journal of solid state - characteristics of dry powder inhaler

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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 Pfizer 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 field, tend to be complex and correlations between specific properties and performance seem to 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 field 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 first of two papers that discuss static and dynamic methods of characterizing dry powder inhaler formulations. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:1282– 1301, 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 scientific activities since the degree of subdivision, or size, is all that separates nano- particles from boulders. 1 Pharmaceutical powders are, in the first 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. Smyth’s 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: [email protected]) Journal of Pharmaceutical Sciences, Vol. 96, 1282–1301 (2007) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association

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Page 1: Journal of Solid State - Characteristics of Dry Powder Inhaler

Physical Characterization of Component ParticlesIncluded in Dry Powder Inhalers. I. Strategy Review andStatic 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 PAPADOPOULOS3

1Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Campus Box #7360,1310 Kerr Hall, Kerr Hall, Chapel Hill, North Carolina 27599-7360

2DMV-Fonterra Excipients, Goch, Germany

3Pfizer 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 thelungs has been studied extensively in the last decade. The focus for different researchgroups has been on aspects of the powder formulation, which relate to solid state, surfaceand interfacial chemistry, bulk properties (static and dynamic) and measures ofperformance. The nature of studies in this field, tend to be complex and correlationsbetween specific properties and performance seem to be rare. Consequently, the adoptionof formulation approaches that on a predictive basis lead to desirable performance hasbeen an elusive goal but one that many agree is worth striving towards. The purpose ofthis paper is to initiate a discussion of the use of a variety of techniques to elucidate dryparticle behavior thatmight guide the data collection process. If themany researchers inthis field can agree on this, or an alternative, guide then a database can be constructedthat would allow predictive models to be developed. This is the first of two papers thatdiscuss static and dynamic methods of characterizing dry powder inhaler formulations.� 2007Wiley-Liss, Inc. and theAmericanPharmacists Association JPharmSci 96:1282–1301, 2007

Keywords: aerosols; thermodynamics; surface chemistry; solid state; pulmonarydrug delivery; pulmonary; preformulation; physicochemical; formulation; physicalcharacterization

INTRODUCTION

The behavior of particles is the foundation onwhich dry powder inhaler (DPI) performance isbuilt. Interest in particles may be viewed as one ofthe oldest scientific activities since the degree ofsubdivision, or size, is all that separates nano-

particles from boulders.1 Pharmaceutical powdersare, in the first instance, of greatest importancefor oral dosage forms where particle behavior iscrucial to the processes involved in tablet andcapsule manufacture and ultimately in theirdissolution and drug availability. This interestextends to aerosol products that are highlydependent on the physico-chemical and per-formance characteristics of the particles thatdeliver drugs to the lungs.

Aerosol particles are prepared in respirablesizes (<5 mm) and exhibit unique propertiesbased on the forces of interaction which areknown to occur.2 Classically dry powder aerosol

1282 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

Hugh D.C. Smyth’s present address is Currently, College ofPharmacy, University of New Mexico, Albuquerque, NM87131.

Correspondence to: Anthony J. Hickey (Telephone: (919) 962-0223; Fax: (919) 966-0197.; E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 96, 1282–1301 (2007)� 2007 Wiley-Liss, Inc. and the American Pharmacists Association

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formulations are prepared as blends with largelactose carrier particles.3 The forces give rise toparticle–particle and particle–surface interac-tions as depicted in the schematic shown inFigure 1.3–5This is a simplified viewof the possiblenature of particle interactions but illustrates thelikely complexity of a situation in which particleforces are confounded based on surface physicaland chemical heterogeneity. The usual particulateinteractions of electrostatic, capillary and vander Waals (proximity) forces and mechanicalinterlocking3,4 occur but are confounded with theadditional complexities associated with the solidstate of the presence of amorphous regions,impurities (in lactose mostly proteins andsome fats) and specific polar/non-polar regions(dispersive, acid/base energetics).

One of the first manifestations of the effect ofvarious forces of interaction on particles is thatobserved in packing (bulk and tapped density)differences and variability in flow. Flow has beenshown to be a key property of the DPI formulationas it aids in metering, fluidization, and disper-sion.6,7 In itself it is not a variable, but a dependentvariable based on particle size, shape and forces ofinteraction. The interplay of these factors isdifficult to address directly but it is possible thatusing complementary techniques a framework canbe constructed from which the nature of particlescan be used to predict powder performance.

Figure 2 outlines a number of methods thatmay be used to characterize powders intended foruse in inhalers. For ease of reference thesetechniques have been divided into local and bulksurface analysis, static and dynamic bulk char-acteristics and performance measures. In the lastdecade a number of publications have appearedwhich attempt to correlate certain properties withefficiency of inhaler performance. However, it isclear that the quantity of data required to conducta thorough assessment may prohibit compre-hensive assessment in a single study or by a singleresearch group.

