Penicillin acid degradation

Clavulanic acid protects penicillins from degradation by inactivating a wide range of beta-lactamase enzymes... 

The chemical structure of the penicillins remained in doubt throughout the war years despite considerable efforts and much speculation by a group led by Karl Folkers at Merck, and the Oxford group comprising Robert Robinson, Chain, Abraham and others. One of the major problems was that the initial microanalysis had not revealed the presence of a sulfur atom, and it was not until penicillamine was revealed in 1943 as the major acid degradation products of all the known penicillins that realistic structures could be... 

In acidic media the picture is different. Cationic (CTAB) and a non-ionic surfactant (Ci 2 E23) reduced the degradation of several penicillins by a factor of 4 to 12, while an anionic surfactant (NaLS) increased the rate [141]. In all cases the rate constants first increased or decreased rapidly and then approached a constant value above the solubilizer CMC. In contrast to the penicillins, the acid degradation of cefazolin, a relatively acid-unstable cephalosporin, was not influenced by the presence of any of the surfactants, suggesting that this antibiotic is not sufficiently bound to any of the surfactant micelles. The log P values for the affected penicillins (at pH 2.1) are in the range 2.7 (propicillin) to 1.70 (penicillin G) while that of cefazolin is 0.39. It is fairly clear that stabilization of the pencillins is the result of the decreased hydrogen ion activity in the vicinity of the cationic head groups of the micelles. Results for propicillin are shown in Fig. 11.22. 

Degradation. Penicillins are rapidly hydroly2ed by aqueous alkaU to the corresponding peniciEoic acids (30) which are stable as salts, but which decarboxylate on acidification to yield penilloic acids (31). 

Penicillins are also degraded by aqueous acids via initial reaction of the sidechain carbonyl group with the P-lactam. PeniciEenic acids (33) are obtained when hydrolysis is carried out at pH 4, penillic acids (34) at pH 2. 

Some compounds exhibit pH behavior in which a bell-shaped curve is obtained with maximum instability at the peak [107]. The peak corresponds to the intersection of two sigmoidal curves that are mirror images. The two inflection points imply two acid and base dissociations responsible for the reaction. For a dibasic acid (H2A) for which the monobasic species (HA-) is most reactive, the rate will rise with pH as [HA-] increases. The maximum rate occurs at pH = (pA) + pK2)/2 (the mean of the two acid dissociation constants). Where an acid and base react, the two inflections arise from the two different molecules. The hydrolysis of penicillin G catalyzed by 3,6-bis(di-methylaminomethyl)catechol [108], is a typical example. For a systematic interpretation of pH-degradation profiles, see the review papers by van der Houwen et al. [109] and Connors [110]. 

The rate of acid-catalyzed degradation of the penicillins also depends largely on the nature of their acylamido side chain. Structure-activity-relationship studies undertaken for the rational design of orally active penicillins have shown that the stability in gastric juice increases with the sum of Taft s inductive substituent constants (of values) of the 6-amino side chain [95]. 

Fig. 5.7. The acid-catalyzed hydrolysis of penicillins involves first the formation of an acylium ion (5.22), which, by reacting with H20, yields penicil-loic acids 5.24 (Pathway b). The participation of a neighboring 6-acylamido group increases the rate of hydrolysis. During this intramolecular reaction (Pathway a), oxazolylthiazolidines (5.23) are formed and then give rise to the degradation products penicilloic acids 5.24, penicillenic acids 5.25,...

In cephalosporins, the C(6) position corresponds to C(5) in penicillins or penicilloic acids. During the degradation of cephalosporins, epimerization at C(6) is generally not observed. However, there are exceptions to this rule. An investigation of the degradation kinetics of cefdinir (5.39a, Fig. 5.11) and its C(7)-epimer (5.39b) in aqueous solution showed that, after /3-lactam ring... 

Examples of such an approach are found in the synthesis of strychnine [22] and morphine [23], labours which have been said to bear resemblance to Sysiphus s torment [24], since they involve linear sequences of more than 25 steps. However, the most illustrative example is found, perhaps, in the synthesis of penicillin (10 ). in the course of which the penicilloic acid derivative JJL was synthesised, though through a laborious and lenghty route. Because this intermediate was easily available from natural penicillin, it was convenient to resort to such a method of degradation in order to make it available in sufficient quantities for studying the last step -that requires the formation of a P-lactam- and thus accomplishing successfully the total synthesis [25]. 

The stability of several -lactam antibiotic in aqueous solutions is pH dependent. Optimum stability for monobasic penicillins in general is exhibited at pH 6-7, while for the amphoteric penicillins this coincides with the isoelectric point (18). A fast degradation occurs at both acidic and basic conditions. At pH 2.6, acid-labile -lactams such as penicillin G, methicillin, and nafcillin disappear almost completely while acid-resistant compounds like penicillin V and isoxazolyl penicillins survive (19). 

Various degradation products of penicillin G have been demonstrated in the cooked meat (21). The major product formed after cooking was identified as the lactate ester of penicilloic acid. Moreover, formation of bound residues was also suggested. 

---