Advanced Drug Delivery Reviews 64 (2012) 275–284

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Advanced Drug Delivery Reviews

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Drug–lactose binding aspects in adhesive mixtures: Controlling performance in drypowder inhaler formulations by altering lactose carrier surfaces☆

Qi (Tony) Zhou, David A.V. Morton ⁎Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, VIC 3052, Australia

☆ This review is part of the Advanced Drug Delivery Reas a Carrier for Inhalation Drug Delivery”.⁎ Corresponding author. Tel.: +61 3 99039523; fax:

E-mail address: david.morton@monash.edu (D.A.V. M

0169-409X/$ – see front matter © 2011 Elsevier B.V. Adoi:10.1016/j.addr.2011.07.002

a b s t r a c t

a r t i c l e i n f o

Article history:Received 10 February 2011Accepted 7 July 2011Available online 18 July 2011

Keywords:Dry powder inhalerLactose carrierAdhesive mixtureAerosol performanceForce control agentsCohesive–adhesive balanceSurface modificationMechanical dry powder coatingSurface coating characterization

For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactosecarriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patientuse. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesiveand adhesive forces experienced by the drug particles under stresses induced in the flow environment duringaerosolization. Surface modification with appropriate additives has been proposed as a practical and efficientway to alter the inter-particulate forces, thus potentially controlling the formulation performance, and thisstrategy has been employed in a number of different ways with varying degrees of success. This paper reviewsthe main strategies and methodologies published on surface coating of lactose carriers, and considers theireffectiveness and impact on the performance of dry powder inhaler formulations.

views theme issue on “Lactose

61 3 99039583.orton).

ll rights reserved.

© 2011 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2752. Engineering of surface morphological properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

2.1. Smooth lactose carrier surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2762.2. Rough lactose carrier surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

3. Surface coating of lactose carrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2773.1. Solvent-based coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2773.2. Mechanical dry coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

3.2.1. Mechanofusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2783.2.2. Theta-composer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

3.3. Other coating strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2813.4. Characterization of the coating quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2815. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

1. Introduction

The performance of dry powder inhaler (DPI) formulations can bea strong function of the balance of cohesive and adhesive forces

experienced by the drug particles [1]. In this article we consider themost common DPI formulation approach, consisting of an adhesivemixture of micronized drug with lactose carriers acting as a flow andfluidization aid. However it has been shown that in some formulations,a further excipient additive (for example, additional fine lactose ormagnesium stearate) where included, can act as a de-agglomerationfacilitator or force control agent [2].

Lactose has been adopted as the safe excipient of choice forpulmonary delivery [3]. The form of lactose used in such formulations

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should be well controlled, and generally contains a large size fraction(in the order of approximately 40 to 200 μm) and a fine size fraction(in the order of approximately 1 to 40 μm). The large size fraction actsas a carrier to aid in a range of processes such as powder flow andfluidization as well as acting as a diluent to help in dose metering. Thefine size faction of lactose has been empirically observed to boost theapparent de-agglomeration efficiency of the micronized drug, as it isreleased from the powder mass (although its mechanism of action isnot clear [4]).

As a result, micronized drug exists in an environment with anumber of possible contact neighbors, including other drug particles,fine lactose particles or coarse lactose particles. Powders are largelyaggregated and can exist in a huge variety of agglomerates of varyingsizes, structures and compositions. Despite this highly complex“multi-particulate nightmare” [5], it has been rather simplisticallyassumed that aerosolization of the drug would generally be improvedby simply reducing the forces between drug and carrier [6]. In practicethe situation is not so simple, and apparent stronger bonds betweenparticles can surprisingly yield improved fine particle deliveryefficiency [7]. The anomalies in these cases can be attributed to thecomplexities of de-agglomeration mechanisms within different de-vices. For good control over DPI product performance, a fundamentalunderstanding is required of the formulation, of the device, of thepatient behavior and of the environment, including the complex inter-relationships between each [7].

To simplify this highly complex scenario it may be helpful to breakthe aerosolization process from a DPI to occur into two definablestages or processes, namely: fluidization of the powder bed, followedby drug detachment from its neighbors into respirable sizes [8], andwhere both of these stages are influenced by the adhesion/cohesion ofthe powder.

Many attempts have been made to engineer particles and surfaceswith low adhesion/cohesion properties, and hence to control theforces between particles, including between micronized drug parti-cles and between drug and excipient carriers [8,9]. Several philoso-phies have been investigated. These include the creation of particles(drug or carrier) with highly crystalline, low surface energy andatomically smoothed surfaces, which provide a surface of consistentlow energy, and remove the stickiness associated with amorphousand associated forms of disordered material [10,11]. The removal ofsurface cracks or faults on larger lactose particles is perceived toremove areas which provide shelter into which fine particles becometrapped [12]. In contrast, creating very rough surfaces with features ofdimensions smaller than the finest constituent particles, may reducethe surface contact area, therefore, inherently reduce particulateinteractions [13]. Such features are often also associated with lowdensity porous particles [14].