The following sections describe the principlesbehind specific techniques and include analysis ofa range of lactose particles intended as carriersfor drug (e.g., albuterol sulfate25) to illustratethe application of these techniques and theconclusions that can be drawn. Figure 3 showsthe basis for inclusion of lactose in albuterol DPIformulations. Lactose is intended to act as adiluent, allowing metering of small quantities ofdrug in larger, manageable quantities of lactose.26

In addition, since lactose carrier particles are large(>50 mm) they act as fluidizing agents in thedispersionof thedrugandwhenacted onbyairflowshear forces facilitate the generation of primaryparticles of drug that can be carried on theinspiratory flow into the lungs of patients. Thedispersion process is recognized to be a highlycomplex process that is far from being completelyunderstood. It is generally recognized that thecomplex nature of the dispersion process is notattributed to any single specific factor. A body ofknowledge suggests that fine lactose (i.e., smallparticles that are in the respirable size range)mayoccupy ‘‘active sites’’ on the surfaces of largerlactose particles. This is one factor that mayinfluence dispersion. This paper is the first in atwo-part sequence that discuss the range ofmethods, outlined in Figure 2, that might beemployed to evaluate blend formulations intendedfor use in DPIs. In the following sections of thispaper, a summary of specificmethods employed forthe static characterization of albuterol-lactoseblends27–31 is given. Dynamic characterization ofdry powder aerosols is described in the secondpaper25 of this two-paper series.

BACKGROUND

Solid State Characterization

In any formulation, including dry powder inhala-tion pharmaceutical aerosols, the solid-state32

of the drug and excipient are importantaspects of the physical and chemical stability,pharmaceutical and therapeutic performance ofthe drug product. Briefly, it is important toconsider crystalline solids,33–36 crystalline poly-morphs,37,38 crystal hydrates,39 amorphous,40–43

liquid crystals,44 nanocrystals, and solid-statephase transitions.1–20 Indeed, the subject of alocal polymorphism with single crystals is extre-mely topical and the subject of some veryrecent debate.45–48 Solid-state phase transitions

Figure 1. Causes of the various types of interactionsbetween fines and carrier particles.

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include polymorphic interconversions, poly-hydrate interconversions, hydration-dehydrationconversion, and order-to-disorder transforma-tions. Additionally, these solid-state phase transi-tions can be thermodynamic transitions andkinetic transitions.

It is important to recognize that a number ofother partially ordered/disordered phases49 areknown to exist in the solid-state that can be ofpharmaceutical significance given the chemistryof many pharmaceuticals and effects of pharma-ceutical processing, and they include quasi-crystals, plastic crystals, disordered nanocrystals

(i.e., non-amorphous disordered solids lackinglong-range crystalline order),50 liquid crystals(thermotropic and lyotropic thermodynamicallystable phases observed in surfactants, bio-polymers, and biomaterials), and polyamorph-ism.51 It has been demonstrated that theamorphous form of an aerosolized drug has atremendous effect on absorption in the deeplung,52 and, hence, it quite likely that the degreeof order/disorder present in the solid aerosolparticle, particularly at the surface of the aero-solized particle, has significant therapeutic andbiological 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 fines from carrierparticles as the static powder is dilated and aerosolized (left to right).

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Water53–56 associated with the sugar carriermay interact with the drug through the interfacebetween the drug and carrier; presence of a littlewater can have significant effects on drug surfacemolecular mobility/transformation/instability.57

A disordered phase, such as an amorphousphase having similar mechanical and physicalproperties of a supercooled liquid existing attemperatures below its thermodynamic crystal-lization temperature but has not been givensufficient time to anneal and crystallize to itsthermodynamically stable ordered phase, inher-ently has a higher degree of molecular mobi-lity.58,59 Additionally, disordered phases, such asan amorphous40 phase or non-amorphous disor-dered nanocrystals, often originate at surfaces andinterfaces, especially in pharmaceutical particlesdue to processing effects. Gas and vapor absorp-tion occurs into these disordered regions located atthe surface, and absorption phenomenon is knownto accelerate where disordered surface regions arepresent. Water vapor absorption provides watermolecules for participation inhydrolysis reactions,and oxygen gas absorption provides oxygen mole-cules for participation in oxidation reactions inthe solid-state. Molecular mobility is furtheredincreased as water acts as a plasticizer, andfurther physical60 and chemical instability61

occurs over pharmaceutically relevant time-scales.

The classical methods of evaluating the solidstate are X-ray powder diffraction14,18,37,50,62–65

and thermal analyses.39,49,66–70 X-ray diffractionof 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 limitof 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) thatis, order-to-disorder (e.g., melting) and disorder-to-order (e.g., crystallization) phase transitionsalso 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 powdersurface energetics.77,78 Crystallization of lactosefrom the amorphous state79 and albuterol-lactoseparticulate interactions80 have been observedusing atomic force microscopy (AFM), a powerfulsurface and nanoimaging analytical technique

that will be presented in-depth. The presenceof water molecules in the bulk powder can beassessed by Karl Fischer analysis to about 0.1%water content but more sophisticated approachesemploy water vapor sorption,81–86 particularly toassess the presence of amorphous material63,87

and to probe the nature of water-pharmaceuticalsolid interactions53–56,60,86,88 at the molecularlevel, including phase transitions that are inducedby the level of hydration present in the solid-statestructure.86 This is a particularly importantapproach to the assessment of hygroscopicsolids,89,90 and aerosols.74,91–98

Surface Analyses

Scanning Electron Microscopy (SEM)

SEM is recognized as unique tool in the visualexamination of particles and their surfaces. Theresolution is of the order of nanometers (magni-fications in the range 20–100,000�). A fine beamof electrons of medium energy (5–50 keV) scans agold-palladium coated sample producing second-ary electrons, backscattered electrons, light orcathodoluminescence and X rays. The latter allowfor X-ray microanalysis for specific elements.SEM is routinely used for imaging particles inthe micron and smaller size range and forexamining the surfaces of larger particles. Theresolution allows identification of specificsurface geometric features that are indicative ofstructural phenomena.

