Ebook Pulmonary drug delivery: Part 2

8
Particle Engineering for Improved
Pulmonary Drug Delivery Through
Dry Powder Inhalers
Waseem Kaialy1,∗ and Ali Nokhodchi2,3,†
School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, UK
2
School of Life Sciences, University of Sussex, UK
3
Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences,
Iran
1

Abbreviations
List of Abbreviations
𝛼
𝜌true or Dtrue
API
AFM
CI
CCM
d50%
Dae
Db
Dg or De
Dt
DPI
EM
ED
ER

Angle of repose
True density
Active pharmaceutical ingredient
Atomic force microscope
Carr’s index
Cooling crystallised mannitol
Median diameter
Aerodynamic diameter
Bulk density
Geometric diameter
Tap density
Dry powder inhaler
Emission
Emitted dose
Elongation ratio

∗
†

Pulmonary Drug Delivery: Advances and Challenges, First Edition. Edited by Ali Nokhodchi and Gary P. Martin.
© 2015 John Wiley & Sons, Ltd. Published 2015 by John Wiley & Sons, Ltd.


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Pulmonary Drug Delivery

FPD
FPF
GAS

GSD
HR
IGC
IL
LPPs
MMAD
PGSS
pMDI
PSD
PSG
RD
RESS
SCF
SEDS

8.1

Fine particle dose
Fine particle fraction
Gas antisolvent
Geometric standard deviation
Hausner ratio
Inverse gas chromatography
Impaction loss
Large porous particles
Mass median aerodynamic diameter
Precipitation from gas saturated solutions
Pressurised metered dose inhalers
Particle size distribution
Pressure swing granulation

Recovered dose
Rapid expansion of supercritical fluid solution
Supercritical fluid
Solution enhanced dispersion by SCF

Introduction

Oral drug delivery is the most commonly used delivery route for many drugs due to its several advantages, which include ease of administration and high patient acceptability. Nevertheless this route of
drug delivery does have a number of associated disadvantages such as possible unpredictable absorption rates [1], the potential for drug degradation by the digestive acid and enzymes, as well as drug
inactivation in the liver and the lack of organ selectivity (compared to that achievable by other routes
including the pulmonary). Drug delivery by inhalation has been employed routinely for the treatment
of localized diseases such as asthma and other pulmonary conditions. Delivery via the airways has
also been used in the treatment or management of systemic diseases (e.g., diabetes) [2, 3]. Recombinant human deoxyribonuclease (rhDNase, dornase alpha) was the first recombinant protein approved
for therapeutic use by inhalation delivery [4]. It is apparent, therefore, that this route of drug delivery
is important, but performance of inhalation products is still generally poor. This is one of the main
reasons for interest in the modification of drug or carrier particles by particle engineering, so as to
enhance the performance of formulations in vivo, and as assessed in vitro.

8.2

Dry Powder Inhalers

Dry powder inhalers (DPIs) comprise a pharmaceutical dosage form of increasing popularity with
attractive features such as the provision of a propellant-free means of drug delivery and such formulations have rapidly increased in number, worldwide. Some of the most commonly used DPI dosage
forms are shown in Figure 8.1. More discussion and details on specific inhaler devices are available
elsewhere (see Chapter 3).

8.3

Particle Engineering to Improve the Performance of DPIs

In attempts to enhance the efficiency of delivery from DPIs, several techniques have been utilised to
prepare particles of active pharmaceutical ingredients (APIs) and carriers (e.g., lactose or mannitol),


Particle Engineering for Improved Pulmonary Drug Delivery

EasyhalerTM

TurbulaherTM

DiskhalerTM

AerolizerTM

ClickhalerTM

RotahalerTM

HandihalerTM

173

SpinhalerTM

TwisthalerTM

NovolizerTM

Figure 8.1 Some common DPI devices

under controlled conditions. These include simple crystallization techniques, spray-drying, freezedrying, supercritical fluid (SCF) technology and antisolvent technology. These are considered in turn.

8.3.1

Crystallization

A crystallization process is characterized by the formation of supersaturation, nucleation and crystal growth, in addition to secondary phenomena including aggregation, agglomeration, breakage,
re-dissolution and aging [5]. Crystallization is usually associated with several challenges including poor mixing and crystal break/agglomerate formation [6]. Fundamentally, the difference of the
chemical potential between the supersaturated solution and the solid crystal face is the driving force
for crystallization. Typically, supersaturation can be created in the crystallization media by cooling,
evaporation of the solvent and/or the addition of an antisolvent.
Batch cooling crystallization is a widely used technique for the production of high-value chemicals
[7]. The slow crystallization rate is the main disadvantage of the cooling crystallization technique [8].
This is due to the relatively large width of the metastable zone that requires a high supersaturation
to induce crystallization [9]. Nevertheless, slow cooling is advantageous in terms of attaining the
maximum yield, minimum agglomeration [10], fewer defects in the crystal lattice [11] and high
product purity [12].
Antisolvent crystallization is a process where an organic product can be recovered from aqueous
solutions through the addition of non-solvent compounds by which the solute solubility is decreased,
without creating a new liquid phase [13]. The successful antisolvent must be miscible with the mother
liquid but in which the solute is insoluble. Under such conditions, solute solubility is reduced but
not completely inhibited. Antisolvent crystallization using alcohols does suffer from disadvantages
including the requirement for solvent recovery and the risk associated with the use of flammable
solvents at high reaction temperatures [14]. Crisp et al. [15] reported that the crystal size increased
as the antisolvent proportion decreased. The antisolvent crystallization technique has been proven
to be a potential technique for the preparation of particles, such as salbutamol sulphate [16] and
budesonide [17], both generated an improved DPI performance upon aerosolization (Figure 8.2).
It has been documented that the properties of an antisolvent crystallized product are dependent
on several processing parameters such as the type of the antisolvent [18], solution concentration [19], agitation intensity [20], antisolvent addition rate [21] and mixing conditions [22]. During

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Pulmonary Drug Delivery
(a)

Salbutamol sulphate

(b)

Budesonide

Figure 8.2 Engineered drug particles prepared by antisolvent crystallization for DPI systems: (a) salbutamol sulphate (Source: Reproduced from [16], with permission from Elsevier) and (b) budesonide (Source:
Reproduced with permission from [17]. Copyright © 2008, American Chemical Society)

crystallization, mechanical stirring can introduce random energy fluctuations within the solution
leading to a heterogeneous distribution of local concentrations, resulting in heterogeneous crystal
growth [23]. On the other hand, particles with a narrow size distribution and a regular particle
shape can be prepared by suspending the crystals in a gel [24], in which secondary nucleation
(heterogeneous nucleation) occurs to a much lesser extent [25].

