The preparation of amorphous solid dispersion (ASD) formulations is a promising strategy to improve the bioavailability of an active pharmaceutical ingredient (API). By dissolving the API in a polymer it is stabilized in its amorphous form, which usually shows higher water solubility than its crystalline counterpart. To prevent recrystallization, the long-term physical stability of ASD formulations is of big interest. In this work, the solubility of the APIs acetaminophen and naproxen in the excipient polymers poly(vinylpyrrolidone) (PVP K25) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was calculated with three models: the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the Flory-Huggins model (FH), and an empirical model (Kyeremateng et al., J. Pharm. Sci, 2014, 103, 2847-2858). PC-SAFT and FH were further used to predict the influence of relative humidity (RH) on the API solubility in the polymers. The Gordon-Taylor equation was applied to model the glass-transition temperature of dry ASD and at humid conditions. The calculations were validated by 18 months-long stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. The results of the three modeling approaches for the API solubility in polymers agreed with the experimental solubility data, which are only accessible at high temperatures in dry polymers. However, at room temperature FH resulted in a lower solubility of the APIs in the dry polymers than PC-SAFT and the empirical model. The impact of RH on the solubility of acetaminophen was predicted to be small, but naproxen solubility in the polymers was predicted to decrease with increasing RH with both, PC-SAFT and FH. At 25 °C/60% RH and 40 °C/75% RH, PC-SAFT is in agreement with all results of the long-term stability studies, while FH underestimates the acetaminophen solubility in PVP K25 and PVPVA64.

The purpose of this work is to compare the long-term physical stability of amorphous solid dispersion (ASD) formulations based on three different commercially used excipients, namely, poly(vinylpyrrolidone) K25 (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxypropyl methylcellulose acetate succinate 126G (HPMCAS), at standardized ICH storage conditions, 25 °C/0% relative humidity (RH), 25 °C/60% RH, and 40 °C/75% RH. Acetaminophen (APAP) and naproxen (NAP) were used as active pharmaceutical ingredients (APIs). 18 month long stability studies of these formulations were analyzed and compared with the API/polymer phase diagrams, which were modeled and predicted by applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor or Kwei equation. The study showed that, at dry storage, the solubility of the APIs in the polymers and the kinetic stabilizing ability of the polymers increase in the following order: HPMCAS < PVPVA64 < PVP. RH significantly reduces the kinetic stabilization as well as NAP solubility in the polymers, while the impact on APAP solubility is small. The impact of RH on the stability increases with increasing hydrophilicity of the pure polymers (HPMCAS < PVPVA64 < PVP). The experimental stability results were in very good agreement with predictions confirming that PC-SAFT and the Kwei equation are suitable predictive tools for determining appropriate ASD compositions and storage conditions to ensure long-term physical stability.

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An exploratory analysis of a large representative dataset obtained in a fluidized bed drying process of a pharmaceutical powder has revealed a significant correlation of spectral intensity with granulate humidity in the whole studied range of 1091.8–2106.5 nm. This effect was explained by the dependence of powder refractive properties, and hence light penetration depth, on the water content. The phenomenon exhibited a close spectral similarity to the well-known stochastic variation of spectral intensities caused by the process turbulence (the so-called “scatter effect”). Therefore, any traditional scatter-corrective preprocessing incidentally eliminates moisture-correlated variance from the data. To preserve this additional information for a more precise moisture calibration, a time-domain averaging of spectral variables has been suggested. Its application resulted in a distinct improvement of prediction accuracy, as compared to the scatter-corrected data. Further improvement of the model performance was achieved by the application of a dynamic focusing strategy when adjusting the model to a drying process stage. Probe fouling was shown to have a minor effect on prediction accuracy. The study resulted in a considerable reduction of the root-mean-square error of in-line moisture monitoring to 0.1%, which is close to the reference method's reproducibility and significantly better than previously reported results.