期刊
MOLECULAR PHARMACEUTICS
卷 19, 期 1, 页码 318-331出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.1c00805
关键词
telmisartan; drug loading; amorphous solid dispersion; hot-melt extrusion
Maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) can reduce pill burden without compromising dissolution performance. By incorporating bases to modify pH during HME, the drug loading (w/w) of telmisartan in ASDs was significantly increased from 5% to 50%. The stability of the polymer Soluplus when extruded with a strong base was also examined.
Oral drug therapy requiring large quantities of active pharmaceutical ingredients (APIs) can cause a substantial pill burden, which can increase nonadherence and worsen healthcare outcomes. Maximizing the drug loading of APIs in oral dosage forms is essential to reduce pill burden. This can be challenging for poorly water-soluble APIs without compromising performance. We show a promising strategy for maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) without compromising their dissolution performance. We examine potential increases in the drug loading (w/w) of telmisartan in ASDs by incorporating bases to modify pH during HME. Telmisartan is a weakly acidic, poorly water-soluble API with pH-dependent solubility. It is practically insoluble at physiological pH, but its solubility increases exponentially at pH values above 10. Telmisartan was extruded with the polymer Soluplus and various bases. With no base, the maximum drug loading achieved by extrusion was only 5% before crystalline telmisartan was detected. Including a strong, water-soluble base (NaOH or KOH) increased the maximum amorphous drug loading to 50%. These results indicate that telmisartan has pH-dependent solubility in a molten polymer, similar to that in an aqueous solution. We also examine the stability of Soluplus when extruded with a strong base, using solid-state nuclear magnetic resonance (ssNMR) to determine that NaOH (but not KOH) causes degradation by hydrolysis. Supersaturation was maintained for at least 20 h during dissolution testing of a 50% telmisartan ASD in biorelevant media.
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