8.3.2

Spray-drying

Spray-drying is a drying technique in which a dry powder is produced by evaporating the liquid from
the atomized feed when it mixes with the drying hot gas medium. In DPIs, the spray-drying technique
has been employed to produce not only drug particles [26–29] but also carrier particles [26, 30, 31].
A few examples are shown in Figure 8.3.

Spray-dried drug particles can produce higher respirable fractions than micronized particles, and
this has been ascribed to their spherical shape resulting in less drug–carrier contact area and in turn
less drug–carrier adhesive forces [23] (Figure 8.4). Moreover, spray-dried particles may have more
homogenous particle size distribution (PSD) [33].
One of the most important advantages of spray-drying techniques is the opportunity to generate
particles with pre-determined characteristics, e.g., size, morphology, shape and density, seeking to
optimize the powder properties such as bulk density, flowability and dispersibility [34]. Such characteristics of the spray-dried particles can be controlled by manipulating several parameters including
the composition of the solvent [35] and coating of particles by an excipient (e.g., leucine). In addition,
other parameters such as solute concentration, solution feed rate, gas feed rate, drying rate, viscosity
of the liquid feed and relative humidity are able to alter the characteristics of the resultant spray-dried
particles [36].
Various methods can be employed to determine aerosol PSDs, which depend on various geometric
features or physicochemical properties of powders being measured. Among these, Dae is the most
used and most relevant parameter to express aerosol particle size [37], a parameter that also accommodates particle shape. Furthermore, the Dae relates to the main mechanisms of particle deposition
and is defined as the diameter of a sphere having the same volume and a unit density. This assumes
that such a ‘hypothetical’ particle impacts on the same stage of the impactor during aerosolization
(or has the same impaction characteristics) as the real particles being measured [38]. The theoretical
Dae of particles (Dae = Dg × (𝜌true /X)0.5 ) can be calculated from the particle true density (𝜌true or Dtrue )
and geometric diameter (Dg ) [39].


Particle Engineering for Improved Pulmonary Drug Delivery

(a)

Gentamicin

(c)

Budesonide

2 μm

(b)

175

5 μm

Cromolyn

1 μm

(d)

Mannitol

200 μm

Figure 8.3 SEM photographs for different particles used in DPI systems: (a) gentamicin (Source: Reproduced from [27], with permission from Elsevier), (b) cromolyn (Source: Reproduced with permission from
[28]. Copyright © 2007 Wiley-Liss, Inc.), (c) budesonide (Source: Reproduced from [29] with kind permission from Springer Science and Business Media) and excipient: (d) mannitol (Source: Reproduced from
[31], with permission from Elsevier)

Micronized drug
High drug-carrier
contact area

Carrier surface

Spray-dried drug

Less drug-carrier
contact area

Carrier
Carrier surface
surface

Figure 8.4 Schematic representation of drug–carrier interactions of a micronized drug and a spray-dried
drug (SEM images taken from Louey et al. (Source: Reproduced from [32] with kind permission from
Springer Science and Business Media)


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Pulmonary Drug Delivery
Table 8.1 Comparison between drug carrier, Pulmosphere® and large porous particle DPI formulations
Formulation type

cm –3 )

Density (g
Mean geometric
diameter (μm)

Drug-carrier

Pulmospheres®

Large porous particles

1 ± 0.5
<5

∼0.4
∼5

0.1–0.5
>10

As seen, Dae can be changed by changing three factors: particle size, particle density and particle
shape factor (X). For example, to decrease the Dae particle size and particle density can be decreased
and dynamic shape factor can be increased. By definition, the particle in which the Dae is equal to
the physical diameter is a water droplet with a density of 1 g cm –3 . A drug particle that has a particle
density more than 1 g cm –3 will have Dae higher than its Dg . In practice, Dae is usually measured by
the techniques that are dependent on inertial impaction. Indeed, aerosol PSD can be expressed in two
ways: based on the number of particles (count median Dae ) or mass (mass Dae ).
An advantage of the spray-drying technique is the capability to produce large porous particles
(LPPs). LPPs are particles with mass density significantly less than 1 g cm –3 , such that a low (respirable) aerodynamic diameter (Dae ) can be achieved but with the particles having a mean geometric
diameter (Dg or De ) greater than 10 μm [40], or even as high as 20 μm [41] (Table 8.1). LPPs can be
prepared by a standard, one-step pharmaceutical spray-drying process using ‘generally recognized
as safe’ (GRAS) excipients [42].
The advantages of LPPs are summarized as follows:
a. Increased aerosolization efficiency due to lower powder aggregation owing to a lower contact area
between larger particles resulting, in less total van der Waals forces. Several studies have shown
that LPPs increase the amount of respirable particles, both in vitro [43, 44] and in vivo [3, 45].
b. Formulations containing LPPs may confer a longer time for drug delivery to occur, because they
can escape the natural clearance mechanisms present in the airways such as the mucociliary escalator (Chapter 1) and phagocytosis by alveolar macrophages [41].
c. Formulations containing LPPs of APIs with relatively low water solubility (i.e., relatively
lipophilic LPPs) have been produced so as to generate sustained release from inhaled products
[42].

Despite these advantages, some disadvantages have been stated in connection with LPP formulations. For example, LPP formulations can impose a limit on the deliverable dose because they can
carry only a small mass of drug due to the low density (by definition) of such particles, so they provide
only a practical means of delivery for potent and low-dose drugs [46].
Generally, there are only two basic strategies by which aerosol particles can be made. In strategy 1,
aerosol particles are produced with approximately a unit density (g cm –3 ), with the respirable particle
size requiring a geometric size between 1 and 5 μm. In strategy 2, the density of particles can range
between 0.04 and 0.6 g cm –3 , but the mean Dg of the particles should be between 3 and 15 μm.
Biodegradable microspheres have been produced with a sponge-like appearance, having a mean
Dg of about 5 μm, a Dae of about 7 μm and density of about 0.4 g cm –3 [30]. Such formulations were
prepared using a two-step procedure: (1) preparation of a fluorocarbon-in-water emulsion by adding
phosphatidylcholine as a surfactant with dispersal using high-pressure homogenization. Then, the
emulsion is combined with a second solution consisting of the API and other wall-forming materials
(e.g., co-surfactants, sugars, salts, etc.), (2) spray-drying of the resulting aqueous dispersion [30].


Particle Engineering for Improved Pulmonary Drug Delivery

177

Advantages of biodegradable microsphere formulations in DPIs include the following [47]:
a. Higher respirable fraction due to the good aerodynamic properties ascribed to the hollow porous
particle design.
b. Biodegradable, non-immunogenic and non-toxic properties.
c. The possibility of changing the particle characteristics (e.g., morphology, density and size).