Lactose monohydrate is regarded as a material that is prone tohighly variable and relatively sticky surface areas: such areas havebeen termed “active sites” [15]. As noted earlier, one form of activesite is a physical surface feature larger than the drug particles thatprovides shelter to trap finer particles, and reduce the probability oftheir liberation during product use. An alternative form of active site isan area which has a raised surface energy, related to polar ordispersive forces, enhanced van der Waals forces, surface disorder,moisture, charge, chemical contamination or other physico-chemicalsurface features. This definition has resulted in numerous studies thatapproached the perceived problem attempting to coat the lactosecarrier surfaces by using appropriate additives (also termed ForceControl Agents or FCAs) to reduce the force holding drug particles, andmask any active sites, believing it would enhance drug particleaerosolization efficiency. The choice of FCAs is limited by toxicologicalconcerns, and this precluded the use of some materials like inorganicoxides (i.e. colloidal silica) — the traditional anti-adherents [16].

We have examined in this paper, the strategies and practicalmethods that have been used in lactose surface treatment including a

focus on coating and a current perspective on implications for the drypowder inhaler formulations based on such an adhesive mixture.

2. Engineering of surface morphological properties

Surface morphology is believed to affect particle adhesion byincreasing or reducing contact area. Thereby, modifying surfacemorphological properties may be an effective way to alter cohesion/adhesion, thus, influencing aerosol performance. However, sucheffects of surface roughness on the fine particle fraction are not firmlyestablished [8]. Indeed, it is notable that both smoothing lactosesurfaces and creating rough lactose surfaces have been reported toresult in an increase in the fine particle fraction (FPF) delivered by therespective DPI as discussed in the following Sections 2.1 and 2.2.

2.1. Smooth lactose carrier surfaces

Lactose carriers have been crystallized from carbopol gel whichresulted in a smoother surface and better measured dispersion of drugfrom a DPI [17]. The surface roughness was in this case quantifiedusing a parameter of “surface factor”measured by optical microscopy.The FPF of salbutamol sulfate aerosolized by a Rotahaler device fromthe binary mixture increased from 14.7% with the control lactose to21.5% with the re-crystallized lactose at 60 l/min. Surface treatmentswith ethanol also smoothed the lactose carrier surface and improvethe drug deposition [18,19]. Coating of lactose powders with lactoseaqueous solution and hydroxypropyl methylcellulose (HPMC, as abinder) using a Wurster fluidized bed was demonstrated to increasethe smoothness of the particle surface [20]. The arithmetic meanroughness (Ra) value measured by atomic force microscopy (AFM)decreased from 0.95 μm to 0.61 μm and the specific area decreasedfrom 0.148 m2/g to 0.125 m2/g after surface coating for 180 min. Theaerosol performance of salbutamol sulfate from the binary mixtureswas improved with an increase of respirable particle percent (RP)from 14.6% to 34.9%. But it is also interesting to note that after surfacecoating for 240 min, the Ra value of the lactose was further decreasedto 0.48 μm, but RP of the DPI formulation decreased to 31.7%.

Reducing the surface roughness, to produce a smooth surface canbe argued to allow an increased surface contact area, for example, fortwo flat surfaces in contact. So although it may reduce the areas suchas crevices, hollows and other traps for particles to sit within, andreducing so called surface “active sites”, there is also a potential forreduced ease of particle release from the smoothed surface.

2.2. Rough lactose carrier surfaces

In contrast, a fluid-bed has also been used for coating coarselactose carriers with fine lactose, resulting in an increased surfaceroughness of lactose carriers [13]. Hence different fluid bed coatingconditions used appear to have resulted in different effects on thesurface morphology of the coated lactose particles. In this study, theRa value of the lactose surface measured by atomic force microscopy(AFM) increased from 159 nm for the untreated lactose to 216 nm forthe coated lactose while the FPF increased from 16.4% to 18.9% from aRotahaler after surface coating. Such improvement was relativelysmall, and was attributed to the reduced contact area by introducingmicroscopic asperities that is smaller than drug particles on the carriersurface (Fig. 1) [21].

These conflicting observations may be explained by the differentcharacterization tools/parameters used, as well as the significantcomplexity and limited understanding of the relationship betweenlactose surface morphology and the aerosol performance. Furthermore,the cohesion–adhesion forces are dependent on many surface propertyvariables, not only simple surface morphology [8]. Surface engineeringoften alters not only the morphology but also changes other surfaceproperties such as surface crystallinity or surface chemistry during the

Fig. 1. Effect of surface roughness of lactose carriers on particulate interactions betweenmicronized drug particles and lactose carrier surfaces: (a) smooth carrier surface;(b) carrier surface with microscopic asperities that is smaller than drug particles;(c) individual drug particles trapped in the carrier surface; (d) drug cluster trapped inthe carrier surface.

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process. Such changes in other properties rather than morphology mayhave greater impact on the aerosol performance thanmorphology itself,and other variables as discussed elsewhere in this review, includingeffect of device geometry, air flow, and nature of the drug particles willcontribute to the behavior.