Atomic Force Microscopy (AFM)

AFM offers a unique opportunity to examinesurface structure of a variety of materials withmesoscopic scale resolution (10�6–10�9 m), andquantify the individual particle and excipientinteraction by direct force measurement in avariety of environmental conditions.99–101

The relevant adhesive/cohesive force compo-nents considered inDPI systemare intermolecularvan der Waals force, capillary force, and electro-static force.102 The adhesion force measurementof powder includes vibration,103 centrifuga-tion,104–106 and impact separation,107–109 beforethe advent of direct measurement of colloid probetechnique.110,111 Bulk adhesion leads to globaladhesion characteristics,112 but DPI requires theknowledge of adhesion forces from microscopicanalysis for the purpose of elucidating the funda-mental mechanism such as work of adhesion and

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surface energetics,113,114 and the prediction115 offormulation stability, and redispersion.

There are several factors that link the see-mingly straightforward AFM colloid probe techni-que to the force measurement. They include thefollowing: (1) the cantilever tip consistency; (2) thephysical and chemical properties of colloid probeand substrate surfaces; (3) environmental issues,such as temperature and relative humidity; and(4) the contact area determination or normal-ization.

Perhaps the most important influence of adhe-sion/cohesion forces is related to the colloid probeand substrate surface roughness, which is mostlycharacterized by the root mean square deviation(Rrms) in a given area. There was evidence thatadhesion of drug particles to carrier surfacesincreased with surface roughness116 if particledeformation was negligible, or decreased,117 or anoptimum surface roughness existed;118 but theadhesion still relies on the true contact area ofinteraction. The adhesion force distributed morewidely when a rough surface was used becausethe asperity radius or the effective contact area ismore scattered.119–121 The influence of surfaceroughness on the force distribution between singleparticles and both smooth and rough substrateshas been reported.117,122–124

Recently, the surface chemistry influenceincludingmorphology (amorphous/crystalline sur-face domains,125 polymorphs126,127), surface freeenergy and work of adhesion,113,128,129 and hydro-phobicity130 were studied extensively. By scan-ning simultaneously the AFM topographic andphase image, Price et al.131 studied the physicaltransformation of lactose crystal by milling pro-cess, and observed morphology and physico-mechanical changes (amorphous recrystalliza-tion) on the surface of crystalline material inaccordance to the elevated humidity. Hootonet al.132 compared different polymorphs of sul-fathiazole (I, III, IV) and their correspondingsurface energy and work of adhesion (based onJohnson-Kendall-Roberts (JKR) theory133) deter-minedagainst highly orientatedpyrolytic graphite(HOPG) and polymorph particles. Ward et al.134

utilized both AFM and Raman microscopy toidentify and map surface amorphous domains ofsorbitol. Besides the AFM phase imaging, theanalysis of the adhesion data over a given surfacearea (force volume scans135,136) will give a distri-bution of adhesion 3-D profile.137 The introductionof the ternary system138 such as different surfacefines139 or force control agents140 represents a

surface property modification to produce ahigher fine particle fraction (FPF) by enhancingaerosolization. Forces were examined usingcolloid probe technique and the cohesive-adhesivebalance approach (CAB).141 Measuring inter-particulate forces in liquid, together with thesurface energetics measurement such as contactangle and inverse gas chromatography canbeusedfor the characterization or prediction of suspen-sion stability of pressurized metered dose inhalers(pMDIs).114,142,143

Particulate adhesion is a dynamic process withthe 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 particulateforces were reported at elevated RH dependingon three different contact asperity scenario(nano-contact128), possible long range electrostaticinteraction,144 ormorphology change (local recrys-tallization and particle fusing of micronizedsulbutamol sulphate125), (amorphorization ofzanamivir145) induced by moisture. The thicknessof the adsorbed water146 affects the adhesion forceand depends on the hydrophobicity of surfacematerial.117

Both heterogeneous asperity (geometric varia-tions in the contact zone) and heterogeneoussurface energy will cause the logarithmic normaldistribution of the forces.124,147Once the adhesion/cohesion forces are determined, drug particlesurface energetics and interparticulate forces canbe correlated.114,131 The key issue for quantifyingsurface energies and work of adhesion by AFM isthe characterization of the contact area betweenthe probe and the substrate surface. Oneapproach148 describes a probe tip self-imagingtechnique in which the geometry of the probe isrecorded reversely. Association with the Young’smodulus, of both probe and substrate, can then beused to estimate the contact area. Work ofadhesion can be calculated according to the JKRtheory.

Inverse Gas Chromatography (IGC)

IGC is a technique for studying solids using gaschromatography principles. A solid analyte ispacked into or coated onto a chromatographycolumn and a series of nonpolar and polarprobe gases are eluted. Interactions between thegaseous probe molecules and the stationary phaseresult in a characteristic net retention volume,

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which is used in the determination of the freeenergy of adsorption and other thermodynamicsurface parameters.

The technique has been used to study theadhesional properties of polymers,149 fibers,150

and composite materials.151 More recently IGChas been applied to pharmaceuticals, such as inthe study of DPI152–154 and pMDI155 formulations,for which adhesional properties are thought toplay a crucial role. IGC can be used for determina-tion of surface energy and surface acid/baseproperties which directly influence adhesionalproperties. The technique for determining surfaceenergy and acid/base interactions of surfaces byIGC are based on the work of Schultz et al.151

though some subsequent experimenters havedeviated from the method.

