`
`Martin J Telko and Anthony J Hickey PhD DSc
`
`INTRODUCTION
`DRY POWDER INHALERS
`Development of the DPI
`Principles of Operation
`POWDER AND AEROSOL PHYSICS/PHYSICOCHEMICAL CHARACTERIZATION
`Crystallinity and Polymorphism
`Moisture Content and Hygroscopicity
`Particle Size
`Aerodynamic Diameter and Dynamic Shape Factor
`Fine-Particle Fraction
`Polydispersity
`Particle Sizing Techniques
`Surface Area and Morphology
`Forces of Interaction
`Surface Morphology
`Surface Area and Morphology Measurements
`DRUG PROPERTIES AND MANUFACTURE
`The Active Pharmaceutical Ingredient
`Active Pharmaceutical Ingredient Preparation
`FORMULATION
`Excipients
`Large Porous Particles
`Agglomerates
`PHARMACEUTICAL PROCESSING
`SUMMARY
`
`A drug product combines pharmacologic activity with pharmaceutical properties. Desirable per-
`formance characteristics are physical and chemical stability, ease of processing, accurate and
`reproducible delivery to the target organ, and availability at the site of action. For the dry powder
`inhaler (DPI), these goals can be met with a suitable powder formulation, an efficient metering
`system, and a carefully selected device. This review focuses on the DPI formulation and develop-
`ment process. Most DPI formulations consist of micronized drug blended with larger carrier
`particles, which enhance flow, reduce aggregation, and aid in dispersion. A combination of intrinsic
`physicochemical properties, particle size, shape, surface area, and morphology affects the forces of
`interaction and aerodynamic properties, which in turn determine fluidization, dispersion, delivery
`to the lungs, and deposition in the peripheral airways. When a DPI is actuated, the formulation is
`fluidized and enters the patient’s airways. Under the influence of inspiratory airflow, the drug
`particles separate from the carrier particles and are carried deep into the lungs, while the larger
`carrier particles impact on the oropharyngeal surfaces and are cleared. If the cohesive forces acting
`on the powder are too strong, the shear of the airflow may not be sufficient to separate the drug
`from the carrier particles, which results in low deposition efficiency. Advances in understanding of
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`DRY POWDER INHALER FORMULATION
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`aerosol and solid state physics and interfacial chemistry are moving formulation development from
`an empirical activity to a fundamental scientific foundation. Key words: dry powder inhaler, DPI,
`formulation development, particles, physico-chemical properties, drug delivery.
`[Respir Care 2005;
`50(9):1209–1227. © 2005 Daedalus Enterprises]
`
`INTRODUCTION
`
`Formulation development encompasses an array of pro-
`cesses in which an active pharmaceutical ingredient is in-
`corporated into a drug product. While biological activity is
`a prerequisite for a successful dosage form, it is not the
`sole determinant. Factors such as stability, processibility,
`delivery, and availability to the target organ contribute to
`an efficacious pharmaceutical system. Optimization of
`these factors is a key development task, and the final prod-
`uct is often a compromise between pharmaceutical and
`practical (ie, economic/engineering) considerations. For-
`mulation development is challenging because molecules
`with pharmacologic activity often display poor physico-
`chemical properties. In fact, the same molecular charac-
`teristics that confer pharmacologic activity (eg, high re-
`ceptor affinity)
`frequently limit a compound’s
`pharmaceutical utility, making it difficult or even unsuit-
`able for delivery.1,2 This is particularly true for many of
`the compounds that are identified by high-throughput
`screening methods.2,3
`Development of pharmaceuticals for inhalation is a par-
`ticular challenge, as it involves the preparation of a for-
`mulation and the selection of a device for aerosol disper-
`sion. The lungs have lower buffering capacity than other
`delivery sites (eg, the gastrointestinal tract or the blood),
`which limits the range of excipients that could enhance
`delivery outcomes. An additional variable, unique to pul-
`monary delivery, is the patient, both in terms of inhalation
`mode and respiratory-tract anatomy and physiology.4 There
`are many more ways to administer an inhaled aerosol than
`there are to swallow a tablet. Variability in delivered dose
`
`Martin J Telko and Anthony J Hickey PhD DSc are affiliated with the
`School of Pharmacy, University of North Carolina, Chapel Hill, North
`Carolina.
