acetaminophen), pilocarpine, tropa alkaloids (atropine, scopolamine), xylomethazoline and the antimicrobial preservatives methyl and propyl parahydroxybenzoate. In the field of oncology, melphalan and bendamustine hydrochloride are highly susceptable to hydrolysis with a shelf life of 1.5 h for melphalan and 3.5 h for bendamustine at room temperature. 

The plasma level of paracetamol can be determined by gas-liquid chromatography, by its UV absorption spectrum following extraction, and by its colorimetric reaction with nitrous acid to form a yellow coloured nitrophenol (the Glynn and Kendal method). Paracetamol can be detected in urine by a screening test which consists of its hydrolysis to /7-aminophenol, followed by its reaction with o-cresol and ammonia to form a blue in-dophenol. 

Under addic conditions (pH 1) at room temperature, aspirin hydrolyses in a few horns whereas paracetamol can be stored at room temperature rmder acidic conditions (pH 1) for many days without much hydrolysis occurring. We will return to the properties of esters and amides in a little more detail in Chapters 3 and 4. 

A variation on the basic hydrolysis process is transesterifl-cation which is a widespread process in biological systems (c.f. the action of aspirin, choline esterase inhibitors and phosphorylation of proteins) but can also occur in vitro. In this case, the ester transfers the acyl group to the base carrying out the hydrolysis. Thus, for instance, if the base is paracetamol, as has been observed in mixtures of aspirin and paracetamol, acetylated paracetamol is produced (Fig. 5.38). 

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