Physical and chemical stability of drug nanoparticles☆
Graphical Abstract
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
References (136)
Nanotechnology: what it can do for drug delivery
J. Control. Release
(2007)Nanostructure-mediated drug delivery
Nanomed. Nanotechnol. Biol. Med.
(2005)- et al.
Biodegradable nanoparticles for drug and gene delivery to cells and tissue
Adv. Drug Deliv. Rev.
(2003) - et al.
Applications of carbon nanotubes in drug delivery
Curr. Opin. Chem. Biol.
(2005) - et al.
Polymeric micelles as new drug carriers
Adv. Drug Deliv. Rev.
(1996) - et al.
Microemulsion-based media as novel drug delivery systems
Adv. Drug Deliv. Rev.
(2000) - et al.
Therapeutic opportunities for targeted liposomal drug delivery
Adv. Drug Deliv. Rev.
(1996) - et al.
Inhaled nanoparticles — a current review
Int. J. Pharm.
(2008) - et al.
Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation
Eur. J. Pharm. Biopharm.
(2006) - et al.
Nanoparticles for drug delivery to the lungs
Trends Biotechnol.
(2007)
Biodegradable polymeric nanoparticles as drug delivery devices
J. Control. Release
Solid lipid nanoparticles (SLN) for controlled drug delivery — a review of the state of the art
Eur. J. Pharm. Biopharm.
Solid lipid nanoparticles for parenteral drug delivery
Adv. Drug Deliv. Rev.
Recent advances in liposomal drug-delivery systems
Curr. Opin. Biotechnol.
Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle do
J. Control. Release
Formulation of amphotericin B as nanosuspension for oral administration
Int. J. Pharm.
Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates
Adv. Drug Deliv. Rev.
Freeze-drying of nanoparticles formulation, process and storage considerations
Adv. Drug Deliv. Rev.
The role of solid nanoparticle technology in the parenteral delivery of poorly water-soluble drugs
Int. J. Pharm.
Nanotoxicity: the growing need for in vivo study
Curr. Opin. Biotechnol.
Production and characterization of Hesperetin nanosuspensions for dermal delivery
Int. J. Pharm.
Nanosuspensions a promising formulation for the new phospholipase A2 inhibitor PX-18
Int. J. Pharm.
A comparative study of top-down and bottom-up approaches for the preparation of micro/nanosuspensions
Int. J. Pharm.
Industrial perspective in ocular drug delivery
Adv. Drug Deliv. Rev.
Templated open flocs of anisotropic particles for pulmonary delivery with pressurized metered dose inhalers J
Pharm. Sci.
Role of polymeric stabilizers for drug nanocrystal dispersions
Curr. Appl Phys.
Characteristics of polymers enabling nano-comminution of water-insoluble drugs
Int. J. Pharm.
Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion
Eur. J. Pharm. Sci.
Understanding the structure and stability of paclitaxel nanocrystals
Int. J. Pharm.
Cyclodextrins as stabilizers for the preparation of drug nanocrystals by the emulsion solvent diffusion method
Int. J. Pharm.
A novel formulation technique for metered dose inhaler (MDI) suspensions
Int. J. Pharm.
Studies on pharmacokinetics and tissue distribution of oridonin nanosuspensions
Int. J. Pharm.
Buparvaquone mucoadhesive nanosuspension: preparation, optimisation and long-term stability
Int. J. Pharm.
Diclofenac nanosuspensions influence of preparation procedure and crystal form on drug dissolution behaviour
Int. J. Pharm.
Development of an oral rutin nanocrystal formulation
Int. J. Pharm.
Kinetic solubility and dissolution velocity of rutin nanocrystals
Eur. J. Pharm. Sci.
Nanosuspensions as a new approach for the formulation for the poorly soluble drug tarazepide
Int. J. Pharm.
Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology
Eur. J. Pharm. Biopharm.
Preparation and characterization of intravenously injectable nimodipine nanosuspension
Int. J. Pharm.
An investigation into the distribution of lecithins in nanosuspension systems using low frequency dielectric spectroscopy
Int. J. Pharm.
Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs
Int. J. Pharm.
Development of ascorbyl palmitate nanocrystals applying the nanosuspension technology
Int. J. Pharm.
Production and characterisation of highly concentrated nanosuspensions by high pressure homogenisation
Int. J. Pharm.
Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine
Int. J. Pharm.
Preparation and in vitroin vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base
Eur. J. Pharm. Biopharm.
Preparation and cytotoxic activity of hydroxycamptothecin nanosuspensions
Int. J. Pharm.
Formulation and pharmacokinetic evaluation of an asulacrine nanocrystalline suspension for intravenous delivery
Int. J. Pharm.
Nanosuspensions for the formulation of poorly soluble drugs I. Preparation by a size-reduction technique
Int. J. Pharm.
Neuroprotective effects of a nanocrystal formulation of sPLA2 inhibitor PX-18 in cerebral ischemia reperfusion in gerbils
Brain Res.
In vitro and in vivo evaluation of silybin nanosuspensions for oral and intravenous delivery
Nanotechnology
Cited by (794)
Self-assembled sodium alginate polymannuronate nanoparticles for synergistic treatment of ophthalmic infection and inflammation: Preparation optimization and in vitro/vivo evaluation
2024, International Journal of Biological MacromoleculesTargeting the breast tumor microenvironment by plant-derived products and their nanoformulations
2024, Journal of Drug Delivery Science and TechnologyMitigating amphotericin B cytotoxicity through gliadin-casein nanoparticles: Insights into synthesis, optimization, characterization, in vitro release and cytotoxicity evaluation
2024, International Journal of Biological MacromoleculesImpact of carrier particle surface properties on drug nanoparticle attachment
2024, International Journal of PharmaceuticsMetal/metal oxide nanoparticles: A revolution in the biosynthesis and medical applications
2024, Nano-Structures and Nano-Objects
- ☆
This review is part of the Advanced Drug Delivery Reviews theme issue on “Nanodrug Particles and Nanoformulations for Drug Delivery”.