Current Status and Challenges of Analytical Methods for Evaluation of Size and Surface Modification of Nanoparticle-Based Drug Formulations

Abstract

The present review discusses the current status and difficulties of the analytical methods used to evaluate size and surface modifications of nanoparticle-based pharmaceutical products (NPs) such as liposomal drugs and new SARS-CoV-2 vaccines. We identified the challenges in the development of methods for (1) measurement of a wide range of solid-state NPs, (2) evaluation of the sizes of polydisperse NPs, and (3) measurement of non-spherical NPs. Although a few methods have been established to analyze surface modifications of NPs, the feasibility of their application to NPs is unknown. The present review also examined the trends in standardization required to validate the size and surface measurements of NPs. It was determined that there is a lack of available reference materials and it is difficult to select appropriate ones for modified NP surface characterization. Research and development are in progress on innovative surface-modified NP-based cancer and gene therapies targeting cells, tissues, and organs. Next-generation nanomedicine should compile studies on the practice and standardization of the measurement methods for NPs to design surface modifications and ensure the quality of NPs.

Keywords: nanomedicine; nanoparticle; size; standardization; surface chemistry.

Fig. 1

Size ranges and evaluation methods for nanoparticle-based pharmaceutical products

Fig. 2

Size evaluation method selection based on dosage form, size distribution, and dispersibility of nanoparticle-based pharmaceutical products. AFM, atomic force microscopy; DLS, dynamic light scattering; EM, electron microscopy; FFF, field flow fractionation; LD, laser diffraction; MALS, multi-angle light scattering; NTA, nanoparticle tracking analysis; SAXS, small-angle X-ray scattering; SEC, size-exclusion chromatography

Fig. 3

Plot of publications vs. year of first report on size evaluation methods. 1, electron microscopy; 2, atomic force microscopy; 3, small-angle X-ray scattering; 4, dynamic light scattering; 5, nanoparticle tracking analysis; 6, laser diffraction; 7, field flow fractionation; 8, analytical ultracentrifugation; 9, multi-angle light scattering; 10, acoustic spectroscopy; 11, differential centrifugal sedimentation/disc centrifugation; 12, Coulter counter; 13, focused beam reflection measurement; 14, resonant mass measurement/suspended microchannel resonator. Search word was set to exact match with legend. Publications as of December 3, 2021

Fig. 4

Plot of publications vs. year of first report on surface chemistry evaluation methods. 1, cryo-electron microscopy; 2, X-ray photoelectron spectroscopy; 3, Auger electron spectroscopy; 4, time-of-flight secondary ion mass spectroscopy; 5, tip-enhanced Raman spectroscopy; 6, atomic force microscopy-infrared spectroscopy; 7, electroacoustic spectroscopy/colloid vibration current/electric sonic amplitude; 8, electrophoretic light scattering/laser Doppler electrophoresis/phase analysis light scattering/zeta potential; 9, small-angle X-ray scattering; 10, Raman spectroscopy; 11, infrared spectroscopy; 12, circular dichroism. Direct methods are enclosed by circle. Search word was set to exact match with legend. Publications as of December 10, 2021