(T0930-06-39) Stability of Nifedipine Amorphous Solid Dispersions (ASDs) with Low Drug Loading in Rodent Chow

Purpose: Amorphous solid dispersions (ASDs) are a leading strategy for enhancing the oral bioavailability of poorly water-soluble drugs. However, ASDs tend to crystallize over time, particularly under stress conditions such as high humidity, elevated temperatures, or high drug loadings (≥30% w/w), ultimately compromising their solubility advantage. In multidose animal studies spanning weeks to years, standard oral dosing becomes labor-intensive and impractical. A feed-based delivery system enables continuous, voluntary drug intake and offers a practical approach for evaluating ASD physical stability under extended dosing conditions. In this study, we selected nifedipine (NIF), a BCS Class II compound, as a model drug to explore the application of low drug-load ASDs in mouse chow for manufacturing, storage and use stability assessment. We evaluated 5% drug-loaded ASDs formulated with Polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA 64), Hypromellose acetate succinate (HPMC-AS 912), and a ternary ASD containing ethyl cellulose (EC). Our goal was to identify ASDs that maintain the ability to generate supersaturation and withstand stress conditions, as evaluated by accelerated stability testing (80°C/75% RH, 7 days). Non-sink dissolution testing was used as a sensitive method for detecting recrystallization at low drug concentrations.

Methods: Binary ASDs were prepared by spray-drying 5% NIF with 95% of either PVP/VA 64 or HPMC-AS 912. A ternary formulation was subsequently developed by combining 5% NIF, 90% HPMC-AS 912, and 5% (EC). The ternary system was designed to leverage the supersaturation-promoting properties of HPMC-AS 912 and the moisture resistance of hydrophobic EC to enhance physical stability under stress conditions. All formulations were subjected to stressed stability testing at 80°C/75% RH for 7 days. Physical characterization was conducted using differential scanning calorimetry (DSC) to determine glass transition temperatures (Tg) and evaluate crystallinity. Dissolution studies were performed under non-sink conditions in phosphate-buffered saline (PBS) over 120 minutes at a target concentration of 300 µg/mL to evaluate supersaturation behavior and recrystallization sensitivity and decreased dissolution.

Results: Figure 1 shows the supersaturation profiles and thermal characteristics of binary NIF ASDs of HPMC-AS912 and PVP/VA 64. Under non-sink dissolution conditions in PBS (300 µg/mL) as seen in Figure 1A, both ASDs achieved supersaturation relative to crystalline NIF, with the HPMC-AS 912 formulation exhibiting better supersaturation performance. The area under the curve (AUC) for the HPMC-AS 912-based ASD was 13.1 mg·min/mL, compared to 5.48mg·min/mL for the PVP/VA 64-based ASD. DSC analysis in Figure 1B confirmed elevated glass transition temperatures in both ASDs relative to amorphous NIF (Tg = 46.6°C). The PVP/VA 64 ASD exhibited a Tg of 106°C, while the HPMC-AS 912 ASD reached 113°C. Following accelerated stability testing (80°C/75% RH, 7 days), both ASDs showed reduced supersaturation (Figure 2A), though the HPMC-AS 912 ASD maintained higher supersaturation than the PVP/VA 64 ASD. Post-stress DSC results (Figure 2B) revealed a decline in Tg presumably due to plasticization by water: from 113°C to 105°C for the HPMC-AS 912 ASD, and from 106°C to 102°C for the PVP/VA 64 ASD. No DSC evidence of recrystallization was detected in either formulation. The ternary ASD, formulated with 90% HPMC-AS 912, 5% EC, and 5% NIF, is presented in Figure 3. Under non-sink dissolution conditions (Figure 3A), the ternary ASD achieved supersaturation relative to crystalline drug, and a performance declined under stressed conditions. Compared to the binary ASD of 95% HPMC-AS 912 w/ 5% NIF, the ternary system displayed slightly lower supersaturation, with an AUC of 4.81 mg·min/mL versus 5.46 mg·min/mL. DSC analysis of the ternary ASD showed a Tg of 111°C before stress and 108°C after 7-day exposure to 80°C/75% RH. No DSC evidence of crystallization was observed by DSC following stress exposure.

Conclusion: NIF:HPMC-AS 912 outperformed NIF:PVP/VA 64 in maintaining supersaturation and showed higher stressed stability. Stressed stability studies revealed a reduction in supersaturation for both systems, with HPMC-AS 912 retaining higher levels. DSC confirmed Tg depression through plasticization after stress, but no recrystallization was observed. EC in the NIF:HPMC-AS 912:EC ternary ASD helped reduce the rate of supersaturation loss but did not enhance supersaturation capacity overall. Non-sink dissolution was sensitive enough to detect differences in low level recrystallization behavior among formulations.

References: 1. Wang, Z., Lou, H., Dening, T. J., & Hageman, M. J. (2023). Biorelevant dissolution method considerations for the appropriate evaluation of amorphous solid dispersions: Are two stages necessary? Journal of Pharmaceutical Sciences, 112(6), 1089–1107

Acknowledgements: This work was supported in full by a grant from the Department of Pharmaceutical Chemistry and the Stella Endowment Funds, University of Kansas.


Figure 1. Analysis of nifedipine ASDs: 95% PVP/VA 64 w/ 5% NIF and 95% HPMC-AS 912 w/ 5% NIF


Figure 2. Accelerated stability analysis (80°C/75% RH, 7 days) of 5% NIF w/ 95% PVP/VA 64 and 95% HPMC-AS 912


Figure 3. Accelerated stability analysis (80°C/75% RH, 7 days) of ternary nifedipine ASDs:5% NIF w/ 90% HPMC-AS 912 w/ 5% EC