Results (Part 1)
The results derived from the initial combinations evaluated (OXY A/TXA A and OXY B/TXA B) were inconsistent in terms of OXY concentration over the time evaluated. In the OXY A/TXA A combination solutions, using both diluents, OXY concentration was observed to decline rapidly, becoming undetectable by the assay method within one hour (Figure 1A). The experiment was stopped on observation of this phenomenon and did not continue to 6 hours as originally planned. No significant change in TXA concentration was observed across the duration of the study.
It is noted that the OXY concentrations at t=0 showed significant variation between experiments. This warrants further investigation, however, it should be noted that while t=0 samples are taken immediately on completion of mixing, there is necessarily a time period to prepare and transfer the sample for LC-MSMS analysis, where any interaction will continue to occur and may vary between samples.
The second combination evaluated (OXY B/TXA B) showed a modest drop in OXY concentration immediately after addition of the mixed solution to the IV infusion bag; however, unlike the first combination, the OXY concentration remained stable thereafter (Figure 1B). The TXA concentration across samples in this second experiment remained stable throughout.
The compatibility of the reverse combinations (OXY A/TXA B and OXY B/TXA A) was evaluated in terms of OXY concentration when mixed in glass vials over a period of 30 minutes. The results show that the OXY B/TXA A combination showed a similar rapid decline in oxytocin concentration to that observed with OXY A/TXA A, while oxytocin concentration remained stable in OXY A/TXA B (Figure 1C).
The HPLC chromatograms of TXA A and TXA B were reviewed to look for differences that might correlate with these observations. These chromatograms are shown in Figure 1D and Figure 1E. While both TXA products met British Pharmacopoeia assay and related substances specifications, it is clear that TXA A contains significantly more impurities than TXA B. In particular, a pair of early eluting peaks observed at ~5.5 min and ~ 7.5 min (circled in Figure 1D) were several times larger than the main TXA peak by area. This offers one possible line of enquiry to explain the results observed, specifically that these impurities in TXA A, and possibly other impurities not detected by the HPLC method, interact with OXY on mixing to reduce its solution concentration.
Results (Part 2)
The results for the 19 combinations of OXY and TXA injection products evaluated over a period of one hour are shown in Table 3. Five of the 19 combinations of products showed a significant decrease in OXY concentration immediately on mixing such that the OXY concentration at the start of the stability assessment (t=0 minutes) was greater than 10% (14.8% - 29.0%) below the nominal concentration of the solution (i.e. outside the BP assay limits for the oxytocin injection product). In two of these combinations (OXY 1/TXA 4 and OXY 1/TXA 18) the OXY concentration continued to decline during the stability period resulting in solutions at t=60 minutes post-mixing containing 1.9% and 29.5% of the nominal initial OXY concentration respectively. The three remaining combinations, where losses were observed immediately on mixing (OXY 1/TXA 11, OXY 1/TXA 16 and OXY 2/TXA 8), showed no further significant change in OXY concentration during the period of stability assessment. All other combinations showed no significant losses on mixing and remained stable throughout the study.