Current Pharmaceutical Design - Volume 20, Issue 3, 2014

Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area.

Solid dispersions have been widely studied as an attractive formulation strategy for the increasingly prevalent poorly watersoluble drug compounds, including herbal medicines, often leading to improvements in drug dissolution rate and bioavailability. However, several challenges are encountered with solid dispersions, for instance regarding their physical stability, and the full potential of these formulations has yet to be reached. Solid dispersions have mainly been used to produce immediate release systems using watersoluble polymers but an extended release system may provide equal or better performance due to enhancement in the pharmacokinetics and low variability in plasma concentration. Progress in processing technologies and particle engineering provides new opportunities to prepare particle-based solid dispersions with control of physical characteristics and tailored drug release kinetics. Spray-drying and electrospraying are both technologies that allow production and continuous manufacturing of particle-based amorphous solid dispersions in a single step process and electrospinning further allows the production of fiber based systems. This review presents the use of spray drying and electrospraying/electrospinning as techniques for preparing particle-based solid dispersions, describes the particle formation processes via numerical and experimental models and discusses particle engineering using these techniques. Examples are given on the applications of these techniques for preparing solid dispersions and the challenges associated with the techniques such as stability, preparation of final dosage form and scale-up are also discussed.

Supercritical fluid particle design (SCF PD) offers a number of routes to improve solubility and dissolution rate for enhancing the bioavailability of poorly water-soluble drugs, which can be adopted through an in-depth knowledge of SCF PD processes and the molecular properties of active pharmaceutical ingredients (API) and drug delivery system (DDS). Combining with research experiences in our laboratory, this review focuses on the most recent development of different routes (nano-micron particles, polymorphic particles, composite particles and bio-drug particles) to improve solubility and dissolution rate of poorly water-soluble drugs, covering the fundamental concept of SCF and the principle of SCF PD processes which are typically used to control particle size, shape, morphology and particle form and hence enable notable improvement in the dissolution rate of the poorly water-soluble drugs. The progress of the industrialization of SCF PD processes in pharmaceutical manufacturing environment with scaled-up plant under current good manufacturing process (GMP) specification is also considered in this review.

Hot melt extrusion (HME) is a powerful technology to enhance the solubility and bioavailability of poorly water-soluble drugs by producing amorphous solid dispersions. Although the number of articles and patents about HME increased dramatically in the past twenty years, there are very few commercial products by far. The three main obstacles limiting the commercial application of HME are summarized as thermal degradation of heat-sensitive drugs at high process temperature, recrystallization of amorphous drugs during storage and dissolving process, and difficulty to obtain products with reproducible physicochemical properties. Many efforts have been taken in recent years to understand the basic mechanism underlying these obstacles and then to overcome them. This article reviewed and summarized the limitations, recent advances, and future prospects of HME.

In recent years, nanosuspensions have been accepted as a valuable drug delivery system for poorly water-soluble drugs. Topdown and bottom-up technologies are the two main approaches for generating nanosuspensions. Several products manufactured by the top-down technologies have been successfully commercialized demonstrating that the processing features of the technologies are adaptable to industrial scale operation and meeting high pharmaceutical quality control standards. Nanosuspensions of poorly soluble drugs have shown to achieve dramatic improvements on the in vivo performance of the drugs including the enhancement of bioavailability and elimination of food effect when administered orally. This review will focus on the preparation of nanosuspensions by the top-down technologies. The influence of drug physicochemical properties on the nanosuspension forming process and the subsequent conversion into a dry powder form will be discussed with proposed mechanisms. In addition, the criteria for selection of stabilizers will be reviewed. The characteristics of drugs and stabilizers as well as their interaction effects on the redispersion properties of a dry powder prepared from a nanosuspension will be highlighted. The different administration routes of nanosuspensions are also presented with their potential therapeutic benefits.

This review focuses on using precipitation (bottom-up) method to produce water-insoluble drug nanocrystals, and the stability issues of nanocrystals. The precipitation techniques for production of ultra-fine particles have been widely researched for last few decades. In these techniques, precipitation of solute is achieved by addition of a non-solvent for solute called anti-solvent to decrease the solvent power for the solute dissolved in a solution. The anti-solvent can be water, organic solvents or supercritical fluids. In this paper, efforts have been made to review the precipitation techniques involving the anti-solvent precipitation by simple mixing, impinging jet mixing, multi-inlet vortex mixing, the using of high-gravity, ultrasonic waves and supercritical fluids. The key to the success of yielding stable nanocrystals in these techniques is to control the nucleation kinetics and particle growth through mixing during precipitation based on crystallization theories. The stability issues of the nanocrystals, such as sedimentation, Ostwald ripening, agglomeration and cementing of crystals, change of crystalline state, and the approaches to stabilizing nanocrystals are also discussed in detail.

