Effect of TPGS surfactant on dissolution sensitivity of a poorly water-soluble drug using high-shear wet granulation

d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) has been widely used in a variety of oral applications to enhance dissolution, solubility, and/or bioavailability of poorly-water soluble drugs. In addition, the use of TPGS could potentially minimize achlorhydric effects typically existing in patients co-administered with proton pump inhibitors (PPI) or H2 receptor blockers. The incorporation of TPGS in tablets, however, can have undesirable effects on compaction, physical stability, and processing.

Highlights

• We demonstrated a systematic approach using HSWG to effectively incorporate TPGS into solid oral formulations to capitalize on the bioperformance enhancement of TPGS while maintaining tablet integrity.

• TPGS-based HSWG formulations minimize achlorhydric effects and dissolution sensitivity against various attributes of a poorly water-soluble drug.

• TPGS-based HSWG formulations enable excellent downstream processing and improve flow properties of drug A (poor flow, cohesivity, and agglomeration) through a HSWG process.

• Formulation robustness was demonstrated through similar dissolution profiles despite containing different attributes of a poorly water-soluble drug.

Therefore, the goal of this study was to develop a systematic approach using high-shear wet granulation (HSWG) to effectively incorporate TPGS into solid oral formulations to enhance bioavailability under achlorhydric conditions without tablet defects. TPGS levels were optimized and defined based on dissolution, bioperformance, physical stability, and tablet properties. TPGS-containing HSWG formulations had significantly improved processing and flow properties and outperformed dry granulation formulations in dissolution and bioperformance under achlorhydric conditions. Furthermore, the formulation robustness of the HSWG formulations was demonstrated through similar dissolution profiles despite containing different attributes of a poorly water-soluble drug. Therefore, HSWG formulations with the addition of TPGS can be used to minimize not only achlorhydric effects but also the sensitivity of dissolution against variable attributes of a poorly water-soluble drug. More on the effect of TPGS surfactant on dissolution sensitivity

Keywords Wet granulation, TPGS, Dissolution, Surfactant, Poorly water-soluble drug, Bioavailability, Poloxamer 407 (Lutrol F 127), polyoxyl 35 castor oil (Cremophor EL), sodium lauryl sulfate (Texapon K 12 P PH),d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), Polysorbate 80