Physical Characterization of Component Particles

Included in Dry Powder Inhalers. I. Strategy Review and

Static Characteristics
ANTHONY J. HICKEY,
1
HEIDI M. MANSOUR,
1
MARTIN J. TELKO,
1
ZHEN XU,
1
HUGH D.C. SMYTH,
1
TAKO MULDER,
2
RICHARD MCLEAN,
3
JOHN LANGRIDGE,
2
DIMITRIS PAPADOPOULOS
3
1
Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Campus Box #7360,
1310 Kerr Hall, Kerr Hall, Chapel Hill, North Carolina 27599-7360
2
DMV-Fonterra Excipients, Goch, Germany
3
Pzer Inc., Sandwich, Kent, UK
Received 23 September 2006; revised 13 January 2007; accepted 24 January 2007
Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20916
ABSTRACT: The performance of dry powder aerosols for the delivery of drugs to the
lungs has been studied extensively in the last decade. The focus for different research
groups has been on aspects of the powder formulation, which relate to solid state, surface
and interfacial chemistry, bulk properties (static and dynamic) and measures of
performance. The nature of studies in this eld, tend to be complex and correlations
betweenspecic properties and performance seemto be rare. Consequently, the adoption
of formulation approaches that on a predictive basis lead to desirable performance has
been an elusive goal but one that many agree is worth striving towards. The purpose of
this paper is to initiate a discussion of the use of a variety of techniques to elucidate dry
particle behavior that might guide the data collection process. If the many researchers in
this eld can agree on this, or an alternative, guide then a database can be constructed
that would allow predictive models to be developed. This is the rst of two papers that
discuss static and dynamic methods of characterizing dry powder inhaler formulations.
2007 Wiley-Liss, Inc. and the AmericanPharmacists AssociationJ PharmSci 96:12821301, 2007
Keywords: aerosols; thermodynamics; surface chemistry; solid state; pulmonary
drug delivery; pulmonary; preformulation; physicochemical; formulation; physical
characterization
INTRODUCTION
The behavior of particles is the foundation on
which dry powder inhaler (DPI) performance is
built. Interest in particles may be viewed as one of
the oldest scientic activities since the degree of
subdivision, or size, is all that separates nano-
particles fromboulders.
1
Pharmaceutical powders
are, in the rst instance, of greatest importance
for oral dosage forms where particle behavior is
crucial to the processes involved in tablet and
capsule manufacture and ultimately in their
dissolution and drug availability. This interest
extends to aerosol products that are highly
dependent on the physico-chemical and per-
formance characteristics of the particles that
deliver drugs to the lungs.
Aerosol particles are prepared in respirable
sizes (<5 mm) and exhibit unique properties
based on the forces of interaction which are
known to occur.
2
Classically dry powder aerosol
1282 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
Hugh D.C. Smyths present address is Currently, College of
Pharmacy, University of New Mexico, Albuquerque, NM
87131.
Correspondence to: Anthony J. Hickey (Telephone: (919) 962-
0223; Fax: (919) 966-0197.; E-mail: ahickey@unc.edu)
Journal of Pharmaceutical Sciences, Vol. 96, 12821301 (2007)
2007 Wiley-Liss, Inc. and the American Pharmacists Association
formulations are prepared as blends with large
lactose carrier particles.
3
The forces give rise to
particleparticle and particlesurface interac-
tions as depicted in the schematic shown in
Figure 1.
35
This is asimpliedviewof the possible
nature of particle interactions but illustrates the
likely complexity of a situation in which particle
forces are confounded based on surface physical
and chemical heterogeneity. The usual particulate
interactions of electrostatic, capillary and van
der Waals (proximity) forces and mechanical
interlocking
3,4
occur but are confounded with the
additional complexities associated with the solid
state of the presence of amorphous regions,
impurities (in lactose mostly proteins and
some fats) and specic polar/non-polar regions
(dispersive, acid/base energetics).
One of the rst manifestations of the effect of
various forces of interaction on particles is that
observed in packing (bulk and tapped density)
differences and variability in ow. Flow has been
shown to be a key property of the DPI formulation
as it aids in metering, uidization, and disper-
sion.
6,7
Initself it is not a variable, but a dependent
variable based on particle size, shape and forces of
interaction. The interplay of these factors is
difcult to address directly but it is possible that
using complementary techniques a frameworkcan
be constructed from which the nature of particles
can be used to predict powder performance.
Figure 2 outlines a number of methods that
may be used to characterize powders intended for
use in inhalers. For ease of reference these
techniques have been divided into local and bulk
surface analysis, static and dynamic bulk char-
acteristics and performance measures. In the last
decade a number of publications have appeared
which attempt to correlate certain properties with
efciency of inhaler performance. However, it is
clear that the quantity of data required to conduct
a thorough assessment may prohibit compre-
hensive assessment in a single study or by a single
research group.
The following sections describe the principles
behind specic techniques and include analysis of
a range of lactose particles intended as carriers
for drug (e.g., albuterol sulfate
25
) to illustrate
the application of these techniques and the
conclusions that can be drawn. Figure 3 shows
the basis for inclusion of lactose in albuterol DPI
formulations. Lactose is intended to act as a
diluent, allowing metering of small quantities of
drug in larger, manageable quantities of lactose.
26
Inaddition, since lactose carrier particles are large
(>50 mm) they act as uidizing agents in the
dispersionof the drugandwhenactedonbyairow
shear forces facilitate the generation of primary
particles of drug that can be carried on the
inspiratory ow into the lungs of patients. The
dispersion process is recognized to be a highly
complex process that is far from being completely
understood. It is generally recognized that the
complex nature of the dispersion process is not
attributed to any single specic factor. A body of
knowledge suggests that ne lactose (i.e., small
particles that are in the respirable size range) may
occupy active sites on the surfaces of larger
lactose particles. This is one factor that may
inuence dispersion. This paper is the rst in a
two-part sequence that discuss the range of
methods, outlined in Figure 2, that might be
employed to evaluate blend formulations intended
for use in DPIs. In the following sections of this
paper, asummaryof specic methods employedfor
the static characterization of albuterol-lactose
blends
2731
is given. Dynamic characterization of
dry powder aerosols is described in the second
paper
25
of this two-paper series.