8.3.3

Spray-freeze-drying

Historically, spray-freeze-drying was introduced in 1994 [48]. A solution, which includes the API,

is sprayed into a vessel containing a cryogenic liquid such as nitrogen, oxygen or argon. This results
in a quick freezing of the generated droplets, which are then lyophilized to produce porous spherical
particles suitable for inhalation. Despite this technique being successfully applied to produce protein
particles, it still has a number of disadvantages which include the high cost, long processing time,
safety concerns and possible denaturing effects of the proteins (due to the stresses associated with
freezing and drying) [49].

8.3.4

Supercritical Fluid Technology

A SCF is a material that can be considered to be either a gas or a liquid. It has the gaseous properties in terms of penetrability but the liquid-like properties in ability to dissolve materials. This
technique has been driven by the need to generate particles with controlled physical properties. It can
provide an attractive particle engineering option to enhance aerosol performance in inhalation therapy [50]. For example, engineered drug particles using SCF technology showed reduced surface free
energy in comparison to micronized drug particles [51]. Manipulation of the operating conditions
such as temperature, pressure, nozzle flow rates and solution concentrations may enable the accurate
control of particle size, shape and morphology [52]. The main SCF processes can be classified as
follows [53]:
8.3.4.1

Rapid Expansion of Supercritical Fluid Solution (RESS)

In this method, the API is dissolved or solubilized in a SCF, then the rapid expansion of the
SCF through a heated orifice leads to a high degree of supersaturation due to the reduction in the
SCF density. This change results in a reduction of solvation power, producing a precipitation of
the drug [54].
8.3.4.2

Gas Antisolvent (GAS) Recrystallization

Here the SCF functions as an antisolvent to cause precipitation within the liquid solution. This technique has a number of advantages, such as the ability to control particle size of the resulting particles
and producing void-free crystals [55].
8.3.4.3

Solution Enhanced Dispersion by SCF (SEDS)

The SEDS method employs the same principle of the use of antisolvent in solvent-based crystallization processes [49, 53]. The SCF is mixed rapidly with an organic solution containing the API, in
which the latter is highly soluble. This leads to a large volume expansion and reduction in the solvent
density, and results in a high level of supersaturation [36]. This technique has demonstrated a high
capability to control the physical properties of particles [56].


178

Pulmonary Drug Delivery

Salmeterol xinafoate

Budesonide

Lactose

5 μm
(a)

(b)

(c)

Figure 8.5 (a) Salmeterol xinafoate (Source: Reproduced with permission from [52]. Copyright © 1999,

American Chemical Society), (b) budesonide (Source: Reproduced from [59], with permission from Elsevier) and (c) lactose engineered particles prepared by SCF technology (Source: Reproduced from [60],
with permission from Elsevier)

8.3.4.4

Precipitation from Gas Saturated Solutions (PGSS)

This technique is similar to the RESS technique because the SCF functions as a solvent rather
than antisolvent in both techniques [49]. In this technique, the SCF is dissolved in a molten solute
before it is subjected to the rapid expansion conditions [57] and it has been used to engineer drugs
such as salmeterol xinafoate [52], salbutamol sulphate [58], budesonide [59] and excipients such as
lactose [60].
In DPI systems, SCF technology can provide an attractive particle engineering option to enhance
aerosol performance for inhalation therapy. For example, both SCF–salbutamol sulphate [58] and
SCF–lactose carrier [59] particles generated an improved pulmonary drug delivery of the API from
a DPI. A few examples are shown above in Figure 8.5.

8.3.5

Pressure Swing Granulation (PSG) Technique

Since the drug particles in DPI formulations are very fine, the control of their cohesiveness is a key
factor in determining DPI performance. One of the most effective methods in reducing such cohesiveness between particles in DPI systems is to present the particles as granules, which are easily
disintegrated into aerosol form during inhalation. In order to manufacture such ‘soft’ granules, the
PSG technique can be applied [61]. This procedure consists of two processes that are continually
alternated, comprising compaction and granulation–fluidization processes. Therefore, the PSG process can be considered as a cyclic fluidization and compaction process that is conducted by alternating
upward and downward gas flow [62].
The resulting formulated particles have excellent characteristics, rendering them attractive for use
in DPI systems. These properties include ideal size distributions, the generation of high fine particle
fractions (FPFs), the required granule strength for ease of disintegration into aerosol form during

inhalation, excellent granule dispersibility and the provision of good drug re-dispersion (i.e., generates a high percentage of the emitted dose (ED)) [61].

8.4

Engineered Carrier Particles for Improved Pulmonary Drug Delivery
from Dry Powder Inhalers

Maximizing the efficiency of drug aerosolization still provides a major challenge in the development of DPI formulations. A slight change in particle physicochemical properties is likely to have a


Particle Engineering for Improved Pulmonary Drug Delivery

179

considerable effect on drug aerosolization behaviour. Thus, the use of suitably engineered particles
might be an essential factor for improving DPI performance. Several techniques have been described
to achieve this outcome including antisolvent crystallization [63], batch cooling crystallization [64]
and freeze-drying [65]. These methods were used to modify two common carriers, lactose and mannitol particles, to improve the aerosolization of API from DPI formulations.
For example, antisolvent crystallization techniques using binary non-solvents including
ethanol–butanol, ethanol–acetone and acetone–butanol produced lactose particles which when
incorporated into DPI formulations of albuterol sulphate lead to an enhanced aerosolization
performance [66–68]. In comparison to commercial lactose, engineered lactose particles were less
elongated and more irregular in shape with rougher surfaces. In addition the generated lactose
also contained a higher fine particle content and displayed a higher porosity. These particles
appeared as ‘secondary’ particles comprised of smaller ‘primary’ subunits having different sizes
and morphologies, according to the type of non-solvent used during crystallization. Moreover, the
commercial lactose employed as a comparator was in 𝛼-lactose monohydrate form (Chapter 7),
whereas engineered lactose particles were mixtures of 𝛼- and 𝛽-lactose [67].
When the volume ratio of non-solvent used during crystallization was changed, the amount of
amorphous, 𝛼- and 𝛽-anomer content of lactose was altered and such a strategy could be employed