`
`Anthony J Hickey PhD DSc presented a version of this article at the 36th
`RESPIRATORY CARE Journal Conference, Metered-Dose Inhalers and Dry
`Powder Inhalers in Aerosol Therapy, held April 29 through May 1, 2005,
`in Los Cabos, Mexico.
`
`This research was partly supported by National Heart, Lung, and Blood
`Institute grant number HL67221. Martin J Telko is supported by a U.S.
`Pharmacopeia graduate fellowship.
`
`Correspondence: Anthony J Hickey PhD DSc, 1311 Kerr Hall, Dispersed
`Systems Laboratory, Division of Drug Delivery and Disposition, School
`of Pharmacy, CB 7360, University of North Carolina, Chapel Hill NC
`27599. E-mail: ahickey@unc.edu.
`
`to an individual or a population of patients can be sub-
`stantial.5,6 Consequently, reproducible therapeutic effect is
`difficult to assure.
`Treating respiratory diseases with inhalers requires de-
`livering sufficient drug to the lungs to bring about a ther-
`apeutic response. For optimal efficacy, drug administra-
`tion must be reliable, reproducible, and convenient. This
`goal can be achieved by a combination of formulation,
`metering, and inhaler design strategies.7 The technical and
`clinical aspects of device design and selection have been
`extensively reviewed elsewhere.8 –10 The following discus-
`sion outlines the design of dry powder inhaler (DPI) for-
`mulations to achieve the delivery goals. Formulation de-
`velopment and characterization strategies and processing
`methods will be discussed, with emphasis on their effect
`on stability, manufacturing feasibility, delivery, and bio-
`availability. To that end, an understanding of dry powder
`physics and surface chemistry is essential. The text fo-
`cuses on broad concepts and examples, with only sparing
`use of equations.
`
`DRY POWDER INHALERS
`
`Development of the DPI
`
`Inhaled drug delivery systems can be divided into 3
`principal categories: pressurized metered-dose inhalers
`(pMDIs), DPIs, and nebulizers, each class with its unique
`strengths and weaknesses. This classification is based on
`the physical states of dispersed-phase and continuous me-
`dium, and within each class further differentiation is based
`on metering, means of dispersion, or design. Nebulizers
`are distinctly different from both pMDIs and DPIs, in that
`the drug is dissolved or suspended in a polar liquid, usu-
`ally water. Nebulizers are used mostly in hospital and
`ambulatory care settings and are not typically used for
`chronic-disease management because they are larger and
`less convenient, and the aerosol is delivered continuously
`over an extended period of time. pMDIs and DPIs are
`bolus drug delivery devices that contain solid drug, sus-
`pended or dissolved in a nonpolar volatile propellant or in
`a dry powder mix (DPI) that is fluidized when the patient
`inhales. The clinical performance of the various types of
`inhalation devices has been thoroughly examined in many
`clinical trials, which have been reviewed by Barry and
`O’Callaghan,10 and more recently by Dolovich et al.8 Those
`authors concluded that none of the devices are clinically
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`Table 1. Dry Powder Inhalers Versus Metered-Dose Inhalers
`
`Advantages of the Dry Powder Inhaler
`Environmental sustainability, propellant-free design
`Little or no patient coordination required
`Formulation stability
`Disadvantages of the Dry Powder Inhaler
`Deposition efficiency dependent on patient’s inspiratory airflow
`Potential for dose uniformity problems
`Development and manufacture more complex/expensive
`
`(Adapted from Reference 18.)
`
`superior and that device selection should be guided by
`other factors, such as convenience, cost, and patient pref-
`erence.
