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Mol Pharm. 2017 Dec 4;14(12):4154-4160. doi: 10.1021/acs.molpharmaceut.7b00422. Epub 2017 Aug 16.

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

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Department of Pharmacy, University of Copenhagen , DK-2100 Copenhagen, Denmark.
Department of Micro- and Nanotechnology, Technical University of Denmark , DK-2800 Lyngby, Denmark.
Philips BioCell A/S , DK-3450 Allerød, Denmark.
Bioneer:FARMA, University of Copenhagen , DK-2100 Copenhagen, Denmark.
Faculty of Science and Engineering, Åbo Akademi University , Tykistökatu 6A, 20521 Turku, Finland.


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.


crystalline; oral drug delivery; precipitation; supersaturation

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