BACKGROUND
Solid State Characterization
In any formulation, including dry powder inhala-
tion pharmaceutical aerosols, the solid-state
32
of the drug and excipient are important
aspects of the physical and chemical stability,
pharmaceutical and therapeutic performance of
the drug product. Briey, it is important to
consider crystalline solids,
3336
crystalline poly-
morphs,
37,38
crystal hydrates,
39
amorphous,
4043
liquid crystals,
44
nanocrystals, and solid-state
phase transitions.
120
Indeed, the subject of a
local polymorphism with single crystals is extre-
mely topical and the subject of some very
recent debate.
4548
Solid-state phase transitions
Figure 1. Causes of the various types of interactions
between nes and carrier particles.
PHYSICAL CHARACTERIZATION OF DPI PARTICLES I 1283
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
include polymorphic interconversions, poly-
hydrate interconversions, hydration-dehydration
conversion, and order-to-disorder transforma-
tions. Additionally, these solid-state phase transi-
tions can be thermodynamic transitions and
kinetic transitions.
It is important to recognize that a number of
other partially ordered/disordered phases
49
are
known to exist in the solid-state that can be of
pharmaceutical signicance given the chemistry
of many pharmaceuticals and effects of pharma-
ceutical processing, and they include quasi-
crystals, plastic crystals, disordered nanocrystals
(i.e., non-amorphous disordered solids lacking
long-range crystalline order),
50
liquid crystals
(thermotropic and lyotropic thermodynamically
stable phases observed in surfactants, bio-
polymers, and biomaterials), and polyamorph-
ism.
51
It has been demonstrated that the
amorphous form of an aerosolized drug has a
tremendous effect on absorption in the deep
lung,
52
and, hence, it quite likely that the degree
of order/disorder present in the solid aerosol
particle, particularly at the surface of the aero-
solized particle, has signicant therapeutic and
biological effects.
Figure 2. Methods and analyses to establish general physicochemical properties
(PCA), surface analyses, bulk characteristics and performance properties.
Figure 3. Schematic diagram illustrating the detachment of nes from carrier
particles as the static powder is dilated and aerosolized (left to right).
1284 HICKEY ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
Water
5356
associated with the sugar carrier
may interact with the drug through the interface
between the drug and carrier; presence of a little
water can have signicant effects on drug surface
molecular mobility/transformation/instability.
57
A disordered phase, such as an amorphous
phase having similar mechanical and physical
properties of a supercooled liquid existing at
temperatures below its thermodynamic crystal-
lization temperature but has not been given
sufcient time to anneal and crystallize to its
thermodynamically stable ordered phase, inher-
ently has a higher degree of molecular mobi-
lity.
58,59
Additionally, disordered phases, such as
an amorphous
40
phase or non-amorphous disor-
dered nanocrystals, oftenoriginate at surfaces and
interfaces, especially in pharmaceutical particles
due to processing effects. Gas and vapor absorp-
tion occurs into these disordered regions located at
the surface, and absorption phenomenon is known
to accelerate where disordered surface regions are
present. Water vapor absorption provides water
molecules for participationinhydrolysis reactions,
and oxygen gas absorption provides oxygen mole-
cules for participation in oxidation reactions in
the solid-state. Molecular mobility is furthered
increased as water acts as a plasticizer, and
further physical
60
and chemical instability
61
occurs over pharmaceutically relevant time-
scales.
The classical methods of evaluating the solid
state are X-ray powder diffraction
14,18,37,50,6265
and thermal analyses.
39,49,6670
X-ray diffraction
of solid-state materials gives important insight,
based on the degree of long-range order present,
into the extent and nature of the crystallinity,
microstructure, and nanocrystallinity with a limit
of detection of about 10% to give a signal.
63
Thermal analysis indicates polymorphs, hydrates,
binding interactions, amorphous and thermotro-
pic and lyotropic phase transitions, in general,
based on the gain and loss of enthalpy (heat) that
is, order-to-disorder (e.g., melting) and disorder-
to-order (e.g., crystallization) phase transitions
also with a limit of detection of around 10%.
63
Thermal analysis has been employed in investi-
gating lactose crystallinity,
71
amorphous charac-
ter,
72,73
physical studies on DPIs,
74
water vapor-
solid interactions,
75,76
and assessment of powder
surface energetics.
77,78
Crystallization of lactose
from the amorphous state
79
and albuterol-lactose
particulate interactions
80
have been observed
using atomic force microscopy (AFM), a powerful
surface and nanoimaging analytical technique
that will be presented in-depth. The presence
of water molecules in the bulk powder can be
assessed by Karl Fischer analysis to about 0.1%
water content but more sophisticated approaches
employ water vapor sorption,
8186
particularly to
assess the presence of amorphous material
63,87
and to probe the nature of water-pharmaceutical
solid interactions
5356,60,86,88
at the molecular
level, including phase transitions that are induced
by the level of hydration present in the solid-state
structure.
86
This is a particularly important
approach to the assessment of hygroscopic
solids,
89,90
and aerosols.
74,9198
Surface Analyses
Scanning Electron Microscopy (SEM)
SEM is recognized as unique tool in the visual
examination of particles and their surfaces. The
resolution is of the order of nanometers (magni-
cations in the range 20100,000). A ne beam
of electrons of medium energy (550 keV) scans a
gold-palladium coated sample producing second-
ary electrons, backscattered electrons, light or
cathodoluminescence and X rays. The latter allow
for X-ray microanalysis for specic elements.