`First approved in 1956, the pMDI was the first modern
`inhaler device.11 With a global market share of about 80%,
`the pMDI remains the most widely used device.12 The
`development of DPIs has been motivated by the desire for
`alternatives to pMDIs, to reduce emission of ozone-deplet-
`ing and greenhouse gases (chlorofluorocarbons and hy-
`drofluoroalkanes, respectively) that are used as propel-
`lants, and to facilitate the delivery of macromolecules and
`products of biotechnology. Concurrently, DPIs proved suc-
`cessful in addressing other device and formulation-related
`shortcomings of the pMDI. DPIs are easier to use, more
`stable and efficient systems. Because a pMDI is pressur-
`ized, it emits the dose at high velocity, which makes pre-
`mature deposition in the oropharynx more likely.13,14 Thus,
`pMDIs require careful coordination of actuation and inha-
`lation. Despite enhancements to their design (eg, use of
`spacers),15 incorrect use of pMDIs is still a prevalent prob-
`lem; Giraud and Roche found that poor coordination of
`actuation and inhalation caused decreased asthma control
`in a substantial proportion of patients treated with corti-
`costeroid pMDIs.16 Since DPIs are activated by the pa-
`tient’s inspiratory airflow, they require little or no coordi-
`nation of actuation and inhalation. This has frequently
`resulted in better lung delivery than was achieved with
`comparable pMDIs.17
`Since DPIs are typically formulated as one-phase, solid-
`particle blends, they are also preferred from a stability and
`processing standpoint.18 Dry powders are at a lower en-
`ergy state, which reduces the rate of chemical degradation
`and the likelihood of reaction with contact surfaces. By
`contrast, pMDI formulations, which include propellant and
`cosolvents, may extract organic compounds from the de-
`vice components.19 Table 1 summarizes the main advan-
`tages and disadvantages of the DPI (versus the pMDI). For
`more detail on the evolution of aerosol delivery devices,
`excellent reviews are available.11,20
`The development of several new DPI devices, which
`have been reviewed elsewhere,18,21–23 and the commercial
`
`success of the bronchodilator-corticosteroid combination
`product Advair (GlaxoSmithKline, Research Triangle Park,
`North Carolina) have further stimulated interest in and
`development of DPIs.7
`
`Principles of Operation
`
`Figure 1 shows the principles of DPI design. Most DPIs
`contain micronized drug blended with larger carrier parti-
`cles, which prevents aggregation and helps flow. The im-
`portant role these carrier particles play is discussed later in
`this article. The dispersion of a dry powder aerosol is
`conducted from a static powder bed. To generate the aero-
`sol, the particles have to be moved. Movement can be
`brought about by several mechanisms. Passive inhalers
`employ the patient’s inspiratory flow. When the patient
`activates the DPI and inhales, airflow through the device
`creates shear and turbulence; air is introduced into the
`powder bed and the static powder blend is fluidized and
`enters the patient’s airways. There, the drug particles sep-
`arate from the carrier particles and are carried deep into
`the lungs, while the larger carrier particles impact in the
`oropharynx and are cleared. Thus, deposition into the lungs
`is determined by the patient’s variable inspiratory air-
`flow.24 –26 Inadequate drug/carrier separation is one of the
`main explanations for the low deposition efficiency en-
`countered with DPIs.27 Dose uniformity is a challenge in
`the performance of DPIs. This is a greater concern with
`powders than with liquids because of the size and discrete
`nature of the particulates.
`Various dispersion mechanisms have been adopted for
`DPIs.22 While most DPIs are breath-activated, relying on
`inhalation for aerosol generation, several power-assisted
`devices (pneumatic, impact force, and vibratory) have been
`developed or are currently under development. These de-
`vices are being considered for the delivery of systemically
`active drugs that have narrow therapeutic windows.28 It is
`important to note that these “active” inhalers are not sub-
`ject to the same limitations as passive inhalers and have a
`different advantage/disadvantage profile. Moreover, it has
`been suggested that if shear and turbulence could be stan-
`dardized by using a dispersion mechanism that is indepen-
`dent of the patient’s breath, high delivery efficiency and
`reproducibility might be achieved. Thus, an active inhaler
`might provide formulation-independent delivery.29 There
`are no commercially available active-dispersion DPIs.
`Therefore, in the interest of brevity, these devices are not
`discussed here; the reader is instead referred to other lit-
`erature.28 –30
`
`POWDER AND AEROSOL PHYSICS/PHYSICOCHEMICAL
`CHARACTERIZATION
`
`The character of particulate systems is central to the
`performance of DPIs. Powders present unique design chal-
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`Fig. 1. Principle of dry powder inhaler design. The formulation typically consists of micronized drug blended with larger carrier particles,
`dispensed by a metering system. An active or passive dispersion system entrains the particles into the patient’s airways, where drug
`particles separate from the carrier particles and are carried into the lung.