3. Surface coating of lactose carrier

3.1. Solvent-based coating

Another approach to engineer lactose surfaces is to coat withappropriate additives so as to reduce the adhesion between drugparticles and lactose surfaces. In this way, both surface roughness andchemistry may be altered. The additives used in this context havebeen termed “force control agents (FCAs)”. Such coating process canbe either solvent-based or solventless. Fluid-bed spray coating is acommon solvent-based approach in pharmaceutics for coatingparticles. However, only a limited number of studies have employeda fluid-bed coating approach to coat lactose carriers for DPI use. Thismay be due to several practical constraints when spray coating finelactose carrier powders whose particle sizes are usually smaller than100 μm in a fluid bed. Coating such fine powders in this way is achallenge as they tend to agglomerate or granulate in the fluid bedespecially when an additive is presented, thus, the process conditionsshould be very carefully chosen [22]. Another challenge for fluid-bedspray coating of lactose carrier for DPI formulations is the choice ofFCAs, including their solubility and solvent choice. The toxicology forinhalation is a major consideration and limitation in selecting suitableFCAs to be used, and further limited in terms of solubility for fluid-bedcoating. It is interesting to note that coating lactose carrier withlactose solution using a fluid bed has been demonstrated to bothincrease and decrease the surface roughness represented as Ra valuemeasured by AFM in two different studies [13,20], although the invitro performance of the DPI formulations in both studies improvedafter surface coating. Given the different process conditions andsolution compositions used across these studies, it is not surprising toobserve the different effects on surface morphology and their impacton the aerosol performance of DPI.

An alternative solvent-based coating technique has also beenemployed to smooth the surface of lactose carrier for a DPI formulation

[23,24]. A typical commercially available lactosewith sizes around 90–150 μm was wetted with ethanol/water (3:5, v/v) solution. Then thewetted particles were dried under vacuum during high speed mixing.Additives such as magnesium stearate (MgSt) or amino acids (0.25%,w/w) were also added into the smoothing solvent as coating material.Such additives were expected to coat the lactose particle surfaceduring the preparation. The results demonstrated that a smoothedsurface of lactose was created after processing with or withoutadditives. However, only the lactose particles processedwith additivesshowed significant increases in FPF, notably from 13.2% for theuntreated lactose to 58.9% for the lactose processed with magnesiumstearate from a mixture of lactose and beclomethasone dipropionateafter aerosolization from a Pulvinal inhaler [25]. Apparently a greaterperformance improving influence may be obtained by the optimumselection of FCA rather than smoothing the surface alone, howeverfurther work will help to clarify how the relative increases in FPF canbe attributed to the changes in surface morphological properties orattributed to the changes in surface chemical properties after coating,or as combined.

3.2. Mechanical dry coating

Solvent-based coating provides disadvantages compared to asolvent-less process: for example it is generally more complex,requiring additional energy and time in adding/removing solvent,plus associated environmental hazards and issues with possibleorganic solvent emission and disposal. As such, mechanical drycoating approaches may be practically a preferred alternative for thesurface modification of lactose carrier.

The use of mechanical methods for coating lactose carriers withFCAs for DPI formulations can arguably be related to the problemsfaced by tablet formulators knowing that whenmagnesium stearate ismore intensely mixed into tablet powder blends, it may increasinglycoat the particles/granules and reduce cohesion such that the granuleswill not adhere to each other under compression. Hence, efficientmixing and coating has been a focus in use of lubricants as FCAs.

Magnesium stearate use in DPI lactose carriers was outlined as earlyas 1987 [26] in a patent application describing the use of magnesiumstearate wet granulated with lactose: however, this approach wasspecified as to prevent adhesion of lactose to devicemechanisms ratherthan alter drug detachment. This was followed by patent applicationsdescribing the use of magnesium stearate blendedwith lactose carriers,to attach to the lactose surface with motivation to either reduce drugattachment force or alternatively to protect against moisture affects oncohesion [27,28]. Further advances indicated that benefit accrued withuse of a number of such FCAs. However, where the combination processof FCA and lactose increased in intensity, particles could be co-milled,which not only appeared to improve coating, but lactose fines weresimultaneously generated [29]. The difficulty in mechanically coatingsurfaces effectively was considered an important factor in explainingthis phenomenon. Conventional blending appears capable of delami-nating MgSt onto coarse particles, but such “coating” layers appearcommonly to be non-continuous and non-uniform [30]. Furthermore, itis suggested that conventional blending may not provide sufficientenergy and shear to uniformly coat fine cohesive particles even whenblending duration is extended to as long as several hours. It has beennoted that ineffective coating was observed after blending MgSt with afine lactose powder (volume median diameter, VMD, approximately20 μm) in a Turbular® mixer for 30 min [31]. Co-milling has beenclaimed in this context as a more effective way to coat smaller lactoseparticles, that conventional blending could not achieve [32]. Co-millingwas argued tobe further improveduponby the useof a selected range ofintensive mechanical dry coating processes [32–34].