Surface free energy is due to Lifshitz-van derWaals (LW) forces and specific acid-base interac-tions,156 which contribute to intermolecular forcesindependently.157,158 Thus, total surface freeenergy, gS, can be represented as the sum ofdispersive and specific (nondispersive) interac-tions as

gS ¼ gDS þ gspS ð1Þ

where gSD designates the dispersive surface free

energy, and gSsp the specific surface energy.

The dispersive component, gSD, can be deter-

mined from the retention volumes of n-alkanes,159160 based on the following equation151

RT lnVN ¼ 2 �NA � A �ffiffiffiffiffiffigDS

q ffiffiffiffiffiffigDL

qþ C ð2Þ

where NA is Avogadro’s number, A is the effectivesurface area of the probe molecule, gS

D and gLD are

dispersive free energies of interacting solid andprobe, and C a constant that depends on thechosen reference state. Given that surface areaand gL

D increase linearly for the homologous series

of alkanes, a plot of RTlnVN versus 2 �NA � A �ffiffiffiffiffiffigDL

q

yields a line with slopeffiffiffiffiffiffigDS

q.

Specific free energy is determined from theretention volumes of polar probes. Using the same

RT lnVN versus 2 �NA � A �ffiffiffiffiffiffigDL

qplot, the specific

free energy of adsorption is the difference betweenRT lnVNof theprobe and then-alkane line. Specificfree energy data for different probes can becombined into two parameters related to thecharacter of the interacting surface by way ofthe acid/base approach to molecular interac-tions.161 Based on this approach specific interac-tions are classified as either electron donor or

electron acceptor type interactions. Donorand (adjusted) acceptor numbers, DN and AN*,represent the ability of a probe to donate oraccept electrons from reference acceptors anddonors.161,162 According to this approach, thesurface can be characterized by acid and baseparameters via the equation

DHspA ¼ KADNþKBAN

� ð3Þ

where DHsp is the specific enthalpy of adsorptionand KA and KB are the acid (acceptor) and base(donor) parameters of the studied surface, respec-tively. Many publications in the pharmaceuticalliterature152–154,163–171 have used an alternativeexpression based on surface free energy ratherthan enthalpy given by the equation

DGspA ¼ KADNþ KBAN

� ð4Þ

Use of Eq. (4) instead of Eq. (3) greatly simplifiesthe experiment, allowing the experimenter todetermine KA and KB from data at a singletemperature by plotting DGA

sp/AN* versus DN/AN* for a number of probes. Determination of KA

and KB from Eq. (3) requires experiments to beperformed at different temperatures so thatspecific enthalpy of adsorption, DHA

sp, can first bedetermined from the temperature dependence ofDGA

sp.While the distinction between Eqs (3) and (4)

appears trivial, data in our lab suggests it is animportant one.172

EXPERIMENTAL

Materials

Lactose monohydrate (RespitoseTM) batches oftwo milled batches (designated as ML A and MLB) and six sieved batches (designated as SV A, SVB, SV C, SV D, SV E, and SV F) were obtainedfrom DMV-Fonterra Excipients. Table 1 indicatesthe physical properties of these excipients assupplied by the manufacturer.

Two milled batches (ML A and ML B) and twosieved batches (SV A and SV D) lactose were usedfor the IGC experiments. Alkane probes used werehexane (99þ%,Aldrich,Milwaukee,WI), heptane(99þ%, Aldrich), octane (99.5þ%, Fluka, Bochs,Germany), nonane (99þ%, Aldrich), and decane(99þ%, Aldrich). Polar probes were chosen tocover a wide DN/AN* range; the probes weretetrahydrofuran (THF) (EM Science, affiliate ofMerck KGaA, Darmstadt, Germany, 99.99%),

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chloroform (100%, Mallinkrodt), acetone (99.7%,Mallinkrodt, Phillipsburg, NJ), ethyl acetate(99.9%, Mallinkrodt), diethyl ether (99%þ, Acros,Morris Plains, NJ), and ethanol (100%, Aaper,Shelbyville, KY).

Methods

Pharmaceutical particles are first characterizedin terms of their physico-chemical properties,some of which are general, and are shown in thematerials section for the powders described.However, additional properties may be studiedmore closely, as they have some significance forthe performance of powders in inhalers. Inparticular, these characteristics relate to poly-morphic behavior, physical and chemical transi-tions, including both thermodynamic and kinetic,and, hence, potential physical and chemicalinstabilities.

Solid State Characterization

X-ray powder diffraction: (Philips 1720 CuKX-ray) patterns were obtained to evaluate thecrystallinity of the lactose (1–2 g) batches aswell as assess the presence of the polymorph,b-anhydrous lactose.

Differential scanning calorimetry: (DSC)employed approximately 18 mg samples of eachof the eight lactose batches sealed in taredaluminum pans and scanned at 58C/min from50 to 2708Cusing a PerkinElmerDSC 6 (Norwalk,CT). Thermograms were processed and analyzedusing the accompanying software, Pyris Thermal

Analysis Instrument Control and Data AnalysisSoftware (v.3.01).

