La muerte como negocio y el juicio de los cemiteristas.

Electrostatic forces affect the adhesional properties and separation efficiency of particles in the formulation. They may influence the transport of particles and can result in undesirable adhesion of charged drug particles to a device or other surfaces, and they may also affect the trajectory and deposition of drug within the lungs. In light of these potential effects, electrostatic forces are clearly an important consideration in DPI formulation development. In recent years they have been the subject of a number of pharmaceutically relevant studies. Different techniques have been applied to the characterization of DPI electrostatics, with different aims and to varying degrees of success. Some of the important past studies of DPI charging phenomena are discussed in the context of the techniques that have been used.

1.8.1. Faraday Cage

The majority of studies of medicinal aerosol electrostatics have made use of Faraday cages, or Faraday-cage based experimental apparatus. A Faraday cage (also Faraday pail or cup) consists of some receiving surface contained within a cup enclosure that shields the inside from the effect of external electric fields. As a charged object (e.g. powder) is deposited on the receiving plate within the cage, it dissipates its electric charges which in turn are detected by an electrometer. One of the

first successful aerosol electrostatic characterizations can be credited to Byron et al.,156 who

developed an experimental apparatus based on an impinger and Faraday cage, which allowed the charge of DPI emissions to be measured. (Recently, more advanced impinger /Faraday cage based

designs were described.157, 158_{) The study included bulk measurements of powders as well as emitted}

dose measurements of commercial DPI products. No effort was made in formulating the material; the study focused on triboelectification of aerosolized pure compounds. While the study suffered from

these obvious drawbacks, the authors were nevertheless able to produce a triboelectric series of pure pharmaceutical compounds and estimate (using an overly simple assumption of mondisperse particle size) the per particle charge level, which was found to be high enough to affect deposition (approximately 200 electronic charges per aerosol drug particle).

Bennett et al.159 _{used a design based on Faraday cage principles to determine the charge of}

pneumatically conveyed lactose powders. Importantly, the authors observed that the presence of various fractions of fine particles affected the charging propensity of the bulk powder.

Electrostatic charge carried by a DPI aerosol cloud has also been measured using a grid probe;160

however, the particles were large and the system was of little pharmaceutical relevance. The effects of particle morphology and crystallinity on triboelectrification of DPIs have been studied, but particle

deposition was not considered.161 _{Moreover, use of the Faraday cage precluded analysis of different}

size fractions and charge distribution. Cassidy et al.162, 163 _{have also studied the propensity of different}

pharmaceutical materials to acquire charge, though their interest pertained to pneumatic conveying and processing; the results of their work are not relevant to respiratory drug delivery. With a slightly different focus, Elajnaf et al.164 _{recently used a corona charger with a Faraday cage based apparatus to}

study the electrostatic charge decay of charged pharmaceutical materials; the powders were compacted into 5mm discs, the discs were charged and the charge dissipation was measured inside a Faraday cage; the authors found dissipation times in the order of tens to hundreds of minutes, which seem extremely high and question the study's relevance to micron-size drug particles delivered from DPIs.

1.8.2. Single Particle Impact Electrostatics

A variation from the Faraday cage powder electrostatic measurements are the recent

measurements of charges associated with single particle impacts.165, 166 _{The studies were able to shed}

some light on the charge transfer experienced during particle-wall collisions. Moreover, unlike regular Faraday cage methods, which measure only the net charge of a larger powder sample and

hence may only provide rough charge-to-mass (Q/M) information, the single impact method can measure actual particle charges. However, the single particle method does not lend itself to particles in the single micron-size, and is more relevant to pneumatic conveying systems than to DPIs; as in previous studies the authors neglected to consider the contact charging process within the formulation which is a likely contribution to the aerosol charging in DPI.

1.8.3. Electrical Single Particle Aerodynamic Relaxation Time (E-SPART)

E-SPART measurements are also based on single particle measurements, but go further than the

single particle impact device. As in previous electrical mobility measurements,167 _{charge is measured}

indirectly by particle behavior within an electric field. The E-SPART Analyzer has been around since at least the 1980s and has been applied to the characterization of many electrostatic particulate

systems, e.g. printer toner particles.168, 169 _{The principles of operation are discussed elsewhere.}170

Briefly, the E-SPART samples aerosols at low flow rates (1L/min) and detects particles by laser Doppler velocimetry. An oscillating electric field within the device causes particles to oscillate and the particles' response to these oscillations supplies information on the particles' count mean

aerodynamic diameter, and charge-to-mass ratio. Saini et al.171 _{recently used the E-SPART to study}

MDI and DPI particle electrostatics. Inhalers were actuated into a collection chamber from which the E-SPART sampled particles over the course of several minutes. While the paper neglects to consider carefully the pharmaceutical implications of the experiments (e.g. it is unclear from the paper which drugs and inhalers were tested) the study showed differentiated and bipolar particle charging, and suggested charging was the result of inhaler and formulation.

1.8.4. Electrical Low Pressure Impaction

The ELPI, described briefly earlier and subject to more in-depth discussion in Chapter 4, is a cascade impactor in which charge depositions on the individual, electrically insulated stages can be measured. The ELPI can classify particle size fractions and measure the charge on each impactor

stage. Unlike the E-SPART it cannot obtain charges for individual particles but rather average charges for mass deposited on a given impactor collection plate. Using the ELPI, tribocharging within

the formulation was implicated as the likely cause of the drug particle charge.172 _{The studies also}

clearly showed for the first time that DPI charging of drug was subject to strong formulation and

device effects.172 _{Furthermore, since impactor stages are electrically isolated, size specificity of}

charging could be evaluated. However, the studies left a lot of questions unanswered, which is why a more thorough investigation is in order.

The studies herein rely heavily on the ELPI. They constitute a more comprehensive investigation of the DPI electrostatic phenomenon, with more variables, a more in-depth look at the accurate determination of magnitude and polarity of charge on particles in the respirable size range over time. Using complementary techniques the physicochemical origins of contact charging are probed.