A range of intensive mechanical dry coating techniques isavailable, including MechanoFusion® processors, the Hybridizer®,the Magnetically Assisted Impaction Coater (MAIC) ® and the Theta-

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composer®. There are common principles to these different mechan-ical dry coating processes: during the coating, smaller or softer guestparticles are coated onto the surface of larger host particles throughintensive mechanical forces. The interactions between the guest andhost particles during the process can be either physical or chemicalbonding, or both [35]. The different types of coating layers are shownin Fig. 2. The coating layers may be either discrete or continuous. Thecontinuous layers may consist of a particle layer (monolayer ormultilayer) or a film layer, which appears to depend on the propertiesof the material, the device design as well as operation conditions. Inprinciple, the guest particles are relatively smaller and softer than thehost particles in order to permit effective immobilization of the guestparticles on the host particle surfaces. The coating device shouldprovide enough strength and energy for the physical or chemicalbonding between the guest and the host particles, ensuring acontinuous layer can be formed. For the fine host particles withrelative small particle size less than 50 μm, the strength of the processshould also be sufficient to overcome strong inter-particle attractiveforces so as to separate individual host particles from agglomerates inorder to expose all surfaces and to coat individual particle surface,rather than to form coated agglomerates [31]. Dry coating processeshave been widely applied for applications in various areas such ascosmetic, metallurgy, ceramics, cement, inks, foods and photography[36]. They have also attracted intensive interest for its applications insome pharmaceutical areas [37].

3.2.1. MechanofusionThe term “mechanofusion” has been adopted as a generic term for

many intensive dry coating processes [35], and is used in this reviewin this context, but the original term, “MechanoFusion®” related to asuite of process equipment developed by Hosokawa Micron, Japan,largely applied to non-pharmaceutical applications. Various mechan-ofusion processes have been reported as dry coating process for use informulating DPIs. Mechanofusion is reported as notably effective incoating lactose carrier particles whose particle size is generally muchfiner than the traditional 40 to 200 μm, or for drug powders finer than5 μm, without the byproduct of co-milling such as size reduction, andso is claimed as attractive as a single step dry coating process [38].

Fig. 2. Schematic of mechanical dry powder coating. Reprint from ref. [35] withpermission from Elsevier.

A typical mechanofusion system consists of outer cylinder vesseland an inner raft with processor blades extended from the raft. Thevessel or the processor rotates at speeds between 500 and10,000 rpm. In the context of mechanofusion processing, tip speedmay be a more appropriate descriptor of intensity/speed, as vesseldiameters may vary considerably. A gap of approximately 1–3 mmbetween the vessel and the processor is designed to allow the powderto be compressed and sheared during the coating process. Conse-quently, as the shaft or the vessel rotates, the processor continuouslysweeps close to the vessel wall, ensuring all the powder is in constantand violent motion. Due to the high rotational speed of the processors,the powder is propelled towards the wall, and as a result the mixtureexperiences very high shear forces at the processor face, andcompressive stresses between wall and processor. The energy isintended to be sufficient to break up agglomerates of guest and hostparticles, but due to the fixed geometry, and control of speed, it isbelieved that energy input is controlled such that size reduction ofhost primary particles can be minimized. In an earlier version(Mechanofusion® AMS, Hosokawa Micron, Japan), the inner raftand processor are fixed while the outer vessel rotates during theprocessing [35] (Fig. 3). For more recent Hosokawa Micron designs,the outer vessel is fixed and the processor rotates for the coating(Fig. 4) [39]. Various processors with different shapes and geometriescan be chosen according to the purpose and the nature of the coating[40].

Begat et al. [33] applied such amechanofusion process to coat bothdrug particles of salbutamol sulfate and lactose carrier with threeFCAs, MgSt, leucine and lecithin. The lactose carrier used in this studywas a relative fine powder with VMD around 10 μm rather than moreconventional coarse carriers with VMD ranging from 40 to 200 μm. Itis interesting that the in vitro performance (reflected by FPF of theemitted dose) of the binary mixtures from a Monohaler device wasonly improved for those containing the coated drug particles. Thereduction in adhesion forces between lactose carrier surface and drugparticles appeared to result in drug particles sticking together, asmeasured by AFM and the cohesive–adhesive balance (CAB) ap-proach. This work was extended for carrier-free high drug dose DPIformulations [40,41].

Kumon et al. [34], also dry coated lactose carriers using amechanofusion process aiming to improve aerosolization. Lactosecarriers of Sorbolac® 400 (VMD approximately 8 μm), Pharmatose®325 M (VMD approximately 60 μm) and Lactohale® 100 (VMDapproximately 145 μm) were coated with either MgSt or sucrosestearate, or processed without any additives. The coating for the finestlactose powder of Sorbolac 400 was reported to be unsuccessful asattributed to the small particle size and the mechanofusion device

Fig. 3. Schematic of an early model of Mechanofusion® AMS system.Reprint from ref. [35] with permission from Elsevier.

Fig. 4.Mechanofusion®AMSMini systemswith (a) Nobilta and (b)Nanocular processors.Reprint from ref. [40] with permission from Elsevier.

