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Interplay of Adsorption, Supersaturation and the Presence of an Absorptive Sink on Drug Release from Mesoporous Silica-Based Formulations

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Abstract

Purpose

Mesoporous silica-based formulations of poorly soluble drugs may exhibit incomplete drug release due to drug remaining adsorbed on the silica surface. The goal of this study was (1) to evaluate the adsorption tendency of atazanavir from aqueous solution onto mesoporous silica (SBA-15) and (2) to determine if the drug release from mesoporous silica formulations was promoted by the presence of an absorptive compartment during dissolution testing.

Methods

Atazanavir (ATZ) formulations with different drug loadings were prepared by incipient impregnation. The solid-state properties of the formulations were analyzed by X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectroscopy and thermogravimetric analysis. Drug release was compared for closed compartment versus absorptive dissolution testing at gastric and intestinal pH.

Results

XRD and DSC showed that all formulations were amorphous. Infrared spectra indicated intermolecular interactions between silanol groups in SBA-15 and carbonyl groups in atazanavir. Nanoconfinement of drug in silica mesopores was suggested by thermal analysis. Closed compartment dissolution testing showed incomplete drug release, largely due to the adsorption tendency of ATZ. However, coupled dissolution-absorption studies showed complete release over a 240 min time period. This suggested that the depletion of drug in the dissolution medium due to drug diffusion across the membrane promotes drug release. Drug release was further improved when the formulation was first added to fasted state gastric pH conditions followed by pH-shift to intestinal conditions, which was attributed to the higher solubility of atazanavir at low pH. However, ATZ mesoporous silica formulations showed a poorer overall absorption behavior relative to a polymer-based amorphous solid dispersion formulation.

Conclusion

This study highlights that absorptive dissolution conditions promote drug desorption from the silica surface and hence, enhance drug release. Further, the influence of solution pH on drug release underscores the need to consider how variations in physiological conditions may impact the performance of mesoporous silica-based formulations.

Drug release and adsorption tendency in the absence and presence of an absorptive sink during dissolution testing

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Abbreviations

ASD:

Amorphous Solid Dispersions

ATZ:

Atazanavir

DL:

Drug Loading

DSC:

Differential Scanning calorimeter

FTIR:

Fourier Transform Infrared Spectroscopy

GI:

Gastrointestinal

HPLC:

High pressure liquid chromatography

HPMC:

Hydroxypropyl Methylcellulose

LLPS:

Liquid-Liquid Phase Separation

MPS:

Mesoporous Silica-based Drug Delivery Systems

PXRD:

Powder X-ray Diffraction

TGA:

Thermogravimetric Analysis

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA

    Siddhi S. Hate & Lynne S. Taylor

  2. Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, 46285, USA

    Susan M. Reutzel-Edens

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Hate, S.S., Reutzel-Edens, S.M. & Taylor, L.S. Interplay of Adsorption, Supersaturation and the Presence of an Absorptive Sink on Drug Release from Mesoporous Silica-Based Formulations. Pharm Res 37, 163 (2020). https://doi.org/10.1007/s11095-020-02879-9

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