Pharmaceutical Research

, 36:105 | Cite as

A Single Hydrogen to Fluorine Substitution Reverses the Trend of Surface Composition Enrichment of Sorafenib Amorphous Solid Dispersion upon Moisture Exposure

  • Yuejie Chen
  • Huijun Chen
  • Shan Wang
  • Chengyu Liu
  • Feng QianEmail author
Research Paper



To reveal the underlying mechanism inducing the opposite trends of surface composition enrichment of spray dried amorphous solid dispersions (ASD) of sorafenib and regorafenib, two compounds only differ in hydrogen to fluorine substitution.


Sorafenib/PVP and regorafenib/PVP ASDs were prepared by spray drying. Morphology of ASDs was visually inspected and examined by SEM. The surface compositions of ASDs were analyzed by XPS. Glass transition temperature (Tg) of ASDs was determined by DSC. Water vapor sorption isotherms of ASDs were studied by moisture sorption analyzer. Molecular interaction between the drug and the polymer was analyzed by solution NMR.


In 10% and 20% drug loading sorafenib/PVP ASDs, short time moisture exposure induced PVP enrichment on the surface, and the appearance of initial ASDs powder became gel-like after water uptake. While in 30% sorafenib/PVP and any regorafenib/PVP ASDs regardless of drug loading, moisture exposure induced surface drug enrichment, while their powder-like appearance and average particle size remained unchanged. Meanwhile, sorafenib/PVP had similar water vapor sorption isotherms as regorafenib/PVP, before and after moisture induced phase separation. NMR study demonstrated a hex atomic ring H-bonding interaction between the drug and PVP, with a 1:1 drug: monomer stoichiometry molar ratio, which persisted in sorafenib/PVP but not regorafenib/PVP system under 95%RH moisture.


Moisture exposure could lead to drug or polymer enrichment on the surface of ASDs, while the viability of drug-polymer interaction persisting in water environment contributed to such surface composition enrichment.


amorphous solid dispersion amorphous phase separation drug-polymer interaction physical stability surface composition 



Two-dimensional nuclear Overhauser effect spectroscopy


Amorphous solid dispersion


Differential scanning calorimetry


Molecular weight


Nuclear magnetic resonance


Physical mixture of ASD and pure polymer


Poly(vinyl pyrrolidone)


Powder X-ray diffraction


Scanning electron microscopy


Glass transition temperature


Melting point


X-ray photoelectron spectroscopy


Supplementary material

11095_2019_2632_MOESM1_ESM.docx (15 kb)
ESM 1 (DOCX 14 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education)Tsinghua UniversityBeijingPeople’s Republic of China

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