Benzylpenicillin degradation

The second-order rate constant k for the catalysed degradation of penicillin with an ionised carboxyl at C(3) is 0.354M s at 30°C compared with 8.2 x 10 M s for benzylpenicillin methyl ester. This rate difference of 4-fold is insignificant. The calculated first-order rate constant Atq for undissociated benzylpenicillin degradation is 10-fold greater than that for the methyl ester of benzylpenicillin. This is also probably too small to be indicative of intramolecular catalysis by the carboxyl group. 

The early investigations of the reactions of the penicillin class of compounds were largely of a degradative nature, and were primarily associated with structure elucidation. These have been discussed in detail (B-49MI51102) and some of the principal transformations are outlined in Schemes 2, 3 and 4 using benzylpenicillin as an example. Some of these reactions will be discussed in greater detail later in this section. 

Lindblom and Blander (1980) have given a number of examples of relevance in the pharmaceutical industry. These include C-alkylations, 0-alkylations, and A-alkylations. The C-alkylation of phenylacetonitrile, (mono- and di-) alkylation of benzylpenicillin with a-chlorodiethyl carbonate (where the acid part and the halide part in the esterification would have degraded quickly under normal conditions adopted for the reaction), A-alkylation of purines and adenine, etc. are discussed at some length and the supremacy of PTC is clearly shown. 

Korany et al. [28] used Fourier descriptors for the spectrophotometric identification of miconazole and 11 different benzenoid compounds. Fourier descriptor values computed from spectrophotometric measurements were used to compute a purity index. The Fourier descriptors calculated for a set of absorbencies are independent of concentration and is sensitive to the presence of interferents. Such condition was proven by calculating the Fourier descriptor for pure and degraded benzylpenicillin. Absorbance data were measured and recorded for miconazole and for all the 11 compounds. The calculated Fourier descriptor value for these compounds showed significant discrimination between them. Moreover, the reproducibility of the Fourier descriptors was tested by measurement over several successive days and the relative standard deviation obtained was less than 2%. 

Semisolid Dosage Forms The nature of the base (vehicle) used for the fabrication of semisolid dosage forms affects their hydrolytic stability. Increased degradation of benzylpenicillin sodium in hydrogels of various natural and semisynthetic polymers has been reported [14]. Also at pH 6 in Carbopol hydrogels, the percentage of undecomposed pilocarpine at equilibrium is a function of the apparent viscosity of the medium [15]. 

Many dmgs associate to form micelles in aqueous solution (see section 6.3) and several smdies have been reported of the effect of this self-association on stability. In micellar solutions of benzylpenicillin (500 000 units cm ) the apparent rate of the hydrogen-ion-catal-ysed degradation was increased twofold, but that of water- and hydroxide-ion-catalysed hydrolysis was decreased twofold to threefold. Consequently, the pH profile was shifted to higher pH values and the pH of minimum degradation was found to be 7.0 compared to 6.5 for monomeric solution (8000 units cm ). When compared at the respective pH-rate profile minima, micellar benzylpenicillin was reported to be 2.5 times as stable as the monomeric solutions under conditions of constant pH and ionic strength. 

Fig. 10.3 Degradation products of benzylpenicillin in solution A, penicilloic acid B, penicillenic acid C, penillic acid.

The interaction of a non-enzymatic degradation product, D-benzylpenicillenic acid (formed by cleavage of the thiazolidine ring of benzylpenicillin in solution see Fig. 10.3B), with sulphydryl or amino groups in tissue proteins, to form hapten-protein conjugates, is also of importance. In particular, the reaction between D-benzylpenicillenic acid and the e-amino group of lysine (a,e-diamino- -caproic acid, NH2(CH2)4.CH(NH2).COOH) residues... 

Penicilloic acids (III) react instantly in aqueous solution with mercuric chloride 19d giving penicillamine (VII) and penaldic acid (VI). Penaldic acids decarboxylate rapidly to form the corresponding penilloaldehyde (VIII). This degradation forms the basis for a sensitive analytical method for benzylpenicillin. ... 

Figure 83. Effect of ionic strength on degradation rates described by Eq. (2.108). , Benzylpenicillin, pH 8.75, 60°C o, carbenicillin, pH 10.47,35°C. (Reproduced from Refs. 382 and 394 with permission.)...

In 1929, Fleming discovered that the mould Penicillium notatum inhibits the growth of bacteria. In 1941 Florey and Chain succeeded in isolating the active agent, known as penicillin, in the form of its sodium salt. The structural elucidation was achieved by chemical degradation and was confirmed in 1945 by X-ray analysis of penicillin G (benzylpenicillin). The structures were shown to be (3/S,5i ,6/ )-6-(acylamino)-2,2-dimethyl-7-oxopenam-3-carboxylic acids ... 

The amounts of penicilloylated proteins in commercial benzylpenicillin and semisynthetic penicillins seem to vary considerably. Whereas up to 200-300 parts/ 10 of penicilloy 1-protein in benzylpenicillin preparations were reported by Batchelor et al. (1967) and also by Butcher and Stewart (1970), other groups have only detected less than 10 parts/10 of proteinaceous impurities in commercial benzylpenicillin (Dursch 1968 Preud homme and Lunel 1969 Weidenmuller and Ziegler 1970 Walsh et al. 1971 Ottens et al. 1971 Vilim et al. 1976). As described by Ottens et al. (1971), the methods used for the determinations, i.e., dialysis, membrane filtration, and gel filtration followed by penicilloyl and protein analysis, have several drawbacks. Penicillin degradation products and polymers were found to influence the determinations, making these somewhat unreliable. 

Fig.3. Dimerization of benzylpenicillin (/ = benzyl) via reactions between the degradation products benzylpenicillenic acid and benzylpenicilloic acid...

Bundgaard and Larsen (1978 a) have studied the kinetics and mechanism of the sucrose-accelerated degradation of benzylpenicillin and a number of semisyn-... 

Fig. 15. pH-rate profiles for the degradation of benzylpenicillin in aqueous solution (7) and for the degradation due to glycerol (2), sorbitol (J), and sucrose (4) all at a concentration of 10% W/V, at 35 °C k denotes a pseudo-first-order rate constant for penicillin degradation. (Bundgaard and Larsen 1978 b)... 

Recently, penicillamine has been detected in neutral benzylpenicillin solutions and shown to be a degradation product of penicillenic acid at neutral pH (Jemal et al. 1978). 

Bundgaard H, Larsen C (1978 a) Kinetics and mechanism of the sucrose-accelerated degradation of penicillins in aqueous solution. Int J Pharm (Amst) 1 95-104 Bundgaard H, Larsen C (1978 b) Kinetics and mechanism of reaction of benzylpenicillin and ampicillin with carbohydrates and polyhydric alcohols in aqueous solution. Arch Pharm Chem Sci 6 184-200... 

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