The Influence of Excipients on the Physicochemical and Biological Properties of a Bactericidal, Labile Ester Prodrug in a Salt Form – A Case Study of Cefetamet Pivoxil Hydrochloride

The article presents an innovative approach to a bactericidal drug design based on a cephem prodrug analogue – cefetamet pivoxil hydrochloride. The emergence of cefetamet pivoxil hydrochloride excipient systems (mannitol, hydroxypropyl methyl cellulose, pregelatinised starch, lactose monohydrate, magnesium stearate, polyvinylpyrrolidone) caused changes in the physicochemical properties of cefetamet pivoxil hydrochloride. They are significant for planning the development of an innovative pharmaceutical formulation. The biological activity profile of the prodrug was also modified. FTIR spectra were used to study interactions between cefetamet pivoxil hydrochloride and the excipients. The theoretical approach to the analysis of experimental spectra enabled precise indication of cefetamet pivoxil hydrochloride domains responsible for interaction with the excipients. The interactions between cefetamet pivoxil hydrochloride and the excipients resulted in some  important physicochemical modifications: acceptor fluid-dependent changes in solubility and the dissolving rate as well as a decrease in the chemical stability of cefetamet pivoxil hydrochloride in the solid state, especially during thermolysis. The interactions between cefetamet pivoxil hydrochloride and the excipients also had biologically essential effects. There were changes in its permeability through artificial biological membranes simulating the gastrointestinal tract, which depended on the pH value of the acceptor solution. Cefetamet pivoxil hydrochloride combined with the excipient systems exhibited greater bactericidal potential against Staphylococcus aureus. Its bactericidal potential against Enterococcus faecalis, Pseudomonas aeruginosa and Proteus mirabilis doubled. The new approach provides an opportunity to develop treatment of resistant bacterial infections. It will enable synergy between the excipient and the pharmacological potential of an active pharmaceutical substance with modified physicochemical properties induced by the drug carrier

STABILITY STUDIES OF CEFTIOFUR SODIUM IN AQUEOUS SOLUTIONS AND IN THE SOLID PHASE

Ceftiofur sodium (CFT), a third-generation cephalosporin for parenteral use, is commonly used in veterinary medicine against aerobic Gram-positive and Gram-negative bacteria as well as certain anaerobes. Its broad spectrum of activity and resistance to beta-lactamases result from the presence of methoxyimino and aminothiazole moieties at C-7 in the cephalosporin structure. The aim of this study was a comprehensive evaluation of the stability of CFT in the solid phase and in aqueous solutions. A fast and sensitive HPLC isocratic method was used for the determination of CFT degradation in the solid phase and in aqueous solutions. CFT degradation occurred according to a first-order reaction depending on the substrate concentration. The kinetic and thermodynamic parameters of CFT degradation in the solid phase were calculated. General acid-base hydrolysis of CFT was not observed in the solutions of hydrochloric acid, sodium hydroxide, phosphate (pH 5.84 – 7.25), acetate (pH 3.65 – 5.48) and borate (pH 7.49 – 10.07) buffers. CFT was the most stable in the pH range 2 – 6. The susceptibility of CFT to degradation under the influence of stress factors (pH, temperature, buffer components concentration, relative air humidity) should be considered in terms of storage conditions and the preparation of the product for administration