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used. The larger lactose particles were rounded and the surfaces weresmoothed after the mechanofusion process. The in vitro results from aJethaler device demonstrated that the mechanofused batches pro-cessedwithMgSt achieved the highest FPF value of 42.4% compared to20.8% for the untreated batch, with a drug concentration of 2% w/w inthe mixture. The mechanofused batches without additives exhibited apoorer performance (FPF of 13.2% with 2% drug). Such improvementwas explained by the increase in similarity of surface properties ofelectron donation between drug and carrier surfaces aftermechanofusion.

However, it is interesting to note that in this study, the dispersiveenergy of the lactose carriers, measured by inverse gas chromatog-raphy (IGC) was increased after the mechanofusion with MgSt, whichin principle should strengthen the adhesion forces between drugparticle and lactose surfaces. In a further study, Kumon et al. [42] alsodemonstrated that the width of the distribution of adhesive forcesbetween drug particle and carrier surfaces was reduced aftermechanofusion. It was proposed that the improvement in DPIperformance after this mechanofusion processing was due to boththe increase in surface energy and the reduction in range of adhesiveforces on the lactose surfaces. However, such observations ofincreased surface energy could also be due to the limitation of theinfinite dilution method used for the IGC surface energy measure-ment. For IGC surface energy measurement at infinite dilution, onlyvery small proportions of the surface, namely the highest energy sites,are examined. Thus, the surface energy values measured at infinitedilution may not represent the properties of the majority of thesurfaces [43,44]. It was also shown that the surface dispersive energyof a mixed salbutamol sulfate powder with MgSt decreased when theIGC measurement was extended to a higher coverage on the samplesurfaces at finite dilution [45]. In a more recent study, the surfaceenergy of the mechanofused fine lactose powder with MgSt wasmeasured using IGC under finite dilution conditions. The results hereinstead indicated substantial reductions in dispersive energy for themajority of the lactose surfaces after mechanofusion, although a high

dispersive energy was demonstrated at infinite dilution [46]. Thisindicates that the mechanofusion processing may create a very smallproportion of lactose surface area with a high energy, possibly due tothe intensive interactions during the surface processing. However, themechanofusion appears to decrease the energy of the majority of thehost particle surface area by covering most high-energy sites with thelower surface energy coatingmaterial. These IGC data at finite dilutionare also in good agreement with the observations that the cohesiveforces are substantially reduced and the powder flowability issubstantially improved for fine particles after mechanofusion treat-ment [47].

Zhou et al. [47] showed that the flowability of a fine lactosepowder, Pharmatose 450M (VMD approximately 20 μm), improvedfrom “poor flow” to “free-flowing” characteristics after mechanofu-sion with 1% w/wMgSt. There was no apparent change in particle sizewhile the particles were rounded and the surfaces were smoothed,which was in good agreement with previous observations (Fig. 5)[34]. These modifications in particle shape and morphology may bedue to the attrition or plastic deformation occurring as a result of highshear and interaction process [48]. Interestingly, the improvement inflow after dry coating with MgSt was greater than with standardglidant, fumed silica, for this fine milled lactose powder. A nearcomplete nano-scale ultra-thin layer of MgSt was demonstrated asformed on the lactose particle surface after dry coating using XPS andToF-SIMS (see Section 3.4) [49,50]. Such a coating layer is claimed toreduce the attractive forces between particles and, thus, decrease thepowder cohesion improving the powder flow. It is also shown that theimprovement in powder flow after surface coating is mainlyattributed to the modification of surface chemical properties ratherthan the changes of surface morphological properties [51]. A furtherstudy demonstrated that the dry coating process with MgSt not onlyimproved the powder flowability but also the fluidization (asmeasured by a Freeman FT4 powder rheometer, Freeman Technology,UK) and de-agglomeration (measured by real-time laser diffraction)behavior of model fine milled lactose powders [39]. The fluidizationand de-agglomeration behavior of the coated powders appearedmoreconsistent under the varying air flow rates, indicating the aerosoli-zation is less dependent on the air flow and therefore, giving a morestable performance. The aerosolization performances of a range ofmicronized drug powders from aMonohaler were also indicated to beimproved significantly after the mechanofusion with 5% MgSt [40].The dispersion behaviors of coated drug particles from the binary DPIformulations containing similar mechanofused fine lactose carriershave been reported [38], indicating that coated fine lactose powderswith free-flowing characteristics are promising candidates acting ascarriers for DPI formulation, given that a free-flowing carrier withrelative smaller sizes is perceived as desirable for a binary DPIformulation [18].

3.2.2. Theta-composerThe Theta-composer is an alternative type of mechanical dry

coating technique. It consists of a faster (approximate 500–3000 rpm)inner elliptical rotor and a slower outer elliptical vessel (approximate30 rpm) [35]. The rotor and the vessel rotate in the oppositedirections, forcing host and guest particles mixtures pass the smallclearance between the vessel and the rotor by high shear andcompression stresses (Fig. 6). Hence the process may provide similaroutcomes to the mechanofusion style approach described above.

