Stability of 25 mg/mL Azacitidine Suspensions Kept in Fridge after Freezing

Abstract

<jats:title>Abstract</jats:title><jats:p>Azacitidine is supplied as lyophilized powder to be reconstituted with sterile water for injection. The molecule is very unstable in aqueous medium (temperature-dependent process). Advance preparation and leftover management are made difficult by such poor stability. This study evaluates the stability of 25 mg/mL azacitidine suspensions kept for a 1-month period at –20 °C, followed by a 5-day period at 5 °C. Three batches of 7 polypropylene syringes were filled with 2 mL of Vidaza</jats:p>

Development and Validation of a New Storage Procedure to Extend the In-Use Stability of Azacitidine in Pharmaceutical Formulations

“…It is known that rapid and reversible hydrolysis of the azacitidine occurs in an aqueous medium, which leads to N-formyl RibosylGuanylUrea (RGU-CHO) formation, which is irreversibly hydrolyzed into RibosylGuanylUrea (RGU). It is a two-stage degradation [ 7 , 8 , 9 , 10 , 11 , 23 ]. These hydrolysis products do not produce toxicological or therapeutic effects, but they lead only to decreasing azacitidine potency [ 9 , 10 , 24 ].…”

“…However, already at time zero, chromatograms showed, besides the azacitidine peak with an average retention time (RT) of 4.3 min, the presence of four other peaks, including two peaks attributed to RGU-CHO and RGU with an average RT of 2.9 min and 2.0 min, respectively [ 7 , 8 , 9 , 10 , 11 , 23 ], and other two peaks with an average RT of 2.5 min and 3.6 min, which were more clearly detected in chromatograms obtained from Vidaza ® (50 µg/mL) subjected to heat stress (see the violet line, Figure 1 ).…”

“…Instead, when refrigerated sterile water for injection (2–8 °C) is used, the suspension remains stable for another 22 h if stored at 2–8 °C [ 5 ]. Indeed, the azacitidine is very unstable in an aqueous solution [ 6 , 7 , 8 , 9 ] and it is rapidly hydrolyzed to several degradation products (DPs) in a temperature-dependent process [ 10 , 11 ].…”

“…However, published results are not that recent, heterogeneous in terms of quality and relevance, and many of them do not take practical needs into account and the results need to be confirmed using the formulation currently administered in clinical practice (i.e., a 25 mg/mL aqueous azacitidine suspension) [ 18 , 19 ]. Moreover, most of the studies considered only chemical stability and did not evaluate a potential variation over time of the physical and microbiological parameters of reconstituted Vidaza ® [ 7 , 10 , 11 , 12 , 20 , 21 ].…”

Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes

“…This failure can be either a primary failure (lack of any response to azacitidine), a secondary failure (disease progressed after a first response, serum drug level is low) or a toxicity failure (azacitidine treatment was terminated due to severe side effects) [15,16]. A part of these failures can be attributed to the chemical and pharmacological properties of this drug, as azacitidine is sensitive to water, undergoing rapid and reversible hydrolysis, producing N-formylribosylguanylurea, followed by its irreversible hydrolysis to ribosylguanylurea (Figure 1) [17,18], which explains its short half-life after administration. Additionally, because of its hydrophilic nature, poor cell internalization has been observed, which is a common problem for most hydrophilic drugs.…”