Highly supersaturated aqueous drug solutions are often generated during drug testing and upon delivery to the patient. The phase behavior of such solutions appears complex and poorly understood, with the formation of colloidal drug aggregates often being reported. In this study, the phase behavior of eight hydrophobic poorly water-soluble drug molecules in highly supersaturated aqueous solutions was examined, and colloid formation was explained in terms of liquid− liquid phase separation (LLPS). A relationship was found between the concentration at which LLPS was observed and the theoretically predicted amorphous "solubility" value, where the latter was predicted based on the thermodynamic properties of the crystalline solid/supercooled liquid and solution activity coefficients. A phase diagram for the ritonavir−water system as a function of temperature was used to demonstrate that LLPS occurs in the metastable region of the phase diagram, and thus LLPS is a precursor to crystallization. Using an amorphous solid dispersion of ritonavir and poly(vinylpyrrolidone), it was shown that there is an upper limit to the extent of supersaturation achievable by a supersaturating dosage form and that this limit is dictated by the LLPS phase transition concentration. The approaches outlined in this study provide an alternative way to assess the properties of supersaturating systems, including the determination of the amorphous solubility.

The use of polymeric additives is an increasingly common approach for inhibiting crystallization from the supersaturated solutions used to enhance the delivery of poorly water-soluble drugs. Maintaining supersaturation by employing polymeric additives depends on their ability to inhibit nucleation and crystal growth. In solution crystallization, nucleation initiates the process of crystallization, and therefore adequate control over crystallization from supersaturated solutions cannot be achieved without understanding the mechanism of nucleation inhibition by polymers. In this study, the effectiveness of a group of chemically diverse polymers, including several recently synthesized cellulose derivatives, on induction times in aqueous solutions was quantified. Nucleation was quantified by measuring the induction time for the appearance of particulates from unseeded desupersaturation experiments for three model pharmaceutical compounds: celecoxib, efavirenz, and ritonavir. Induction times in the absence of the polymers varied from approximately 2 min for celecoxib to 2 h for ritonavir. Some polymers were found to extend induction times by up to a factor of 5–6 at the highest supersaturations tested. The effectiveness of the various polymers appeared to depend on the hydrophobicity of the polymer relative to that of the drug. The hydrophobicity of the polymer most likely influences the ability of the polymer to form polymer–solute interactions relative to polymer–solvent and polymer–polymer interactions. Polymer–solute interactions would be expected to hinder the reorganization of a cluster of solute molecules into an ordered crystal structure.

The use of supersaturating dosage forms, such amorphous dispersions, is an increasingly common approach for improving delivery of poorly water-soluble drugs. Crystallization must be prevented to maintain supersaturation, and so, the presence of an effective crystal growth inhibitor in solution is desirable to prolong supersaturation. In this study, the effectiveness of a group of chemically diverse polymers, including a number of novel cellulose derivatives, at inhibiting the crystal growth of ritonavir from solution was quantified, enabling key polymer properties important for crystal growth inhibition of ritonavir to be elucidated. In general, the greater effectiveness of the cellulose derivatives relative to the synthetic polymers was ascribed to a moderate level of hydrophobicity, the semirigid structure of the cellulose polymers, and their amphiphilicity. Interestingly, some of the novel cellulose polymers were found to be more effective crystal growth inhibitors than commercially available cellulose derivatives. Orthogonal partial least-squares analysis further pointed to the importance of polymer hydrophobicity. These properties of the cellulose-based polymers are likely to promote adsorption onto the crystallizing drug surface. Given the diversity of impact of polymers on crystal growth inhibition, it is clearly important to consider this factor when choosing a polymer for a supersaturating dosage form.

The formation of colloidal drug aggregates of lipophilic drugs is thought to be of relevance for the oral delivery of poorly water-soluble drugs. In this study, the underlying basis for colloid formation from amorphous solid dispersions and the impact of additives on colloidal stability were evaluated. A relationship was found between the concentration at which colloidal droplets formed upon dissolution of an amorphous solid dispersion and the liquid-liquid phase separation (LLPS) transition concentration, whereby the latter is related to the theoretical amorphous "solubility" value. The composition of the dispersed phase in ritonavir-polymer-water solutions was confirmed to be a noncrystalline, ritonavir-rich droplet phase. Additives were found to impact the size, stability, and crystallization behavior of the colloidal phase. In general, charged additives reduced the kinetics of droplet coalescence, but had a variable effect on crystallization kinetics, either promoting or inhibiting crystallization. Through proper selection of formulation components, it thus appears possible to promote the formation of ∼ 250-350 nm colloidal droplets of ritonavir following dissolution of an amorphous solid dispersion, and to inhibit coalescence and crystallization from these two-phase supersaturated solutions.

The presence of an effective crystal growth inhibitor in solution is desirable to prolong supersaturation since residual crystalline material in an amorphous formulation resulting from the manufacturing process or formed during storage or dissolution can potentially have a significant impact on the extent and duration of supersaturation. In this study, the effectiveness of a group of chemically diverse polymers, including several recently synthesized cellulose derivatives, on solution crystal growth of three structurally diverse compounds (celecoxib, efavirenz, and ritonavir) was quantified at different extents of supersaturation and compared. Despite the different chemical properties and structures of the model compounds, nonspecific hydrophobic drug-polymer interactions appeared to be important in determining the impact of a given polymer on crystal growth for of all these drug compounds. Specific intermolecular interactions were also found to be important for crystal growth inhibition of celecoxib and efavirenz by the hydrophilic polymer, PVPVA. These interactive forces-hydrophobicity and specific intermolecular interactions-are likely to promote adsorption of the polymer onto the surface of the crystalline drugs, thus influencing crystal growth. The effectiveness of the polymers also depended on the rate of crystallization of the drug molecules. At a similar supersaturation ratio of ∼1.2, ritonavir and celecoxib had slower normalized crystal growth rates (0.20 and 0.91 mg min(-1) m(-2), respectively), while the normalized crystal growth rate of efavirenz was significantly higher (2.97 mg min(-1) m(-2)), resulting in lower levels of crystal growth inhibition by the polymers for efavirenz.