Original research
remained clear, colourless and no visible precipitation was noted. However, a massive white precipitation was noted for the high concentration (4500 mg/240 mL). A sample of the recovered precipitant paste (0.11 g) was dissolved in 3 mL of 0.1 M NaOH. Injection of the solution revealed a massive (off-scale) aciclovir peak. For comparison, a solution of guanine in 0.1 M NaOH was injected producing a peak at its expected earlier retention time. This confirmed the precipitate to be aciclovir. Sub-visible liquid particles All samples scanned for sub-visible liquid particle analysis were within the USP <788> sub-visible particle testing require- ments. 18 However, no samples of the high concentration at in-use temperature were scanned for sub-visible particle analysis due to the significant visible precipitation. pH Changes Changes in the pH of the aciclovir solution from base- line in the two elastomeric devices are summarised in tables 1 and 2. Overall, the pH gradually decreased during storage at room temperature and substantially during exposure to in-use temperature of 32°C. The highest reduction was observed at the low concentration, which was the most diluted in terms of NaOH content (each vial of aciclovir IV infusion formulation contained 92.9mg NaOH in 20mL). Aciclovir concentration Figures 1 and 2 show the percentage of aciclovir remaining within the infusers during room temperature storage and expo- sure to 32°C, respectively. The mean (SD) percentage of aciclovir remaining at each time point for the Accufuser and Easypump devices is shown in tables 3 and 4, respectively. Aciclovir solu- tion demonstrated high stability at room temperature with >98% remaining unchanged for 14 days. At 32°C aciclovir remained stable at the low (200 mg/240 mL) and intermediate (2400 mg/240 mL) dose with >95%active pharmaceutical ingredient remaining after 24 hours. However, at the high dose (4500 mg/240 mL) there was a rapid decline in aciclovir concen- tration with ≥20% loss within 4 hours of exposure to 32°C. This decline in concentration parallels the massive white precipitation observed during this temperature. Following forced degradation, only strong acidic conditions (1M HCl) stored at 60°C for 24 hours resulted in conversion
Samples were collected from each device for visual analysis of colour, clarity and any precipitation at similar time points of sampling for concentration measurement. The pH of these samples was measured using an Orion double junction semi- micro pH electrode with Eutech pH700 pH metre (Eutech Instru- ments, Singapore). The study was run in two batches: low and high dose initially, followed by the intermediate dose. Sub-visible particles assessment was performed using Zetasizer Nano serious (Malvern Instruments, Worcestershire, UK) in the initial phase of the study. In the second phase, sub-visible particle counts were performed at 0 hours (just after reconstitution) and at 24 hours, 168 hours, 336 hours and 360 hours using a Beckman Coulter HIAC 9703+ Series precision liquid particle sampler. The HIAC analysis of each sample was performed in triplicate for each of the three replicate devices at each time point. Forced degradation Forced degradation of aciclovir was investigated under the following conditions: (1) water, kept at room temperature (RT); (2) water, kept in the oven (initially 60°C but changed to 38°C after 20 hours); (3) 0.1 M HCl, kept at RT; (4) 1 M HCl, kept at RT; (5) 0.1 M NaOH, kept at RT; (6) 1 M NaOH, kept at RT; (7) 3% H 2 O 2 , kept at RT; (8) 0.1 M HCl, kept in the oven (initially 60°C but changed to 38°C after 20 hours); (9) 1 M HCl, kept in the oven (initially 60°C but changed to 38°C after 20 hours); (10) 0.1 M NaOH, kept in the oven (initially 60°C but changed to 38°C after 20 hours); and (11) 1 M NaOH, kept in the oven (initially 60°C but changed to 38°C after 20 hours) The room temperature on sampling days was determined to be 19.0±0.5°C. During 14 days of room temperature storage, aciclovir solution in both the Easypump II LT 270–27-S and Accufuser VAWC0100L elastomeric infusion pumps was clear and colourless with no visible precipitation in samples collected or within the body of the infusers. However, from day 7 onwards, small crystals were noted at the tip of the sampling tube for the intermediate and high concentration while the body of the infuser was clear. During the subsequent exposure to in-use temperature of 32°C, at the low concentration (200 mg/240 mL) and intermediate concentration (2400 mg/240 mL) the solution RESULTS Colour, clarity and precipitation
Table 1 Observed change in pH of aciclovir solution in the Accufuser VAWC0100L elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C
Observed mean±SD pH and change in mean pH from baseline by concentration Low concentration Intermediate concentration
High concentration
Temperature condition
Time (hours)
Observed pH
Δ pH
Observed pH
Δ pH Observed pH
Δ pH
Room temperature (<20°C)
0
10.24±0.01 10.30±0.01 10.27±0.03 10.17±0.03 10.02±0.06 9.85±0.07 9.67±0.09 9.47±0.11 9.26±0.15 7.43±0.24 6.91±0.02 6.86±0.04
0.00 0.05 0.03
11.20±0.00 11.16±0.04 11.08±0.01 11.06±0.00 10.93±0.02 10.95±0.03 10.70±0.04 10.58±0.03 10.44±0.03 10.45±0.04 10.45±0.04 10.37±0.03
0.00
11.25±0.01 11.25±0.01 11.27±0.01 11.22±0.02 11.25±0.05 11.15±0.04 11.04±0.08 10.94±0.11 10.88±0.13 10.44±0.05 10.28±0.09 10.06±0.21
0.00 0.00 0.01
12 24 48 96
−0.04 −0.12 −0.14 −0.27 −0.25 −0.50 −0.62 −0.76 −0.75 −0.75 −0.83
−0.07 −0.23 −0.39 −0.57 −0.77 −0.99 −2.81 −3.33 −3.38
−0.03 −0.01 −0.11 −0.21 −0.31 −0.37 −0.82 −0.98 −1.20
120 168 240 336 344 348 360
In-use temperature (32°C)
Sime FB, et al . Eur J Hosp Pharm 2023; 0 :1–6. doi:10.1136/ejhpharm-2023-003784
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