Solubility Enhancement and Precipitation Inhibition of Poorly Water Soluble Compounds Utilizing Hot Melt Extrusion Technology

<p>Soluplus® (SOL), a graft amorphous copolymer, composed of polyethylene glycol, vinyl acetate and vinylcaprolactam in a ratio of 13: 30: 57, was utilized to prepare solid dispersions containing felodipine (FEL) or ketoconazole (KTZ) using hot-melt extrusion technology. The melting point depression approach was utilized to determine the miscibility and solubility of the model compounds within Soluplus® , of which felodipine demonstrated higher solubility when compared to ketoconazole (14% vs 4.3% w/w) at room temperature (298K). Moreover, the solubility parameters of FEL, KTZ and SOL were calculated as 21.76, 26.51 and 21.64, respectively. </p> <p>Polarized light microscopy, Fourier transform infrared spectroscopy (FT-IR), Raman microscopy, differential scanning calorimetry (DSC), X-Ray diffraction (XRD), and scanning electron microscopy (SEM) were explored to characterize the FEL-SOL solid dispersions, and FEL was found to be molecularly dispersed in the matrix at a concentration of 10% w/w, which also demonstrated a higher solubility. </p> <p>A central composite design (CCD) was applied to optimize the processing parameters for KTZ-SOL solid dispersions and the final formulation containing 29.8% drug was extruded at a temperature of 140°C and screw speed of 31 rpm. The robustness of the design was also examined. </p> <p>A solid dispersion system of paclitaxel (PTX) was also developed to increase the aqueous solubility in order to overcome the side effects of its commercial products Taxol® , which was accomplished with the addition of a non-ionic surfactant, Cremophor® EL. PolyOx™ WSR N-80 (Molecular weight: 200,000 Da) was utilized as the matrix carrier, in which the concentration of PTX was determined as 30%. Various surfactants and solubilizers, including sodium lauryl sulfate (SLS), Lutrol® F68 (F68) and polyethylene glycol (PEG) 3350 were incorporated into the formulation. Of these, PEG 3350 was found to increase the solubility of PTX to 9.29 μg/ml (9-fold); however, the formulation started to precipitate after 2 hours due to the high energy amorphous state of PTX. 5% hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF) successfully postponed the precipitation and maintained the solubility up to 12 hours by forming hydrogen bonds with PTX. This finding was confirmed by FT-IR analysis. </p>

Name thesis:degree_name

Ph.D. in Pharmaceutical Sciences

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomolecular Sciences

Year dc:date.available

2014

Author dc:creator

• Lu, Jiannan

Contributors dc:contributor

• Michael A. Repka
• John O'Haver
• Seongbong Jo

• Design of experiment
• Hot melt extrusion
• Poorly water soluble compounds
• Solid dispersion
• Solubility enhancement
• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://egrove.olemiss.edu/etd/1490

OAI identifier oai:identifier

oai:egrove.olemiss.edu:etd-2489