Data collected after 1 h and 24 h of incubation indicated that with each treatment scenario, there was a consistent and measurable decline in IR concentration. However, in 5 of the 6 treatment scenarios (1a, 1b, 2a, 2b, 3b), the concentration of IR remaining after 24 h was greater than 91% of that present at time 0. Therefore, IR remained within acceptable limits of degradation and was considered chemically stable for this time period. Treatment scenario 3a, which contained the highest concentration of LV (IR, 0.32 mg/mL; LV, 3.60 mg/mL) exhibited a higher rate of decline in IR concentration than the other 5 treatment scenarios. The mean concentration (± standard deviation [SD]) of IR remaining at 1 h, expressed as a percentage of the concentration at time 0, was between 88.56% ± 0.79% and 89.08% ± 4.83% (Tables 2-4). At 24 h the mean concentration (± SD) had further declined to 76.30% ± 0.69% to 78.34% ± 0.81% of that present at time 0. In addition to having the highest concentration of LV, treatment scenario 3a also had the highest pH (6.50) (Table 2). This relatively high pH contributed to the accelerated conversion of IR to the ring-opened carboxylate observed in treatment scenario 3a. The conversion of IR to the ring-opened carboxylate was pH-dependent (Figure 2); IR concentrations declined slowly between pH 4 and pH 6 and more rapidly above pH 6. The observation that treatment scenario 3a exhibited the most rapid decline in IR concentration should have been expected, because this was the only treatment scenario in which the pH of the mixture was greater than 6.

These data also show that the quantitative decline in IR observed in the pH dependency experiment (Figure 2) was similar to the decline observed at 0.5 h for each treatment scenario, supporting the notion that pH, possibly in combination with continuous exposure to fluorescent light, is the only factor contributing to an accelerated decline in IR concentration. The decline in IR concentration in scenario 3a (Tables 2-4) resulted in mean concentrations (± SD) after 0.5 h that were between 91.57% ± 1.22% and 95.09% ± 3.14%, values that are in close agreement with concentrations remaining after 0.5 h in the pH dependency experiment (Figure 2). In the latter experiment, 96.79% and 94.82% of the IR remained at pH 6.27 and 6.79, respectively. Since these experiments did not control for exposure to light, it is impossible to separate the contribution of continuous exposure to fluorescent light from the contribution of pH to the decline in IR concentration. However, previous work by Dodds and others demonstrated that the ring-opened carboxylate is a photolabile species and that photodegradation requires the presence of the ring-opened carboxylate. Nonetheless, during the stability study, analyses of IR exposed to both increasing pH and continuous light revealed only the ring-opened carboxylate product, which is produced by hydrolysis of the lactone ring that is in equilibrium with IR. Other degradation products, produced by sodium hypochlorite oxidation or photodegradation during continuous light exposure, were not observed.
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The rates and proportion of the pH-dependent conversion of IR to the ring-opened carboxylate observed in this study were similar to those previously reported. Both Fassberg and Stell and Dodds and others have demonstrated that IR is more stable in acidic solution (pH 5) than in neutral or basic solutions. Dodds and others3 found that the photodegradation rate of IR in saline was 0.0245/h, which corresponds to a half-life of 28.28 h and a time of 4 h, 15 min to achieve 90% of the initial concentration. Commercially available IR solutions contain lactic acid, which lowers the pH and makes the product more stable2,3 by preventing conversion to the ring-opened carboxylate (which undergoes photodegradation). The photodegradation rate of IR in 0.05 mol/L phosphate buffer at pH 5 was 0.0022/h, which corresponds to a half-life of 315 h and a time of about 48 h to achieve 90% of the initial concentration. The dilution of commercial product in saline yields a solution with pH of about 3. As a result, further investigations by Rivory and others18 did not reveal significant degradation during infusions of 60 to 90 min.

Chamorey and Milano9 have also evaluated the stability and compatibility of IR (0.36, 1.44, and 2.8 mg/mL in D5W) mixed with the L-isomer of LV (Elvorin, 0.4 and 4.0 mg/mL in D5W [Elvorin is the commercially available form of the L-isomer of LV in Europe]). The current study and the study conducted by Chamorey and Milano evaluated similar concentrations of LV and IR in solutions of similar pH, and the 2 studies had similar results. However, Chamorey and Milano reported a 32% loss in IR concentration immediately after mixing of a solution containing 0.36 mg/mL IR and 4 mg/mL L-LV. In contrast, in the study reported here there was little difference in the nominal and initial concentrations of IR at time 0 in any solution, including the solution containing 3.60 mg/mL LV. However, after 1.0 h the mean IR concentration had declined to between 88.56% ± 0.79% and 89.08% ± 4.83% of the concentration at time 0, and after 24 h the concentration had declined to between 76.30% ± 0.69% and 78.34% ± 0.81%. This difference in results may be explained by the fact that Chamorey and Milano stored solutions at -20°C until “all samples were taken”. Thus, conversion of IR to the ring-opened carboxylate might have occurred during storage at -20°C for at least 2 h or during the time required to allow the samples to thaw.

The studies reported here demonstrated conversion of IR to the ring-opened carboxylate following mixing with racemic LV. The 24-h stability data also suggest that IR (0.30 to 0.56 mg/mL) and LV (0.27 to 0.94 mg/mL) could be mixed in the same diluent bag and infused together, as suggested by Chamorey and Milano. Future research should focus on evaluating additional concentrations of racemic LV between 0.94 and 3.6 mg/mL, to more precisely define the limits of LV concentration that can be used while maintaining IR stability.
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In conclusion, IR and LV solutions, even those containing 3.60 mg/mL of LV, are physically compatible and chemically stable for a sufficient period of time to allow Y-site infusion, provided the period of contact (time from mixing to entry into the body) is short (less than 30 min).