An approach for pH-independent release of poorly soluble ionizable drugs using hot melt extrusion
Hot melt extrudates with combinations of Soluplus® and Aqoat® AS-L or Eudragit® EPO were investigated to improve drug release and to overcome the pH-dependent release of poorly water-soluble basic (itraconazole, ITZ) and acidic (mefenamic acid, MFA) drugs. The release of ITZ was improved in both 0.1 N HCl and PBS pH 6.8 by hot-melt extrusion with combinations of Soluplus®:Aqoat® AS-L and can be adjusted by varying the ratio of the polymers.
At the ratio Soluplus®:Aqoat® AS®LF 75:25 an almost pH-independent release was achieved without any drop in the drug concentration within 24 h. A pH-independent and extended release (over 24 h) was obtained from milled extrudates when formulated in erodible matrix tablets using 15% Methocel® K15M as the carrier. The release of MFA from extrudates with Soluplus® was immediate only in PBS pH 6.8.
From extrudates with cationic Eudragit® EPO the release of MFA was slow at 0.1 N HCl and PBS pH 6.8, due to poor drug solubility and insoluble Eudragit® EPO, respectively. However, in the medium with an intermediate pH of 5.5, both MFA and Eudragit® EPO are highly ionized, and the release was fast, complete, and stable within 24 h. These release behaviors could be to some degree applicable for immediate or enteric, but not for extended-release formulations.
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Materials
The materials were used as received: ITZ (BASF SE, Ludwigshafen, Germany), MFA (Sigma Aldrich, Chemie GmbH, Steinheim, Germany), PEG 6000-vinylcaprolactam-vinyl acetate graft copolymer (Soluplus®; BASF AG, Ludwigshafen, Germany), hydroxypropyl methylcellulose acetate succinate (HPMCAS, Shin-Etsu Aqoat® AS-LF; ShinEtsu Chemical Co.,Ltd), aminoalkyl methacrylate copolymer E (Eudragit® E PO; Evonik Industries AG, Darmstadt, Germany), hydroxypropyl methylcellulose (HPMC, Methocel® K15M, Colorcon Ltd., Dartford Kent, UK), co-processed lactose monohydrate, povidone K30 and crospovidone (Ludipress®; BASF SE, Ludwigshafen, Germany), microcrystalline cellulose (Avicel® PH 102; FMC BioPolymer, Newark, USA), croscarmellose sodium (AC-Di-Sol®; FMC BioPolymers, Philadelphia, PA, USA), talc (Luzenac® pharma; Luzenac Europe, Toulouse, France).
May Darwich, Valentyn Mohylyuk, Karl Kolter, Roland Bodmeier, Andriy Dashevskiy, An approach for pH-independent release of poorly soluble ionizable drugs using hot melt extrusion, Journal of Drug Delivery Science and Technology, 2024, 106027, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106027.
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