(M1130-08-53) Antioxidant Inclusion for the Preservation of Physical, Chemical, and Functional Properties of Polymeric Surfactants and Stabilizers during Terminal Sterilization (Gamma Irradiation)

Purpose: Sterility is a critical quality attribute of parenteral dosage forms (1,2), and needs to be assured using a suitably designed, validated, and controlled manufacturing process to ensure patient safety (3). However, ready-to-use long-acting injectable suspensions (LAIS) are not amenable to sterile filtration and present unique challenges for conventional terminal sterilization due to their chemical nature (dispersed system) and the risk of compromising physical and chemical stability. Consequently, LAIS are often sterilized using gamma irradiation, which assures sterility, but the ionizing radiation may cause the polymers to either fragment and/or cross-link, which can compromise their structure and functionality. This loss in functional properties can potentially lead to issues with long-term resuspendability. This research aims to understand the effectiveness of antioxidants (free radical scavengers) inclusion in reducing polymer radiolysis (degradation caused by radiation), with a particular focus on polymeric surfactants and polymeric stabilizers used in LAIS formulations.

Methods: Mechanistic studies were conducted to investigate the effects of antioxidants inclusion on polymer radiolysis mitigation and sustenance of physicochemical stability, as well as functional properties of widely used parenteral excipients: polysorbate 20 & poloxamer 338 (non-ionic surfactants), and polyethylene glycol 3350 (polymeric stabilizer). Preliminary work involved gamma irradiation of neat aqueous solutions of these excipients (and with antioxidants added) at concentrations typical for parenteral suspensions [1%, 3%, and 5% w/v for all excipients]. Five antioxidants with varying physical and chemical characteristics were tested at six different concentrations (0.1% to 2% w/v). Synergistic effects of mannitol (a known radical scavenger) and antioxidants were also investigated. Samples were prepared in 2R ISO Type 1 glass vials (2.2 mL fill volume) with headspace purged with nitrogen and were irradiated at nominal 25 kGy gamma dose at ambient temperature. Non-irradiated solutions served as a control group. pH and viscosity were measured, as these tests are indicators of physicochemical stability. Analytical methods for high-performance liquid chromatography and size exclusion chromatography with charged aerosol detection (HPLC-CAD and SEC-CAD) were developed for each excipient to quantify residual levels post-irradiation; and to study irradiation-induced molecular weight shifts, which are indicators of chemical stability. Select antioxidants were added to suspensions (prepared using naproxen as a model drug) and subjected to gamma irradiation at a nominal 25 kGy dose. Preservation of polymer stabilization properties, post gamma irradiation, was investigated by characterizing suspension flocculation properties (sediment height and water content in sediment) and polymer chemical structure (by analyzing the supernatant using HPLC and size exclusion chromatography).

Results: A drop in pH and increase in viscosity was observed for neat aqueous polymer solutions upon gamma irradiation (versus non-irradiated controls). SEC-CAD chromatograms obtained for irradiated samples showed a broad second peak at early retention time along with a decrease in corresponding main peak intensity, which corroborates higher molecular weight specie generation. Further, from HPLC-CAD data, all the excipients were found to show a loss in potency, i.e., loss in main peak intensity at all concentration levels when exposed to gamma irradiation. The inclusion of antioxidants mitigated polymer degradation and magnitude of polymer preservation was directly proportional to antioxidants concentration. SEC-CAD chromatograms showed that inclusion of antioxidants led to mitigation / minimization of radiation induced polymer cross-linking. Model suspension with antioxidants included showed preservation of the flocculated state, whereas suspensions lacking antioxidant showed complete deflocculation upon irradiation.

Conclusion: Gamma irradiation affects the structure and physicochemical properties of polymers in the solution state which was mitigated by antioxidants inclusion. Inclusion of mannitol with antioxidants showed synergistic effects in preserving polymer integrity and functionality. Addition of antioxidants preserved the flocculation properties of a model suspension post-irradiation. This observation suggests that the inclusion of antioxidants has a protective effect for the polymers in the suspension and could potentially improve long-term resuspendability, which is a critical quality attribute for ready to use suspensions.

References: 1.Lambert WJ. Considerations in developing a target product profile for parenteral pharmaceutical products. AAPS Pharm SciTech. 2010;11(3):1476-81.
2.Kolluru LP, Atre P, Rizvi SA. Characterization and applications of colloidal systems as versatile drug delivery carriers for parenteral formulations. Pharmaceuticals. 2021;14(2):108.
3.Lambert BJ, Hansen JM, Bryans TD, Lam S. Sterility Assurance Across-Sectors—New Paradigms and Tools. Frontiers in Medical Technology. 2021; 3:622710.