Iida et al. have reported the use of Theta-composer for coatinglactose (Pharmatose 200M, VMD approximately 70 μm) with sucrosetristearate for DPI formulations [52]. The surfaces of the lactoseparticles were smoother after the processing indicated as a decreasein measured surface area. The respirable particle percentage (RP)values of the resulting formulations containing salbutamol sulfatefrom a Jethaler increased from 17.4% for the untreated lactose batch to46.8% for the lactose processed with 10% w/w sucrose tristearate as a

Fig. 5. SEMmicrographs of a) untreated; b) mixed with MgSt; c) mechanofused with MgSt; d) mixed with FS; e) mechanofused with FS; f) mechanofused without additives batchesof lactose samples at magnification of 3500×.Reprint from ref. [47] with permission from John Wiley and Sons.

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FCA with an increase in sucrose tristearate concentration. A furtherstudy concluded that the RP increased with an increase in processingspeed although the differences appeared unlikely to be significant[53]. Significant increase of RP was also observed for the DPI formu-

lation containing micronized salbutamol sulfate and dry coatedlactose carrier with MgSt using a Theta-composer [54]. The coatingprocess with MgSt as a FCA was demonstrated to increase the contactangle of lactose due to the hydrophobic nature of MgSt and hencemay

Fig. 6. Schematic of Theta-composer.Reprint from ref. [35] with permission from Elsevier.

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reduce the influence of high humidity on the aerosol performance[54].

The effect of surface coating, but of a micronized drug, pranlukasthydrate, with hydrophilic colloidal silica (AEROSIL® 200, VMD 16 nm)has been reported using a Theta-composer [55]. The RP increasedsignificantly after the surface modification but only greater than thespray dried batch at the silica concentration of 5%. The use of colloidalsilica for the inhalation, as alluded to earlier, may also bring theconcerns in lung toxicity [16].

Other mechanical dry coating techniques such as the Hybridizer[56,57] and Magnetically Assisted Impaction Coater (MAIC) [58,59]have also shown their ability to engineering particles for the featuredpurposes, although reports of their use to engineer lactose carriers forDPI were not found.

3.3. Other coating strategies

Alternative non-solvent based strategies to surface coating includemethods to condense material onto a surface from the vapor phase.One of the more innovative approaches for surface treating finelactose particles, employed a plasma vapor deposition approach toprovide a siloxane surface coating from a plasma downstream reactor[60]. But the use of Siloxane is likely to raise lung toxicity issues. Priorto this, surface coating of particles has been suggested via thecondensation of the volatile amino acid, L-leucine, onto drug or carrierparticles [61,62].

3.4. Characterization of the coating quality

Appropriate characterization of the coating quality on the particlesurfaces formed froma suitable coating process is critical for the processcontrol, process optimization and understanding the influences ofsurface coating on the bulk powder behavior. Such characterization is amajor challenge especially when precise quantification of the coatingquality is required. This ismainly due to: (1) the coating could be a verythin film or layer (as thin as a few nano-meters) and (2) a thin coatingfilm or layer is on the surface of complex-shaped micron-scale particle.Thus, the appropriate characterization tools should not only have theability to accurately capture the information of the thin coating layer,but also require the high spatial resolution as the subject particles arerelatively very small.

In early studies, energy dispersive X-ray (EDX) analysis was usedto characterize the distribution of lubricant on the particle surfacesafter traditional blending MgSt with coarse subject particles [63,64].When combined with scanning electron microscopy (SEM), EDX canprovide qualitative chemical information of the particle surfaces [63].Nevertheless, unpublished attempts to detect a thin layer of MgSt ofthe mechanofused lactose samples using EDX have not beensuccessful and not reported due to the extremely low Mg contenton the mechanofused particle surfaces and the insensitivity of themethod used. In addition, EDX has a corresponding depth ofapproximately 1–2 μm [65]. As the coating layer is likely to be much

thinner than 1 μm, the information detected will not only come fromthe coating but also from the host particles beneath the coating layer.

Raman microscopy is another potential candidate for characteri-zation of dry coating layers. With a mapping technique, both spectraland spatial information of the measured sample can be obtained.Therefore, this technique provides measurement on both thechemical and morphological character of the target materials aswell as the distribution of such properties in two or three spatialdimensions [66]. However, Ramanmicroscopy usually has a relativelylow spatial resolution of a few micro-meters [67,68]. For the lactosecarrier particles with sizes smaller than 100 μm, this spatial resolutionmay not provide useful distribution information on the coating layers.Furthermore, the irradiation depth of the Ramanmicroscopymay alsobe greater than 1 μm.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is ananalytical technique used to image and record organic and inorganicmass spectral data of solid material surfaces. This is a highly sensitivetechnique that provides chemical information regarding elemental,isotopic and molecular structure from the upper surface struc-ture [69,70]. The chemical information can be collected only fromthe top one or two molecular layers of the particle surfaces [70].Moreover, ToF-SIMS providesmapping of chemical compositions withrelatively higher spatial resolution of 20–100 nm, compared with EDXand Raman. Thus, ToF-SIMS is considered a promising technique toprobe the surface coating quality [71]. In pharmaceutical area, ToF-SIMS has been used to characterize coating of tablets, granules orpellets [68]. However, ToF-SIMS only provides qualitative or semi-quantitative chemical information.

