The Science Journal of the American Association for Respiratory Care

Conference Proceedings

December 2002 / Volume 47 / Number 12 / Page 1419

The Electrospray and Its Application to Targeted Drug Inhalation

Alessandro Gomez PhD

Introduction
Experimental System and Methods
Liquid Break-Up, Droplet Dispersion, and Monodispersity
Required Liquid Physical Properties and Scaling Laws
Electric Charge: Consequences and the Need to Neutralize the Droplets
The Need for Multiplexing
The BattellePharma Electrospray Nebulizers
This review explains the fundamentals of electrostatic spray (electrospray) atomization, with emphasis on operation in the so called cone-jet mode, which produces droplets with a very narrow size distribution. Since the control of droplet size is key to maximizing distal lung deposition, the electrospray should be well-suited to targeted drug inhalation. Electrospray droplets are a few micrometers in diameter, but they originate from a much larger nozzle, which allows nebulization of suspensions without clogging. Also discussed are: the physical principles of the break-up of the liquid ligament; droplet dispersion by Coulombic forces; and the most important scaling law linking the droplet size to liquid flow rate and liquid physical properties. The effects of the most critical of those properties may result in some restrictions on drug formulation. Droplets produced by electrospray are electrically charged, so to prevent electrostatic image forces from causing upper respiratory tract deposition. The charge is neutralized by generating a corona discharge of opposite polarity. Briefly discussed are the main differences between the laboratory systems (with which the electrospray has been quantitatively characterized during research in the past 10 years) and commercial electrospray inhalers under development at BattellePharma. Some remarkable miniaturization has incorporated liquid pump, power supply, breath activation, and dose counter into a palm-size portable device. The maximum flow rates dispersed from these devices are in the range of 8-16 |gmL/s, which makes them suitable for practical drug inhalation therapy. Fabrication is economically competitive with inexpensive nebulizers. Dramatic improvements in respirable dose efficiency (up to 78% by comparison with commercial metered-dose inhalers and dry powder inhalers) should ensure the commercialization of this promising technology for targeted drug inhalation.
Key words: targeted drug delivery, inhalation, nebulization, electrospray, electrostatic spray, aerosol.
[Respir Care 2002;47(12):1419–1431]

Introduction

Deposition of inhaled aerosol occurs by 3 physical mechanisms: inertial impaction, gravitational sedimentation, and Brownian diffusion. Targeting deposition to specific areas of the respiratory tract can be achieved by controlling the size of the aerosol droplets, which in turn affects the deposition mechanism. The objective is to deliver the drug directly to the site of action and thereby minimize the dose required to achieve an adequate response to the inhalation therapy. This approach may be particulary advantageous when cost and/or adverse effects are of concern.

Aerosol generators for drug inhalation range from relatively simple, inexpensive types to large, expensive, and complex systems. Examples of the first category are jet nebulizers, pressurized metered-dose inhalers, and dry powder inhalers, which generate a polydisperse distribution of aerosol droplets or particles. At the other end of the spectrum are much more complex alternatives, such as the modified Sinclair-La Mer generator, capable of generating (by condensation methods) monodisperse particles to be stored in a large volume prior to inhalation. However, construction and operation of that type of generator is complex and confines its use to research applications. A few liquid nebulization technologies have recently emerged that offer control of the distribution and size of the aerosol droplets, are amenable to miniaturization, and are sufficiently inexpensive to provide appealing alternatives to traditional inhalers. The present review focuses on technologies that use one or more electrosprays to nebulize liquid formulations. The term electrostatic spray (also known as electrohydrodynamic spray or electrospray) is used in this review with reference to systems in which the dispersion of the liquid relies solely on its electric charging, so that nebulization and gas flow processes are relatively uncoupled. The potential for an electrospray-based technology for targeted inhalation was first recognized by Tang and Gomez. Recent developments at Battelle Pharma have generated considerable interest in this approach. Figure 1 shows the latest prototypes of inhalers developed by BattellePharma, including a portable device and a benchtop alternative. High-voltage electricity supply, pumping, droplet discharging, and breath activation have been folded into a successfully miniaturized system.

To be able to rely on the extensive characterization in the literature and to avoid being encumbered by the "bells and whistles" of commercial devices, attention here is restricted to a particular type of electrospray that captures the salient features of the BattellePharma inhalers. Such a spray can be implemented very simply by feeding a liquid with sufficient electrical conductivity and moderate surface tension through a capillary tube and charging it by a metal electrode in contact with the liquid and maintained at several kilovolts relative to a ground electrode a short distance away. This type of electrospray has the additional feature of a tight control of the size distribution of the aerosol, as will be shown below. The objective is to review the physical principles underlying the operation of such an electrospray and to examine the potential limitations imposed by certain requirements in the physical properties of the aerosolized liquid, which ultimately may constrain drug formulation. This review draws heavily from the work of Tang and Gomez.

The entire text of this article is available in the printed version of the December 2002 RESPIRATORY CARE.

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