Physical and chemical stability of drug nanoparticles

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Abstract

As nano-sizing is becoming a more common approach for pharmaceutical product development, researchers are taking advantage of the unique inherent properties of nanoparticles for a wide variety of applications. This article reviews the physical and chemical stability of drug nanoparticles, including their mechanisms and corresponding characterization techniques. A few common strategies to overcome stability issues are also discussed.

Introduction

With significant attention focused on nanoscience and nanotechnology in recent years, nanomaterial-based drug delivery has been propelled to the forefront by researchers from both academia and industry [1], [2], [3]. Various nano-structured materials were produced and applied to drug delivery such as nanoparticles [4], nanocapsules [5], nanotubes [6], micelles [7], microemulsions [8] and liposomes [9]. In general, the term “nanoparticles” refers to particles with sizes between 1 and 100 nm. However, submicron particles are also commonly referred as nanoparticles in the field of pharmaceutics and medicine [10], [11], [12], [13], [14]. Nanoparticles are categorized as nanocrystals [10], polymeric [15], liposomal [9] and solid lipid nanoparticles (SLN) [16] depending on their composition, function and morphology. Given the extensive available literature reviews on SLN, polymeric and liposomal nanoparticles [4], [9], [15], [16], [17], [18], this article will focus only on nanocrystals (pure drug nanoparticles).

The unique nano-scale structure of nanoparticles provides significant increases in surface area to volume ratio which results in notably different behavior, both in-vitro and in-vivo, as compared to the traditional microparticles [10], [11], [12]. Consequently, drug nanocrystals have been extensively used in a variety of dosage forms for different purposes [10], [11], [14], [19], [20], such as improving the oral bioavailability of poorly water-soluble drugs by utilizing enhanced solubility and dissolution rate of nanoparticles [21], [22], [23]. In the field of pulmonary drug delivery, the nanoparticles are able to deliver the drugs into the deep lungs, which is of great importance for systemically absorbed drugs [11], [14]. In addition, injection of poorly water-soluble nanosuspension drugs is an emerging and rapidly growing field that has drawn increasing attention due to its benefits in reducing toxicity and increasing drug efficacy through elimination of co-solvent in the formulation [10], [20].

Despite the advantages of drug nanocrystals, they present various drawbacks including complex manufacturing [12], [24], [25], [26], nanotoxicity [27] and stability issues [10], [19], [20]. Stability is one of the critical aspects in ensuring safety and efficacy of drug products. In intravenously administered nanosuspensions, for example, formation of larger particles (> 5 μm) could lead to capillary blockade and embolism [20], and thus drug particle size and size distribution need to be closely monitored during storage. The stability issues of drug nanoparticles could arise during manufacturing, storage and shipping. For instance, the high pressure or temperature produced during manufacturing can cause crystallinity change to the drug particles [12], [26], [28]. Storage and shipping of the drug products may also bring about a variety of stability problems such as sedimentation, agglomeration and crystal growth [29], [30], [31]. Therefore, stability issues associated with drug nanocrystals deserve significant attention during pharmaceutical product development. This article reviews existing literature on drug nanoparticle stability, including theory/mechanisms, methods used to tackle the stability problems and characterization techniques, and provides recommendations to improve the current practices. Since the stability issues related to nanoparticle dry powders are usually trivial, this review will only focus on stability of nanosuspensions (drug nanoparticles dispersed in a liquid medium).

Section snippets

Effect of dosage form on stability

The unique characteristics of drug nanoparticles have enabled their extensive application in various dosage forms including oral, parenteral, ocular, pulmonary, dermal and other specialized delivery systems [10], [11], [13], [20], [32]. Although different dosage forms may share some common stability issues, such as sedimentation, particle agglomeration or crystal growth, their effects on drug products are quite different. For instance, particle agglomeration could be a major issue in pulmonary

Characterizing stability of drug nanoparticles and nanoparticle formulations

Selection of characterization techniques for drug nanoparticles stability is dependent on the nature of stability issues and product dosage form. A few commonly used stability characterization techniques are listed in Table 2.

Recommendations of general strategies for enhancing stability of nanoparticle formulations

Strategies to address different stability issues are usually tailored according to different aspects, such as therapeutic requirements, dosage form and manufacturing complexity. For example, as the particle size is reduced, the sedimentation rate is decreased so that the particles can stay suspended longer in nanosuspensions. The general wisdom is that the smaller the nanoparticles are, the better. Unfortunately, too small particles are not always desirable, as they may create undesired plasma

Conclusions

The stability of drug nanoparticles remains a very challenging issue during pharmaceutical product development. Stability is affected by various factors such as dosage form (nanosuspension vs. dry solid), dispersion medium (aqueous vs. non-aqueous), delivery route (oral, inhalation, IV or other routes), production technique (top-down vs. bottom-up) and nature of drug (small molecules vs. large biomolecules). Despite the significant challenges associated with stabilizer screening, adding a

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Nanodrug Particles and Nanoformulations for Drug Delivery”.

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