`
`lenges. Powders are 2-phase gas-solid systems. When pow-
`ders are static, they behave as solids; when they flow, they
`resemble liquids, easily assuming the shape of the con-
`taining vessel.31 When a powder is dispersed in air, as is
`the case after actuation of a DPI, in many ways it conforms
`to its carrier gas (unlike gases or vapors, pharmaceutical
`powders are nonequilibrium systems). Whereas gas and
`liquid behavior is understood and accurately predicted by
`equations derived from first principles, physical equations
`governing powders are often empirical or rely on assump-
`tions that are only approximations to real systems, such as
`homogeneity in size and shape of particles. As a conse-
`quence, equations describing the behavior of solids are
`less predictive than their fluid counterparts. The reader is
`referred to texts on multiphase flow phenomena.32–36
`Powder properties can vary widely. Powder features,
`such as the physicochemical properties and morphology of
`its constituent particles and the distribution of particle sizes,
`contribute to variability. Unlike liquid solutions or gas
`mixtures, powders are never completely homogeneous (at
`primary particulate scale) and segregation by size, which
`is a function of external forces, is always a potential prob-
`lem. The aerodynamic behavior, which has a profound
`effect on the disposition of drug from a DPI, is particularly
`sensitive to powder properties.
`
`Crystallinity and Polymorphism
`
`Many pure organic substances, including most drugs,
`are crystalline. A crystal is a solid in which the molecules
`
`or ions are arranged in an ordered, repeating pattern (the
`unit cell) extending in 3 spatial dimensions. Crystalline
`systems are defined by the intermolecular spacing (ie, bond
`lengths and bond angles) of the unit cell, which can be
`determined by x-ray diffraction.37 There are 7 crystal
`classes, which yield 14 distinct lattice structures.38 The
`arrangement of molecules into crystals is governed by non-
`covalent interactions, including hydrogen bonding, van der
`Waals forces, -stacking, and electrostatic interactions.39
`Nearly one third of all drugs are known to display poly-
`morphism,40 which is the ability of a solid to exist in more
`than one crystal from. A prominent example of a poly-
`morphic pharmaceutical is carbamazepine, which has 4
`known polymorphs, one of which was discovered almost
`30 years after identification of the first polymorphs.41 De-
`termination of the polymorphic forms of a drug is an im-
`portant part of the formulation-development process, be-
`cause polymorphic forms are not equivalent. Different
`polymorphs are at different energy states and thus have
`different properties, including stability, solubility, and even
`bioavailability.38 Identification of all polymorphs of a drug
`also has important economic implications, because a sep-
`arate patent can be granted for each polymorph.40
`It is also possible to generate a noncrystalline solid. In
`most cases this involves cooling a fluid so rapidly that its
`molecules lose mobility before assuming their lattice po-
`sitions. A noncrystalline material is considered amorphous
`because it lacks long-range order. Amorphous materials
`have higher Gibbs free energies than crystals; thermody-
`namic laws predict that, in the long-term, materials seek to
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`Fig. 3. Hygroscopic growth. Particles absorb moisture as they
`traverse the humid environment of the airways, resulting in in-
`creased particle size.
`
`Knowledge of crystallization and polymorphism is still
`unfolding, and the ability to predict polymorphism remains
`imperfect. In most solids, a large number of different in-
`termolecular interactions are possible, but few are actually
`observed.48 The difficulties involved in crystallization are
`illustrated by several reported cases of “disappearing poly-
`morphs.” These cases were characterized by difficulty in
`resynthesis of a polymorph after initial synthesis, despite
`seemingly identical procedure and conditions.49 Control-
`ling crystallization is at the heart of “particle engineering,”
`which is a term that is used with increasing frequency in
`the pharmaceutical and chemical literature. Control over
`the crystallization process could yield particles with pre-
`cisely engineered morphology; co-crystallization (inclu-
`sion of functional impurities into the crystal) could then
`become a formulation strategy, resulting in “supramolecu-
`lar pharmaceutics.”47
`
`Moisture Content and Hygroscopicity
`
`Hygroscopicity is the intrinsic tendency of a material to
`take on moisture from its surroundings. The hygroscopic-
`ity is affected by the crystallinity of the material and the
`morphology of the particles. Hygroscopic drugs present a
`greater risk of physical and chemical instability. Moisture
`uptake and loss due to changes in relative humidity can
`result in local dissolution and recrystallization, leading to
`irreversible aggregation through solid bridge formation,22
`which can adversely affect aerosol generation and lung
`deposition.50 Hygroscopicity can also alter the adhesive
`and cohesive properties, or, in more extreme situations,
`substantially increase particle size.51 Hygroscopic growth
`(Fig. 3) involves the uptake of moisture, which will reach
`equilibrium in droplets as a function of the water activity
`of the solution formed and the surrounding atmosphere of
`water vapor; the Kelvin-Gibbs equation describes the phe-
`nomenon involved.52 Hygroscopic growth has implications
`for the equilibrium moisture content of the particles in the
`dosage form prior to aerosol generation; it can cause chem-
`ical or physical instability of the product. For aerosols, the
`physical instability is more important, because agglomer-
`ation may be irreversible and lead to an inability to gen-
`erate aerosol particles of respirable size. As aerosol parti-
`cles enter the lungs, they experience a high-humidity
`
`Fig. 2. Crystal habit. Inhibition of growth in one of more spatial
`directions (ka, kb, and kc) results in particles with plate or needle
`morphology.