Surface Analysis

Scanning Electron Microscopy (SEM)

Scanning electron microscopy (SEM, model 6300,JEOL, Peabody, NY) was employed for imaging ofmorphology, size, and surface characteristics ofsieved and milled lactose particles. An electronbeam with an accelerating voltage of 15 kV wasused at 600� magnification. The powders wereplaced on double-sided adhesive carbon tabs (TedPella, Inc., Redding, CA) which was adhered toaluminum stubs (Ernest F. Fullam, Inc., Latham,NY) and were coated with a gold-palladium alloythin film (150–250 A) using a sputter-coater(Polaron 5200, Structure Probe Supplies, WestChester, PA) operating at 2.2 kV, 20 mV, 0.1 torr(under argon) for 90 s. Analysis of the SEMmicrographs was performed using NIH Image Jsoftware (National Institutes of Health, NIH,Bethesada, MD).

Micrographs were subjected to image analysesto facilitate estimation of the relative abundance ofsurface fine particles on a series of powdersystems. The images used were at various magni-fication levels allowing good resolution of the fineparticles while maximizing the field of view foradequate inclusion of the large carrier particles.Image processing included modifying the thresh-old value of the 8-bit digital image such that thesurface fine particles could be distinguished fromthe textured background of the large carrierparticles. 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 79E 10% 1 cm, 400 nm 0.016 0.008 0.008 0.013 0.007 0.008 0.008 0.010Sulphated ash 0.08 0.07 0.05 0.08 0.09 0.06 0.06 0.06UV-absorption 210–220 nm 0.048 0.037 0.047 0.049 0.049 0.063 0.038 0.038UV-absorption 270–300 nm 0.012 0.014 0.016 0.015 0.015 0.014 0.009 0.012Acid value 0.23 0.21 0.27 0.25 0.27 0.18 0.22 0.24Specific rotation 55.3 55.3 55.3 54.9 55.0 55.0 55.0 55.0Particle size (Malvern; mm)d10 29.9 29.1 29 30.9 29.6 31.5 4.20 4.13d50 61.1 59.7 61.4 60.9 59.1 59.7 54.6 52.0d90 101.9 97.6 104.7 99.4 98.5 97.3 174.9 167.5

Specific surface area (m2/g) 0.34 0.43 0.44 0.46 0.41 0.30 0.89 0.87

*Batches selected fromaPrincipalComponentsStatisticalAnalysis of this data,which is supplied for the convenience of the reader.

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ground threshold. Note: surface particles becomedominant feature of image.

Because of the shadowing effects from SEMimaging and the presence of large particle edgeeffects, the particle size and counting analysis wasonly performed on particles thatwere comprised of1–50 pixels. This would correspond to particleprojected areas of approximately 0.2–10 mm2

(�5 pixels/mm).

Atomic Force Microscopy (AFM)

Images were acquired using the TopometrixExplorer AFM (ThermoMicroscopes, Sunnyvale,CA) under ambient conditions (23–258C; 35–40%RH). Steel stubs (Ted Pella, Inc.) were used formounting samples. Cantilever mounting glue wassuperglue. Sample mounting glue was Mikro-StikTM (Ted Pella, Inc.). Silicon nitride cantilevertips (non-contact tips without coating) were PPP-NCL (NanosensorsTM, Neuchatel, Switzerland)with the following specifications: Thickness: 7 mm(range: 6–8 mm); Mean width: 38 mm (range: 30–45 mm); Length: 225 mm (range: 215–235 mm);Force constant: 48 N/m (range: 21–98 N/m);Average Resonance Frequency: 190 kHz. Nanoto-pographic images were obtained for all batches(six sieved and two milled). Scan rates were doneat 5 and 10 mm/s in non-contact acquisition mode.Scan ranges were 10 mm� 10 mm, 5 mm� 5 mm,and 1 mm� 1 mm. Images with resolution set at100, 300, 400, and 500 were obtained. Best imageswere obtained by using a combination of aslower scanning rate and higher resolution.Sensitivity to electromagnetic waves and vibra-tion increased significantly at these optimalsettings. ThermoMicroscopes SPM lab analysissoftware (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 ofmaximumstability by using the following procedure:

(1) A small amount of powder was droppedfrom a height (0.5 m) onto clean overheadprojector transparencies.

(2) Powder sample discs were painted withMikroStikTM adhesive until excess solventhad visibly evaporated.

(3) The disc was inverted (adhesive side down)on a position on the transparency thatcontained a dilute region of powder.

(4) Un-adhered particles were removed bygentle tapping of disc on bench.

(5) This method achieves good particle dilution(easy particle optical identification duringAFM imaging), and particles are typicallyadhered in the plane of imaging (surfacefacing up) to facilitate non-contact topo-graphical imaging.

Inverse Gas Chromatography: experimentswere conducted with a Hewlett-Packard 5890Series II gas chromatograph with flame ionizationdetector. The chromatograph was modified toallow installation of straight 205 mm, 4 mm IDglass columns.DryN2was employed as carrier gasat a flow rate of 30 mL/min. Lactose monohydratewas packed into deactivated glass columns andplugged with silanated glass wool. Packed col-umns were allowed to equilibrate for 6 h after atemperature change before injections were made.Injections were made with a 1 mL-Hamiltonsyringe; injection volumes were <0.01 mL (basedon detector response). Each injection was made atleast three times and averaged; the relativestandard deviations in the retention times ofsingle probes on a given column were<1% in eachcase. In addition, each batch was examined withseveral packed columns.Dead-timewas calculatedusing the retention times of heptane, octane, andnonane.173Datawereanalyzed onMSExcel.Probesurface 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 lactosebatches which are in good agreement withprevious reports.31 Since there are no distinctionsbetween them and the data overlay they are notidentified individually.