to optimize the aerosolization performance of lactose in the DPI formulation containing albuterol
sulphate [66].
In a further study, it was shown that not only was the efficiency of aerosol delivery dependent upon
the non-solvent type employed but also upon the degree of saturation of lactose solution used during
crystallization [63]. If the crystallization procedure is controlled, lactose particles may be engineered
with more predictable aerosolization properties.
These findings have been extended from lactose to mannitol, when the latter was identified as
providing a possible improved alternative excipient in DPI formulation. The morphology of mannitol
particles was dependent on the manufacturing technique employed (Figure 8.6). The efficiency of
drug dispersion from powders containing crystallized mannitol was influenced by the proportion of
water present in the acetone or ethanol non-solvent used in the crystallization procedure [69, 70].
However, regardless of the ratio of acetone–water or ethanol–water used in the recrystallization
procedure, all crystallized mannitol carriers showed better performance than commercial mannitol
when incorporated in DPI formulations [69, 70].
Solid-state analyses demonstrated that all mannitol samples were crystalline with no detected amorphous content. A change in the ratio of acetone–water or ethanol–water led to samples of mannitol
with a different polymorphic content [69, 70].
Formulations containing mannitol crystals grown in solutions having a lower supersaturation (20%,
w/v) produced higher FPF of the API in comparison to that from formulations which incorporated
mannitol crystals grown from high supersaturation (50%, w/v) (i.e., 31.6 ± 2.3% vs. 14.2 ± 4.4%).
This was attributed to the elongated habit, smoother surface and higher ‘intrinsic’ fines content of the
former formulations.
Although freeze-dried mannitol did not produce a powder with a smaller geometric size than
commercial mannitol, a smoother surface morphology resulted (Figure 8.6). The use of freezedried mannitol generated the weakest salbutamol sulphate–mannitol adhesive forces within the
powder mix, whereas commercial mannitol generated the highest salbutamol sulphate–mannitol
adhesive forces. It was shown that the smoother the mannitol surface the weaker the salbutamol
sulphate–mannitol adhesive forces [64]. However, mannitol-containing products with higher
powder porosity and weaker salbutamol sulphate–mannitol adhesive forces generated a higher
FPF of salbutamol sulphate. It was concluded that the freeze-drying of aqueous mannitol solutions
provides an attractive approach to preparing an excipient suitable as an excipient for blending into a
dry powder aerosol formulation. Such a strategy might provide an avenue to generate an enhanced

pulmonary drug delivery and maximal yield. It is a method that is simple, reasonably cost-effective
and has a low safety risk, since no organic solvents are used.


180

Pulmonary Drug Delivery

(a)

(c)

50 μm

50 μm

(b)

(d)

50 μm

50 μm

Figure 8.6 SEM photographs for (a) mannitol crystallized from acetone, (b) from ethanol, (c) cooling
crystallized mannitol (CCM) (Source: Reproduced with permission from [64]. Copyright © 2012, American
Chemical Society) and (d) and freeze-dried mannitol (unpublished SEMs)

In addition to ‘engineered lactose’ and ‘engineered mannitol’, an ‘engineered mannitol–lactose’
complex was another approach that has been investigated for a better aerosolization performance [71].

Antisolvent crystallization has proved to be successful in preparing engineered mannitol, lactose and
mannitol–lactose mixtures with improved aerosolization properties (Figure 8.7).
In comparison to commercial carriers, all crystallized mannitol–lactose particles showed a more
regular shape, a higher fines content and a higher specific surface area (Figure 8.7). Carriers crystallized using a higher mannitol–lactose ratio produced particles with a higher elongation ratio, a
more irregular shape and a smaller true density. Mannitol was altered from a spheroidal to a needle
shape, but also there was a change in its polymorphic form from 𝛽-form to 𝛼-form. Similarly, lactose
has changed from the 𝛼-anomer form present in commercial lactose to a 𝛽-anomer form by crystallization. Crystallized mannitol–lactose mixtures did not generate a markedly better aerosolization
performance than either engineered mannitol and/or engineered lactose alone. However, formulators
can anticipate that an appropriate particle size and a suitable solid-state and morphology of lactose
carrier can be generated and controlled by the judicious addition of mannitol to the crystallization
medium containing lactose [71].
Among all carriers investigated by Kaialy et al. [64, 65], the lowest FPF of salbutamol sulphate was
generated by commercial mannitol (15.4 ± 1.1%) and cooling crystallized mannitol (14.2 ± 4.4%);
whereas freeze-dried mannitol produced the highest FPF (46.9 ± 3.6%).
The presence of water in the crystallization of mannitol from either acetone or ethanol using a
non-solvent precipitation technique has a considerable effect on the physical properties of the resultant engineered mannitol particles. The initial degree of supersaturation used during crystallization
of mannitol using a batch-cooling crystallization approach appeared to be a critical factor in the


Particle Engineering for Improved Pulmonary Drug Delivery
50 μm (b) Commercial

mannitol

50 μm(d) Crystallised

mannitol:lactose
(15:05)

mannitol:lactose

(10:10)

(g) Crystallised

mannitol:lactose
(0:20)

mannitol:lactose
(20:0)

50 μm (e) Crystallised

8

Elongation ratio

50 μm

50 μm (c) Crystallised

lactose

(f) Crystallised
20 μm

mannitol:lactose
(05:15)

Elongation ratio
Roughness

6

3
2.5

4

2

2

1.5

0

Roughness

50 μm (a) Commercial

181

1
a

b

c
d
e

Carrier product

f

g

Figure 8.7 SEM images, (⧫) elongation ratio (ER), (○) roughness (mean±SE, n ≥3000) for (a) CM (commercial mannitol), (b) CL (commercial lactose) and different crystallized mannitol–lactose particles: (c)
20:0, (d) 15:05, (e) 10:10, (f) 05:15 and (g) 0:20 (Source: Reproduced from [71] with kind permission
from Springer Science and Business Media)

control of the physicochemical and aerosolization properties of crystallized mannitol. For example,
improved inhalation performance was obtained from the formulations containing mannitol crystallized from lower supersaturations, due to a reduction in the SS–mannitol adhesion forces. In addition,
DPI formulations containing lactose particles crystallized from solutions having a lower degree of
saturation demonstrated an improved DPI performance in terms of both better drug content homogeneity and higher amounts of drug likely to be delivered to the lower airway regions. It was also
shown for mannitol–lactose mixtures that the crystallized mannitol–lactose carrier properties were
dependent on the mannitol–lactose ratio used during the crystallization.
In general, it can be concluded that the carrier particles (lactose or mannitol) with a higher fines content, higher specific surface area, smaller mean diameter, higher porosity, higher elongation ratio (up
to ∼5) and smaller drug–carrier adhesion properties generated a higher FPF of salbutamol sulphate
upon aerosolization. The use of particle engineering for carrier particles offers great opportunity for
improving DPI performance through careful manipulation of the carrier physicochemical properties.
In addition, the DPI performance improvements can be related to changes in key physicochemical
properties of the carrier, which can be optimized by controlling the crystallization process factors.


