The purpose of this study was to predict the stability of meropenem in a mixed infusion. The hydrolysis of meropenem in aqueous solution was found to be accelerated by pH, and by increasing concentrations of sodium bisulfite (SBS) and L-cysteine. Equations were derived for the degradation rate constants (k obs ) of pH, SBS and L-cysteine, and fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (E a ) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the characteristic pH curve. From these results, an equation was derived giving the residual ratio (%) of meropenem at any time after mixing an infusion containing SBS and/or L-cysteine at any temperature, and in the pH range 4.0-10.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).Key words stability prediction; meropenem; pH; sodium bisulfite (SBS); L-cysteine; degradation rate constant Carbapenems are the most potent β-lactam antibiotics and were first developed in the 1980s to enhance resistance to β-lactamases. The early carbapenems were not very hydrolytically stable, however, limiting drug administration to controlled intravenous infusions. In the search for a more stable compound with better toxicity profile, the basic nuclear structure was maintained and a dimethyl carbamoyl-pyrrolidinylthio group was added as a weakly basic C-2 side-chain. This resulted in a reduction of central toxicity and nephrotoxicity, while maintaining anti-pseudomonal activity. In addition, the improvement of stability (DHP-I stability) in vivo and the improvement of activity against Haemophilus influenzae, etc., were achieved by introducing 1-β-methyl group into the carbapenem frame, resulting in the creation of meropenem. The improvement in nephrotoxicity was the key advance in allowing the global development of meropenem as a single agent. 1)Meropenem is a broad-spectrum carbapenem, active against several clinically relevant Gram-positive and Gram-negative aerobes, anaerobic bacteria and Pseudomonas aeruginosa. The bactericidal activity of meropenem results from the inhibition of cell wall synthesis through the inactivation of penicillin-binding proteins.Sodium and fluorouracil. 8) However, there are no reports of detailed kinetic studies on the degradation of meropenem in the presence of SBS.The prediction of the stability of a drug in an intravenous admixture (mixed infusion) is important for accurate and safe drug administration. Generally, the stability of a drug in a mixed infusion can be predicted from the pH profile and Arrhenius equation of the degradation rate constants, if the temperature and pH of the test solution are known. Although meropenem is generally administered as an infusion in saline, in some cases it may be mixed with other substances, such as amino acids. 9)A method for predicting the pH of mixed infusions was developed in orde...

The purpose of this study was to predict the stability of imipenem in a mixed infusion. The hydrolysis of imipenem in aqueous solution was found to be accelerated by pH, and by increasing concentrations of sodium bisulfite (SBS) and L-cysteine. Equations were derived for the degradation rate constants (k(obs)) of pH, SBS and L-cysteine and fractional rate constants were estimated by nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of imipenem at any time after mixing an infusion containing SBS and/or L-cysteine at any temperature and at pH 4.0-10.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).

The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of octreotide was found to be accelerated by pH, and by increasing concentrations of SBS. Equations for the degradation rate constants (k obs ) of pH and SBS were derived. The fractional rate constants were estimated by the nonlinear least-squares method (quasiNewton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of octreotide at any time after mixing an infusion containing SBS at any temperature in the pH range 4.0-7.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).Key words stability prediction; octreotide; pH; sodium bisulfite (SBS); pH characteristic (PHC) curve; degradation rate constant, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.1-3) The cyclic structure of octreotide ( Fig. 1) seems to play an important role in determining its unique pharmacological activity.Octreotide is increasingly used to treat symptoms of sickness and vomiting in terminal care patients suffering from gastrointestinal ileus. It is also used, in combination with standard therapies, in the symptom management of inoperable bowel obstructions in terminal cancer patients. [4][5][6] In Japan, octreotide is usually administered subcutaneously, but in the U.S. it is more often administered by deep subcutaneous (intrafat) or intravenous injection.3) The pharmacokinetics of octreotide are similar to those of many other agents administered continuously via intravenous or subcutaneous infusion, 7) and similar changes in pharmacokinetics would be expected if octreotide were to be administered by continuous intravenous administration instead of sustained subcutaneous administration, i.e., without the need for special equipment (e.g., miniature pump).We have been unable to find any reports describing the time-dependent stability of octreotide in amino acid infusions under different pH, temperature and ingredient such as sodium bisulfite. Especially, we have been unable to find reports evaluating such time-dependent stability of octreotide in amino acid infusions quantitatively.Hanamura et al. 8) report on the stability of octreotide in glucose and saline infusions, but its stability in amino acid infusion fluids was not investigated in detail. We have been unable to find any reports describing the stability of octreotide in amino acid infusions. Sodium bisulfite (SBS), which is used as a stabilizer in injectable preparations, is known to degrade various drugs, including thiamine, 9) epinephrine, 10) gabexate mesilate, 11) nafamostat mesilate, 12) urokinase, 13) morphine, 14)fluorouracil 15) and imipenem. 16) However, there ...