Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

Abstract

Precipitation inhibitors are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.

In-line derivative spectroscopy as a promising application to a small-scale in vitro transfer model in biorelevant supersaturation and precipitation testing

“…Ketoconazole expressed high supersaturation, exceeding the thermodynamic solubility of the drug in FaSSIF pH 6.5, during the in vitro transfer model experiment. Due to its thermodynamically instable state, supersaturation leads to drug precipitation, resulting in a decreased amount of API in solution. As expected, the supersaturation and precipitation behaviour of ketoconazole can be related to the physicochemical properties and the pH‐dependent solubility of the API (Table ) .…”

Calculation of drug-polymer mixing enthalpy as a new screening method of precipitation inhibitors for supersaturating pharmaceutical formulations

“…Due to this, there is an innate tendency for the supersaturated solution to return to a lower energy state, through precipitation. Therefore, to derive maximum benefit from supersaturation of the API, such formulations often include a precipitation inhibitor to sustain the period over which the API remains in solution (Price, 2018). This formulation approach is often referred to as the "spring and parachute" model (Guzman, 2007).…”

“…Currently, the mechanistic details of precipitation inhibition are not fully understood, and the specific molecular properties that yield efficient precipitation inhibitors have not yet been clarified. Given this uncertainty, a variety of hypotheses for the molecular mechanisms of precipitation inhibition have been proposed (Warren, 2010;Price, 2018). Additionally, it appears that precipitation inhibition is also an API-specific process.…”

“…Analytical techniques such as UV spectroscopy, HPLC or nephelometry are then applied to track changes in concentration of API in solution or precipitation over time. These concentration time profiles are then used to provide a measure of PI effectiveness (Price et al, 2018). One of the recent developments in this area is the µDISS™ profiler, which applies in situ UV probes in combination with liquid handling to study supersaturation and precipitation in real time.…”

“…In addition to the time and cost resources involved, this approach is unlikely to lead to certain identification of the most effective precipitation inhibitor, but rather to "one that works". To date, most supersaturating formulations incorporate one of a standard set of polymers, such as hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP) or hydroxypropyl methyl cellulose (HPMC) (Warren, et al 2010;Price, 2018). To overcome these drawbacks, there have recently been various attempts to establish a more mechanistic rational for precipitation inhibitor selection, as reviewed by Price et al (Price, 2018).…”