182

Pulmonary Drug Delivery

8.5

Relationships between Physical Properties of Engineered Particles
and Dry Powder Inhaler Performance

Pharmacologically potent drugs usually display poor physicochemical properties, thus formulation
development is often considered challenging [64]. In fact, the molecular properties that are responsible for pharmacological activity can also be responsible for the compound’s pharmaceutical utility
limitation [72]. Particle–particle (drug–drug, drug–excipient and excipient–excipient) interactions
are critical to the performance of DPI formulations. These interactions are mainly dependent on the
physicochemical properties of the interacting particles. Any small change in the physical properties
of the particles may result in dramatic changes in aerosolization performance [73]. Therefore, to
develop a high-quality DPI delivery system, it is critical to have a full understanding of the physicochemical properties of drug and excipient particles. Assessment of the physicochemical properties at
the molecular, particulate and bulk level is necessary for full characterization of the aerosol formulations. Failure to study one of these areas may lead to a significant lack of understanding in terms
of particle formation processes, performance prediction, batch-to-batch variations, particle interactions and the overall DPI performance. The formulation design and physicochemical properties of
the excipient can significantly affect the respiratory deposition pattern of the inhaled drug–carrier
mixture. It is possible that apparently small changes in particle characteristics will result in unacceptable variability in aerosol performance. Furthermore, there are often multiple factors in play and
thus the control of any individual factor would likely be insufficient for optimizing drug delivery
from inhaler devices. Nevertheless some of the properties that require consideration in this context
are particle size, powder flow properties, particle shape, particle surface texture, fine particle content
(and addition) and particle surface area. These factors are considered in turn.

8.5.1

Particle Size

Particle size is the most important factor in determining the site of deposition in the respiratory airways [74] and moreover, it also affects both the safety and the efficiency of orally and nasally inhaled
drug products [75, 76]. In theory, the larger the particle size the stronger the inter-particulate forces.
However, the performance of a fine particle powder is determined not only by the inter-particulate
forces, but also by the gravitational forces acting upon such particles. Whilst van der Waals forces
are directly proportional to the particle size, the gravitational forces are proportional to the cube of
the particle size, so as a result, fine particles are highly cohesive and have poor flowability [73].
Mass median aerodynamic diameter (MMAD) of the aerosol particles is very important, because it

determines the site of deposition of drug particles within the airways, irrespective of the Dg (up to a
certain diameter, which is approximately 20 μm). However, the total deposited mass of an inhaled
aerosol cannot be predicted by the MMAD and geometric standard deviation (GSD) alone [77].
Nevertheless, a linear relationship was found between experimental drug MMAD determined by
impaction method and the percentage of drug particles <5 μm in geometric size [78].
PSD polydispersity is important in terms of aerosol quality and efficiency. An aerosol PSD is generally described by a log-normal distribution and, therefore, the degree of dispersion is best represented
by the GSD. Lower GSD values indicate a narrower PSD. Aerosol PSD can be designated as being
either monodisperse or polydisperse. If monodisperse, the size of all the aerosol particles is nearly
the same, and the GSD <1.2 μm. On the other hand, polydisperse or heterodisperse distribution is
characterized by non-uniform size and the aerosol particle sizes significantly differ from each other
with GSD ≥1.2 μm [79]. Usually, aerosols employing excipients as formulation components produce
GSD values of around 2. The value of an aerosol GSD can affect its aerosolization performance. For
example, if two aerosols with the same MMAD of 2 μm are compared, increasing GSD from 1 to
3.5 will result in a reduction in the alveolar deposition from 60% to 30% [80]. In general, aerosol


Particle Engineering for Improved Pulmonary Drug Delivery

183

particles with a narrow size distribution are preferred in terms of targeting deposition of particles
within a specific airway region.
FPF is the percentage of particles in the fine particle range (usually <5 μm) [81]. In theory, FPF
refers to the percentage fraction of the drug that is pharmacologically active and in some studies has
been equated to the ‘respirable fraction’ [82]. However, an in vitro measured ‘respirable fraction’
might overestimate the actual in vivo ‘respirable fraction’ [83].
During mixing, the larger the carrier particles, the higher the inertial and frictional press-on (pushon) forces, which have the potential to increase the adhesive forces in the mixture, depending on the
carrier payload [84].
It has been shown that the aerosol dispersion is affected by aerosol particle size [32]. Generally,
increasing the median diameter (d50% ) of the aerosol particle decreases the FPF obtained following

aerosolization [85–87]. For example, in the case of patients with severe airflow obstruction, small
particle aerosols (1.8 μm) were therapeutically more efficacious than large particle aerosols (4.6 and
10.3 μm) [88].
Different inhalers might produce different aerosol PSDs with the same drug resulting in variations in the final product therapeutic effect [88]. For 𝛽 2 -agonists, it should be considered that the
adrenoreceptors exist in high concentrations in the small airways [89] and small aerosol particles
of such agents (with MMAD < 2 μm) are preferred in the treatment of asthma [88]. Other studies
have shown that in patients with severe respiratory tract airway obstruction, the optimal and the most
suitable particle size of salbutamol sulphate and ipratropium bromide aerosol is approximately about
3 μm [90, 91]. However, a more recent study indicated that there is more than one optimal 𝛽 2 -agonist
particle size and the 3 and 6 μm particles are more potent as bronchodilators in comparison to the
same drug with particle size of 1.5 μm [92].
Although aerosol particle size is the most important factor in determining the amount of drug
deposited in the lungs of a healthy adult, in the case of airway obstruction, the effect of aerosol particle
size on therapeutic effect becomes less evident [93]. Generally, the total lung deposition increases
in the case of an airflow obstruction [94]. In addition, the tendency of the particles to deposit on the
central airways increases when the lung airways are narrower [95].
Semi-empirical methods have been developed that correlate aerosol particle size with the deposition of drug particles in the lungs, and these can be used as a general guide when assessing the effect
of particle size on the deposition of particles in the lungs [96]. Aerosol particles smaller than 0.5 μm
have two limitations. First, they keep moving by Brownian motion and as a result, they settle very
slowly and may not deposit at all because of their high airborne stability [97]. Second, 0.5 μm spherical particles can carry into the lungs only 0.1% of the mass that a 5 μm sphere can carry. Accordingly
particles of API as small as 0.5 μm particles may be considered to be an inefficient means of airways
delivery.
It has been suggested that only aerosol particles with a Dae between 1 and 5 μm can reach the
lower respiratory tract [98]. Such a Dae is also suggested as being the optimal particle size range for
the delivery of APIs to the airways, irrespective of differences in patient lung function. However,
the optimal particle size range of aerosol particles is dependent both on the drug being used and the
precise site of action of this drug in the lungs, although the latter is still not usually well defined [99].
In fact, the type of the API and inhaler device used in the DPI formulation blends may have
an effect on the preferred carrier size for optimising aerosolization performance. For example,
carrier fractions containing smaller size particles have been reported to improve aerosolization

performance only when employing turbulent shear inhalers (e.g., Diskus®, Rotahaler®, Aerolizer®,
Handihaler®, Turbuhaler®, Turbulizer®) rather than inhalers generating inertial forces (e.g.,
AirmaxTM , TwisthalerTM and NovolizerTM ) [100].
Nevertheless, carrier powders are usually sieved so as to obtain the 63–90 μm size fractions before
blending with the drug [101, 102]. Theoretically, particle sieving is ideal for a particle size above
75 μm and is less suitable for particles below 38 μm due to the particle cohesiveness. Mechanical


