A stability-indicating HPLC-UV method to determine the physicochemical stability of NE bitartrate hydrochloride injectable solutions was successfully designed and validated. Our study showed that stability was maintained for 365 days in PP syringes and COC vials when stored at −20±5°C and +5±3°C.
The long-term stability of 0.2 and 0.5 mg/mL NE solutions diluted in NS in PP syringes and ready-to-use COC vials had not been investigated before. The closest in terms of study design assessed the stability of 0.1, 0.2, 0.4, and 0.04 mg/mL NE solutions in amber glass vials, and 0.01 mg/mL NE solutions diluted in D5W stored in 10 mL PP syringes for 12 months at +2°C to 8°C and ambient temperature. Results were partly comparable with ours as the stability of 0.1, 0.2, and 0.4 mg/mL solutions was maintained over the study period when stored refrigerated. However, NE injection solutions, 0.01 mg/mL in 10 mL PP syringes, were seen to be stable for only 6 months when stored refrigerated and 28 days when stored at ambient temperature. Previous studies successfully assessed the stability of NE solutions over shorter periods, with storage at ambient or refrigerated temperatures, in polyvinyl chloride bags, PP syringes, with dilution in NS or D5W exposed to or protected from light, with different NE concentrations.
The NE commercial solution used for our stability assay was devoid of antioxidative stabilizing agents.
The degradation pathways of catecholamines via their oxidative reaction responsible for coloring have been widely described. Oxidation leads to the formation of noradrenochromes which account for the greyish-brown color. This oxidative process is catalyzed by oxygen, heat, alkalinization with a pH value >6, heavy metal ions, and exposure to UV or daylight. The analogues and metabolites of noradrenochromes have been reported as being neurotoxic and cardiotoxic in the literature. No acceptance limits have been defined regarding the content of degradation products in current NE monographs. In the chromatograms of the degraded solutions, we identified one peak corresponding to the formation of a degradation product for a 0.2 mg/mL NE solution stored in 20 mL and 50 mL, and two peaks corresponding to the formation of two degradation products for an NE solution stored in 50 mL. According to our forced degradation study, these peaks could be assimilated to the degradation compounds eluted in acid conditions.
The sensitivity of catecholamine degradation to light has previously been shown, but it could not be responsible for the NE degradation in our study because each container tested was stored in a closed enclosure. Other studies have assumed that the major determinant of the degradation process is pH. Our initial pH values (3.30–3.60) were within the limits recommended. As the degradation products identified in the degraded solutions were also identified in acid forced degradation conditions, a very slight variation in pH might be one of the factors catalyzing the degradation process. Finally, many converging arguments have forced us to assume that temperature plays a major role in catalyzing the degradation process of NE, as sub-visible particulate contamination was low when stored in frozen and refrigerated conditions, while solutions stored at ambient temperature became colored. The assumption that stability is prolonged with refrigerated or frozen storage has already been raised, and many studies have successfully used freezing to lengthen drug stability. Protocols using microwaves for defrosting have also been published.
Our results also support the claim that COC vials offer longer stability than PP syringes since the coloring of solutions was delayed by 1 month when stored in the former.
The strong point of our study lies in the implementation of ready-to-use containers. The COC vials provide an original design for a high-quality container meeting the criteria of authority requirements for pharmaceutical primary containers. The safety and efficacy of COC vials to maintain the long-term stability of injectable solutions have previously been demonstrated. The counting of sub-visible particles is another strong point, as this was not performed in previous stability studies.
Variability in solution concentrations prepared at the patient’s bedside is a major issue. This inter-operator variability can result in the administration of under- or over-concentrated solutions with adverse effects, especially in the case of high-risk medication. Preparing injectable solutions at the patient’s bedside is also a microbiological challenge. The centralized preparation of ready-to-use solutions would undeniably improve the security of parenteral administration but requires time-demanding organization. To this end, fast methods of dosage need to be developed for routine use. Several methods with reversed-phase HPLC combined with UV detection have been developed in previous studies. We also chose UV to detect degradation products as the main degradation products of NE contain chromophores in their chemical structure, as previous studies have shown. This method is compatible with routine practice and more common than other methods (ie, electrochemical detection or photodiode array detection).
The compounding of ready-to-use syringes and COC vials raises the question of how a single-dose protocol in ICU services should be defined, as the prepared ready-to-use solutions are compounded to be administered as such. Analyses have not been pursued beyond the date originally envisaged for the end of the study as 365-day stability is sufficient to provide ICUs with ready-to-use solutions in routine practice. During our assay, we did not seek to identify leachables and extractables from the COC as such tests have previously been performed and confirmed the low risk of COC packaging. The PP syringes in our study were not designed for aqueous drug storage although this is regular practice in ICUs. Our stability assay took place before the US Food and Drug Administration alert to healthcare professionals not to administer compounded drugs stored in Becton Dickinson (BD) syringes (2015). More recently, BD has announced that it is no longer using material associated with a loss of drug potency, so that their syringes are now suitable for storing compounded drugs.
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