DSC data are shown in Figure 5 and are in goodagreement with previous reports.30,175 A dehydra-tion peak occurs at approximately around 1408Cand a melt peak at about 2008C followed by thedecomposition peak. In the case of a sieved sample(SV-94) shownat the top of the plot there is a small,almost indistinguishable peak at about 2408Cwhich would indicate the presence of b-lactose.31

Lactose batches had similar XRPD and DSCprofiles. This appears to indicate that the presenceof polymorph and/or amorphous content was notdetectable within the limits of these analyticaltechniques, that is, under 10% (w/w) content.

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Surface Analysis

SEM imaging and image analysis of sieved lactoseindicate the following: (1) relatively uniformparticle 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 cubicmorphology with some nanocrevices. Contrast-ingly, SEM micrograph analysis of milled lactoseindicate the following: (1) relatively non-uniformparticle shape distribution; (2) significantlymore particle aggregates (stronger surface andinterfacial interactions); (3) relatively wide parti-cle size distribution; (4) many particles under10 microns; and (5) irregularily shaped morphol-ogy, increased surface roughness, nanocrevices,

and surface fines. These results are in excellentagreement with SEM imaging analysis on sievedand milled lactose reported previously.27,31

Additionally, SEM was employed to study thepresence of surface fines that may have signifi-cance for the performance of the powder systems.Various groups have investigated the use ofternary blends to modify the interactions betweenthe carrier particles and micronized drug parti-cles. This approach relies on the hypothesis thatthe ‘‘inert’’ fine particles added to the carriersystem will occupy highly charged or energeticsites and thereby improve the deaggregationkinetics of drug particles during dispersion froma DPI device. Our observations that there may besignificant differences between the powder sys-tems in the quantity of surface fines and thatsurface fines may be associated with certaincrystal faces requires investigation so thatthese variables can be included in the statisticalanalysis and interpretation of relative powderperformance.

There are few documented methods for thequantification of surface fines. However, an alter-native approach used to complement the imageanalysis technique involved the washing ofthe lactose particles and measurement of sizeusing a laser diffraction instrument (MalvernMastersizer).

Figure 6A,B shows SEMand digitized images ofa lactose surface illustrating the manner in whichsurface features are highlighted. There appearedto be a trend to variation but of no statisticallysignificant 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)figures for six sieved (SV) and two milled (ML) lactosebatches.

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not presented. Figure 7A shows fines estimationby Malvern Laser Diffraction in saturated isopro-panol (data supplied by the manufacturer) andwashing with oil and decanting the small particlesfor assessment by laser diffraction. Clear dif-ferences between milled and sieved samples butnot between batches prepared in the same wayare observed. Also a difference in the number ofparticles observed in IPA and oil for sievedparticles was observed despite the same generaltrend to similarities between batches. This dif-ference may be explained by the different physicalproperties of the suspending media. Figure 7Bshows that the particle size defining the tenthpercentile of the distribution was larger for sievedparticles (�20–35 mm) than for milled (�5 mm)consistent with the smaller number of fines in thesieved sample than milled.

AFM imaging, currently, is labor intensiveand operator dependent. Significant sample pre-

paration time, microscope setup, scanning time,and image analysis hinders the capturing oflarge data sets. Combined with relatively smallsurface area mapping the issue of obtainingstatistically relevant samples is apparent.

That is, there is a need to obtain information ontopography and roughness from a number ofparticles 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) showevidence of tip contamination from surface finesdespite scanning in non-contact mode. Particu-larly ‘‘dusty’’ samples are likely to result in tip-fine particle contamination. Scanning at loweramplitudes with higher set-points (degree ofinteraction of cantilever with surface) can mini-mize this phenomenon but also gives rise todecreased image resolution. Many studies in the

Figure 6. A: Scanning electron micrograph of lactose particle: B: digital image ofparticle; (C) sieved lactose; and (D) milled lactose.

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literature have used modified lactose (decanted,compressed, air-jet treated) to avoid this.

Figure 8 is a representative image obtained byAFM showing clear geometric features (rough-ness) on the surface. AFM image analysis of sievedlactose indicatesa relatively smooth surface, at thenanometer level, with some nanocrevices. AFMimage analysis of milled lactose indicates detailedvisibility of highly irregular surface morphologywith many nanocrevices (surface defects) thatserve as high surface energy sites.

IGC—Two sieved (SV A and SV D) and twomilled (ML A and ML B) Respitose batches wereevaluated with respect to dispersive surface freeenergy at 608C, 458C, and 308C (in that order) withat least three replicates. Variations in dispersivesurface energy were slightly, with an averagedispersive free energy of 41.7� 1.0 mJ/m2. DSCascertained that no bulk physical changes hadtaken place as a consequence of the IGC experi-ment. While there do not appear to be anysignificant differences in the dispersive surfacefree energies of the four batches at any of thetemperatures, there do appear to be differencesbetween the milled and the sieved batches whenstudied across the temperature range. This isevident in Figure 9. The slopes, which represent

Figure 7. A: Fines analysis (particles <5 mm) andB: Fines analysis particle size of the tenth percentile ofthe distribution (d10) obtained by laser diffraction.

