Measuring and Modeling Water Sorption in Amorphous Indomethacin and Ritonavir

Abstract

The amorphous state of an active pharmaceutical ingredient (API) enhances its water solubility compared to its crystalline state. However, it is well known that amorphous substances can absorb significant amounts of water therewith inducing API recrystallization. This work explores methods to obtain reliable information about water sorption in amorphous APIs and its modeling. Experimental water-sorption curves over a broad humidity range were obtained by measuring the mass increase of well-defined films of amorphous APIs. Water-sorption isotherms modeled using perturbed-chain statistical associating fluid theory (PC-SAFT) showed better accordance with the experimental data than those obtained using the Flory−Huggins model. Crank's diffusion equation was used to describe the water-sorption kinetics providing Fickian diffusion coefficients of water in indomethacin and in ritonavir. Stefan−Maxwell diffusion coefficients were obtained by converting Fickian diffusion coefficients using water activity coefficients obtained from PC-SAFT. Finally, the free-volume theory was applied to explain the persistent water concentration dependency of the Stefan−Maxwell diffusion coefficients.

Predicting the Water Sorption in ASDs

“…The PVP-IND solutions contained 58 wt% ethanol for both drug loads and were spun at 2000 rpm for the drug load of 0.2 and at 1150 rpm for a drug load of 0.5. These specifications allowed the preparation of ASD films with thicknesses of ~7-9 µm, making them comparable to the PVP and PVPVA films and the amorphous IND films from our previous works [9,10]. Furthermore, the geometry of all considered films represents an ideal cylinder, and all films share the same circular base area with a diameter of 14.5 mm.…”

“…We utilized concepts from the free-volume theory to predict the water-concentration dependency of Ð w using the water concentration dependencies of Ð wa and Ð wp . As demonstrated in previous studies [10,11], the free-volume theory can be used to describe the water-concentration dependencies of Ð wa in amorphous APIs, and of Ð wp in PVP-based polymers. The central assumption of the free-volume theory is that solvent(water) diffusion coefficients depend on the free volume of the system, which is the volume that is not occupied by the molecules of that system.…”

“…As a result, the plasticization factors Ψ w for most ASDs, polymers and APIs are similar. As a consequence, we use a piecewise-linear polynomial of the experimentally determined water concentration dependency of Ð wa (Ψ w ) and Ð wp (Ψ w ) from previous work [10,11] (summarized in Table 2) for safe interpolations when predicting Ð w (Ψ w ) in this study (see Figure 2c).…”

“…The binary interaction parameter k ij = −0.0621 between PVPVA and IND was fitted in this study to the solubilities of IND in PVPVA which is shown in Figure S1 in the Supporting Information. a taken from previous work [9], b taken from previous work [10], c estimated using the Simha-Boyer rule [25] using ρ 0i and T g,0i .…”

“…The specific volume v NE 0a of IND in non-equilibrium was assumed to be identical to the specific volume of v EQ 0a in equilibrium calculated by PC-SAFT without NET-GP and the non-equilibrium parameter between water and API was set to zero (k NE wa = 0). The water-concentration dependency of Ð wa for water in IND was calculated from a previous work [10] which determined the Maxwell-Stefan diffusion coefficient Ð wa of water in IND. Ð wa considers molecular friction instead of segmental friction.…”