`
`minimize their free energies by transitioning to lower en-
`ergy states (eg, crystallization). Whether this will occur at
`a timescale that need be of concern to the pharmaceutical
`scientist is governed by the chemical kinetics of the sys-
`tem.
`Different polymorphs can be discerned in terms of var-
`ious physicochemical properties. Polymorphs usually dif-
`fer in density, melting point, solubility, and hygroscopic-
`ity. The most stable polymorph frequently has the highest
`density, highest melting point, and lowest solubility. Dis-
`criminating analytical methods to characterize polymorphs
`include x-ray diffraction and thermal analysis, such as
`differential scanning calorimetry.38 To reduce the risk of
`transformation during processing or storage, the most sta-
`ble polymorph is typically selected for development, pro-
`vided its other properties are manageable.
`While crystallinity refers to the geometry of the unit
`cell, crystal habit describes the morphology of particles,
`which can vary independently of the crystal lattice struc-
`ture if crystal growth rates (during precipitation) vary in
`some dimension (Fig. 2).42 Crystal habit is important be-
`cause particle shape affects aerodynamic behavior and,
`thus, lung deposition. Crystallization and crystal habit are
`influenced by various factors, including identity of sol-
`vent,43,44 impurities present during crystallization,45 and
`processing variables such as temperature, pH, solution vol-
`ume, and viscosity.46
`Some compounds will spontaneously incorporate sol-
`vent molecules into the lattice structure upon crystalliza-
`tion or storage at certain conditions. This phenomenon has
`been referred to as pseudopolymorphism, and is relevant
`for many drugs that exist as solvates or hydrates.47 It is
`important to understand the conditions that will result in
`hydration, because, as with true polymorphs, hydrates dif-
`fer in their physicochemical properties.
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`Fig. 4. Strategies for altering the aerodynamic diameter. A: Aero-
`dynamic diameter equation. B: Large, low-density porous parti-
`cles. C: Needle-shaped particles. Particles in both B and C are
`expected to have aerodynamic diameters smaller than their size
`would suggest. Dae ⫽ aerodynamic diameter. Deq ⫽ unit density of
`equivalent volume sphere. p ⫽ particle density. o ⫽ unit density.
`X ⫽ dynamic shape factor.
`
`environment (99.5% relative humidity at 37°C). Although
`they may not reach equilibrium during transit, susceptible
`aerosol particles may be subject to hygroscopic growth,
`which increases particle dimensions and affects lung dep-
`osition.53 Hygroscopic growth can be prevented by coating
`the drug particles with hydrophobic films.52 However, no
`such approach has been successfully implemented in a
`marketed formulation.
`The equilibrium moisture content of a drug and excip-
`ient must be determined over a range of relative humidi-
`ties, so that storage conditions can be defined and other
`protective measures considered. Excipients that modify
`the hygroscopic properties of a drug may need to be con-
`sidered.
