Effect Of Nucleophilic Attack On Penicillin Stability

Figure 8.2 • Synthesis of phenoxymethylpenicillin.

crystalline material in use today. Crystalline penicillin must be protected from moisture, but when kept dry, the salts will remain stable for years without refrigeration. Many penicillins have an unpleasant taste, which must be overcome in the formation of pediatric dosage forms. All of the natural penicillins are strongly dextrorotatory. The solubility and other physico-chemical properties of the penicillins are affected by the nature of the acyl side chain and by the cations used to make salts of the acid. Most penicillins are acids with pKa values in the range of 2.5 to 3.0, but some are amphoteric. The free acids are not suitable for oral or parenteral administration. The sodium and potassium salts of most penicillins, however, are soluble in water and readily absorbed orally or parenterally. Salts of penicillins with organic bases, such as benzathine, procaine, and hydrabamine, have limited water solubility and are, therefore, useful as depot forms to provide effective blood levels over a long period in the treatment of chronic infections. Some of the crystalline salts of the penicillins are hygroscopic and must be stored in sealed containers.

The main cause of deterioration of penicillin is the reactivity of the strained lactam ring, particularly to hydrolysis. The course of the hydrolysis and the nature of the degradation products are influenced by the pH of the solution.18,19 Thus, the j-lactam carbonyl group of penicillin readily undergoes nucleophilic attack by water or (especially) hydroxide ion to form the inactive penicilloic acid, which is reasonably stable in neutral to alkaline solutions but readily undergoes decarboxylation and further hydrolytic reactions in acidic solutions. Other nucleophiles, such as hydroxyl-amines, alkylamines, and alcohols, open the j-lactam ring to form the corresponding hydroxamic acids, amides, and esters. It has been speculated20 that one of the causes of penicillin allergy may be the formation of antigenic penicil-loyl proteins in vivo by the reaction of nucleophilic groups (e.g., e-amino) on specific body proteins with the j-lactam carbonyl group. In strongly acidic solutions (pH <3), penicillin undergoes a complex series of reactions leading to various inactive degradation products (Fig. 8.3).19 The first step appears to involve rearrangement to the penicillanic acid. This process is initiated by protonation of the j-lactam nitrogen, followed by nucleophilic attack of the acyl oxygen atom on the j-lactam carbonyl carbon. The subsequent opening of the j-lactam ring destabilizes the thiazoline ring, which then also suffers acid-catalyzed ring opening to form the penicillanic acid. The latter is very unstable and experiences two major degradation pathways. The most easily understood path involves hydrolysis of the oxazolone ring to form the unstable penamaldic acid. Because it is an enam-ine, penamaldic acid easily hydrolyzes to penicillamine (a major degradation product) and penaldic acid. The second path involves a complex rearrangement of penicillanic acid to a penillic acid through a series of intramolecular processes that remain to be elucidated completely. Penillic acid (an imidazoline-2-carboxylic acid) readily decarboxyl-ates and suffers hydrolytic ring opening under acidic conditions to form a second major end product of acid-catalyzed penicillin degradation—penilloic acid. Penicilloic acid, the major product formed under weakly acidic to alkaline (as well as enzymatic) hydrolytic conditions, cannot be detected as an intermediate under strongly acidic conditions. It exists in equilibrium with penamaldic acid, however, and undergoes decarboxylation in acid to form penilloic acid. The third major product of the degradation is penicilloaldehyde, formed by decarboxylation of penaldic acid (a derivative of malonaldehyde).

By controlling the pH of aqueous solutions within a range of 6.0 to 6.8 and refrigerating the solutions, aqueous preparations of the soluble penicillins may be stored for up to several weeks. The relationship of these properties to the pharmaceutics of penicillins has been reviewed by Schwartz and Buckwalter.21 Some buffer systems, particularly phosphates and citrates, exert a favorable effect on penicillin stability, independent of the pH effect. Finholt et al.22 showed that these buffers may catalyze penicillin degradation, however, if the pH is adjusted to obtain the requisite ions. Hydroalcoholic solutions of penicillin G potassium are about as unstable as aqueous solutions.23 Because penicillins are inactivated by metal ions such as zinc and copper, it has been suggested that the phosphates and the citrates combine with these metals to prevent their existence as free ions in solution.

Oxidizing agents also inactivate penicillins, but reducing agents have little effect on them. Temperature affects the rate of deterioration; although the dry salts are stable at room temperature and do not require refrigeration, prolonged heating inactivates the penicillins.

Acid-catalyzed degradation in the stomach contributes strongly to the poor oral absorption of penicillin. Thus, efforts to obtain penicillins with improved pharmacokinetic and microbiological properties have focused on acyl functionalities that would minimize sensitivity of the j-lactam ring to acid hydrolysis while maintaining antibacterial activity.

Substitution of an electron-withdrawing group in the a position of benzylpenicillin markedly stabilizes the penicillin to acid-catalyzed hydrolysis. Thus, phenoxymethylpenicillin, a-aminobenzylpenicillin, and a-halobenzylpenicillin are significantly more stable than benzylpenicillin in acid solutions. The increased stability imparted by such electron-withdrawing groups has been attributed to decreased reactivity (nucleophilicity) of the side chain amide carbonyl oxygen atom toward participation in j-lactam ring opening to form penicillenic acid. Obviously, a-aminobenzylpenicillin (ampicillin) exists as the protonated form in acidic (as well as neutral) solutions, and the ammonium group is known to be powerfully electron-withdrawing.

Bacterial Resistance

Some bacteria, in particular most species of Gram-negative bacilli, are naturally resistant to the action of penicillins. Other normally sensitive species can develop penicillin resistance (either through natural selection of resistant individuals or through mutation). The best understood and, probably, the most important biochemical mechanism of penicillin resistance is the bacterial elaboration of enzymes that inactivate penicillins. Such enzymes, which have been given the nonspecific name penicillinases, are of two general types: j-lactamases and acylases. By far, the more important of these are the j-lactamases, enzymes that catalyze the hydrolytic opening of the j-lactam ring of penicillins to produce inactive penicilloic acids. Synthesis of bacterial j-lactamases may be under chromosomal or plasmid R factor control and may be either constitutive or inducible (stimulated by the presence of the substrate), depending on the bacterial species. The well-known resistance among strains of Staphylococcus aureus is apparently entirely because of the production of an inducible j-lactamase. Resistance among Gram-negative

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  • edward
    Which product is form when penillic acid on hydrolysis?
    2 years ago
  • tanja
    How does penicillin behave in acidic and basic solutions?
    2 years ago
  • togo
    Why acidic nature and ionic nature of penicilin are important?
    2 years ago
  • yusef mebrahtu
    Why is penicillin G unstabal to acid?
    1 year ago
  • bernardo
    Why penicillin g is unstable to acid?
    1 year ago
  • Liisi
    Why penicilline g unstable inacidic condition?
    1 year ago
  • kaylin
    How penicillin G gets deactivated under acidic pH?
    1 year ago
    How penincilin acid stability was improved?
    1 year ago
  • markus
    How does acid hydrolysis penicillin?
    1 year ago
  • filippo
    How does penicillin behave in acidic and basic media?
    11 months ago
  • markus
    What is the acid is degradation of penicillin to penicillin acid of stomach?
    11 months ago
  • jana borrego
    What is the physiological effect of decarboxylation of penicillin?
    9 months ago
  • robert
    How penicillinG gets deactivated under acidic PH?
    2 months ago
  • hamilcar
    What is the reactivity of the carbonyl on penicillin g?
    15 days ago

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