SEM is routinely used for imaging particles in
the micron and smaller size range and for
examining the surfaces of larger particles. The
resolution allows identication of specic
surface geometric features that are indicative of
structural phenomena.
Atomic Force Microscopy (AFM)
AFM offers a unique opportunity to examine
surface structure of a variety of materials with
mesoscopic scale resolution (10
6
10
9
m), and
quantify the individual particle and excipient
interaction by direct force measurement in a
variety of environmental conditions.
99101
The relevant adhesive/cohesive force compo-
nents consideredinDPI systemare intermolecular
van der Waals force, capillary force, and electro-
static force.
102
The adhesion force measurement
of powder includes vibration,
103
centrifuga-
tion,
104106
and impact separation,
107109
before
the advent of direct measurement of colloid probe
technique.
110,111
Bulk adhesion leads to global
adhesion characteristics,
112
but DPI requires the
knowledge of adhesion forces from microscopic
analysis for the purpose of elucidating the funda-
mental mechanism such as work of adhesion and
PHYSICAL CHARACTERIZATION OF DPI PARTICLES I 1285
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
surface energetics,
113,114
and the prediction
115
of
formulation stability, and redispersion.
There are several factors that link the see-
mingly straightforward AFM colloid probe techni-
que to the force measurement. They include the
following: (1) the cantilever tip consistency; (2) the
physical and chemical properties of colloid probe
and substrate surfaces; (3) environmental issues,
such as temperature and relative humidity; and
(4) the contact area determination or normal-
ization.
Perhaps the most important inuence of adhe-
sion/cohesion forces is related to the colloid probe
and substrate surface roughness, which is mostly
characterized by the root mean square deviation
(R
rms
) in a given area. There was evidence that
adhesion of drug particles to carrier surfaces
increased with surface roughness
116
if particle
deformation was negligible, or decreased,
117
or an
optimum surface roughness existed;
118
but the
adhesion still relies on the true contact area of
interaction. The adhesion force distributed more
widely when a rough surface was used because
the asperity radius or the effective contact area is
more scattered.
119121
The inuence of surface
roughness on the force distribution between single
particles and both smooth and rough substrates
has been reported.
117,122124
Recently, the surface chemistry inuence
including morphology (amorphous/crystalline sur-
face domains,
125
polymorphs
126,127
), surface free
energy and work of adhesion,
113,128,129
and hydro-
phobicity
130
were studied extensively. By scan-
ning simultaneously the AFM topographic and
phase image, Price et al.
131
studied the physical
transformation of lactose crystal by milling pro-
cess, and observed morphology and physico-
mechanical changes (amorphous recrystalliza-
tion) on the surface of crystalline material in
accordance to the elevated humidity. Hooton
et al.
132
compared different polymorphs of sul-
fathiazole (I, III, IV) and their corresponding
surface energy and work of adhesion (based on
Johnson-Kendall-Roberts (JKR) theory
133
) deter-
minedagainst highlyorientatedpyrolytic graphite
(HOPG) and polymorph particles. Ward et al.
134
utilized both AFM and Raman microscopy to
identify and map surface amorphous domains of
sorbitol. Besides the AFM phase imaging, the
analysis of the adhesion data over a given surface
area (force volume scans
135,136
) will give a distri-
bution of adhesion 3-Dprole.
137
The introduction
of the ternary system
138
such as different surface
nes
139
or force control agents
140
represents a
surface property modication to produce a
higher ne particle fraction (FPF) by enhancing
aerosolization. Forces were examined using
colloid probe technique and the cohesive-adhesive
balance approach (CAB).
141
Measuring inter-
particulate forces in liquid, together with the
surface energetics measurement such as contact
angle andinverse gas chromatography canbe used
for the characterization or prediction of suspen-
sion stability of pressurized metered dose inhalers
(pMDIs).
114,142,143
Particulate adhesion is a dynamic process with
the increase/decrease of relative humidity (RH%).
The capillary forces arise frommoisture condensa-
tion in the gap between two contiguous surfaces,
and become dominant as the humidity increases.
Both increase and decrease of particulate
forces were reported at elevated RH depending
on three different contact asperity scenario
(nano-contact
128
), possible long range electrostatic
interaction,
144
or morphology change (local recrys-
tallization and particle fusing of micronized
sulbutamol sulphate
125
), (amorphorization of
zanamivir
145
) induced by moisture. The thickness
of the adsorbed water
146
affects the adhesion force
and depends on the hydrophobicity of surface
material.
117
Both heterogeneous asperity (geometric varia-
tions in the contact zone) and heterogeneous
surface energy will cause the logarithmic normal
distributionof the forces.
124,147
Once the adhesion/
cohesion forces are determined, drug particle
surface energetics and interparticulate forces can
be correlated.
114,131
The key issue for quantifying
surface energies and work of adhesion by AFM is
the characterization of the contact area between
the probe and the substrate surface. One
approach
148
describes a probe tip self-imaging
technique in which the geometry of the probe is
recorded reversely. Association with the Youngs
modulus, of both probe and substrate, can then be
used to estimate the contact area. Work of
adhesion can be calculated according to the JKR
theory.
Inverse Gas Chromatography (IGC)
IGC is a technique for studying solids using gas
chromatography principles. A solid analyte is
packed into or coated onto a chromatography
column and a series of nonpolar and polar
probe gases are eluted. Interactions between the
gaseous probe molecules and the stationary phase
result in a characteristic net retention volume,
1286 HICKEY ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
which is used in the determination of the free
energy of adsorption and other thermodynamic
surface parameters.
The technique has been used to study the
adhesional properties of polymers,
149
bers,
150
and composite materials.
