Darlene Santiago1, Adlin Mendoza2, Zuleyka Morales2, Javier Santos3. 1. School of Pharmacy, University of Puerto Rico; darlene.santiago@upr.edu. 2. School of Pharmacy, University of Puerto Rico. 3. Molecular Science Research Building, University of Puerto Rico.
Abstract
PURPOSE: Hot melt extrusion (HME) has demonstrated to be an adequate compounding method for poorly-soluble pharmaceutical drugs, as it increases its solubility by fixing its amorphous solid-state using polymers (plasticizing) and other ingredients (non- plasticizing). However, it's amorphous state of the drug and the stability of the amorphous state will greatly depend on its interactions with these (plasticizing or not). METHODS: In this study, we aimed at characterizing the impact of the combination of plasticizing (TPGS) and anti-plasticizing (PVP) ingredients in amorphous celecoxib prepared using HME in terms of chemical interactions between the components (FTIR, Raman and NMR), viscoelasticity (loss and storage modulus) and required energy for flow (activation energy). Different celecoxib/PVP/TPGS ratios were studied to understand the synergistic effect of PVP and TPGS in inhibiting the crystallization of celecoxib when preparing amorphous dispersions using HME. We aimed at linking the viscoelastic properties of the melt with the resulting amorphous state described by the chemical interactions upon extrusion. RESULTS: The amorphous state of celecoxib was evidenced by strengthening of H-bonding between celecoxib and PVP, lack of characteristic crystalline peaks of celecoxib, and deshielding of aromatic protons. The melt was also characterized in terms of viscoelastic temperature dependent behavior (liquid G"; elastic G'), where increasing amounts of TPGS and PVP showed opposites effects; TPGS reduced the viscoelastic response whereas PVP increased it. Calculated melt activation energies (Ea) from the temperature dependent viscosity revealed a threshold of TPGS concentration where samples with 1% w/w of TPGS showed higher flow activation energies (higher Ea) independent of the drug/polymer ratios, compared to samples with higher amounts of TPGS. CONCLUSIONS: Low drug content combined with anti-plasticizing (PVP) amounts and relatively low plasticizing (TPGS) amounts yields an amorphous dispersion that is characterized with strong H-bonding due to efficient mixing using HME.
PURPOSE: Hot melt extrusion (HME) has demonstrated to be an adequate compounding method for poorly-soluble pharmaceutical drugs, as it increases its solubility by fixing its amorphous solid-state using polymers (plasticizing) and other ingredients (non- plasticizing). However, it's amorphous state of the drug and the stability of the amorphous state will greatly depend on its interactions with these (plasticizing or not). METHODS: In this study, we aimed at characterizing the impact of the combination of plasticizing (TPGS) and anti-plasticizing (PVP) ingredients in amorphous celecoxib prepared using HME in terms of chemical interactions between the components (FTIR, Raman and NMR), viscoelasticity (loss and storage modulus) and required energy for flow (activation energy). Different celecoxib/PVP/TPGS ratios were studied to understand the synergistic effect of PVP and TPGS in inhibiting the crystallization of celecoxib when preparing amorphous dispersions using HME. We aimed at linking the viscoelastic properties of the melt with the resulting amorphous state described by the chemical interactions upon extrusion. RESULTS: The amorphous state of celecoxib was evidenced by strengthening of H-bonding between celecoxib and PVP, lack of characteristic crystalline peaks of celecoxib, and deshielding of aromatic protons. The melt was also characterized in terms of viscoelastic temperature dependent behavior (liquid G"; elastic G'), where increasing amounts of TPGS and PVP showed opposites effects; TPGS reduced the viscoelastic response whereas PVP increased it. Calculated melt activation energies (Ea) from the temperature dependent viscosity revealed a threshold of TPGS concentration where samples with 1% w/w of TPGS showed higher flow activation energies (higher Ea) independent of the drug/polymer ratios, compared to samples with higher amounts of TPGS. CONCLUSIONS: Low drug content combined with anti-plasticizing (PVP) amounts and relatively low plasticizing (TPGS) amounts yields an amorphous dispersion that is characterized with strong H-bonding due to efficient mixing using HME.
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