`
`Particle Size
`
`Particle size is the single most important design variable
`of a DPI formulation. Methods for determining particle
`size and distribution use various geometric features or phys-
`icochemical properties.54 Among these, aerodynamic di-
`ameter is the most relevant to lung delivery and ultimately
`to therapeutic effect. There is substantial literature from
`the fields of industrial hygiene, environmental and occu-
`pational medicine, and pharmaceutical sciences that links
`aerodynamic size and size distribution to the probability of
`deposition in specific lung sites. The statistical basis for
`these relationships in terms of variability in airways ge-
`ometry and lung physiology, both between individuals and
`within an individual, has been sufficient to allow the de-
`velopment of semi-empirical models correlating particle
`size with lung deposition.55
`
`Aerodynamic Diameter and Dynamic Shape Factor
`
`Aerodynamic diameter is the most appropriate measure
`of aerosol particle size, because it relates to particle dy-
`namic behavior and describes the main mechanisms of
`aerosol deposition; both gravitational settling and inertial
`impaction depend on aerodynamic diameter. To reach the
`peripheral airways, where drug is most efficiently absorbed,
`particles need to be in the 1–5 m aerodynamic diameter
`range.56 Particles larger than 5 m usually deposit in the
`oral cavity or pharynx, from which they are easily cleared.
`In contrast, particles smaller than 0.5 m may not deposit
`at all, since they move by Brownian motion and settle very
`slowly. Moreover, they are inefficient, as a 0.5-m sphere
`delivers only 0.1% of the mass that a 5-m sphere carries
`into the lungs. In a series of studies, the optimal particle
`size of aerosol particles was examined for several different
`therapeutic agents in patients with different disease states.
`Although some differences due to patient lung function
`were noted, the optimal size was always in this 1–5 m
`range.57– 60
`
`The aerodynamic diameter, Dae, is defined by the diam-
`eter of an equivalent volume sphere of unit density Deq
`with the same terminal settling velocity as the actual par-
`ticle. For particles larger than 1 m, the following expres-
`sion describes the relationship between these dimensions.
`
`Dae ⫽ Deq冑冉 p
`
`oX
`
`冊
`
`where
`p and o are particle and unit densities, and is the
`
`dynamic shape factor. Pharmaceutical powders are rarely
`spherical, and shape factors are dimensionless measures of
`the deviation from sphericity. The dynamic shape factor is
`the ratio of the actual resistance force experienced by the
`nonspherical falling particle to the resistance force expe-
`rienced by a sphere having the same volume.61 Dynamic
`shape factors are determined either experimentally or us-
`ing more complex models that are beyond the scope of this
`paper. A very thorough review of this concept, with values
`for common shapes, is provided by Hinds.61
`The above equation merits closer examination. As dis-
`cussed, it is the aerodynamic diameter that determines lung
`disposition, irrespective of geometric particle size (to a cer-
`tain point). The aerodynamic diameter can be decreased by
`decreasing the particle size, decreasing particle density, or
`increasing the dynamic shape factor. This concept is shown
`graphically in Figure 4, and is discussed in more detail below.
`All 3 of these approaches have been applied.
`
`Fine-Particle Fraction
`
`“Fine-particle fraction” is the percentage of particles in
`the fine-particle range (1–5 m). “Fine-particle mass” is
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`the total mass of the particles that are in the fine-particle
`range.62 The fine-particle component of aerosols is usually
`defined as the percentage of particles that are smaller than
`5 m aerodynamic diameter, or, in the case of certain
`particle-sizing instruments, a cut-off diameter that is close
`to 5 m. Quite often this may be in the 6 –7 m range. The
`danger of adopting these values as definitive measures of
`equivalency is associated with the effect of particle size on
`deposition.63 This is considered more later in this article.
`
`Polydispersity
`
`For drug delivery it is the convention to consider the
`mass associated with each particle size as the frequency
`term in the distribution, since this relates directly to dose.
`Conventional statistical properties apply to populations of
`particles (ie, mode, mean, and median). It is usual to de-
`fine the central tendency of numbers of aerosol particles
`by the mass median aerodynamic diameter, which reflects
`the particle size that divides the distribution in half as a
`function of mass. Monomodal distributions may conform
`to log-normal mathematical interpretation, in which case
`the breadth of the distribution can be expressed in terms of
`the geometric standard deviation, which is usually derived
`by dividing the particle size at the 84th percentile by the
`median size, to achieve a dimensionless number greater
`than 1.