X-ray photoelectron spectroscopy (XPS) may also provide usefulchemical information regarding the surface as a result of coating. XPSis a spectroscopic technique that measures the elemental composi-tion, empirical formula, and to some extent chemical state andelectronic state of the elements that exist on the material surface [72].With XPS the chemical information is obtained from the top layer(typically 2–10 nm) of the material surface being analyzed. Thus, thechemical information collected from XPS is only related to theirsurface properties. Unlike ToF-SIMS, the results obtained from XPS aremore quantitative as the composition ratio of each component on thesurface can be calculated from the ratio of each element. Therefore, ithas been popular in characterizing thin coating films [73–76].

There is a lack of literature regarding the appropriate character-ization of the quality of the coating layers generated by mechanicaldry coating approach on fine pharmaceutical particles. Green et al.[49] briefly reported the examination of coating layers produced bymechanofusion on micronized pharmaceutical drug and excipientpowders. The study confirmed the existence of the coating film ofmagnesium stearate on the fine particle surface by XPS and Ramanmicroscopy, but detailed information on coating was not investigated.A series of recent studies reported successful characterization ofmechanical surface coating of MgSt on either the coated fine lactose orthe coated micronized drug particles [77,78]. XPS and ToF-SIMS wereemployed to characterize the coverage of the coating both qualita-tively and quantitatively. The results indicated that a near-completecoverage of MgSt on the fine particles was achieved after themechanofusion processing for 10 min. Such MgSt coating layer wassuggested to be as thin as a few nano-meters [50]. Successful char-acterization of coating quality facilitates the fundamental study of therelationship between surface coating and their bulk behavior. Theresults from the subsequent studies indicated the flow and aerosol-ization behaviors of fine particles were strongly dependent on thecoating coverage [51].

4. Discussion

Drug aerosolization from a DPI is a more complex phenomenonthan a process simply dependent on the attachment forces of discrete

Fig. 7. Diagram of an idealized view of drug adhered to lactose carrier.

Fig. 8. SEM micrograph of a more realistic drug/lactose mixture containing micronizedsalbutamol sulfate (2.5%, VMD 3 μm), Sorbolac® 400 (20%, VMD 7 μm) and Inhalac230® (77.5%, VMD 90 μm), which was mixed for 60 min at 49 rpm using a Turbula®mixer (scale bar represents 300 μm).

282 Q.(T.) Zhou, D.A.V. Morton / Advanced Drug Delivery Reviews 64 (2012) 275–284

drug from a lactose surface. Two critical events may be considered toexplain observed effects. First, the powder should be fluidized, re-suspended and carried from an inhaler device by air flow, termed hereas “entrainment” into air flow [39]. Recent work illustrated the effectof particle size and surface modification on the fluidization of finelactose particles following mechanofusion with magnesium stearate[39]. Particles as small as 10 μm appeared to be easily fluidized wherethe cohesion was substantially reduced as a result of coating. A criticalsize was identified where the lactose changes from free flowing topoorly flowing reflecting the balance of gravity forces compared tocohesion forces. Hence it was suggested that these fine lactosepowdersmight be used as fine carriers, with increased surface area fordrug attachment. However, previous work alternatively argues abenefit of increasing cohesion rather than reducing it in a fluidizationcontext, explained as a benefit of the subsequent de-agglomeration[79]. But increasing the cohesion of the powder may alternatively beviewed as a risk-prone approach as it may consequently compromisethe flow and fluidization of the powder, and make performance lessconsistent especially with variable flows. Coating both drug andlactose carriers may provide an alternative solution to facilitate bothfluidization and de-agglomeration by reducing both cohesion andadhesion in the mixture [33].

Secondly, the powder should be de-agglomerated into a suitablefine particle form during the aerosolization, often previously termedas “dispersion” (or probably more appropriate in this context, “de-agglomeration”). Thus, the performance of a DPI depends on thebalanced effect of both cohesion between drug particles as well asadhesion between drug particles and carrier surfaces. Single detach-ment measurements are generally unrepresentative of the DPIperformance as particles will experience forces from multiplesurrounding particles in contact in a real system. It has been shownthat de-agglomeration efficiency of drugs like salbutamol sulfate orbudesonide is not easily predicted from the attachment forces, andformulation performance is also strongly dependant on specificdevices used [2,80]. The fluidization and dispersion mechanismsmay be entirely different during the aerosolization of the powders foreach different inhaler device, where geometry will provide changes inairflows resulting in different experiences for each particulate entity:leading to exposure to different potential de-agglomeration mecha-nisms [81,82]. For example, it was shown that two different types ofsurface-modified DPI formulations exhibited markedly differentperformance in contrasting active and passive inhaler devices, withformulation A performing much better in passive device whileformulation B performed similarly better in the active device. Suchdifferences in aerosol performance for two coated formulations werein this case attributed to the difference in their flow properties,examined using a high speed camera [7]. Thus, the observationemphasizes that it is critical that the device should match theformulation, which allows the dispersion forces generated by/throughthe device to match with the requirements for efficient powder de-agglomeration [6]. It should also be noted that although FPF is heavilyused for the evaluation of DPI performance, this single parameter maynot fully represent the safety and efficacy of the DPI formulations [83].It provides no detail as to the size distribution of the aerosol below thespecified size cut, and this size distribution may well alter aerosoltransport and deposition behavior. Together with uniformity ofdelivered dose, fine particle dose, and/or aerodynamic particle sizedistributions, the performance of the DPI needs to be well character-ized and appropriately correlated with their in vivo performance,especially under realistic patient-use conditions such as varying airflow rates [84].

