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.