Some solution thermodynamic properties of penicillin derivatives. The effect of ionic strength and temperature on the solubility and acid-base properties of the amoxycillin, ampicillin and 6-aminopenicillanic acid

The penicillins are naturally occurring compounds produced by different microorganisms and the first class of antibiotic available for humans. These molecules have a selective anti-bacterial toxicity and perform their activity interfering on the growth processes and on the proliferation of the microorganism. Some penicillins behave inhibiting the cellular wall growth of bacteria, others interfering with their mechanism of the proteic synthesis. The fundamental part of penicillins is represented by the -lactam ring which is associated to a thiazolidine molecule (Figure 1). The penicillins differ for the lateral acyl chain condensed with the amino group; the lateral chain and the substituent influence the pharmacokinetic, the biochemical and the antibacterial properties (against both gram-positive and gram-negative organisms) of penicillins. The substituent on the amino group influences the antimicrobial spectra, the susceptibility to the acidic ambient, the sensibility to the -lactamase and the pharmacokinetic properties. The substitution on the condensed carbon in position 2 increases the stability to the -lactamase. The 6-aminopenicillanic acid is an intermediate product with special importance to pharmaceutical industry since is the main starting block for the preparation of numerous semisynthetic penicillins (β-lactam antibiotics) to obtain new derivatives with enlarged spectrum of biological activity, by means of acylation, esterification, amidation and hydroxyamidation reactions, etc. Among the different penicillin types, the amino-penicillins are undoubtedly the most important, since the amino-group is bounded to a large radical that avoid the attack of the penicillinase to the β-lactam ring, and allowing them to have a large anti-bacteria activity. Amoxicillin and ampicillin are the most important amino-penicillins since are effective against many different bacteria including H. influenzae, N. gonorrhoea, E. coli, Pneumococci, Streptococci, and Staphylococci. In different industrial fields, the knowledge of the drug solubility is a very important property for pharmaceutical product design, because it affects the drug efficacy, its future development and formulation efforts, and also influences the pharmacokinetics, such as the release, transport and the degree of absorption in the organism. Solubility data involving new drugs are frequently not available in the literature. Although some thermodynamic models can be used to predict drug solubility, the availability of experimental data is still fundamental for an appropriate model development and evaluation. Since many years, our research group has undertaken a systematic study of the modelling of the acid-base properties and solubility of different ligand classes of acidic and basic non-electrolytes and zwitterions in experimental conditions simulating those of natural waters and biological fluids. The information obtained from this kind of investigations allowed us to determine the total solubility of the ligands and of its neutral species, as well as the corresponding activity coefficients determined using the Setschenow equation. Data regarding their thermodynamic properties appear till now few and quite confusing, and any systematic modelling studies regarding their dependence on the experimental conditions (ionic medium, ionic strength and temperature) is reported. These kind of investigations allow to propose simple semi-empirical equations that allow to model the dependence of the thermodynamic parameters on ionic strength, ionic medium and temperature, and to predict the behavior of the ligands in a wide range of experimental conditions. In this order, the main scope of this paper is to give an important contribution on the knowledge of the thermodynamic properties (log KH, solubility and formation enthalpies) and behavior of three different biological active molecules (see Figure 1), namely: (2S,5R,6R)-6-Amino-3,3-dimethyl-7-oxo-4- thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid or 6-aminopenicillanic acid [6APA]; (2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid or amoxicillin [Amox] and 2S,5R,6R)-6-([(2R)-2-amino-2-phenylacetyl]amino) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid or ampicillin [AMP]) in NaCl aqueous solutions at different temperature and in a fairly wide ionic strength range. Moreover, since penicillin derivatives are readily inactive in presence of water, alkalis, acids, oxidizers and heavy metals, the hydrolysis of the β-lactam ring was accurately studied as a function of pH, ionic strength and time using both the UV-vis spectroscopy and NMR.