`When considering particle size, the degree of polydis-
`persity (ie, the range of particle sizes around the mode) is
`also important. The simplest and preferred system exhibits
`a single mode. However, many pharmaceutical aerosols
`will exhibit more than one mode. It is conceivable that 2
`completely different aerosol distributions (eg, small me-
`dian size with narrow distribution or large median size
`with broad distribution) could give exactly the same fine-
`particle fraction. However, within the fine-particle frac-
`tion, the aerosol would exhibit different sizes, leading to
`differences in regional lung deposition, resulting in vari-
`ations in therapeutic effect. Thus, degree of dispersity is an
`important consideration for both quality and efficacy of
`pharmaceutical aerosols.64 The nature of the aerosol dis-
`tribution must be established accurately if its implications
`for deposition and efficacy are to be understood.
`Another consideration relates to the standard DPI for-
`mulation, which is frequently bimodal, because it contains
`micronized drug and substantially larger carrier particles.
`Recognizing the potential for multimodal distributions is
`important to the application of statistical methods to the
`interpretation of the data. Traditional methods of data in-
`terpretation (eg, log-normal mathematical fits to distribu-
`tions65) may be superseded by other mathematical ap-
`proaches66 or nonlinear curve-fitting using calibration
`data.67
`
`Fig. 5. The electrical low-pressure impactor. (Courtesy of Dekati
`Ltd, Tampere, Finland.)
`
`Particle Sizing Techniques
`
`Several techniques are available for determining parti-
`cle size distributions; they have been described in depth
`elsewhere65 and will be covered briefly here. The aerosol
`sizing techniques can be classified as (1) inertial methods,
`(2) light-scattering methods, or (3) imaging methods.
`
`Cascade Impactor. Cascade impactors,68,69 including
`multi-stage liquid impingers, are the most widely used
`instruments for sizing aerosols; they are recommended by
`both the United States and the European pharmacopeias.
`Their utility stems from the fact that they directly measure
`aerodynamic size, rather than equivalent volume diameter
`(based on cross-sectional area) like the other methods. The
`theory of cascade impactor operation has been described
`in depth elsewhere.70 Briefly, cascade impactors contain
`several stages, with orifices of decreasing size, stacked on
`top of each other. When the aerosol is drawn through the
`impactor, the particles deposit on different stages, based
`on their inertia. After each run, the impactor is disassem-
`bled and the mass of particles deposited on each stage is
`determined, mostly via analytical methods (dissolution in
`solvent, followed by chromatography or ultraviolet absor-
`bance). A cut-off diameter is associated with each stage of
`the impactor. This diameter varies with airflow, so the
`impactor must be calibrated for different flow rates. This
`airflow dependence allows investigation of the effect of
`different inspiratory flow rates on deposition.
`The electrical low-pressure impactor71 (Figure 5) is a
`rather recent modification of the cascade impactor. Parti-
`cles passing through the electrical low-pressure impactor
`are charged before traversing the cascade of stages. Their
`impact on the stages produces an electrical current that is
`detected and converted into particle-size data that can be
`interpreted immediately. The utility of the electrical low-
`pressure impactor has been demonstrated in the sizing of
`particles in diesel engine exhaust71–76 and other combus-
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`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
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`DRY POWDER INHALER FORMULATION
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`Fig. 6. Particle sizing via laser-light scattering.
`
`Fig. 7. Particle sizing via digital image analysis.
`
`tion processes.77 A limitation of the electrical low-pressure
`impactor is that it is not suitable for particles larger than 20
`m, so it cannot be used to size carrier particles, which
`limits its utility for sizing pharmaceutical aerosols. Based
`on a PubMed search, reference to electrical low-pressure
`impactors in medical/pharmaceutical journals is limited to
`a single publication, in which an electrical low-pressure
`impactor was used for sizing sub-micron size pMDI par-
`ticles.78 However, the electrical low-pressure impactor has
`great potential to simplify the aerosol sizing process and is
`likely to make an impact in the field in the future.
`
`Light Scattering and Laser Diffraction. Light-scatter-
`ing methods, especially laser-light-scattering, are quite
`commonplace in formulation development. The operating
`principle of laser-light scattering is depicted in Figure 6.
`An expanded laser beam is passed through a sample that is
`being drawn through a measuring zone. Different size par-
`ticles diffract the light at d