Figure 8. Atomic force microscopic image of the sur-face of lactose particle: (A) sieved lactose; and (B) milledlactose.

Figure 9. Dispersive free energies of two sieved (SV)and two milled (ML) lactose monohydrate versustemperature. Relative standard deviation was <2.5%in each case (n¼ 4).

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surface entropy, are larger for the sievedthan the milled batches. As a result, highersurface enthalpies are obtained for the SVthan the ML batches (106–110 mJ/m2 vs. 98–101 mJ/m2).

Examination of the specific interactions revealsdifferences between the milled and the sievedbatches, as well as among the two sieved and twomilled batches.172 These differences are presentedin Table 2. No standard deviations are available,since only one best-fit line was obtained fromthe average enthalpy data obtained from fourcolumns per batch.However, the differences in theenthalpy data from column to column were small,with RSD <3% for most probes.

The batches appear to be quite similar, which isexpected given that they are the same materialfrom a single manufacturer (DMV-Fonterra Exci-pients). Since KA and KB values are unitless,differences between KA and KB for a materialcannot be interpreted directly as signifying amoreacidic or more basic surface. However, comparingKA and KB for different batches allows thesecomparisons to be made. Lactose is known to bean acidic material and the differences in acidicparameter are small. Nonetheless, the differencesobserved are real, as the sieved batches are similarto one another (0.146) but differ from the milledbatches (0.158 and 0.167). The larger KA of themilled batches may in part be explained by itslarger surface area (0.87–0.89m2 forML vs. 0.34–0.46 m2 for SV batches). The differences in KB aremore marked and might be more indicative ofactual material variations. Since lactose is anacidicmaterial, the differences inKBare likely tiedto other surface properties, perhaps to the pre-sence of impurities at the surface. However, sinceKA is obtained from the slope of the line and KB

from the intercept, determination of KB is lessprecise than determination of KB.

DISCUSSION

Differences were noted in the particles sizedistribution, particularly with respect to fines(d10¼ 30 and 4 mm, respectively) and surface area(�0.4 and 0.9 m2/g, respectively) of sieved andmilled particles. Conventional XRPD and DSCare routinely employed to characterize solids andour data demonstrated that there were few if anydifferences between the batches of lactose studied.However, this data is important to establish thestarting characteristics of any particles employedin comparative studies.

We have illustrated the morphological dif-ferences between lactose particles evident oninspection of images obtained by both SEM andAFM. There are a number of additionalmethods ofrelevance that are based on the use of AFM. Onesuch method employs plots of cohesive-adhesivebalance (CAB) obtained by AFM.115 These pro-vide a direct correlation of the force ratio withthe ratio of the thermodynamic work of cohesion/adhesion. This approach requires the measure-ment across atomic smooth surfaces and bases onthe assumption that the surface contact areas arethe same, thus being normalized.

AFM provides a unique opportunity to com-paratively examine and predict potential pharma-ceutical formulation. Recently, Using cohesivepull-off forces between three drugs as a functionof RH, Young et al.176 correlated these data within vitro aerosolization performance to evaluateAFM prediction. Hooton et al.177 also applied theCAB approach in screening the behavior of novelsugar candidates as carriers for DPI formulation.

Most of the adhesive/cohesive data generatedfor the DPI formulation were pull-off forces in theAFM force curves. They are a mixture of differentfundamental forces. However, the force curves arecapable of generating more abundant informationbesides adhesion such as (1) the long-rangeattractive/repulsive force (electrostatic response)before jump-on-contact with the surface; (2) theelasticity of the sample surface during the contact;(3) Surface deformation (hysteresis).

Due to the limitation of AFM on relatively flatsurface, a majority of substrates used are eitherhigh-pressure compaction tablets or recrystallizedmaterial. These surfaces may not be a truerepresentation of the surfaces in real pharmaceu-tical formulation.

Because of its prevalent use in DPI and otherpharmaceutical formulations, lactose monohy-drate has been studied extensively by IGC.Several

Table 2. Surface Acid/Base Constants withcorresponding Correlation Parameters for Sieved (SV)and Milled (ML) Lactose Monohydrate Batches, inAccordance With Schultz et al.151

Lactose Batch KA KB R2

SV A 0.146 0.463 0.991SV D 0.146 0.354 0.996ML A 0.167 0.379 0.998ML B 0.158 0.331 0.998

Table modified from data reported in Ref.172

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investigators have used IGC to probe batch-to-batch variation and aid in the choice of lactosefor use in the formulation.Yet,most studies to datesuffer from a number of short-comings. First, useof 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 merelybeen descriptive. Surface energy was linked withdispersive properties and different conclusionswere obtained. However, these studies werelimited to select parameters and neglected toaccount for confounding factors. Surface energyin itself is not a property that varies fromone batchof material to the next but an indicator of othervariability, such as impurity/chemical heterogeni-ety profile or surface disorder content at thenanometer level (such as amorphicity, liquidcrystallinity, nanocrystallinity, polymorphism,etc).

Since many DPI formulations are interactiveblends of micronized drug and larger lactosecarrier particles, adhesional properties are impor-tant design considerations. If particles adherestrongly, the inspiratory airflow of the patientduring DPI actuation may be insufficient toseparate micronized drug from the carrier parti-cles, which may result in poor or variable deliveryto the lung. Understanding the adhesional forcesof lactose and drugmay allowmanufacture of drugand choice of excipients to be used to optimize theinteractions.

