(M0930-07-45) Predictive Stability Modeling of Softgels

Purpose: Prediction of shelf-life during formulation development is one of the key aspects to successful drug product development. Additionally, if the assessment process is quick and efficient it can help us compare different formulation possibilities for the product at an early stage of drug development. This study was conducted to determine the shelf-life of two softgel formulations containing 200 mg and 400 mg of Ibuprofen. The aim was to identify the key degradant species and their impact on the stability and longevity and finally predict the stability of the softgels. The moisture-modified Arrhenius equation, ln k = lnA -Ea/RT + B(RH), was employed to model the degradation kinetics of the formulations. Zero-order degradation kinetics were observed, indicating a constant rate of degradation independent of the initial concentration of the degradant species. The shelf-life limiting species for each formulation was identified to be the Ibuprofen Poly-Ethylene Glycol (PEG)-Esters. The stability of the softgels was compared to historical ICH long term stability studies at 25°C/60%RH in blister packaging showed good agreement between modeled and actual data.

Methods: Thirty stress conditions were selected for a total of 21 days between 40°C and 80°C and 11% to 75%RH. The stressed samples were analyzed for impurities via a validated HPLC method for assay and impurities, and these concentrations were modeled using ASAPprime® software (version 6.0.1, FreeThink Technologies)

Results: The degradation of the 200 mg and 400 mg ibuprofen softgels were analyzed, focusing on several degradant species, including those at relative retention time (RRT) 0.18, RRT 0.20, ibuprofen sorbitol ester 1 (RRT 0.34), ibuprofen sorbitol ester 2 (RRT 0.405), RRT 0.417, and the PEG-esters. These species exhibited consistent growth in stressed samples and were subsequently modeled. This software employs the moisture-modified Arrhenius equation: ln k = lnA -Ea/RT + B(RH), and calculates the following terms: E_a (activation energy): indicates sensitivity to temperature. B: the humidity sensitivity factor. ln A: the collision frequency. The degradation data were fitted using zero-order kinetics, which provided the best modeling results. The ASAPprime® model parameters for the degradant species in the 200 mg and 400 mg softgels are summarized in Table 1. The average activation energy (Ea) for various products is 32.1 ± 17.6 kcal/mol (ref: ThermoFisher Accelerated Stability Database). Notably, the PEG-Esters showed lower-than-average Ea values, indicating a lower energetic barrier for degradation and thus higher temperature sensitivity. The average moisture sensitivity (B) term for various products is 0.024 ± 0.024 (ref: ThermoFisher Accelerated Stability Database). The modeled degradant species exhibited low and some negative B values, suggesting low moisture sensitivity, which is consistent with the complete solubilization of ibuprofen in the formulation. Shelf-life predictions for both the 200 mg and 400 mg ibuprofen softgels are presented in Table 2. The PEG-Esters, with retention times (RRT) ranging from 0.41 to 0.82, were identified as the shelf-life limiting degradants for both dosage strengths. This is attributed to their lower probabilities of meeting the specification limit under the given conditions. Figure 1 shows the shelf-life predictions for 200 mg and 400 mg ibuprofen softgels (PEG Esters) along with actual ICH data points. The data points closely align with the predicted values. The intersection with the specification limit (red line) indicates the shelf-life: 5.5 years for the 200 mg softgel (blue line) and 3.8 years for the 400 mg softgel (orange line).

Conclusion: The 21-day accelerated predicative stability study provided several insights into the long-term stability of 200 mg and 400 mg Ibuprofen softgels, and showed accelerated stability can be applied effectively to softgel formulations to predict the shelf-life. First, the shelf-life limiting species for both the 200 mg and 400 mg softgels was identified as the PEG-esters. Second, all modeled degradant species followed zero-order kinetics, indicating that the degradation rate remained constant irrespective of the initial concentration. Lastly, the 200 mg Ibuprofen softgels exhibited greater stability with a shelf-life of 5.5 years, compared to the 3.8-year shelf-life of the 400 mg softgels. The observed differences in stability between the two formulations can be attributed to several factors. The higher ratio of API to KOH in the 400 mg formulation results in less KOH available to neutralize the Ibuprofen, leaving more non-ionized Ibuprofen (R-COOH) to form Ibu-PEG esters, thus accelerating degradation. Additionally, the degree of neutralization of ibuprofen is lower in the 400 mg softgels, leading to a greater proportion of non-ionized Ibuprofen available for degradation. Furthermore, the higher water content in the 400 mg formulation may facilitate hydrolytic degradation reactions, contributing to the shorter shelf-life. These findings offer valuable guidance for optimizing the formulation and storage conditions of Ibuprofen softgels. Accelerated predictive stability modeling is a valuable tool for risk assessment of the degradation pathways, drug-excipient interactions, and enables rapid determination of shelf-life.


Modeled parameters for degradant growth in 200 mg and 400 mg Ibuprofen Softgels


Shelf-life predictions for 200 mg and 400 mg Ibuprofen Softgels in open packaging


% Degradant vs. Time for the PEG-Esters in the 200mg (orange line) and 400 mg (blue line) softgels with real-time ICH data (circles) and the shelf-life (stars) marked at the intersection of the specification limit (red line).