Impact of Polymers on the Precipitation Behavior of Highly Supersaturated Aqueous Danazol Solutions

Abstract

The phase behavior of supersaturated solutions of a relatively hydrophobic drug, danazol, was studied in the absence and presence of polymeric additives. To differentiate between phase separation to a noncrystalline phase and phase separation to a crystalline phase, an environmentally sensitive fluorescent probe was employed. Induction times for crystallization in the presence and absence of polymeric additives were studied using a combination of ultraviolet and fluorescence spectroscopy. It was found that, when danazol was added to aqueous media at concentrations above the amorphous solubility, liquid-liquid phase separation was briefly observed prior to crystallization, resulting in a short-lived, drug-rich noncrystalline danazol phase with an initial size of around 500 nm. The addition of polymers was found to greatly extend the lifetime of the supersaturated two phase system, delaying the onset of crystallization from a few minutes to a few hours. Below a certain threshold danazol concentration, found to represent the amorphous solubility, only crystallization was observed. Thus, although the addition of polymers was unable to prevent danazol from precipitating once a threshold concentration was exceeded, they did inhibit crystallization, leading to a solution with prolonged supersaturation. This observation highlights the need to determine the structure of the precipitating phase, since it is linked to the resultant solution concentration time profile.

pH-Dependent Liquid–Liquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs

“…From the fluorescence studies, it is apparent that the second phase formed is noncrystalline, as it has been previously shown that the fluorescent dyes cannot partition into the crystalline phase, and the optical properties of the dye in the presence of crystalline material are similar to those in the aqueous environment. 43 LLPS concentrations as determined by fluorescence experiments at different pHs are shown in Figure 3. There is an excellent agreement between the LLPS concentration obtained from UV experiments and that obtained using fluorescence.…”

Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction

“…Immediately upon contact with aqueous medium, amorphous drug usually dissolves much more rapidly compared with crystalline dose forms, due to the absence of crystal lattice, and the existence of water-soluble polymers. The solution drug concentration usually reaches various supersaturations depending on the physiochemical properties of the drug and the ASD formulation design (10)(11)(12)(13)(14). The initial drug dissolution is vividly termed as Bspring^ (15,16).…”

Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs

“…There are some reports available regarding formulation strategies that can be applied to inhibit in vivo precipitation. [29][30][31][32][33] The cannabinoid receptor 1 antagonists AZD1175 and AZD2207 are highly lipophilic weak bases with low pH-dependent solubility and high intestinal permeability in the Caco-2 model ( Fig. 1 and Table 1).…”