151
More recently IGC
has been applied to pharmaceuticals, such as in
the study of DPI
152154
and pMDI
155
formulations,
for which adhesional properties are thought to
play a crucial role. IGC can be used for determina-
tion of surface energy and surface acid/base
properties which directly inuence adhesional
properties. The technique for determining surface
energy and acid/base interactions of surfaces by
IGC are based on the work of Schultz et al.
151
though some subsequent experimenters have
deviated from the method.
Surface free energy is due to Lifshitz-van der
Waals (LW) forces and specic acid-base interac-
tions,
156
which contribute to intermolecular forces
independently.
157,158
Thus, total surface free
energy, g
S
, can be represented as the sum of
dispersive and specic (nondispersive) interac-
tions as
g
S
g
D
S
g
sp
S
1
where g
S
D
designates the dispersive surface free
energy, and g
S
sp
the specic surface energy.
The dispersive component, g
S
D
, can be deter-
mined from the retention volumes of n-
alkanes,
159160
based on the following equation
151
RTlnV
N
2 N
A
A

g
D
S
q
g
D
L
q
C 2
where N
A
is Avogadros number, A is the effective
surface area of the probe molecule, g
S
D
and g
L
D
are
dispersive free energies of interacting solid and
probe, and C a constant that depends on the
chosen reference state. Given that surface area
and g
L
D
increase linearly for the homologous series
of alkanes, a plot of RTlnV
N
versus 2 N
A
A

g
D
L
q
yields a line with slope

g
D
S
q
.
Specic free energy is determined from the
retention volumes of polar probes. Using the same
RT lnV
N
versus 2 N
A
A

g
D
L
q
plot, the specic
free energy of adsorption is the difference between
RTlnV
N
of the probe andthe n-alkaneline. Specic
free energy data for different probes can be
combined into two parameters related to the
character of the interacting surface by way of
the acid/base approach to molecular interac-
tions.
161
Based on this approach specic interac-
tions are classied as either electron donor or
electron acceptor type interactions. Donor
and (adjusted) acceptor numbers, DN and AN*,
represent the ability of a probe to donate or
accept electrons from reference acceptors and
donors.
161,162
According to this approach, the
surface can be characterized by acid and base
parameters via the equation
DH
sp
A
K
A
DNK
B
AN

3
where DH
sp
is the specic enthalpy of adsorption
and K
A
and K
B
are the acid (acceptor) and base
(donor) parameters of the studied surface, respec-
tively. Many publications in the pharmaceutical
literature
152154,163171
have used an alternative
expression based on surface free energy rather
than enthalpy given by the equation
DG
sp
A
K
A
DNK
B
AN

4
Use of Eq. (4) instead of Eq. (3) greatly simplies
the experiment, allowing the experimenter to
determine K
A
and K
B
from data at a single
temperature by plotting DG
A
sp
/AN* versus DN/
AN* for a number of probes. Determination of K
A
and K
B
from Eq. (3) requires experiments to be
performed at different temperatures so that
specic enthalpy of adsorption, DH
A
sp
, can rst be
determined from the temperature dependence of
DG
A
sp
.
While the distinction between Eqs (3) and (4)
appears trivial, data in our lab suggests it is an
important one.
172
EXPERIMENTAL
Materials
Lactose monohydrate (Respitose
TM
) batches of
two milled batches (designated as ML A and ML
B) and six sieved batches (designated as SV A, SV
B, SV C, SV D, SV E, and SV F) were obtained
from DMV-Fonterra Excipients. Table 1 indicates
the physical properties of these excipients as
supplied by the manufacturer.
Two milled batches (ML A and ML B) and two
sieved batches (SV A and SV D) lactose were used
for the IGCexperiments. Alkane probes used were
hexane (99 %, Aldrich, Milwaukee, WI), heptane
(99 %, Aldrich), octane (99.5 %, Fluka, Bochs,
Germany), nonane (99 %, Aldrich), and decane
(99 %, Aldrich). Polar probes were chosen to
cover a wide DN/AN* range; the probes were
tetrahydrofuran (THF) (EM Science, afliate of
Merck KGaA, Darmstadt, Germany, 99.99%),
PHYSICAL CHARACTERIZATION OF DPI PARTICLES I 1287
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
chloroform (100%, Mallinkrodt), acetone (99.7%,
Mallinkrodt, Phillipsburg, NJ), ethyl acetate
(99.9%, Mallinkrodt), diethyl ether (99%, Acros,
Morris Plains, NJ), and ethanol (100%, Aaper,
Shelbyville, KY).
Methods
Pharmaceutical particles are rst characterized
in terms of their physico-chemical properties,
some of which are general, and are shown in the
materials section for the powders described.
However, additional properties may be studied
more closely, as they have some signicance for
the performance of powders in inhalers. In
particular, these characteristics relate to poly-
morphic behavior, physical and chemical transi-
tions, including both thermodynamic and kinetic,
and, hence, potential physical and chemical
instabilities.
Solid State Characterization
X-ray powder diffraction: (Philips 1720 CuK
X-ray) patterns were obtained to evaluate the
crystallinity of the lactose (12 g) batches as
well as assess the presence of the polymorph,
b-anhydrous lactose.
Differential scanning calorimetry: (DSC)
employed approximately 18 mg samples of each
of the eight lactose batches sealed in tared
aluminum pans and scanned at 58C/min from
50 to 2708Cusing a PerkinElmer DSC6 (Norwalk,
CT). Thermograms were processed and analyzed
using the accompanying software, Pyris Thermal
Analysis Instrument Control and Data Analysis
Software (v.3.01).