Moreover, lactose carrier-based DPI formulations rarely exist astraditional “ordered mixtures”: i.e. where it is assumed a simplestructure of fine drug stuck on the lactose surfaces, exists asrepresented in Fig. 7. The reality is quite different, with formulationshaving some drug adhered to large lactose, some to itself and some

attached to fine lactose [5]. Much of the fine material may not beattached to a large carrier at all but form agglomerates (see Fig. 8 forexample). In the literature, micronized drug particles have beendemonstrated not to be adhered on the lactose carrier surface butforming drug agglomerates in the case when the lactose carriersurface was coated with FCAs [33]. This appears simply the effect thatthe cohesive forces become dominant over the adhesive forces in adrug–carrier mixture. Thus, it may be more meaningful to examinethe balance between cohesion and adhesion rather than a singleattachment force of drug particle from carrier surface [1].

What then are the implications of the substantial reduction of theattachment force of drug to lactose in such circumstances? Clearly thepotential result can be the reduced function of the lactose as a carrier,leading to good potential fluidization but segregation problems. So,how much of a real benefit can be achieved with respect to drugrelease from such mixtures by solely pursuing modifying the lactosecarrier surface? One study has indicated that at high drug to lactoseratio, coating lactose too well may cause the formulation to segregate[33]: the drug may behave during aerosolization in a manner similarto the drug alone, and the lactose carrier may act not as a carrier, butas a fluidization aid only. A potential solution to thismay be to coat thedrug instead [33], or even both drug and lactose [38], in order tomaximize the benefit.

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It is known that the storage of some DPI formulations under somespecific conditions (such as high relative humidity, RH) may influencetheir aerosol performance [85–87]. The effect of storage on the reductionof aerosol performance was shown to be less for a hydrophobic drug,budesonide, than for a hydrophilic drug, salbutamol sulfate [88]. This canbe explained by the difference in surface interactions with moistureduring the storage for the powders with these different surfacehydrophobic/hydrophilic properties [88,89]. Blending DPI formulationswith MgSt was claimed to substantially improve the resistance toexposure to elevatedmoisture conditions [28]. Given that surface coatingprovides better coating coverage than traditional blending [31,50],surface coating is promising as an approach to protect DPI formulationsfrommoisture attack during the storage. Iida et al. also reported that thesurface coating of lactose carriers with MgSt achieved improved bothaerosol performance and reduced the influence of storage at high RH onthe aerosol performance of the DPI formulation after being stored for7 days. Such improvements in formulation stability during high RHstorage were attributed to the changes in surface hydrophobic/hydro-philic properties after coating with MgSt, a hydrophobic material [54].Stearate salts coatings have also been proposed as means for reducingchemical interactions between drug and lactose carrier surfaces [90].However, work on the long-term stability of such coatings has not beenextensively reported yet.

5. Conclusions

This paper provides a perspective on current reported attempts tocontrol of lactose cohesion (and adhesion) by surface modification.Several methodologies have been discussed. Substantial reduction in adrug attachment force to lactose has been shown after surfacemodification. In addition, improvement in fine particle fluidizationcan also be achieved by reducing the cohesion via surface modifica-tion. Furthermore, Surface coating of lactose may also hide some of itsassociated problems, especially relating to compatibility with mois-ture, with drugs and related forms of stability. The philosophy ofproviding an appropriate surface coating, on one or more componentsof a DPI formulation appears to have strongmerit, in providing a moreuniform and well suited surface energy for the process of efficient andreproducible aerosolization.

However, converting these factors into product performance isproving a far more complex issue given the performance of a DPI is notsolely dependent on the attachment force but dependent on thecombination effect of cohesion and adhesion, plus of the relationshipwith the specific storage and aerosolization conditions provided bythe device, with the physic-chemical properties of excipient, with therange of patient behaviors (especially the inhalation air flow profile),and other influences of the environment, including all the complexinter-relationships between each. In each case, the potential forsuccessful outcomes appears to be dependent on a robust under-standing of these factors, and their inter-relationship.

Acknowledgement

Qi (Tony) Zhou would like to acknowledge the financial support ofPostgraduate Publications Award from Monash University.

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