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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

2D-NOESY:

Two-dimensional nuclear Overhauser effect spectroscopy

ASD:

Amorphous solid dispersion

DSC:

Differential scanning calorimetry

M w :

Molecular weight

NMR:

Nuclear magnetic resonance

PM-ASD:

Physical mixture of ASD and pure polymer

PVP:

Poly(vinyl pyrrolidone)

PXRD:

Powder X-ray diffraction

SEM:

Scanning electron microscopy

T g :

Glass transition temperature

T m :

Melting point

XPS:

X-ray photoelectron spectroscopy

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Authors and Affiliations

  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 University, Beijing, 100084, People’s Republic of China

    Yuejie Chen, Huijun Chen, Shan Wang, Chengyu Liu & Feng Qian

Authors
  1. Yuejie Chen
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  2. Huijun Chen
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  3. Shan Wang
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  4. Chengyu Liu
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  5. Feng Qian
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Correspondence to Feng Qian.

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Chen, Y., Chen, H., Wang, S. et al. A Single Hydrogen to Fluorine Substitution Reverses the Trend of Surface Composition Enrichment of Sorafenib Amorphous Solid Dispersion upon Moisture Exposure. Pharm Res 36, 105 (2019). https://doi.org/10.1007/s11095-019-2632-5

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