Analytical methods for determining the size (distribution) in parenteral dispersions

Abstract

Analytical methods for nanomedicines are rapidly developing and include several potentially useful techniques. Of utmost importance, the physical methods applied must be robust, able to detect particles as small as 1 nm, and be stability-indicating since the nanostructures are designed as drug carriers. An unstable dispersion prevents the reproducible distribution of the active pharmaceutical ingredient(s), which may have clinically significant consequences. Aggregation, agglomeration and/or coalescence represent abnormal growth in the size of nanoparticles or nano-droplets, and are the hallmarks of an unstable dispersion. Hence, accurate quantification of these populations is essential for their safe use in patients. At the moment, the only official physical methods for pharmaceutical dispersions is for lipid injectable emulsions where dynamic light scattering is applied to determine the mean droplet diameter and light obscuration (or extinction) to monitor the stability of the population of large-diameter fat globules (> 5 μm). These two distinctly different size regions of the droplet size distribution have been determined to be clinically important. There are no established pharmacopoeial methods for nanomedicines in the deep submicron range. Stability of the particle or droplet size distribution is particularly important when acutely ill patients in the critical care setting receive injectable dispersions such as propofol for sedation, clevidipine for the treatment of hypertension or amphotericin B to fungal fungal sepsis. This chapter also discusses the growing number of non-pharmacopoeial analytical approaches that help the formulator to establish well defined and stable formulations for parenteral emulsions and dispersions in the deep submicron (i.e. nanometer) range. Furthermore, it explains the mechanisms behind these different analytical techniques, the size range where they can be applied, and their pros and cons compared with alternative approaches.