Track: Formulation and Delivery - Chemical - Formulation - Predictive Modeling
Category: Poster Abstract
Accelerated Stability Assessment for an Oral N-type Calcium Channel Blocker
Purpose: Accelerated Stability Assessment Program (ASAP), enables scientists to quickly and accurately determine product shelf-life. A range of scientifically and statistically designed exposure conditions are used to force a product to fail (hit its stability specification limits). Using these edge-of-failure times (called isoconversion times) at a range of conditions allows the software to project the long-term storage shelf-life based on short-term data. Z-160 is an oral N-type calcium channel blocker for chronic neuropathic and nociceptive pain. The crystalline form of this molecule exhibits low solubility and is poorly bioavailable (BCS class II). Physiochemical properties for Z160 are reported in Figure 1. The amorphous form of the drug along with the dispersion polymer enables fast dissolution and sustained supersaturation in bio-relevant media, which increases bioavailability. Formulations at high drug loadings – 40%A, 70%A - with a commonly used amorphous dispersion neutral polymer, PVP-VA64 (Kolliphor VA64, BASF) were evaluated. Polymer type and active loading have a significant impact on the chemical and physical stability of the amorphous solid dispersion. To understand the effects on chemical and physical stability, these PVP-VA64 formulations were placed on stability, and the results were modeled using ASAPprime® to predict a shelf-life. Methods: Listed in Table 1 are the Z160 formulations assessed in this study and the length of each study. During the stability assessment, it is important to not cross any phase boundaries (e.g glass transition, Tg) as this significantly affects the linearity of degradation rates. As a result, the length of the study is primarily determined by the Tg and degree of water uptake by the SDI. A representative ASAP stability protocol and a representative sample setup is shown in Figure 2. The condition and timepoints are listed along with the appropriate saturated salt solution to maintain that humidity at the specified temperature. Samples were analyzed for chemical stability via assay/impurities HPLC method, and physical stability via mDSC, SEM and XRD. These results were input into the ASAPprime® model and the resulting parameters, ln A, k and B term, were compared. Results: Experiments are ongoing at the time of submission. Results will be available at the time of the conference. Conclusion: ASAP stability studies are being increasingly applied across the pharmaceutical industry. The ASAP model is based on the Arrhenius equation, modified to include a term to account for the effect of humidity on isoconversion rates. Samples are held at more aggressive conditions than a traditional stability test while also taking care not to cross any phase boundaries within the formulation. Statistical methods are applied to ensure a good fit of the data and to provide a deeper understanding of the factors that affect isoconversion rates. ASAPprime® has been shown to be a valuable tool for shelf life prediction of pharmaceutical formulations in a time-efficient manner.