Pharmaceutical scientists often use the term “amorphous solubility” in the context of drug absorption enhancement. However, this terminology often leads to confusion with the uninitiated – which is understandable. After all, the term “solubility” refers to a state of thermodynamic equilibrium, while amorphous materials are in a state of thermodynamic nonequilibrium.

This article aims to explain the concept of the “amorphous solubility” and to clarify its importance when assessing a compound’s developability as an oral drug product.

Crystalline solubility
The solubility of a solid substance (the solute) in a liquid medium (the solvent) is defined as the equilibrium concentration that is reached when the solid is exposed to the solvent. The term solubility thus refers to a state of thermodynamic equilibrium.

The equilibrium solubility of a drug in a given solvent is usually measured using a so-called shake-flask method. In such a protocol, an excess of crystalline drug is added to the solvent, stirred at a constant temperature for a time sufficient to reach equilibrium (usually 24-48 h), after which the remaining solid is separated from the solution phase (e.g., by filtration or centrifugation) and the concentration in solution quantified (e.g., by UV spectrophotometry or UPLC). The concentration measured in this way is the compound's equilibrium solubility.

Profiling the equilibrium solubility of a new drug in physiologically relevant media (e.g., simulated gastric or intestinal fluid) is an essential part of the drug development process, as solubility is a critical determinant of drug absorption: more drug in solution in the gastrointestinal fluids means a higher driving force for absorption and ultimately a higher bioavailability.

Supersaturating formulations
For many current drug candidates, however, the crystalline solubility is (way) too low to allow for adequate absorption. In such cases, a compound can be formulated as a drug delivery system that will release the drug above its crystalline solubility - to generate a state of supersaturation. Achieving drug supersaturation in vivo may be obtained via a number of formulation approaches, for instance following dissolution of a salt or a cocrystal, after dilution of a solution formulation or upon hydration of an amorphous solid dispersion.

Maintaining this state of supersaturation for long enough at the site of absorption can greatly improve oral bioavailability. However, usage of supersaturating drug delivery systems holds the inherent risk of crystallization of the released drug molecules. If crystallization occurs rapidly after release, the absorption-enhancing potential from a supersaturating formulation may be largely negated. The rate and extent of crystallization are highly dependent on the drug’s physicochemical properties and on the conditions in the gastrointestinal tract (pH, mixing behaviour, ionic strength, nutritional state).

The "amorphous solubility" limit
For those compounds that crystallize slowly from their supersaturated solutions, dramatic absorption benefits may be obtained from supersaturating formulations. However, the degree of supersaturation, i.e. the degree to which concentrations can be enhanced above a compound's crystalline solubility, is not endless. The maximum supersaturation that can be attained is dictated by a compound's "amorphous solubility": when this solubility limit is reached, the supersaturated solution will phase-separate into an amorphous drug-rich phase that is in metastable equilibrium with the aqueous phase containing molecularly dissolved drug. This equilibrium is metastable because crystallization can occur from either the phase-separated amorphous drug phase or from the drug-saturated aqueous phase.

This phase-separation effect is comparable to the separation observed when trying to mix oil with water. The point at which this phase separation happens is often referred to by practitioners as the “amorphous solubility”. The scientifically more correct designation of this phenomenon is liquid-liquid phase separation, often abbreviated in scientific journals to LLPS. Nonetheless, the term "amorphous solubility" has been widely adopted in the pharmaceutical community.

Significance of the amorphous solubility
The amorphous solubility limit represents the maximum concentration of molecularly dissolved drug that can be obtained in solution. Since the flux over the gastrointestinal absorptive membrane is directly proportional to the concentration of molecularly dissolved drug, the amorphous solubility provides an indication of the maximum absorption benefit that a supersaturating formulation may provide.

Before initiating a formulation development program for a poorly water-soluble compound, it is therefore highly useful to determine its amorphous solubility. From a drug delivery perspective, the amorphous-to-crystalline solubility ratio is equally important as the actual magnitude of the amorphous solubility, since it provides an indication of how much the bioavailability might be improved by formulating as a supersaturating system such as an amorphous solid dispersion.