Surface Analysis
Scanning Electron Microscopy (SEM)
Scanning electron microscopy (SEM, model 6300,
JEOL, Peabody, NY) was employed for imaging of
morphology, size, and surface characteristics of
sieved and milled lactose particles. An electron
beam with an accelerating voltage of 15 kV was
used at 600 magnication. The powders were
placed on double-sided adhesive carbon tabs (Ted
Pella, Inc., Redding, CA) which was adhered to
aluminum stubs (Ernest F. Fullam, Inc., Latham,
NY) and were coated with a gold-palladium alloy
thin lm (150250 A

) using a sputter-coater
(Polaron 5200, Structure Probe Supplies, West
Chester, PA) operating at 2.2 kV, 20 mV, 0.1 torr
(under argon) for 90 s. Analysis of the SEM
micrographs was performed using NIH Image J
software (National Institutes of Health, NIH,
Bethesada, MD).
Micrographs were subjected to image analyses
to facilitate estimationof the relative abundance of
surface ne particles on a series of powder
systems. The images used were at various magni-
cation levels allowing good resolution of the ne
particles while maximizing the eld of view for
adequate inclusion of the large carrier particles.
Image processing included modifying the thresh-
old value of the 8-bit digital image such that the
surface ne particles could be distinguished from
the textured background of the large carrier
particles. Digitized image corrected for back-
Table 1. Physicochemical Properties of Eight Batches of Lactose as Supplied by the Manufacturer*
Batch SV A SV B SV C SV D SV E SV F ML A ML B
Protein (Kjeldahl N* 6.24) 272 188 93 136 199 225 124 79
E 10% 1 cm, 400 nm 0.016 0.008 0.008 0.013 0.007 0.008 0.008 0.010
Sulphated ash 0.08 0.07 0.05 0.08 0.09 0.06 0.06 0.06
UV-absorption 210220 nm 0.048 0.037 0.047 0.049 0.049 0.063 0.038 0.038
UV-absorption 270300 nm 0.012 0.014 0.016 0.015 0.015 0.014 0.009 0.012
Acid value 0.23 0.21 0.27 0.25 0.27 0.18 0.22 0.24
Specic rotation 55.3 55.3 55.3 54.9 55.0 55.0 55.0 55.0
Particle size (Malvern; mm)
d
10
29.9 29.1 29 30.9 29.6 31.5 4.20 4.13
d
50
61.1 59.7 61.4 60.9 59.1 59.7 54.6 52.0
d
90
101.9 97.6 104.7 99.4 98.5 97.3 174.9 167.5
Specic surface area (m
2
/g) 0.34 0.43 0.44 0.46 0.41 0.30 0.89 0.87
*Batches selectedfromaPrincipal Components Statistical Analysis of this data, whichis suppliedfor the convenience of the reader.
1288 HICKEY ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
ground threshold. Note: surface particles become
dominant feature of image.
Because of the shadowing effects from SEM
imaging and the presence of large particle edge
effects, the particle size and counting analysis was
only performed onparticles that were comprised of
150 pixels. This would correspond to particle
projected areas of approximately 0.210 mm
2
(5 pixels/mm).
Atomic Force Microscopy (AFM)
Images were acquired using the Topometrix
Explorer AFM (ThermoMicroscopes, Sunnyvale,
CA) under ambient conditions (23258C; 3540%
RH). Steel stubs (Ted Pella, Inc.) were used for
mounting samples. Cantilever mounting glue was
superglue. Sample mounting glue was Mikro-
Stik
TM
(Ted Pella, Inc.). Silicon nitride cantilever
tips (non-contact tips without coating) were PPP-
NCL (Nanosensors
TM
, Neuchatel, Switzerland)
with the following specications: Thickness: 7 mm
(range: 68 mm); Mean width: 38 mm (range: 30
45 mm); Length: 225 mm (range: 215235 mm);
Force constant: 48 N/m (range: 2198 N/m);
Average Resonance Frequency: 190 kHz. Nanoto-
pographic images were obtained for all batches
(six sieved and two milled). Scan rates were done
at 5 and 10 mm/s in non-contact acquisition mode.
Scan ranges were 10 mm10 mm, 5 mm5 mm,
and 1 mm1 mm. Images with resolution set at
100, 300, 400, and 500 were obtained. Best images
were obtained by using a combination of a
slower scanning rate and higher resolution.
Sensitivity to electromagnetic waves and vibra-
tion increased signicantly at these optimal
settings. ThermoMicroscopes SPM lab analysis
software (ThermoMicroscopes) and Gwyddion soft-
ware were used in analyzing the AFM micro-
graphic images.
Sample preparation was carried out by mount-
ing to steel discs at or near their plane of maximum
stability by using the following procedure:
(1) A small amount of powder was dropped
from a height (0.5 m) onto clean overhead
projector transparencies.
(2) Powder sample discs were painted with
MikroStik
TM
adhesive until excess solvent
had visibly evaporated.
(3) The disc was inverted (adhesive side down)
on a position on the transparency that
contained a dilute region of powder.
(4) Un-adhered particles were removed by
gentle tapping of disc on bench.
(5) This method achieves good particle dilution
(easy particle optical identication during
AFM imaging), and particles are typically
adhered in the plane of imaging (surface
facing up) to facilitate non-contact topo-
graphical imaging.
Inverse Gas Chromatography: experiments
were conducted with a Hewlett-Packard 5890
Series II gas chromatograph with ame ionization
detector. The chromatograph was modied to
allow installation of straight 205 mm, 4 mm ID
glass columns. Dry N
2
was employed as carrier gas
at a ow rate of 30 mL/min. Lactose monohydrate
was packed into deactivated glass columns and
plugged with silanated glass wool. Packed col-
umns were allowed to equilibrate for 6 h after a
temperature change before injections were made.
Injections were made with a 1 mL-Hamilton
syringe; injection volumes were <0.01 mL (based
on detector response). Each injection was made at
least three times and averaged; the relative
standard deviations in the retention times of
single probes on a given column were <1% in each
case. In addition, each batch was examined with
several packedcolumns. Dead-time was calculated
using the retention times of heptane, octane, and
nonane.