184

Pulmonary Drug Delivery

sieving is preferable for non-cohesive powders, whereas for cohesive powders the use of an air-jet
sieve is preferred [103]. The sieving of particles results in a PSD corresponding to the size of the
smallest square apertures that the particles will pass and, therefore, is related to the particle’s width
rather than its length. Accordingly, sieving usually results in particles larger than sieve-hole diameters, especially for elongated particles, although extensive sieving is expected to favour particles
passing through their shortest diameter [73]. In all cases, it is preferable to use carrier particles with
narrow size distributions, as these particles will contain similar amounts of absorbed material per unit
mass. After the re-dispersion, the large carrier particles will deposit in the mouth and the oropharynx
and are cleared, while the small drug particles will partly penetrate the airways according to a level
dependent upon particle size.
Recently, the effect of lactose particle size on the aerosolization of budesonide from a DPI was
reported. Generally, the smaller the lactose VMD the higher the RD, the higher the ED, the smaller the
MMAD and the higher the FPF of budesonide, which is indicative of an enhanced DPI performance.
However, lactose particles with smaller VMD generated higher amounts of budesonide depositing on
the USP throat, which is likely to be disadvantageous in terms of the increased potential for inducing
local side effects, if the deposition patterns were replicated in vivo. The smaller the lactose VMD the
poorer the budesonide content homogeneity within the DPI formulation, which is detrimental to the
overall patient safety of the DPI formulation safety [102] (Figure 8.8).

8.5.2

Flow Properties

Carrier flowability has a significant effect on drug emission (ED) from the DPI device and as a result
may affect drug delivery to the lungs [104, 105].
Carr’s index (CI) [106, 107] and Hausner ratio (HR) [108] are important measures that are used to
express the inter-particle interactions within powders. CI and HR are directly linked parameters as
they both depend on measuring bulk density (Db or 𝜌b ) and tap density (Dt or 𝜌t ). CI is defined as
the percentage change in volume of a constant mass of powder due to tapping. CI can be calculated
according to the following equation: CI = (1 − Db /Dt ), where Db is the freely settled bulk density
and Dt is the tap density. The higher the difference between the bulk and the tap density within a

IL (%)

(d)

300
250

90

0
50
100 150
Lactose VMD (μm)

(e)

(f)

40

70
y = 18.5081n(x) – 6.6568
R2 = 0.9822

30

y = –12.571n(x) + 63.69

30

R2 = 0.9808

20
10
0

10
100
Lactose VMD (μm)

10

100
Lactose VMD (μm)

MMDA
GSD

4
3.5
3
2.5
2
1.5

3
2.8
2.6
2.4
2.2
2

GSD

350

200
0 20 40 60 80 100 120
Lactose VMD (μm)

50

RD or ED (μg)

R2 = 0.997

400

RD (μg)
ED (μg)

Constant K

0

y = –0.00874x + 13.916

FPF (%)

CV (%)

10
5

(c)
450

MMAD (μm)

(b)

(a)
15

0
50 100 150
Lactose VMD (μm)

50
40

y = –17.851n(x) + 90.629
R2 = 0.9809

30
20
10
0
10

100
Lactose VMD (μm)

Figure 8.8 Relationships between lactose VMD and (•, % CV)(a), (○, RD), (◊, ED)(b), (▴, MMAD),
(Δ, GSD)(c), (⧫, IL)(d), (◽, FPF)(e), and (+) constant K(f) of budesonide obtained from formulations
containing different lactose size fraction powders (mean ± SD, n ≥ 3) (Source: Reproduced from [102],
with kind permission from Elsevier)


Particle Engineering for Improved Pulmonary Drug Delivery

185

powder, the poorer is the powder flowability. In addition, CI can be expressed in terms of volume of
powder as follows: CI = 100 × (Vb − Vt )/Vb , where, Vb is the freely settled volume of a given mass
of powder and Vt is the tapped volume of the same mass of powder. This tapped or packed volume
depends on several factors such as powder PSD, Dtrue (true density) and cohesiveness due to surface
forces. Powder flowability is considered poor when the CI is greater than 25%, and it is considered

good when the CI is below 15%.
CI has the advantage of low cost and being a prescribed USP method, it is easy to apply. However,
CI is not an absolute property of the material, being an empirical technique and having no well-built
theoretical basis. Thus, CI measurement might vary according to the precise methodology used.
Angle of repose (𝛼) is another commonly used method to describe powder flowability. If the powder
is poured onto a flat surface, it will always have the shape of a conical pile. The internal threedimensional angle measured between the surface of the stable slope cone and the horizontal surface
is 𝛼, which is related to the several properties of the powder material such as particle shape, density,
surface area and coefficient of friction [109]. The higher the angle of repose, the poorer is the powder
flowability. However, this method is often less accurate for cohesive powders due to orifice blockage,
so it can be applied accurately only to the powders with low to intermediate cohesive force [110]. In
general, powders with 𝛼 values <25∘ , 35∘ –45∘ , 45∘ –60∘ and >60∘ are considered to be very good
flowing, free flowing, fairly free flowing and cohesive, respectively. Poor agreement has been reported
between 𝛼 and other flow measures [73] and 𝛼 should be used only with other methods designed to
assess powder flowability.
In DPIs, powder dispersion is related to two processes in sequence: powder fluidization of a powder
bed and powder deaggregation [82]. Powders with poor flow properties and excessive cohesive forces
result in poor dispersion properties upon inhalation because of the enhanced particle aggregation and
decreased particle fluidization [111].

8.5.3

Particle Shape

Particle shape is one of the most challenging factors in powder technology to control and define. The
use of different preparation methods can result in different particle shapes for the same material, and
even similar crystallization methods for one material may produce samples with different particle
shapes. Changes in particle shape can affect particle adhesion. For example, particles with irregular
shape have been reported as having high adhesion properties, although, the reverse trend has also
been reported [112]. This apparent disparity was ascribed to the dependence of interaction on the
relative position of the interacting particles [112].

