The purpose of the study is to evaluate the effect of surfactant-plasticizers on the physical stability of amorphous drug in polymer matrices formed by hot melt extrusion. Solid dispersions of a poorly soluble drug were prepared using PVP-K30, Plasdone-S630, and HPMC-E5 as the polymeric carriers and surfactants as plasticizers. The solid dispersions were produced by hot melt extrusion at temperatures 10°C above and below the glass transition temperature (Tg) of the carrier polymers using a 16 mm-Haake Extruder. The surfactants tested in this study included Tween-80 and Docusate Sodium. The particle size of the extrudate was reduced to have mean of 100–200 micron. The physical stability of the solid dispersions produced was monitored at 30°C/60% for six-months and at 60°C/85% for two-months in open HDPE bottles. Modulated differential scanning calorimetry, polarized light microscopy, powder X-ray diffraction and dissolution testing was performed to assess the physical stability of solid dispersions upon stress testing. The dispersions containing HPMC-E5 were observed especially to be susceptible to physical instability under an accelerated stress conditions (60°C/85%RH) of the solid dispersion. About 6% conversion of amorphous drug to crystalline form was observed. Consequently, the system exhibits similar degree of re-crystallization upon addition of the surfactant. However, under 30°C/60%RH condition, the otherwise amorphous Drug-HPMC-E5 system has been destabilized by the addition of the surfactant. This effect is much more reduced in the extruded solid dispersions where polymeric carriers such as Plasdone S-603 and PVP-K30 (in addition to surfactants) are present. Furthermore, the drug release from the solid dispersions was unaffected at the stress conditions reported above. Possible reasons for the enhanced stability of the dispersions are due to the surfactants ability to lower the viscosity of the melt, increase the API solubility and homogeneity in the carrier polymer. In contrast, while it is possible for the surfactants to destabilize the system by lowering the Tg and increasing the water uptake, the study confirms that this effect is minimal. By and large, the surfactants appear to be promising plasticizers to produce solid dispersions by hot melt extrusion, in so doing improving dissolution rate without compromising the physical stability of the systems.
4 Figures and Tables
Fig. 2. pXRD of solid dispersion: initial sample and samples stored for 1, 2, 3-weeks, 1, 2, 3, 4, 5, and 6-months at 30-C/60%RH. (a) API/ Plasdone/Tween-80; (b) API/HPMC-E5/Tween-80; (c) API/PVP-K30/Tween-80; (d) API/PVP-K30/Docusate sodium.
Fig. 3. pXRD of solid dispersion: initial sample and samples stored for 4, 8, 24, 48, 72, 96, 168, 240, 360, 720, and 1,200-h at 60-C/85%RH. (a) API/Plasdone/Tween-80; (b) API/HPMC-E5/Tween-80; (c) API/PVP-K30/Tween-80; (d) API/PVP-K30/Docusate sodium.
Fig. 4. The time dependence of the crystallization of the solid dispersions at 60-C/ 85%RH.
Table II. Increased Water-Uptake by the Surfactant Containing Dispersions had Minimal Effect on the Recrystallization of API when Tested Under both Stability Conditions
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