173
DatawereanalyzedonMSExcel. Probe
surface areas are taken from Schultz et al., 1987.
Other probe properties were obtained from chem-
istry handbooks.
174
RESULTS
Solid State Characterization
XRPD data are shown in Figure 4 for all lactose
batches which are in good agreement with
previous reports.
31
Since there are no distinctions
between them and the data overlay they are not
identied individually.
DSCdata are shown in Figure 5 and are in good
agreement with previous reports.
30,175
Adehydra-
tion peak occurs at approximately around 1408C
and a melt peak at about 2008C followed by the
decomposition peak. In the case of a sieved sample
(SV-94) shownat the topof the plot there is asmall,
almost indistinguishable peak at about 2408C
which would indicate the presence of b-lactose.
31
Lactose batches had similar XRPD and DSC
proles. This appears to indicate that the presence
of polymorph and/or amorphous content was not
detectable within the limits of these analytical
techniques, that is, under 10% (w/w) content.
PHYSICAL CHARACTERIZATION OF DPI PARTICLES I 1289
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
Surface Analysis
SEMimaging and image analysis of sieved lactose
indicate the following: (1) relatively uniform
particle shape distribution; (2) few particle aggre-
gates; (3) relatively narrow size distribution:
(4) few single particles under 10 mm; and (5)
smooth irregularly shaped asymmetric cubic
morphology with some nanocrevices. Contrast-
ingly, SEM micrograph analysis of milled lactose
indicate the following: (1) relatively non-uniform
particle shape distribution; (2) signicantly
more particle aggregates (stronger surface and
interfacial interactions); (3) relatively wide parti-
cle size distribution; (4) many particles under
10 microns; and (5) irregularily shaped morphol-
ogy, increased surface roughness, nanocrevices,
and surface nes. These results are in excellent
agreement with SEM imaging analysis on sieved
and milled lactose reported previously.
27,31
Additionally, SEM was employed to study the
presence of surface nes that may have signi-
cance for the performance of the powder systems.
Various groups have investigated the use of
ternary blends to modify the interactions between
the carrier particles and micronized drug parti-
cles. This approach relies on the hypothesis that
the inert ne particles added to the carrier
system will occupy highly charged or energetic
sites and thereby improve the deaggregation
kinetics of drug particles during dispersion from
a DPI device. Our observations that there may be
signicant differences between the powder sys-
tems in the quantity of surface nes and that
surface nes may be associated with certain
crystal faces requires investigation so that
these variables can be included in the statistical
analysis and interpretation of relative powder
performance.
There are few documented methods for the
quantication of surface nes. However, an alter-
native approach used to complement the image
analysis technique involved the washing of
the lactose particles and measurement of size
using a laser diffraction instrument (Malvern
Mastersizer).
Figure 6A,Bshows SEMand digitized images of
a lactose surface illustrating the manner in which
surface features are highlighted. There appeared
to be a trend to variation but of no statistically
signicant difference. Consequently the data are
Figure 4. X-ray powder diffractograms of six sieved (SV) and two milled (ML)
lactose batches.
Figure 5. Differential scanning calorimetry (DSC)
gures for six sieved (SV) and two milled (ML) lactose
batches.
1290 HICKEY ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
not presented. Figure 7A shows nes estimation
by Malvern Laser Diffraction in saturated isopro-
panol (data supplied by the manufacturer) and
washing with oil and decanting the small particles
for assessment by laser diffraction. Clear dif-
ferences between milled and sieved samples but
not between batches prepared in the same way
are observed. Also a difference in the number of
particles observed in IPA and oil for sieved
particles was observed despite the same general
trend to similarities between batches. This dif-
ference may be explained by the different physical
properties of the suspending media. Figure 7B
shows that the particle size dening the tenth
percentile of the distribution was larger for sieved
particles (2035 mm) than for milled (5 mm)
consistent with the smaller number of nes in the
sieved sample than milled.
AFM imaging, currently, is labor intensive
and operator dependent. Signicant sample pre-
paration time, microscope setup, scanning time,
and image analysis hinders the capturing of
large data sets. Combined with relatively small
surface area mapping the issue of obtaining
statistically relevant samples is apparent.
That is, there is a need to obtain information on
topography and roughness from a number of
particles for each batch (inter-particle variability),
different areas on the same particle face (intra-
particle variability), and different crystal faces
(intra-particle-face variability). AFM images col-
lected in the present studies (e.g., ML B) show
evidence of tip contamination from surface nes
despite scanning in non-contact mode. Particu-
larly dusty samples are likely to result in tip-
ne particle contamination. Scanning at lower
amplitudes with higher set-points (degree of
interaction of cantilever with surface) can mini-
mize this phenomenon but also gives rise to
decreased image resolution. Many studies in the
Figure 6. A: Scanning electron micrograph of lactose particle: B: digital image of
particle; (C) sieved lactose; and (D) milled lactose.
PHYSICAL CHARACTERIZATION OF DPI PARTICLES I 1291
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
literature have used modied lactose (decanted,
compressed, air-jet treated) to avoid this.
Figure 8 is a representative image obtained by
AFM showing clear geometric features (rough-
ness) on the surface. AFMimage analysis of sieved
lactose indicates arelativelysmoothsurface, at the
nanometer level, with some nanocrevices. AFM
image analysis of milled lactose indicates detailed
visibility of highly irregular surface morphology
with many nanocrevices (surface defects) that
serve as high surface energy sites.