All the equations that calculate the inter-particulate forces between particles assume an interaction between perfectly spherical particles with smooth surfaces. Most pharmaceutical solid particles
deviate from spherical shape [113] and therefore, any attempt to calculate the inter-particle forces
between ‘real’ particles with a ‘real’ shape is destined to contain unrealistic assumptions.
In DPI systems, particle shape has a significant effect on the theoretical and the experimental (measured) MMAD. Thus, particle shape can affect particle deposition profile within the airways. Theoretical and experimental Dae values are similar for spherical particles, but they differ if particles are
either irregular or aggregated in the dry state [39]. The dynamic shape factor is the ratio of the actual
drag force (resistance force) experienced on this particle to the drag force experienced on another
particle that has the same volume but spherical shape [114]. Increasing the particle dynamic shape
factor decreases the particle MMAD. By definition, ER is the particle length, along the longest axis,
over the particle width. Particles with a higher ER are more elongated and/or more irregular in shape.
The use of needle-shaped (or acicular shaped) crystals within a DPI formulation are associated with
drawbacks such as their inherent poor flow properties and the limitations incurred during crystallization including filter support-overcrowding and solvent inclusion [115]. Nevertheless, needle-shaped
crystals have a greater ability to stay airborne in an airflow compared with isometric particles that
have the same geometric mean diameter [116, 117].


186

Pulmonary Drug Delivery

Crystal shape can be changed by recrystallization from different solvents as a consequence of the
interactions between a crystal face and the solvent molecule [118]. The growth rate of a crystal face
is related to its attachment energy [119]. This attachment energy is believed to be independent of
temperature and supersaturation. Polar faces of the crystal absorb polar solvents, while non-polar
faces absorb non-polar solvents [120]. By knowing the structure of the intended molecule, it can be
predicted in which axis the crystal will grow. For example, it is known that hydrophilic groups in
drugs can establish hydrogen bonds with polar hydrogen bonding groups (hydrophilic molecules).
Changing the solvent polarity can accordingly lead to a change in crystal morphology. For instance,
by increasing solvent polarity, crystal growth by establishing hydrogen bonds with polar groups will
be enhanced, resulting in accelerated growth in one direction [118].
A comprehensive study of the influence of the shape of different carrier particles (mainly lactose

and mannitol) on the aerosolization performance showed that carriers with higher ER produced higher
amounts of drug delivered to the lower airway regions. However, it was proved that the higher the
carrier ER the poorer the flowability, the higher the amounts of drug loss and the higher the amounts of
drug depositing in the USP throat, all considered disadvantageous in DPI systems [121] (Figure 8.9).
In conclusion, inter-particle forces are inversely related to the distance between the particles, which
is in turn partly dependent on particle shape. Generally, any increase in inter-particle distance caused
by changes in particle shape will reduce the inter-particulate forces resulting in a better drug–carrier
detachment and consequently an improved aerosolization performance.

(a)

(b)
100

500

EM (%)

RD or ED (μg)

550
450
400
350
RD
ED

300
250
0

1

2

4

5

6

90
y = –0.868x + 96.938
[R2 = 0.8653]

85
0

7

ER

(c)

1

2

3

4

5

6

5

6

ER

(d)

220

50

180

40

FPF (%)

FPD (μg)

3

95

140
100
60

30
20
10

20

0
0

1

2

3

4

ER

5

6

7

0

1

2

3

4

7

ER

Figure 8.9 Relationships between carrier ER and salbutamol sulphate recovered dose (RD), emitted dose
(ED) (a); emission (EM) (b), fine particle dose (FPD) (c) and fine particle fraction (d)(mean±SD, n = 3)
(Source: Reproduced from [121], with kind permission from Elsevier)


Particle Engineering for Improved Pulmonary Drug Delivery

8.5.4

187

Particle Surface Texture

The adhesion of particles is a surface phenomenon and, therefore, the drug–carrier adhesion is profoundly affected by the surface morphology of carrier particles and the drug particles [122]. Particle
surface morphology also affects powder dispersion [123].
Several methods may be applied in order to increase particle surface smoothness, such as treating
the drug with a series of saturated fatty acids [116], crystallization from carbopol gels [112] and controlled temperature etching [124]. In addition the modification of drug particle surfaces can be carried

out by coating the particle surfaces with a suitable excipient [125]. Such modified particles usually
exhibit better flowability and dispersibility, which may be ideal for use in carrier-free DPI formulations [126]. For example, it has been shown that amino acids such as leucine can be included in DPI
formulations using powder mixing and/or spray-drying processes to coat the carrier/drug particles
[127, 128]. When applied to untreated salbutamol sulphate particles, the new modulated surfacetreated particles resulted in lower adhesion forces between the particles [128]. Moreover, coating of
drug particles with leucine or phenylalanine reduced the surface energy of the drug particle [129].
Wet-smoothing of particles using a high shear mixer with successive steps of lactose surface wetting and drying has also been applied to increase carrier surface smoothness. This procedure resulted
in particles with a flattened surface and rounded edges, which increased the aerosol flowability and
packing properties [130].
Generally, the use of particles with a smooth surface topography has been reported to decrease the
drug–carrier median separation energy and consequently increase the aerosol drug FPF following
aerosolization. For example, increasing the surface smoothness of lactose carrier particles resulted in
an increase in the flowability and the dispersibility of salbutamol sulphate from the Rotahaler® [86].
Such resultant effects were attributed to a reduction in the binding sites with multiple contact points
on the particle surface, leading to an easier detachment of the API during inhalation.
On the other hand, conflicting results have been reported since a low FPF of the API was determined when carrier particles with a smooth [131] and a rough [132] surface texture respectively. This
could be explained by the existence of an optimum particle rugosity, which provides an optimum in
vitro aerosol particle deposition [133]. Only small corrugations (asperities of a few nanometers in
size) were sufficient to induce significant reduction in adhesion forces between the particles and
consequently accomplish an increase in the FPF [134]. Thus, the carrier surface irregularities will
only reduce the drug–carrier adhesive force where they reduce the total drug–carrier contact area
(Figure 8.10). Such optimum rugosity depends upon the scale of roughness in relation to the size of
the drug/carrier particles [135]. This is discussed in more detail in Chapter 9.
When comparing different pharmaceutical particles, it has been shown that the preferred particles
are likely to be curved-surface particles containing small asperities [136].

