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Effect of Compression on the Molecular Arrangement of Itraconazole-Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation?
Mol Pharm. 2016 06 06; 13(6):1879-93.MP

Abstract

Predensification and compression are unit operations imperative to the manufacture of tablets and capsules. Such stress-inducing steps can cause destabilization of solid dispersions which can alter their molecular arrangement and ultimately affect dissolution rate and bioavailability. In this study, itraconazole-Soluplus solid dispersions with 50% (w/w) drug loading prepared by hot-melt extrusion (HME) were investigated. Compression was performed at both pharmaceutically relevant and extreme compression pressures and dwell times. The starting materials, powder, and compressed solid dispersions were analyzed using modulated differential scanning calorimetry (MDSC), X-ray diffraction (XRD), small- and wide-angle X-ray scattering (SWAXS), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and broadband dielectric spectroscopy (BDS). MDSC analysis revealed that compression promotes phase separation of solid dispersions as indicated by an increase in glass transition width, occurrence of a peak in the nonreversing heat flow signal, and an increase in the net heat of fusion indicating crystallinity in the systems. SWAXS analysis ruled out the presence of mesophases. BDS measurements elucidated an increase in the Soluplus-rich regions of the solid dispersion upon compression. FTIR indicated changes in the spatiotemporal architecture of the solid dispersions mediated via disruption in hydrogen bonding and ultimately altered dynamics. These changes can have significant consequences on the final stability and performance of the solid dispersions.

Authors+Show Affiliations

Drug Delivery and Disposition, KU Leuven , Leuven, Belgium.Soft Matter, Rheology and Technology, Department of Chemical Engineering, KU Leuven , Leuven, Belgium.Drug Delivery and Disposition, KU Leuven , Leuven, Belgium.Polymer Chemistry and Materials, Department of Chemistry, KU Leuven , Leuven, Belgium.Polymer Chemistry and Materials, Department of Chemistry, KU Leuven , Leuven, Belgium.Soft Matter, Rheology and Technology, Department of Chemical Engineering, KU Leuven , Leuven, Belgium. Polymer Technology, Department of Mechanical Engineering, TU Eindhoven , Eindhoven, The Netherlands.Soft Matter, Rheology and Technology, Department of Chemical Engineering, KU Leuven , Leuven, Belgium.Department of Metallurgy and Materials Engineering, KU Leuven , Leuven, Belgium.Drug Delivery and Disposition, KU Leuven , Leuven, Belgium.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27092396

Citation

Singh, Abhishek, et al. "Effect of Compression On the Molecular Arrangement of Itraconazole-Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation?" Molecular Pharmaceutics, vol. 13, no. 6, 2016, pp. 1879-93.
Singh A, Bharati A, Frederiks P, et al. Effect of Compression on the Molecular Arrangement of Itraconazole-Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation? Mol Pharm. 2016;13(6):1879-93.
Singh, A., Bharati, A., Frederiks, P., Verkinderen, O., Goderis, B., Cardinaels, R., Moldenaers, P., Van Humbeeck, J., & Van den Mooter, G. (2016). Effect of Compression on the Molecular Arrangement of Itraconazole-Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation? Molecular Pharmaceutics, 13(6), 1879-93. https://doi.org/10.1021/acs.molpharmaceut.6b00046
Singh A, et al. Effect of Compression On the Molecular Arrangement of Itraconazole-Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation. Mol Pharm. 2016 06 6;13(6):1879-93. PubMed PMID: 27092396.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Compression on the Molecular Arrangement of Itraconazole-Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation? AU - Singh,Abhishek, AU - Bharati,Avanish, AU - Frederiks,Pauline, AU - Verkinderen,Olivier, AU - Goderis,Bart, AU - Cardinaels,Ruth, AU - Moldenaers,Paula, AU - Van Humbeeck,Jan, AU - Van den Mooter,Guy, Y1 - 2016/05/04/ PY - 2016/4/20/entrez PY - 2016/4/20/pubmed PY - 2017/10/20/medline KW - FTIR KW - Soluplus KW - broadband dielectric spectroscopy KW - compression KW - itraconazole KW - liquid crystals KW - molecular mobility KW - small-angle X-ray scattering KW - solid dispersions KW - tablets SP - 1879 EP - 93 JF - Molecular pharmaceutics JO - Mol Pharm VL - 13 IS - 6 N2 - Predensification and compression are unit operations imperative to the manufacture of tablets and capsules. Such stress-inducing steps can cause destabilization of solid dispersions which can alter their molecular arrangement and ultimately affect dissolution rate and bioavailability. In this study, itraconazole-Soluplus solid dispersions with 50% (w/w) drug loading prepared by hot-melt extrusion (HME) were investigated. Compression was performed at both pharmaceutically relevant and extreme compression pressures and dwell times. The starting materials, powder, and compressed solid dispersions were analyzed using modulated differential scanning calorimetry (MDSC), X-ray diffraction (XRD), small- and wide-angle X-ray scattering (SWAXS), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and broadband dielectric spectroscopy (BDS). MDSC analysis revealed that compression promotes phase separation of solid dispersions as indicated by an increase in glass transition width, occurrence of a peak in the nonreversing heat flow signal, and an increase in the net heat of fusion indicating crystallinity in the systems. SWAXS analysis ruled out the presence of mesophases. BDS measurements elucidated an increase in the Soluplus-rich regions of the solid dispersion upon compression. FTIR indicated changes in the spatiotemporal architecture of the solid dispersions mediated via disruption in hydrogen bonding and ultimately altered dynamics. These changes can have significant consequences on the final stability and performance of the solid dispersions. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/27092396/Effect_of_Compression_on_the_Molecular_Arrangement_of_Itraconazole_Soluplus_Solid_Dispersions:_Induction_of_Liquid_Crystals_or_Exacerbation_of_Phase_Separation L2 - https://doi.org/10.1021/acs.molpharmaceut.6b00046 DB - PRIME DP - Unbound Medicine ER -