Production methods for nanodrug particles using the bottom-up approach

Abstract

This review focuses on bottom-up processes such as precipitation (or crystallisation) and single droplet evaporation to produce nanoparticles containing largely pure therapeutics for pharmaceutical applications. Suitable precipitation techniques involve the use of high-gravity, confined impinging liquid jet mixing, multi-inlet vortex mixing, supercritical fluids, and ultrasonic waves. Droplet evaporation methods are spray-based, including nanospray drying, aerosol flow reactor method, spraying of low-boiling point solvent under ambient conditions and electrospraying of low-electrical conducting solutions. A key to the success of yielding stable nanoparticles in these various techniques is to control the particle growth kinetics through evaporation rate of the droplets or mixing rate during precipitation.

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.