A common feature of many new analytical techniques that allows fast and non-destructive analysis of poorly-water-soluble drug is that they generate a large amount of data with a multivariate character within a short time frame, which in turn highlights the need for advanced data analytical methods in extracting information from the complex data set. The current review critically examines how spectroscopy and imaging techniques can be utilized for fast and non-destructive characterization of solid state poorly water-soluble drug formulations. The first part of the present review describes the basics behind many of the currently used methods including Raman, near infrared (NIR), infrared (IR) spectroscopy and X-ray powder diffractometry in characterizing poorly water soluble drugs. Key emphasis was placed on a critical review of the currently used spectral preprocessing methods, and the influence of selected preprocessing on spectral data sets is exemplified. Further the existing uni- and multivariate spectral data analytical methods in analyzing complex spectral data sets are reviewed, covering estimation of spectral peak moments, peak modeling, variations of Principal Component Analysis (PCA), variations of Partial Least Squares (PLS) analysis and Multivariate Curve Resolution (MCR). The second part of the present review discusses hyperspectral imaging, UV imaging, optical microscopy imaging and process imaging methods suitable for characterization of poorly water-soluble solid state drug formulations. Image analytical techniques suitable for analyzing hyperspectral image data set are described. Further, the application of various image analytical techniques leading to the estimation of nucleation and crystal growth rates from polarized light microscopy is described.

A surprisingly large proportion of new chemical entities (NCE) is emerging from the drug discovery pipeline, and many active components extracted from herbal medicines are water insoluble, which represents a great challenge for their development. Nanosuspensions, which are submicron colloidal dispersions of pure drug particles that are stabilised by a small percentage of the excipients, could dramatically enhance the saturated solubility, dissolution rate and adhesion of drug particles to cell membranes. Nanosuspensions are the most suitable for drugs that require high dosing or have limited administrative volume. After 20 years of development, several oral products and one injectable product are commercially available. The aim of this review is to fill the gap between rational formulation designs and the in vivo performance of poorly water-soluble drug nanosuspensions. Specifically, this review will correlate characteristics of nanosuspension formulations, including drug property, particle size, crystallinity, stabiliser and surface property, with their transport, pharmacokinetics, bioactivity and toxicity after delivery by different administration routes. The elucidation of the mechanisms of targeted drug delivery, cellular transport and internalisation of nanosuspensions are also reviewed to interpret the in vivo performance of these nanosuspensions. Moreover, the recent application of nanosuspensions for poorly water-soluble herbal medicines is highlighted.

Many newly discovered drug molecules have low aqueous solubility, which results in low bioavailability. One way to improve their dissolution is to formulate them as nanoparticles, which have high specific surface areas, consequently increasing the dissolution rate and solubility. Nanoparticles can be produced via top-down or bottom-up methods. Top-down techniques such as wet milling and high pressure homogenisation involve reducing large particles to nano-sizes. Some pharmaceutical products made by these processes have been marketed. Bottom-up methods such as precipitation and controlled droplet evaporation form nanoparticles from molecules in solution. To minimise aggregation upon drying and promote redispersion of the nanoparticles upon reconstitution or administration, hydrophilic matrix formers are added to the formulation. However, the nanoparticles will eventually agglomerate together after dispersing in the liquid and hinders dissolution. Currently there is no pharmacopoeial method specified for nanoparticles. Amongst the current dissolution apparatus available for powders, the flow-through cell has been shown to be the most suitable. Regulatory and pharmacopoeial standards should be established in the future to standardise the dissolution testing of nanoparticles. More nanoparticle formulations of new hydrophobic drugs are expected to be developed in the future with the advancement of nanotechnology. However, the agglomeration problem is inherent and difficult to overcome. Thus the benefit of dissolution enhancement often cannot be fully realised. On the other hand, chemical strategies such as modifying the parent drug molecule to form a more soluble salt form, prodrug, or cyclodextrin complexation are well established and have been shown to be effective in enhancing dissolution. Thus the value of nanoformulations needs to be interpreted in the light of their limitations. Chemical approaches should also be considered in new product development.