title: Indomethacin-Kollidon VA64 Extrudates: A Mechanistic Study of pH-Dependent Controlled Release.
abstract: Because of its weakly acidic nature (pKa of 4.5), indomethacin presents an aqueous solubility that significantly increases when changing from acidic to neutral/alkaline pH (1.5 μg/mL at pH 1.2 and 105.2 μg/mL at pH 7.4). We have therefore investigated the impact of the dissolution medium pH on the dissolution performance of indomethacin:Kollidon VA64 extrudates. The impact of the drug loading on the dissolution properties of these systems was also examined (5%, 15%, 30%, 50%, 70%, and 90% drug loading). Time-resolved Raman spectroscopy along with in-line UV-vis spectrophotometry was employed to directly relate changes in dissolution behavior to physicochemical changes that occur to the extrudate during the test. The dissolution tests were performed in pH 2 HCl (to mimic the stomach conditions), and this was then switched during the experiment to pH 6.8 phosphate buffer (to simulate the poststomach conditions). The rotating disc dissolution rate test was also used to simultaneously measure the dissolution rate of both the drug and the polymer. We found that in pH 2 HCl buffer, for the 15% or higher drug-loaded extrudates, Kollidon VA64 preferentially dissolves from the exterior of the compact leaving an amorphous drug-rich hydrophobic shell, which, similarly to an enteric coating, inhibits the drug release. The in situ formation of an enteric coating has been previously hypothesized, and this has been the first time that is directly observed in a pH-variable dissolution test. The dissolution medium switch to pH 6.8 phosphate buffer, due to the large increase of the aqueous solubility of indomethacin at this pH, leads to rapid dissolution of the material forming the coating and therefore total drug release. In contrast, the 5% extrudate is fully hydrated and quickly dissolves at low pH pointing to a dissolution performance dependent on highly water-soluble Kollidon VA64.
authors: School of Pharmacy, Boots Science Building, University of Nottingham , Nottingham, NG7 2RD, United Kingdom.
authors: Francesco
authors: F
authors: Tres
authors: Pharmaceutical Development, AstraZeneca , Macclesfield, SK10 2NA, United Kingdom.
authors: Kevin
authors: K
authors: Treacher
authors: Pharmaceutical Development, AstraZeneca , Macclesfield, SK10 2NA, United Kingdom.
authors: Jonathan
authors: J
authors: Booth
authors: Pharmaceutical Development, AstraZeneca , Macclesfield, SK10 2NA, United Kingdom.
authors: Leslie P
authors: LP
authors: Hughes
authors: Pharmaceutical Development, AstraZeneca , Macclesfield, SK10 2NA, United Kingdom.
authors: Stephen A C
authors: SA
authors: Wren
authors: School of Pharmacy, Boots Science Building, University of Nottingham , Nottingham, NG7 2RD, United Kingdom.
authors: Jonathan W
authors: JW
authors: Aylott
authors: School of Pharmacy, Boots Science Building, University of Nottingham , Nottingham, NG7 2RD, United Kingdom.
authors: Jonathan C
authors: JC
authors: Burley
mesh_terms: D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D065546:Drug Liberation; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism; D013059:Spectrum Analysis, Raman; D014753:Vinyl Compounds / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D005079:Excipients; D011108:Polymers; D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate); D014867:Water; D007213:Indomethacin
keywords: UV−vis spectrophotometry; amorphous solid dispersions; hot melt extrusion; intrinsic dissolution rate; pH-variable dissolution; poorly soluble drugs; time-resolved Raman spectroscopy