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The general strategy in the pharmaceutical industry involves selecting candidates free from physicochemical problems and then developing them using simple dosage forms. In reality, however, formulators frequently deal with challenging compounds, including those with poor aqueous solubility. Enabling formulations that eliminate dissolution/solubility problems are strong options for such candidates – and among all the solutions that can help with dissolution or solubility problems, much attention has been paid to supersaturatable dosage forms, including amorphous solid dispersions (ASDs) and nanocrystals.

It is important to understand that supersaturation is a state of non-equilibrium, so separation into the concentrated and diluted phases is initiated by spinodal decomposition (that is to say, without producing nuclei in the solution). The recent consensus in this field is that phase separation may occur very quickly, even in cases in which solutions remain transparent. The concentrated phase may be transformed into solid nanoparticles and is typically stabilized by polymeric excipients. This phenomenon is often observed in in vitro dissolution studies, but the situation in vivo should be slightly different. Nanoparticles are not expected to be absorbed in the gastrointestinal tract; however, drug molecules may be absorbed before forming a nanoparticle if the permeation process is sufficiently prompt. Because of this, careful investigation of the supersaturated state is required, including consideration of in vitro–in vivo correlation. One fact that is important to recognize is that the presence of nanophases in the supersaturation may not be visible to the naked eye. In addition, the nanophase may or may not contribute to absorption in vivo, which should depend on permeability of the drug molecule.

Achieving physical stability is one problem for supersaturatable enabling formulations; for example, ASDs can cause phase separation or crystallization, which can eliminate their advantages. The most representative manufacturing method for ASDs is hot melt extrusion, which possibly leads to phase separation during storage, because extrusion is usually conducted under high temperature (typically, above 100 °C). As time passes, phase separation may proceed at the storage temperature because the miscibility at high temperatures is generally higher than that after cooling to ambient temperature. Spray-drying is another major method for producing ASDs, but the resultant solids may not have a stable mixing state; mixing behavior is influenced by presence of the solvent and its rapid evaporation during the manufacturing process. Although an accelerated stability test is inevitable in the formulation developmental study, understanding the data for ASDs is not straightforward. From a viewpoint of molecular mobility, you may expect phase separation to proceed faster under higher temperatures, but thermodynamics predict faster phase separation when temperature decreases. We should also bear in mind that the Arrhenius rule, which is the basis of accelerated stability studies, does not hold for ASDs.

Crystallization behavior of amorphous drugs has typically been understood on a case-by-case basis; however, careful investigation has revealed the existence of a universal initiation time for crystallization. Although there is a group of compounds that have a relatively large energy barrier for crystallization, the barrier can be removed by enhancing the nucleation process, such as by increasing the surface area. Initiation time for crystallization can be predicted solely from information on the glass transition temperature – and 3-year stability under room temperature can be assured if the glass transition temperature is higher than 48 °C. Therefore, when reaching the accelerated stability test in the developmental process, perhaps all formulators need to do is confirm the applicability of the universal rule for the formulation of interest. In this regard, chemical modification to enhance the energy barrier for nucleation may be an option for molecular design, if there is a dissolution or solubility problem associated with the candidate.

Despite the many challenges posed by supersaturatable dosage forms, there is no doubt that they are attractive formulation options. Other solubilization technologies – with the help of surfactants, solvents, and so on – can decrease permeability, which means there can be a trade-off for the solubility improvement. Overall, I believe that further improvement of drug development technology will be partially dependent on further understanding of supersaturatable dosage forms.