Abstract
Asymmetric-flow field-flow fractionation (AF4) has been recognized as an invaluable tool for the characterisation of particle size, polydispersity, drug loading and stability of nanopharmaceuticals. However, the application of robust and high quality standard operating procedures (SOPs) is critical for accurate measurements, especially as these complex drug nanoformulations are most often inherently polydisperse. In this review we describe a unique international collaboration that lead to the development of a robust SOP for the measurement of physical-chemical properties of nanopharmaceuticals by multi-detector AF4 (MD-AF4) involving two state of the art infrastructures in the field of nanomedicine, the European Union Nanomedicine Characterization Laboratory (EUNCL) and the National Cancer Institute-Nanotechnology Characterisation Laboratory (NCI-NCL). We present examples of how MD-AF4 has been used for the analysis of key quality attributes, such as particle size, shape, drug loading and stability of complex nanomedicine formulations. The results highlight that MD-AF4 is a very versatile analytical technique to obtain critical information on a material particle size distribution, polydispersity and qualitative information on drug loading. The ability to conduct analysis in complex physiological matrices is an additional very important advantage of MD-AF4 over many other analytical techniques used in the field for stability studies. Overall, the joint NCI-NCL/EUNCL experience demonstrates the ability to implement a powerful and highly complex analytical technique such as MD-AF4 to the demanding quality standards set by the regulatory authorities for the pre-clinical safety characterization of nanomedicines.
Highlights
Nanopharmaceuticals are medicinal products where the active pharmaceutical ingredient (API) is encapsulated in – or associated to – biocompatible nanoparticles (NPs) in order to improve the API safety and/or efficacy profiles compared to the free drug
The results of this inter laboratory comparison (ILC) exercise, recently published [17], confirmed: i) the great robustness of multidetector AF4 (MD-AF4) for measuring the physical properties of multiple liposomal formulation, and ii) small variations in the measurement of particle size can be generated by differences in the sizing detector configurations and by the software for data analysis provided by the different manufacturers
The joint effort, of the two state-of-the-art infrastructures for nanomedicine pre-clinical characterisation, namely NCI-NCI and European Union Nanomedicine Characterisation Laboratory (EUNCL) in developing standard operating procedures (SOPs) and a standard test method has been a key factor in the successful application of MD-AF4 in this highly regulated field
Summary
Nanopharmaceuticals are medicinal products where the active pharmaceutical ingredient (API) is encapsulated in – or associated to – biocompatible nanoparticles (NPs) in order to improve the API safety and/or efficacy profiles compared to the free drug. Among the high resolution analytical techniques considered for steps 2 and 3, asymmetric-flow field-flow fractionation coupled with multiple detectors (MD-AF4) is one of the most versatile for the characterisation of particle size, polydispersity, and stability of complex nanopharmaceuticals [9,11,12,13]. The introduction of the AF4 separation step, allows separation of the free proteins from the nanoparticles prior to the analysis, significantly improving the measurement resolution [9,13,23] For this reason, whenever possible MD-AF4 is the technique of choice for the analysis of physical stability in complex biological media. When an elution method for specific NPs platforms is successfully developed and if a robust SOP is followed, MD-AF4 is a powerful tool for synthesis optimization, quality control and monitoring the stability of the multiple classes of nanopharmaceuticals in complex biological media [17]
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