Solution stability of ciclosidomine.

The stability of N-cyclohexanecarbonyl-3-(4-morpholino)-sydnone imine hydrochloride (ciclosidomine) in solution was studied as a function of pH, temperature, ionic strength, and buffer species. The rate of hydrolysis in the absence of light was found to be apparent first order in drug and general acid- and base-catalyzed reactions. The pH rate profile at an ionic strength of 0.1 M at 60 degrees C had a minimum value near pH 6. Change in ionic strength in the range of 0.05 to 0.2 M did not affect the rate of degradation at pH 7 (carbonate buffer) or pH 2 (phosphate buffer) at 60 degrees C. Similar degradation rates were noticed in air or nitrogen in the dark at pH 3, 5, and 6. However, degradation in light was very rapid in either case at pH 3, 5, and 6, and, therefore, the protection of solutions from light was required during all studies. The time for 10% loss of drug in solution at pH 6 in dilute phosphate or citrate buffer at an ionic strength of 0.154 M was projected to be 9 months at 20 degrees C and 2.6 months at 30 degrees C.

Enhancement of ampicillin partition behavior.

Several ion-pair or adduct forming additives tha" enhanced ampicillin partition behavior were identified and evaluated. At pH 3, picric acid and trichloroacetic acid increased the ampicillin aqueous-octanol partition coefficient 250 and 30 times, respectively. At pH 7, quaternary compounds gave the most significant increases in the partition coefficient. Values for an aqueous pH 7 chloroform system increased from zero in the absence of additives to 2.28, 1.86, 1.82, and 1.70 for equimolar amounts of benzalkonium, tetraheptylammonium, benzethonium, and cetalkonium chlorides, respectively. Extraction of ampicillin from aqueous pH 7 solution was possible by adding a quaternary agent in an equimolar amount. However, extraction of ampicillin from plasma required large molar excesses. Tetraheptylammonium chloride was added at a molar concentration 10(3) times greater than that of the ampicillin. Plasma samples spiked at the 3-microgram/ml level gave 93% recovery (CV 6.7%, n = 16) when extracted three times. The extracts were quantitated by TLC.