Drug particles

Carrier surface
(a)

(b)

(c)

Figure 8.10 Schematic representation of drug–carrier contact geometry in the case of carrier particles
with (a) smooth surface, (b) optimal rough surface and (c) extensively rough surface


188

8.5.5

Pulmonary Drug Delivery

Fine Particle Additives

Similar to surface asperities, the presence of fine particles on the carrier surfaces can decrease the
drug–carrier contact area and increase the drug–carrier separation distance leading to a reduction in
the adhesion forces and as a result improved DPI inhalation performance [112]. This technique is one
of the strategies to improve drug aerosolization in DPI formulations without substantially reducing
the carrier mean size [137]. For example, the mixing of fine carrier particles with a coarse carrier powder improved the aerodynamic properties of salmeterol xinafoate [138], salbutamol sulphate [139]
and beclomethasone dipropionate [140] in the corresponding DPI formulation blends. The type of
these fine particles may be a different material from that which comprises the coarse carrier particles.
For example, it has been shown that the addition of fine mannitol (4.3 μm), sorbitol (6.3 μm) [141]
or glucose (4.4 μm) [139] to DPI formulations containing dissimilar coarse carrier also facilitated
DPI aerosolization. In addition, ternary components have been included in DPI formulation blends
such as l-leucine and magnesium stearate [142]. Similar to fine particles, ternary components might
enhance drug–carrier detachment by decreasing drug–carrier interaction forces.
One mechanism that has been proposed for the increased drug deposition induced by the addition of
fine carrier particles is that the ‘active sites’ or ‘hot spots’ which are high adhesion sites [143] on the

coarse carrier particles are saturated by the fine particle additives or ternary components. Such ‘active’
sites on the carrier surface are attributed to the existence of different carrier surface morphologies,
which results in different physicochemical properties including different adhesive properties to the
carrier surface. These ‘active’ sites are proposed to be on the crystal surface where active molecular
groups are presented to the outside because of the displacement of the groups from the crystal lattice
or as a consequence of misrepresentation of the molecular order. This results in areas on the crystal
surface with more potential for surface interaction than on the normal crystal surface. The presence
of active sites on the surface of carrier particles decreases the apparent ‘respirable’ drug fraction for
the DPI due to the retention of drug particles on these sites within the carrier. When fine particle
additives occupy the active sites on the carrier surface, only the passive or low adhesion sites will
remain available for drug adhesion [144] leading to a low drug–carrier adhesion and consequently
increasing drug–carrier detachment.
An alternative theory has also been proposed for the effect of ternary components based on the
agglomeration between the ternary component and the similar-sized drug particles. This is expected
to decrease the detachment force from the carrier upon inhalation [145], allowing the fine-sized aggregates to penetrate more deeply into the airways. However, both these mechanisms remain hypotheses.
Moreover, it should be remembered that the addition of fine particle additives to the DPI formulation
has some limitations. For example, a significant portion of the micronized lactose exists in amorphous
form and as a consequence the adding fine lactose particles to the DPI formulation will increase the
amorphous content within the powder (Chapter 7). This amorphous form is not the preferred powder
structure for inclusion within DPI formulations because it is unstable [146] and is likely to affect the
powder dispersion and flowability as a function of shelf-life [140].
The engineering of fine particle additives provides a promising approach to enhance the total desirability of DPI formulation. For example, commercial carrier powders (both mannitol and lactose)
might display good flowability but poor aerosolization performance, whereas, in contrast, crystallized carrier powders (both mannitol and lactose), despite exhibiting poor flowability, improved
aerosolization performance [147]. Interestingly, the use of 5% w/w engineered elongated fine mannitol as a ternary additive to lactose–salbutamol sulphate DPI formulations produced formulations
that demonstrated both satisfactory flow properties and improved aerosolization behaviour.

8.5.6

Surface Area

Both surface area and morphology measurements are critical elements of any DPI formulation development. The particle surface area can be considered as one component of the measurement of particle
surface geometry [148]. Any surface modification that leads to an increase in the surface area of the


Particle Engineering for Improved Pulmonary Drug Delivery

189

aerosol particle requires careful consideration since any increase could closely be associated with the
overall biological response [149].
Generally, the total aerosol surface area of the API contained within a DPI is very large due to the
inherent aerosol particle size that is required to be small so as to achieve a therapeutic effect. However
the consequences of this large area, is a tendency to a decreased stability of the formulation, since such
small particles are able to take up more moisture and gain charge more readily than coarse particles
[150]. The high moisture absorption can increase the capillary forces between particles, and this in
turn might impede flow. In addition, an increase in the surface area of the aerosol particles can increase
the inter-particle forces between the aerosol particles leading to an increase in the aerosol particle
aggregation [46]. Many techniques can be used to measure aerosol particle surface area including
inverse gas chromatography (IGC), atomic force microscope (AFM) [46] and nitrogen adsorption,
the latter method being the most commonly used technique [148].
Corrugated particles have a higher surface area than smoother particles with the same volume
diameter and a direct linear relationship has been reported between carrier surface area and carrier
surface energy [148]. Higher aerosol particle surface area may also be attributable to broader PSDs,
higher amounts of fines on the carrier surface or higher degrees of particle surface roughness [151].

8.6

Conclusions

In DPIs, it is the physicochemical properties that combine to be a principal factor that determines

overall DPI aerosolization performance. It is apparent that many physicochemical properties within
the DPI formulation blends can be altered to achieve improved inhalation delivery of the API. However, the effect of one physicochemical property is interdependent upon other properties that are
known to affect drug-carrier interaction upon inhalation. Studying the effect of one physicochemical
property on DPI performance is virtually impossible since a change in one property concomitantly
alters others. Therefore, although a number of studies claim to focus on one parameter, the effect on
others that are varied alongside that particular property are often downplayed or neglected.
The benefits of using carrier particles with smaller size or more elongated shape in terms of improving the aerosolization efficiency of an API must be balanced against resultant disadvantages, such
as poor flowability and dose uniformity, possible formulation instability and potential for increased
side effects. When angular, spherical or elongated mannitol particles are an option, formulators can
anticipate better drug delivery to the lung in the case of the elongated form. Controlling or adjusting
the porosity of carrier powder may also provide an optimization strategy in promoting the aerosolization performance of DPI formulations. Better drug content homogeneity was obtained in the case of
carrier powders with better flow properties and narrower size distributions, although poor aerosolization performance is not an inherent consequence of flow properties. Variations in the particle size
of brittle lactose (>45 μm) particles have much less influence on budesonide deposition profiles in
comparison to the variation in particle size displayed by ductile (<45 μm) lactose particles.
Further insight is required into the relationship between DPI particles physicochemical properties
and their inhalation performance. Designing DPI formulation product with more ‘effective’ physicochemical properties is a feasible strategy to achieve maximum performance.

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