(M1430-09-60) Assessment of Antioxidant to Prevent Degradation in Moisture-Sensitive Tablets

Purpose: The principal objective of this study was to analyze and select appropriate antioxidant in preventing oxidative degradation of the presented tablet dosage form. Antioxidants concentrations were selected based on maximum daily exposure limit set by Inactive ingredients list guidelines.

Methods: Five different antioxidants were selected for this study; butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), propyl gallate, cysteine hydrochloride, and sodium metabisulfite. Active compound is prone to oxidation by exposing to room temperature with high humidity. Antioxidant screening study sample preparation required dispensing, screening, blending, and compression using single station carver press. Five different blend was produced by incorporating each antioxidant as listed above individually. Each blend was compressed at 400 mg unit dosage weight and transferred into clear glass vial for the initiation of the stability study. Furthermore, all five batches of individual vials were stored in 40°C/75%RH storage chamber for the initiation of stability. One (1) vial from each batch was used for testing at the initial (t = 0), t=2 week, t=4 week and t=8 week time points. Ultimately, samples from each vial from the selected storage condition were tested for appearance (visual), assay and related substance testing. However, only impurity levels were monitored over an 8 week period to assess the effectiveness of antioxidant in preventing degradation of the Form E API. In general, all samples tested for assay presented some variation in results; this is a trend that is recognized and attributed to the nature of testing. Thus, the assay values in this evaluation are used for reference only. The primary focus is to observe the trend over time and storage conditions for the related substances. The related substances are assumed to be unaffected by the variations in assay values as the related substances are calculated as % area as related to the assay peak.

Results: Five different antioxidants were assessed for their effectiveness in preventing oxidation of the active compound in the oral solid dosage form. Comparison of total impurity growth over the period of 5 weeks was compiled and presented across all five batches (Figure 2). Specific known impurity AB7345 was also tracked for all the batches and summarized (Figure 1). The appearance of the sample mixture did not change over time throughout study. The data indicate that no change in the physical appearance at 40 °C/75% RH for 2 week, 4 week and 8 week. However, it was noted that impurity formation was seen among samples tested. Some variation was observed in the assay results; however, this cannot be directly linked to the effectiveness of the antioxidant in preserving the API degradation. It is possible that individual tablets were slightly under the average target weight due to minor losses during compression, which may have contributed to the lower assay values seen in these samples. Impurity growth was seen gradually increased for samples that contained propyl gallate, cysteine hydrochloride and sodium metabisulfite with the maximum of cysteine hydrochloride at 4.49%. The butylated hydroxytoluene (BHT) and butylated hydroxy anisole (BHA) whether used individually or in combination, were effective in protecting the API from degradation. Comparative analysis indicated that these antioxidants had a faster O – H bond dissociation enthalpy (BDE) than the other antioxidants studied. Additionally, proton dissociation enthalpy (PDE) and ionization potential (IP) further supported the superior performance of BHT and BHA over propyl gallate, cysteine hydrochloride, and sodium metabisulfite. Sodium metabisulfite was seen with more impurities for samples only at t=0; this is clearly an artifact. Most of the unknown impurities were below LOQ or none detected.

Conclusion: Among all the samples evaluated, butylated hydroxytoluene (BHT) either alone or in combination with  butylated hydroxy anisole (BHA), demonstrated the most effective protection against API degradation. Based on these results, all other antioxidants were excluded from consideration for further development.

References: 1.FDA’s inactive ingredient guide
2.Computational study of synthetic and natural polymer additives — Antioxidant potential of BHA, TBHQ, BHT, and curcumin
https://www.sciencedirect.com/science/article/pii/S0141391022001616

Acknowledgements: Thanks to all individuals who contributed to this project.

Figure 1. AB7345 Known Impurity growth

Figure 2. Total Impurity growth