Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC

Abstract

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

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

“…However, the use of manual microscopy is not highly prevalent in the literature, probably due to the time and labour requirements. To circumvent this, various studies have combined conventional microscopy with video analysis …”

“…utilised such a system to investigate supersaturated solutions of tadalafil in the presence and absence of a PI, HPMC. Samples were viewed under video light microscopes, and multiparticle analysis was carried out on the videos to assess total precipitation as a function of time …”

In vitro methods to assess drug precipitation in the fasted small intestine – a PEARRL review

“…Christfort et al ., developed a video‐microscopic tool to assess the precipitation of tadalafil and the efficacy of precipitation inhibitors. Using a 96‐well microplate, 30 μl of a tadalafil DMSO stock solution was added to FaSSIF with varying concentrations (0.0–5.0% w/v) of HPMC, acting as a precipitation inhibitor.…”

Six years of progress in the oral biopharmaceutics area – A summary from the IMI OrBiTo project

“…For more mechanistic studies of nucleation and precipitation, a video microscopy approach with image analysis has been developed. This approach, based on a high-throughput multiple well plate format, also provides a tool particularly suitable for early risk evaluation of precipitation and the excipients that could be used to avoid this phenomenon (26).…”