Predictive stability, novel HPLC-MS analysis and semi-automatic compounding process for the emergency implementation of a production line of pancuronium in injectable solution

Abstract

During the early months of the COVID-19 pandemic, the international medical product supply chain was tight, causing breaks in the availability of neuromuscular blocking agents essential for the treatment of patients in intensive care units. The present study describes the pharmaceutical development of an injectable 2 mg/mL solution of pancuronium bromide (PC) in a very short lapse of time. The sterile solution was compounded into a good manufacturing practice grade A clean room, filtered (0.2 µm) and filled into 10 mL type I glass, manually sealed with bromobutyl rubber stoppers. A novel HPLC-MS stability indicating method for pancuronium quantification and its degradation product was developed and validated. This fast, sensitive and straightforward method was used to study the stability of the formulation using a semi-predictive method, enabling a very fast attribution of a temporary shelf-life, which was confirmed by a classic prospective stability study. The production line and the analytical tools set-up were performed in six weeks and the semi-predictive stability study was conducted in 90 days, allowing us to predict a shelf life, which was successfully confirmed by prospective study. In conclusion, using innovative methods, we were able to rapidly overcome the shortage of a critical drug.

Keywords: Accelerated stability study; Drug compounding; Drug stability; High-performance liquid chromatography; Mass spectrometry; Pancuronium.

Graphical abstract

Fig. 1

Degradation pathways of PC in aqueous solution, molecular weight and LogP of PC, 3-dPC, 17-dPC and 3,17-ddPC, estimated from Pubchem.

Fig. 2

Typical chromatogram of PC solution and its degradation products (A) in a freshly made solution, (B) after 3 h of HCl 0.1 M exposure, (C) after 1 hour of NaOH 0.1 M exposure and (D) after 96 h at 80 °C. The PC is quantified at m/z = 286.2, Rt = 1.40 min (red chromatogram). The 3-dPC and 17-dPC are quantified at m/z = 265.2, Rt = 1.35 and 1.45 respectively (green chromatogram). Finally, the 3,17-ddPC is quantified at m/z = 244.2, Rt = 1.15 mn (blue chromatogram).

Fig. 2

Typical chromatogram of PC solution and its degradation products (A) in a freshly made solution, (B) after 3 h of HCl 0.1 M exposure, (C) after 1 hour of NaOH 0.1 M exposure and (D) after 96 h at 80 °C. The PC is quantified at m/z = 286.2, Rt = 1.40 min (red chromatogram). The 3-dPC and 17-dPC are quantified at m/z = 265.2, Rt = 1.35 and 1.45 respectively (green chromatogram). Finally, the 3,17-ddPC is quantified at m/z = 244.2, Rt = 1.15 mn (blue chromatogram).

Fig. 3

Kinetics profiles of (A) PC degradation and (B) 3-dPC, (C) 17-dPC and (D) 3,17-ddPC formation from dosage forms stored at (∆) 5 °C ± 3 °C; (○) 25 °C ± 2 °C, 60% RH ± 5% RH; (◊) 40 °C ± 2 °C, 75% RH ± 5% RH; (□) 60 °C ± 2 °C. Each data is the mean ± standard deviation of five experimental determinations.

Fig. 4

Predicted kinetics profiles and confidence interval (5%) of (A) PC, (B) 3-dPC, (C) 17-dPC, and (D) 3,17-ddPC at 5 °C ± 3 °C over 1000 days. Crosses represent the measured results after 365 days and 730 days.