IGCTwo sieved (SV A and SV D) and two
milled (ML A and ML B) Respitose batches were
evaluated with respect to dispersive surface free
energy at 608C, 458C, and 308C(in that order) with
at least three replicates. Variations in dispersive
surface energy were slightly, with an average
dispersive free energy of 41.7 1.0 mJ/m
2
. DSC
ascertained that no bulk physical changes had
taken place as a consequence of the IGC experi-
ment. While there do not appear to be any
signicant differences in the dispersive surface
free energies of the four batches at any of the
temperatures, there do appear to be differences
between the milled and the sieved batches when
studied across the temperature range. This is
evident in Figure 9. The slopes, which represent
Figure 7. A: Fines analysis (particles <5 mm) and
B: Fines analysis particle size of the tenth percentile of
the distribution (d
10
) obtained by laser diffraction.
Figure 8. Atomic force microscopic image of the sur-
face of lactose particle: (A) sieved lactose; and (B) milled
lactose.
Figure 9. Dispersive free energies of two sieved (SV)
and two milled (ML) lactose monohydrate versus
temperature. Relative standard deviation was <2.5%
in each case (n4).
1292 HICKEY ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
surface entropy, are larger for the sieved
than the milled batches. As a result, higher
surface enthalpies are obtained for the SV
than the ML batches (106110 mJ/m
2
vs. 98
101 mJ/m
2
).
Examination of the specic interactions reveals
differences between the milled and the sieved
batches, as well as among the two sieved and two
milled batches.
172
These differences are presented
in Table 2. No standard deviations are available,
since only one best-t line was obtained from
the average enthalpy data obtained from four
columns per batch. However, the differences inthe
enthalpy data from column to column were small,
with RSD <3% for most probes.
The batches appear to be quite similar, which is
expected given that they are the same material
from a single manufacturer (DMV-Fonterra Exci-
pients). Since K
A
and K
B
values are unitless,
differences between K
A
and K
B
for a material
cannot be interpreted directly as signifying a more
acidic or more basic surface. However, comparing
K
A
and K
B
for different batches allows these
comparisons to be made. Lactose is known to be
an acidic material and the differences in acidic
parameter are small. Nonetheless, the differences
observed are real, as the sieved batches are similar
to one another (0.146) but differ from the milled
batches (0.158 and 0.167). The larger K
A
of the
milled batches may in part be explained by its
larger surface area (0.870.89 m
2
for MLvs. 0.34
0.46 m
2
for SV batches). The differences in K
B
are
more marked and might be more indicative of
actual material variations. Since lactose is an
acidic material, the differences inK
B
are likely tied
to other surface properties, perhaps to the pre-
sence of impurities at the surface. However, since
K
A
is obtained from the slope of the line and K
B
from the intercept, determination of K
B
is less
precise than determination of K
B
.
DISCUSSION
Differences were noted in the particles size
distribution, particularly with respect to nes
(d
10
30 and 4 mm, respectively) and surface area
(0.4 and 0.9 m
2
/g, respectively) of sieved and
milled particles. Conventional XRPD and DSC
are routinely employed to characterize solids and
our data demonstrated that there were few if any
differences between the batches of lactose studied.
However, this data is important to establish the
starting characteristics of any particles employed
in comparative studies.
We have illustrated the morphological dif-
ferences between lactose particles evident on
inspection of images obtained by both SEM and
AFM. There are a number of additional methods of
relevance that are based on the use of AFM. One
such method employs plots of cohesive-adhesive
balance (CAB) obtained by AFM.
115
These pro-
vide a direct correlation of the force ratio with
the ratio of the thermodynamic work of cohesion/
adhesion. This approach requires the measure-
ment across atomic smooth surfaces and bases on
the assumption that the surface contact areas are
the same, thus being normalized.
AFM provides a unique opportunity to com-
paratively examine and predict potential pharma-
ceutical formulation. Recently, Using cohesive
pull-off forces between three drugs as a function
of RH, Young et al.
176
correlated these data with
in vitro aerosolization performance to evaluate
AFM prediction. Hooton et al.
177
also applied the
CAB approach in screening the behavior of novel
sugar candidates as carriers for DPI formulation.
Most of the adhesive/cohesive data generated
for the DPI formulation were pull-off forces in the
AFM force curves. They are a mixture of different
fundamental forces. However, the force curves are
capable of generating more abundant information
besides adhesion such as (1) the long-range
attractive/repulsive force (electrostatic response)
before jump-on-contact with the surface; (2) the
elasticity of the sample surface during the contact;
(3) Surface deformation (hysteresis).
Due to the limitation of AFM on relatively at
surface, a majority of substrates used are either
high-pressure compaction tablets or recrystallized
material. These surfaces may not be a true
representation of the surfaces in real pharmaceu-
tical formulation.
Because of its prevalent use in DPI and other
pharmaceutical formulations, lactose monohy-
drate has beenstudiedextensivelyby IGC. Several
Table 2. Surface Acid/Base Constants with
corresponding Correlation Parameters for Sieved (SV)
and Milled (ML) Lactose Monohydrate Batches, in
Accordance With Schultz et al.
151
Lactose Batch K
A
K
B
R
2
SV A 0.146 0.463 0.991
SV D 0.146 0.354 0.996
ML A 0.167 0.379 0.998
ML B 0.158 0.331 0.998
Table modied from data reported in Ref.
172
PHYSICAL CHARACTERIZATION OF DPI PARTICLES I 1293
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
investigators have used IGC to probe batch-
to-batch variation and aid in the choice of lactose
for use inthe formulation. Yet, most studies to date
suffer from a number of short-comings. First, use
of the relationship based on Eq (4) rather than
(3) yields unreliable data which may be contra-
dictory to the more rigorous approach using Eq
(3).
172
Moreover, most studies to date have merely
been descriptive. Surface energy was linked with
dispersive properties and different conclusions
were obtained. However, these studies were
limited to select parameters and neglected to
account for confounding factors. Surface energy
initself is not aproperty that varies fromone batch
of material to the next but an indicator of other
variability, such as impurity/chemical heterogeni-
ety prole or surface disorder content at the
nanometer level (such as amorphicity, liquid
crystallinity, nanocrystallinity, polymorphism,
etc).