While direct measurement of adhesion, forexample, by using centrifugal detachment oratomic force microscopy, is possible, the techni-ques suffer from poor reproducibility because onlyselect or specific interactions betweenparticles areconsidered during each measurement. By con-trast, IGC probes the surface properties of theentire sample of material.

Solid surfaces, such as those of lactose anddrugs, are heterogeneous with varying degreesand distribution of crystallinity, different exposedfunctional groups and a distribution of surfacecontaminants. IGC has the additional benefit ofprobing themost energetic surface sites.When theextremely small concentrations of probe vapor atinfinite dilution are injected into the IGC column,the most active surface sites preferentially inter-act with the probe. This has been cited as thereason why IGC results often do not agree withcontact angle measurements.178

If active sites on a large lactose carrier particleare indeedmore energetic (high Gibbs surface free

energy) then it may preferentially bind a micro-nized drug particle (s). This process can beregarded much in the same way as a high energysurface, such as a clean pure solid surface or aclean pure aqueous surface, spontaneouslyadsorbs hydrocarbon impurities existing in thevapor state from air, since there is a thermody-namic driving force to decrease Gibbs surfacefree energy. Specifically, spontaneous hydrocar-bon adsorption onto clean pure solid surface oraqueous surface favorably decreases polar inter-actions, increases hydrophobicity, and hence,lowers the surface energy.

Thus, many investigators have attempted tolink increased surface energy of a solid respirableparticle with poor aerosol dispersion from a DPIformulation. While the connection between sur-face energy of a solid material and aerosol disper-sion is conceivable based on first principles, it is achallenge to directly confirm experimentally. Thismay be attributed to the fact that the surfaceenergy of a solid-state material, such as that usedin respirable solid particles, is not an independentparameter but rather the Gibbs surface freeenergy thermodynamic manifestation of a collec-tive ensemble of other solid-state surface char-acteristics, such as surface rugosity (amacroscopicproperty), surface amorphous content (a materialproperty), degree of surface hydrophobicity andsurface polarity (material and chemical pro-perties), and the presence of surface impurities(a chemical composition property) that may havebeen adsorbed onto the solid surface (renderingthe solid surface more hydrophobic and lower inGibb’s surface free energy which is a thermodyna-mically-favorable process) from the ambient vaporenvironment or absorbed into the solid powder(i.e., present in the bulk and at the surface) duringthemedicinal chemistry synthesis process. Hence,large scale, experimental design type studies maybe necessary to tease out the relationship betweensurface energy of solid-state respirable particlesand dry powder aerosol dispersion, while simulta-neously and carefully controlling (over bothexperimental and pharmaceutically-relevanttime-scales) these other important surface char-acteristics that directly influence surface energy.

The demonstrable differences between sievedand milled lactose as established by a variety ofphysico-chemical, morphological and surfaceanalytical methods establishes the baselinecharacteristics of powders that will be sub-sequently employed in bulk and dynamicanalyses of flow, electrostatics and aerodynamic

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performance with respect to the dispersion of themodel drug albuterol.

CONCLUSIONS

A number of static and dynamic methods based onsurface, bulk and performance methods may beemployed to characterize the performance of DPIformulations. Six sieved and two milled batches ofa lactose monohydrate were evaluated for theirphysicochemical properties, surface and bulkmorphology.

There were differences in particle size andsurface area between the milled and sievedbatches of lactose. SEM images showed that therewere more fines associated with the milled thansieved lactose batches. Further assessment byimage analysis and particle elutriation allowedquantification of these differences. Atomic forcemicroscopy demonstrated that themilled particlesexhibited greater surface roughness (nanosurfacecrevices and adsorbed surface fines) than thesieved particles. Inverse gas chromatographyindicated similar dispersive forces at the surfaceof all lactoses but differences in the polar forces.There are clear indications that the surfaces ofmilled and sieved particles are different and thesedifferences may be attributed to the differentphysical, chemical, and material properties ofthese surfaces resulting in different Gibbs surfacefree energies. Recognizing also that the surface ofgiven lactose particle is neither chemically norphysically homogenous but rather a composite ofvarious heterogenous regions (both physical andchemical) attributed to the existence of acceptablebut significant amounts of various types of resi-dual lipids and protein on the surface from theextraction process from milk (which is both acomplex fluid and a biocolloidal dispersion) andeffects of pharmaceutical processing to createrespirable particles. These differences were inves-tigatedwith respect to their effects on the dynamicperformance properties relative to drug dis-persion, which is described in the second paper25

of this two-part series.

ACKNOWLEDGMENTS

Dr. Wallace Ambrose at the UNC School ofDentistry, Dental Research, is acknowledgedfor access and expert assistance with SEM.Dr. Richard Superfine and Dr. Michael Falvo of

the UNCNanoscience Research Group at the NIHNIBIB Center for Computer Integrated Systemsfor Microscopy and Manipulation at UNCare acknowledged for expert discussions onAFM. Dr. Michael Chua and Dr. Wendy Solomanare acknowledged for providing access to the UNCSchool of Medicine, Michael Hooker MedicalMicroscopy Facility. Martin J. Telko thanks theUSP for a graduate research fellowship.

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