(W0930-09-48) Impact of Excipient Purity on the Stability of Chemotherapy Drugs

Purpose: Excipients are fundamental components in the drug development process. They are essential in the formulation of stable dosage forms, ensuring that medications maintain their efficacy and safety throughout their shelf life.¹ The development and manufacturing of oncology formulations are particularly complex, requiring stringent quality standards to ensure product consistency, safety, and efficacy.² Given the critical role of excipients and the high stakes involved in oncology therapies, this study aimed to evaluate the effect of excipient purity on the stability of two chemotherapy drugs under accelerated conditions, seeking to understand how varying levels of excipient purity can impact oncological drug formulations.

Methods: The stability of docetaxel and etoposide was assessed over a 12-week period at 40°C using different grades of excipients commonly used in their formulations. Docetaxel (10 mg/g) was dissolved in both high purity (HP) and standard compendial grades of polysorbate 80 and PEG 400, while etoposide (10 mg/g) was dissolved in HP and standard compendial grades of polysorbate 80 and PEG 300. The stability of these actives was assessed by collecting samples at regular time intervals and measuring the recovery of docetaxel and etoposide. All analyses were performed using an Agilent HPLC 1260 system fitted with a Zorbax Eclipse Plus C8 column (4.6 x 150 mm, 5 µm). The docetaxel samples were eluted with a 19/36/45 (v/v) mixture of methanol, water, and acetonitrile at a flow rate of 1.2ml min^-1 and detected by UV 232nm. The etoposide samples were eluted with, a 50/50 (v/v) mixture of methanol and water at a flow rate of 1.0 mL min^-1, with UV detection at 204nm. Injection volumes and run times for both methods were 5 µL, 10 minutes respectively. Identification of any degradation products formed was performed using an ABSciex 3200QTrap mass spectrometer fitted with a Shimadzu Nexera LC System, using +ve electrospray ionization. In both cases, the HPLC conditions were modified to facilitate full elution and detection of all species by using gradient elution and adding 0.1% formic acid to both mobile phases, together with a longer run time of 20min. Any degradation products tentatively identified, were further confirmed by comparing their mass spectra and retention times against known purchased standards. These standards were then further used to assign identities to individual peaks in the original chromatograms.

Results: Docetaxel recovery after 12 weeks at 40°C was 94% in high purity polysorbate 80 and 91% in high purity PEG 400. In contrast, recovery rates in all standard grades tested were below 60% (Figure 1). Several known docetaxel degradation products, including 7-epi docetaxel, 10-oxo docetaxel, and 10-oxo-7-epi-docetaxel, were detected in the standard grades of polysorbate 80 and PEG 400. No degradation products were observed in the high purity grades, as shown in the HPLC chromatograms (Figure 2). Etoposide recovery in high purity Polysorbate 80 was 98% after 12 weeks at 40°C. Two different sources of standard Polysorbate 80 showed similar recovery values of 84%, while a third source had a recovery of only 17%. High purity PEG 300 resulted in a 96% recovery rate, compared to 28% for the standard grade (Figure 3). Cis-etoposide, an a stereoisomer of etoposide, which seems to have no significant biological activity ^3,4, was identified as the main degradation product, and its increase over time was observed only in the standard grade excipients.

Conclusion: In conclusion, the stability study of docetaxel and etoposide under 40°C for 12 weeks demonstrated significant differences in API recovery between high purity and standard grade excipients. Docetaxel exhibited high stability in high purity Polysorbate 80 and PEG 400, while significantly lower recoveries were observed in the standard grades, accompanied by the presence of several known degradation products. Similarly, etoposide showed superior stability in high purity Polysorbate 80 and PEG 300, compared to lower recoveries and increased degradation product formation in standard grades.These findings highlight the critical impact of excipient quality on the stability of pharmaceutical actives. The high purity grades of polysorbate 80 and PEG demonstrated a remarkable ability to maintain the integrity of docetaxel and etoposide, minimizing degradation and ensuring higher recovery rates. In contrast, the standard grades not only exhibited lower recovery rates but also facilitated the formation of degradation products, highlighting the necessity of using high purity excipients in formulation development to ensure drug stability and efficacy.

References: 1. Kar M, Chourasiya Y, Maheshwari R, Tekade RK. Current Developments in Excipient Science: Implication of Quantitative Selection of Each Excipient in Product Development. In Tekade RK, Editor. Basic Fundamentals of Drug Delivery. 2019. Academic Press; p.29-83.
2. Gadhe K, Mishra U, Kanaki N, Movaliya V, Deshpande S, Zaveri M. Regulatory and Quality Compliance of Oncology Products – A Global Perspective. International Journal of Drug Regulatory Affairs 2024. 12(2) p. 1-7.
3. Dewick PM. Chapter 3. Essentials of Organic Chemistry for Students of Pharmacy, Medicinal Chemistry and Biological Chemistry. 2006. 1st Edition, Wiley.
4. Mader RM, Steger GG, Moser K, Rainer H, Krenmayr P, Dittrich C. Instability of the anticancer agent etoposide under in vitro culture conditions. 1991. Cancer Chemother. Pharmacol. 27, p. 354–360.

Figure 1: API recovery of docetaxel (%) in High Purity Polysorbate 80 and 3 different sources of standard grade Polysorbate 80 and in High Purity PEG 400 and 2 different sources of standard grade PEG 400.

Figure 2: HPLC chromatograms of docetaxel in polysorbate 80 and PEG 400, at 40°C after 3 months.

Figure 3: API recovery of Etoposide (%) in High Purity Polysorbate 80 and 3 different sources of standard grade Polysorbate 80 and in High Purity PEG 300 and a standard grade PEG 300.