Since many DPI formulations are interactive
blends of micronized drug and larger lactose
carrier particles, adhesional properties are impor-
tant design considerations. If particles adhere
strongly, the inspiratory airow of the patient
during DPI actuation may be insufcient to
separate micronized drug from the carrier parti-
cles, which may result in poor or variable delivery
to the lung. Understanding the adhesional forces
of lactose and drug may allowmanufacture of drug
and choice of excipients to be used to optimize the
interactions.
While direct measurement of adhesion, for
example, by using centrifugal detachment or
atomic force microscopy, is possible, the techni-
ques suffer from poor reproducibility because only
select or specic interactions betweenparticles are
considered during each measurement. By con-
trast, IGC probes the surface properties of the
entire sample of material.
Solid surfaces, such as those of lactose and
drugs, are heterogeneous with varying degrees
and distribution of crystallinity, different exposed
functional groups and a distribution of surface
contaminants. IGC has the additional benet of
probing the most energetic surface sites. Whenthe
extremely small concentrations of probe vapor at
innite dilution are injected into the IGC column,
the most active surface sites preferentially inter-
act with the probe. This has been cited as the
reason why IGC results often do not agree with
contact angle measurements.
178
If active sites on a large lactose carrier particle
are indeed more energetic (high Gibbs surface free
energy) then it may preferentially bind a micro-
nized drug particle (s). This process can be
regarded much in the same way as a high energy
surface, such as a clean pure solid surface or a
clean pure aqueous surface, spontaneously
adsorbs hydrocarbon impurities existing in the
vapor state from air, since there is a thermody-
namic driving force to decrease Gibbs surface
free energy. Specically, spontaneous hydrocar-
bon adsorption onto clean pure solid surface or
aqueous surface favorably decreases polar inter-
actions, increases hydrophobicity, and hence,
lowers the surface energy.
Thus, many investigators have attempted to
link increased surface energy of a solid respirable
particle with poor aerosol dispersion from a DPI
formulation. While the connection between sur-
face energy of a solid material and aerosol disper-
sion is conceivable based on rst principles, it is a
challenge to directly conrm experimentally. This
may be attributed to the fact that the surface
energy of a solid-state material, such as that used
in respirable solid particles, is not an independent
parameter but rather the Gibbs surface free
energy thermodynamic manifestation of a collec-
tive ensemble of other solid-state surface char-
acteristics, suchas surface rugosity (a macroscopic
property), surface amorphous content (a material
property), degree of surface hydrophobicity and
surface polarity (material and chemical pro-
perties), and the presence of surface impurities
(a chemical composition property) that may have
been adsorbed onto the solid surface (rendering
the solid surface more hydrophobic and lower in
Gibbs surface free energy which is a thermodyna-
mically-favorable process) fromthe ambient vapor
environment or absorbed into the solid powder
(i.e., present in the bulk and at the surface) during
the medicinal chemistry synthesis process. Hence,
large scale, experimental design type studies may
be necessary to tease out the relationship between
surface energy of solid-state respirable particles
and dry powder aerosol dispersion, while simulta-
neously and carefully controlling (over both
experimental and pharmaceutically-relevant
time-scales) these other important surface char-
acteristics that directly inuence surface energy.
The demonstrable differences between sieved
and milled lactose as established by a variety of
physico-chemical, morphological and surface
analytical methods establishes the baseline
characteristics of powders that will be sub-
sequently employed in bulk and dynamic
analyses of ow, electrostatics and aerodynamic
1294 HICKEY ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
performance with respect to the dispersion of the
model drug albuterol.
CONCLUSIONS
Anumber of static and dynamic methods based on
surface, bulk and performance methods may be
employed to characterize the performance of DPI
formulations. Six sieved and two milled batches of
a lactose monohydrate were evaluated for their
physicochemical properties, surface and bulk
morphology.
There were differences in particle size and
surface area between the milled and sieved
batches of lactose. SEM images showed that there
were more nes associated with the milled than
sieved lactose batches. Further assessment by
image analysis and particle elutriation allowed
quantication of these differences. Atomic force
microscopy demonstrated that the milled particles
exhibited greater surface roughness (nanosurface
crevices and adsorbed surface nes) than the
sieved particles. Inverse gas chromatography
indicated similar dispersive forces at the surface
of all lactoses but differences in the polar forces.
There are clear indications that the surfaces of
milled and sieved particles are different and these
differences may be attributed to the different
physical, chemical, and material properties of
these surfaces resulting in different Gibbs surface
free energies. Recognizing also that the surface of
given lactose particle is neither chemically nor
physically homogenous but rather a composite of
various heterogenous regions (both physical and
chemical) attributed to the existence of acceptable
but signicant amounts of various types of resi-
dual lipids and protein on the surface from the
extraction process from milk (which is both a
complex uid and a biocolloidal dispersion) and
effects of pharmaceutical processing to create
respirable particles. These differences were inves-
tigated with respect to their effects onthe dynamic
performance properties relative to drug dis-
persion, which is described in the second paper
25
of this two-part series.
ACKNOWLEDGMENTS
Dr. Wallace Ambrose at the UNC School of
Dentistry, Dental Research, is acknowledged
for access and expert assistance with SEM.
Dr. Richard Superne and Dr. Michael Falvo of
the UNC Nanoscience Research Group at the NIH
NIBIB Center for Computer Integrated Systems
for Microscopy and Manipulation at UNC
are acknowledged for expert discussions on
AFM. Dr. Michael Chua and Dr. Wendy Soloman
are acknowledged for providing access to the UNC
School of Medicine, Michael Hooker Medical
Microscopy Facility. Martin J. Telko thanks the
USP for a graduate research fellowship.
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