Review
Nanosizing: a formulation approach for poorly-water-soluble compounds

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Abstract

Poorly-water-soluble compounds are difficult to develop as drug products using conventional formulation techniques and are frequently abandoned early in discovery. The use of media milling technology to formulate poorly-water-soluble drugs as nanocrystalline particles offers the opportunity to address many of the deficiencies associated with this class of molecules. NanoCrystal® Technology is an attrition process wherein large micron size drug crystals are media milled in a water-based stabilizer solution. The process generates physically stable dispersions consisting of nanometer-sized drug crystals. Nanocrystalline particles are a suitable delivery system for all commonly used routes of administration, i.e. oral, injectable (IV, SC, and IM) and topical applications. In addition, aqueous dispersions of nanoparticles can be post-processed into tablets, capsules, fast-melts and lyophilized for sterile product applications. The technology has been successfully incorporated into all phases of the drug development cycle from identification of new chemical entities to refurbishing marketed products for improving their performance and value.

Introduction

It is estimated that 40% or more of active substances being identified through combinatorial screening programs are poorly soluble in water (Lipinski, 2001, Lipinski, 2002). When these molecules are formulated using conventional methods, the performance of the drug in preclinical screens is oftentimes erratic and highly variable. In the clinic, conventional formulations of poorly-water-soluble drugs are frequently plagued with problems such as poor and highly variable bioavailability. The dosage form is oftentimes affected by the fed–fasted state of the patient and its onset of action is slower than anticipated. All of these issues lead to sub-optimal dosing and poor performance. Generally, it is more expeditious and cost effective to chemically re-design the molecule, than to move a blemished molecule through the development process (Lipinski et al., 1997, Lipper, 1999, Venkatesh and Lipper, 2000, Veber et al., 2002).

Currently, there are a limited number of formulation approaches available for compounds that are poorly soluble in water. The most direct approach for enhancing solubility is to generate a salt. If, however, the compound is non-ionizable, solubility concerns are generally addressed by micronization and/or the development of oil-based solutions in gelatin capsules, i.e. soft-gel technology. In addition, co-solvents, surfactants or complexing agents such as cyclodextrins (Stella and Rajewski, 1997, Loftsson and Brewster, 1996, Akers, 2002) have been employed. Reasonable success has also been met in formulating water-insoluble drugs using emulsion (Nakano, 2000, Floyd, 1999), microemulsion (Lawrence and Rees, 2000) and solid dispersion technology (Leuner and Dressman, 2000, Serajuddin, 1999, Breitenbach, 2002). Although some of these approaches have been successfully utilized, especially for highly potent compounds with low dose requirements, there is a growing need for more effective and versatile ways to handle formulation issues associated with poorly-water-soluble molecules. A broadly based technology applicable to this class of molecule could have a tremendous impact on discovery effectiveness and improve the performance of products suffering from formulation-related issues.

A newer drug delivery approach for poorly-water-soluble compounds has come about in the last few years. In this approach, poorly-water-soluble compounds are formulated as nanometer-sized drug particles. There are various methodologies for generating drug nanoparticle formulations (Tom and Debenedetti, 1991, Pace et al., 1999, Muller et al., 2001, Rogers et al., 2001). This review, however, will focus on NanoCrystal® Technology whereby poorly-water-soluble drugs are formulated as nanometer-sized drug crystals using high-shear media mills. Since this approach has been adapted to handle milligram quantities of drug substance, for the research scientist this technology provides an avenue to improve screening efforts without having to deal with solubility-related performance issues. For the pharmaceutical scientist, this approach provides a universal process suitable for formulation development and commercialization of various dosage forms. The first product to incorporate this technology is Rapamune®, an immune suppressant agent, marketed by Wyeth Research Laboratories.

Section snippets

Nanocrystalline particles

Nanocrystalline particles are nanometer-sized drug particles of a poorly-water-soluble compound. Fig. 1 shows an electron micrograph and a diagrammatic representation of drug particles formulated as a colloidal dispersion. The electron-dense nanometer-sized particles exhibit a defined geometrical shape which is dictated by the morphology of the unprocessed crystalline powder, fracture plane of the crystals and drug/stabilizer interactions. The effects of shape on the properties and biological

Applications for oral delivery

Dissolution kinetics is the primary driving force behind the improved pharmacokinetic properties of nanoparticle formulations of poorly-water-soluble compounds (Liversidge and Cundy, 1995). The dissolution rate of a drug is a function of its intrinsic solubility and particle size. For poorly-water-soluble drugs, surface area of the drug particles drives dissolution. As described by the Nernst–Brunner and Levich modification of the Noyes–Whitney model of dissolution (Dressman et al., 1998,

Applications for injectable products

Nanocrystalline formulations are a suitable dosage form for poorly-water-soluble injectable products (Merisko-Liversidge et al., 1996, Cooper, 2000, Bittner and Mountfield, 2002). The question that is oftentimes raised is why and when would it be advantageous to use nanoparticles as opposed to a more traditional formulation approach. One of the major advantages is that drug nanoparticles provide an opportunity for dosing at significantly higher levels than what can be accomplished using a more

Conclusions

The use of wet milling technology to formulate poorly-water-soluble compounds is a viable approach capable of resolving many of the current issues associated with developing and commercializing poorly-water-soluble molecules. The successful implementation of nanocrystal technology to a chemical entity is primarily driven by solubility properties of the drug and hence can be readily applied to various classes of compounds. Nanocrystalline formulations can be dried and post-processed into

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