Production methods for nanodrug particles using the bottom-up approach☆
Graphical abstract
Introduction
One of the major attractions of using pure drug nanoparticles is their chemical simplicity without the presence of many additives or excipients. New drug compounds have low aqueous solubility, which poses formulation and delivery challenges. Formulating these drugs as organic solutions or oil-in-water emulsions is not always practical due to the toxicity of organic solvents and limitations in the liquid volume conducive for convenient dose administration, storage, and handling. Nanoparticles have very high specific surface areas (i.e. surface area-to-mass ratios) thus can be an alternative for enhancing the dissolution rate of poorly soluble drugs. Regardless of the production method, stability is an important formulation requirement for nanoparticles. Ideally the nanoparticles should be crystalline because amorphous materials are generally unstable, cohesive, potentially hygroscopic, and prone to recrystallisation. The instability will adversely affect the pharmaceutical product as a whole. However, it may be acceptable if the amorphous compound can remain stable for a sufficiently long period of time during processing and storage.
Nanoparticle production methods can be classified into the top-down and bottom-up categories. Top-down approaches involve the size-reduction of large particles to the nanometre range. This can be achieved by milling or high pressure homogenisation and has been discussed in the excellent reviews by Müller [1], [2], [3], [4], [5], [6]. Briefly, in milling the drug particles are broken down by impaction by milling balls. To minimise the amorphous content, the drug particles can be milled whilst suspended in a suitable non-solvent, usually water for hydrophobic drugs. This encourages recrystallisation of any amorphous regions formed during milling. For example, a danazol nanosuspension was produced by milling the drug particles in water containing polyvinylpyrrolidone K-15 [7]. The weight average diameter of the resultant crystalline danazol particles was 222.2 nm [7]. The two major types of high pressure homogenisation are microfluidisation and piston-gap homogenisation. Microfluidisation is essentially air-jet milling, in which the particles are fragmented by collision in a high pressure air jet. On the other hand, piston-gap homogenisation involves forcing a liquid suspension at high pressure through a narrow channel or gap inside a pipe. For aqueous media, bubbles form inside the gap due to a reduction in the static pressure of the liquid in this region [8]. These bubbles collapse upon exiting the narrow gap and the cavitation energy generated consequently breaks up the particles. For non-aqueous media or oil, the particles are comminuted by the collision and high shear though the gap.
In contrast to top-down techniques, bottom-up methods generate nanoparticles by building them from drug molecules in solution. This can be achieved by controlled precipitation (or crystallisation) and evaporation. These processes can occur in the bulk solution or in droplets, depending on the technique. There are pros and cons to both top-down and bottom-up methods. Generally, top-down techniques produce nanoparticles that are mostly crystalline but high energy or pressure is required to achieve nano-range comminution, which may also lead to contamination if a milling medium is used. In contrast, bottom-up processes involve dissolution, followed by precipitation or drying. The mechanical energy input is thus minimal but the resultant nanoparticles can be crystalline or amorphous, depending on the process conditions. Even if the particles are crystalline, the crystal growth rate must be controlled to limit the particle size. Details on these issues and the principles of various bottom-up methods will be discussed in this review.
Section snippets
Basic principles
Precipitation consists of several main steps: chemical reaction (and the subsequent supersaturation), nucleation, solute diffusion and particle growth [9]. Nucleation rate (dN/dt) can be expressed aswhere Kn is the solute nucleation constant, Ci and C⁎ are the solute concentration on the particle surface and saturation concentration, respectively. The value of the parameter a is usually between 5 and 18.
The diffusion rate of solute to the particle surface iswhere Kd is
Basic principles
When a drug solution of concentration C is atomised into droplets of diameter D, the diameter d of the drug particles with density ρ after evaporation of the solvent is given by
The particle density may not reach the true density of the drug and will depend on how the drug precipitating out from the droplet arranges to form the resulting particle.
Spray drying
In spray drying, a drug solution (aqueous or organic) is atomised to fine droplets which are evaporated in a warm air current to form dry
Conclusions
The major aspects of nanoparticle production by bottom-up processes involving solvent precipitation and droplet evaporation have been reviewed in this article. This is an area of growing interest as the number of marketed products employing nanotechnology is expected to increase. Although specific production techniques vary, they converge at the point of controlling the particle growth kinetics through mixing rate during precipitation or evaporation rate of the droplets. The relevant aspects of
References (77)
- et al.
Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation
European Journal of Pharmaceutics and Biopharmaceutics
(2006) - et al.
Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives
International Journal of Pharmaceutics
(2010) - et al.
Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect for the future
Advanced Drug Delivery Reviews
(2001) - et al.
Solid lipid nanoparticles for parenteral drug delivery
Advanced Drug Delivery Reviews
(2004) - et al.
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations
Advanced Drug Delivery Reviews
(2002) - et al.
Fundamentals of crystallization: kinetic effects on particle size distributions and morphology
Chemical Engineering Science.
(1991) - et al.
Engineering of drug nanoparticles by HGCP for pharmaceutical applications
Particuology.
(2008) - et al.
Feasibility of preparing nanodrugs by high-gravity reactive precipitation
International Journal of Pharmaceutics
(2004) - et al.
New technologies for the precipitation of solid particles with controlled properties
Powder Technology.
(2002) - et al.
A novel production method for inhalable cyclosporine A powders by confined impinging jet precipitation
Journal of Aerosol Science.
(2008)
Mixing in a multi-inlet vortex mixer (MIVM) for flash nano-precipitation
Chemical Engineering Science.
Nanoparticles synthesis using supercritical fluid technology — towards biomedical applications
Advanced Drug Delivery Reviews
Nanoparticles production by supercritical antisolvent precipitation: a general interpretation
Journal of Supercritical Fluids.
Ultrasound-assisted crystallization (sonocrystallization)
Ultrasonics Sonochemistry
Sonocrystallisation of sodium chloride particles for inhalation
Chemical Engineering Science.
Particle engineering using sonocrystallization: salbutamol sulphate for pulmonary delivery
International Journal of Pharmaceutics
Preparation of amorphous cefuroxime axetil nanoparticles by sonoprecipitation for enhancement of bioavailability
European Journal of Pharmaceutics and Biopharmaceutics
Comparison of physical and inhalation properties of spray-dried and mechanically micronized disodium cromoglycate
International Journal of Pharmaceutics
Production of spray dried salbutamol sulfate for use in dry powder aerosol formulation
International Journal of Pharmaceutics
Nano spray drying: a novel method for preparing protein nanoparticles for protein therapy
International Journal of Pharmaceutics
Aerosol flow reactor method for synthesis of drug nanoparticles
European Journal of Pharmaceutics and Biopharmaceutics
Respirable form of crystals of cromoglycic acid
Journal of Pharmaceutical Sciences
Aerodynamic properties of elongated particles of cromoglycic acid
Journal of Aerosol Science.
Micro- and nanoparticle production by electrospraying
Powder Technology.
Production of protein nanoparticles by electrospray drying
Journal of Aerosol Science.
Electrospraying of conducting liquids for monodisperse aerosol generation in the 4 nm to 1.8 μm diameter range
Journal of Aerosol Science.
Preparation and characterization of uniform nanosized cephradine by combination of reactive precipitation and liquid anti-solvent precipitation under high gravity environment
International Journal of Pharmaceutics
Production of salbutamol sulfate for inhalation by high-gravity controlled antisolvent precipitation
International Journal of Pharmaceutics
Preparation of inhalable salbutamol sulphate using reactive high gravity controlled precipitation
Journal of Pharmaceutical Sciences
Formation of polymer particles with supercritical fluids: a review
Journal of Supercritical Fluids.
Second generation of drug nanocrystals for delivery of poorly soluble drugs: smartCrystals technology
Dosis.
Surface modified drug nanoparticles
Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution
Injectable compositions, nanoparticles useful therein, and process of manufacturing same
Pharmaceutical colloidal hydrosols for injection
Improvements in pharmaceutical compositions
Hydrosols of pharmacologically active agents and their pharmaceutical compositions comprising them
Pharmaceutical compositions comprised of stabilized peptide particles
Cited by (370)
Lipid nanoparticles for RNA delivery: Self-assembling vs driven-assembling strategies
2024, Advanced Drug Delivery ReviewsBottom-up production of injectable itraconazole suspensions using membrane technology
2024, International Journal of PharmaceuticsTailoring the use of excipients in bottom-up production of naproxen crystal suspensions via membrane technology
2024, International Journal of PharmaceuticsPeptide-metal nanohybrids (PMN): Promising entities for combating neurological maladies
2023, Advances in Colloid and Interface Science
- ☆
This review is part of the Advanced Drug Delivery Reviews theme issue on "Nanodrug Particles and Nanoformulations for Drug Delivery".