Statistical analysis of long-term physical stability testing of amorphous solid dispersions

Abstract

The underlying mechanisms governing amorphous solid dispersions (ASDs) stability are complex and influenced by multiple factors, making it a difficult problem to address comprehensively. The current study investigates how various factors affect the long-term physical stability of ASDs, focusing on both procedural and molecular-level influences. Six drugs were formulated with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as the polymeric carrier, and three preparation methods—two solvent-based processing and one mechanochemical activation—were employed to create the ASDs.

We conducted stability experiments at maximum drug load, exposing the ASDs to five different storage conditions varying in temperature and relative humidity over a one-year period. Results indicated that hydrogen bonding was identified as having a particularly strong impact on stability; however, the role of hydrogen bonding varied according to the intrinsic crystallization tendencies of the specific drugs used. In addition to these empirical observations, logistic regression and survival analysis were used to analyze the experimental data, enabling us to quantitatively assess the influence of different factors on ASDs crystallization rates.

The significant effects of intermolecular hydrogen bonding and storage environment humidity on stability were consistently found in all models, providing a statistically robust framework for predicting stability outcomes based on these variables. Combining experimental stability data of ASDs with statistical analysis enables more robust insights and predictive capabilities, allowing for optimized design and stability forecasting of ASDs dosage forms.

Materials

Caffeine (CFN) was purchased from Sigma-Aldrich (Overijse, Belgium) and fenofibrate (FNB) was supplied by Hangzhou Dayangchem Co. (Hangzhou City, China). Indomethacin (IND) was purchased from Alfa-Aesar (Kandel, Germany). Miconazole (MCN), Naproxen (NAP) and Nimesulide (NSL) were obtained from Janssen Pharmaceutica N.V. (Beerse, Belgium), SA Fagron NV (Waregem, Belgium) and LKT Laboratories (St. Paul, Minnesota, USAs), respectively. Poly(vinylpyrrolidone-co-vinyl acetate) 64 (PVPVA 64).

Jingya Wu, Guy Van den Mooter, Statistical analysis of long-term physical stability testing of amorphous solid dispersions, International Journal of Pharmaceutics, 2025, 125844, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125844.