Physicochemical characterization of solid dispersions prepared using hot-melt extrusion technology

  • Osama Abu Diak

Student thesis: Doctoral ThesisDoctor of Philosophy


The main aim of this thesis was to investigate the feasibility of HME to manufacture solid dispersions of poorly soluble drugs, bicalutamide (BL) and celecoxib (CX), and to characterize the physicochemical properties of the prepared melt extrudates by different analytical techniques. Hot melt extruded solid dispersions of BL were prepared using polyethylene oxide (PEO) or polyvinylpyrrolidone (PVP) as hydrophilic carriers, whereas PVP or Eudragit 4155F was used to prepare the hot- melt extruded solid dispersions of CX. The solid state properties of the prepared solid dispersions were characterized using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) techniques. FT-IR and Raman spectroscopic techniques were also employed to characterize the solid state properties of the hot- melt extrudates.

BL was present mainly as an amorphous form in PEO solid dispersions prepared at drug : polymer ratios of 1:10 and 2:10, whereas solid dispersions at a ratio of 3:10 contained a significant amount of BL in the crystalline form. BL was molecularly dispersed within PVP melt extrudates at all prepared ratios (1:10, 2:0 and 3:10). It was shown that BL-PVP solid dispersions were physically more stable than BL-PEO solid dispersions. This physical solid state stabilization of amorphous BL by PVP may be attributed to the anti-plasticization effect of PVP on amorphous BL and the formation of new intermolecular interactions between BL and PVP that were stronger than the intermolecular interactions between BL individual molecules. Conversely, the physical instability of BL-PEO solid dispersions may be attributed to the solid state plasticization effect of PEO on BL and the lack of any strong specific interactions between BL and PEO. In vitro drug release studies showed significant increase in the dissolution properties of BL from the prepared solid dispersions in comparison to pure BL or the physically mixed samples of BL with the polymer. These results suggest the efficiency of HME in producing solid dispersions of BL that have enhanced dissolution properties and hence potentially improved oral bioavailability, particularly given that BL has absorption properties that are limited by its in-vivo dissolution properties. The increase in drug release from the solid dispersions was dependent on the polymer concentration in the melt extrudates. The higher the polymer : drug ratio, the greater the improvement in the dissolution properties of BL. The significant increase in the dissolution properties of BL may be attributed to the effect of the polymer in enhancing the wetting properties of BL and the presence of BL in an amorphous form within the melt extrudates.

PVP was efficient in stabilizing the amorphous form of CX in both the solid state and during dissolution. The prepared hot-melt extruded solid molecular dispersions at 50 and 70% w/w PVP concentration remained stable without evidence of re-crystallization after storage for three months (40°C, 75% RH). Conversely, these results were only achieved using a high concentration of Eudragit 4155F (90% w/w) suggesting that PVP was more efficient in stabilizing the solid state properties of amorphous CX. This physical stabilization effect exerted by PVP may be attributed to its anti-plasticization effect on amorphous CX and the presence of strong intermolecular interactions which were stronger than the intermolecular interactions between the amorphous CX molecules. Conversely, it was shown using the Gordon- Taylor equation, that ideal mixing between CX and Eudragit 4155F in which the adhesive forces are equal to the cohesive forces existed in the CX:Eudragit 4155F binary system at 1:9 and 7:3 ratios. Conversely, non-ideal mixing existed in the midrange compositions of CX:Eudragit 4155F at 3:7 and 1:1 ratios suggesting that the adhesive forces between CX and Eudragit 4155F were weaker than the cohesive forces in such systems. Additionally, the glass transition (Tg) values of CX-Eudragit 4155F solid molecular dispersions were significantly lower than the Tg values of corresponding CX-PVP solid molecular dispersions. The polymer concentration dependent physical stability of CX-Eudragit 4155F solid dispersions may be attributed to the increase in the local viscosity of amorphous CX due to the formation of solid molecular dispersions and hence a reduction in the molecular mobility of the amorphous drug molecules.

Both PVP and Eudragit 4155F solid molecular dispersions generated supersaturated concentrations of CX which were maintained for up to 72 h achieving drug concentrations that were significantly greater than the equilibrium solubility of crystalline CX. The supersaturated drug concentrations achieved by Eudragit 4155F may be attributed to the solubilising effect of the polymer on CX particularly given that Eudragit 4155F significantly increased the solubility of crystalline CX at PBS 7.4 in which Eudragit 4155F had been dissolved or from the physically mixed samples. The solubilising effect of Eudragit 4155F on CX may be attributed to the formation of a soluble complex during dissolution as was confirmed by solution 'H NMR. Conversely, there were not any solubilising effects of PVP on CX either in PBS 7.4 in which PVP had been dissolved or from the physically mixed samples. However, the efficient stabilizing effects of PVP on the supersaturated concentrations of CX may be attributed to drug/polymer interactions as was confirmed by solution 'H NMR

CX has poor compaction properties that make formulation into solid dosage forms difficult. HME was efficient in developing hot-melt extruded tablets of CX using PVP as a model hydrophilic matrix. It is well known that drug release rate from hot-melt extruded tablets is slow because of the high density of these tablets. Supercritical carbon dioxide (SCCO2) was used efficiently to enhance the drug release rate of CX from the prepared hot-melt extruded tablets. Exposure of the tablets to SCCO2 resulted in the formation of foamed like structure of increased porosity and hence increased surface area.

Hot melt extruded Eudragit 4155F polymeric matrix was efficient in releasing CX to in-vitro simulated colon medium (pH 7.4). The solid state properties of the hot- melt extrudates and the drug release properties were highly dependent on the extrusion temperature used to manufacture such tablets.
Date of AwardDec 2009
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SupervisorGavin Andrews (Supervisor) & David Jones (Supervisor)

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