(BQ) Part 1 book “Pulmonary drug delivery” has contents: Lung anatomy and physiology and their implications for pulmonary drug delivery, the role of functional lung imaging in the improvement of pulmonary drug delivery, formulation strategies for pulmonary delivery of poorly soluble drugs,… and other contents.
Pulmonary Drug Delivery Advances in Pharmaceutical Technology A Wiley Book Series Series Editors: Dennis Douroumis, University of Greenwich, UK Alfred Fahr, Friedrich–Schiller University of Jena, Germany ˝ Jurgen Siepmann, University of Lille, France Martin Snowden, University of Greenwich, UK Vladimir Torchilin, Northeastern University, USA Titles in the Series Hot-Melt Extrusion: Pharmaceutical Applications Edited by Dionysios Douroumis Drug Delivery Strategies for Poorly Water-Soluble Drugs Edited by Dionysios Douroumis and Alfred Fahr Computational Pharmaceutics Application of Molecular Modeling in Drug Delivery Edited by Defang Ouyang and Sean C Smith Forthcoming titles: Novel Delivery Systems for Transdermal and Intradermal Drug Delivery Edited by Ryan F Donnelly and Thakur Raghu Raj Singh Pulmonary Drug Delivery Advances and Challenges Edited by ALI NOKHODCHI AND GARY P MARTIN This edition first published 2015 ©2015 John Wiley & Sons, Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services, and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs, and Patents Act 1988 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks, or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required, the services of a competent professional should be sought The advice and strategies contained herein may not be suitable for every situation In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom Library of Congress Cataloging-in-Publication Data applied for A catalogue record for this book is available from the British Library ISBN: 9781118799543 Set in 9/11pt TimesLTStd by SPi Global, Chennai, India 2015 Contents List of Contributors Series Preface Preface Lung Anatomy and Physiology and Their Implications for Pulmonary Drug Delivery Rahul K Verma, Mariam Ibrahim, and Lucila Garcia-Contreras 1.1 1.2 1.3 1.4 1.5 1.6 Introduction Anatomy and Physiology of Lungs 1.2.1 Macro- and Microstructure of the Airways and Alveoli as It Pertains to Drug Delivery 1.2.2 Lung Surfactant 1.2.3 Pulmonary Blood Circulation Mechanisms of Aerosol Deposition 1.3.1 Impaction 1.3.2 Sedimentation 1.3.3 Interception 1.3.4 Diffusion Drug Absorption 1.4.1 Mechanisms of Drug Absorption from the Lungs Physiological Factors Affecting the Therapeutic Effectiveness of Drugs Delivered by the Pulmonary Route 1.5.1 Airway Geometry 1.5.2 Inhalation Mode 1.5.3 Airflow Rate 1.5.4 Mechanism of Particle Clearance 1.5.5 Lung Receptors 1.5.6 Disease States 1.5.7 Effect of Age and Gender Difference Computer Simulations to Describe Aerosol Deposition in Health and Disease 1.6.1 Semiempirical Models 1.6.2 Deterministic Models 1.6.3 Trumpet Models (One-Dimensional) 1.6.4 Stochastic, Asymmetric Generation Models 1.6.5 Computation Fluid Dynamics (CFD)-Based Model xiii xvii xix 2 5 6 7 8 9 10 11 11 11 12 12 12 13 13 vi Contents 1.7 Conclusions References The Role of Functional Lung Imaging in the Improvement of Pulmonary Drug Delivery Andreas Fouras and Stephen Dubsky 2.1 13 14 19 Introduction 2.1.1 Particle Deposition 2.1.2 Regional Action of Delivered Drug 2.1.3 The Role of Functional Lung Imaging in Pulmonary Drug Delivery 2.2 Established Functional Lung Imaging Technologies 2.2.1 Computed Tomography 2.2.2 Ventilation Measurement using 4DCT Registration-based Methods 2.2.3 Hyperpolarized Magnetic Resonance Imaging 2.2.4 Electrical Impedance Tomography 2.2.5 Nuclear Medical Imaging (PET/SPECT) 2.3 Emerging Technologies 2.3.1 Phase-contrast Imaging 2.3.2 Grating Interferometry 2.3.3 Propagation-based Phase-contrast Imaging 2.3.4 Functional Lung Imaging using Phase Contrast 2.3.5 Laboratory Propagation-based Phase-contrast Imaging 2.4 Conclusion References 19 20 22 22 23 23 24 24 25 25 26 26 27 28 28 29 30 31 Dry Powder Inhalation for Pulmonary Delivery: Recent Advances and Continuing Challenges Simone R Carvalho, Alan B Watts, Jay I Peters, and Robert O Williams III 35 3.1 3.2 Introduction Dry Powder Inhaler Devices 3.2.1 Overview 3.2.2 Recent Innovations in Dry Powder Inhaler Technology 3.3 New Developments in DPI Formulations and Delivery 3.3.1 Particle Surface Modification 3.3.2 Particle Engineering Technology for Pulmonary Delivery 3.4 Characterization Methods of Dry Powder Inhaler Formulations 3.5 Conclusion References Pulmonary Drug Delivery to the Pediatric Population – A State-of-the-Art Review Marie-Pierre Flament 4.1 4.2 Introduction Patient Consideration 4.2.1 Anatomy and Physiology of Children’s Lungs 36 37 37 39 43 43 44 50 52 53 63 63 64 64 Contents vii 4.2.2 Nasal Versus Oral Inhalation 4.2.3 Patient-related Factors Influencing Aerosol Deposition 4.2.4 Age and Dosage Forms of Choice 4.3 Delivery Systems for the Pediatric Population 4.3.1 Nebulizers 4.3.2 Pressurized Metered Dose Inhalers 4.3.3 Dry Powder Inhalers 4.3.4 Interfaces 4.4 Recommendations 4.5 Conclusion References 65 66 67 69 69 72 73 74 80 82 82 Formulation Strategies for Pulmonary Delivery of Poorly Soluble Drugs Nathalie Wauthoz and Karim Amighi 87 5.1 Introduction 5.1.1 In vivo Fate of Inhaled Poorly Water-soluble Drugs 5.1.2 The Pharmacokinetics of Inhaled Poorly Water-soluble Drugs Administered for Local and Systemic Action 5.1.3 Formulation Strategies for Pulmonary Delivery of Poorly Water-soluble Drugs 5.2 Co-solvents 5.3 Cyclodextrins 5.4 PEGylation 5.5 Reduction of Size to Micro-/Nanoparticles 5.5.1 Nanocrystal Suspension 5.5.2 Nanocrystals in a Hydrophilic Matrix System 5.5.3 Nanoclusters 5.6 Solid Dispersion/Amorphization 5.7 Micelles 5.8 Liposomes 5.9 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers 5.10 Conclusion References Lipidic Micro- and Nano-Carriers for Pulmonary Drug Delivery – A State-of-the-Art Review Yahya Rahimpour, Hamed Hamishehkar, and Ali Nokhodchi 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Introduction Pulmonary Drug Delivery Liposomal Pulmonary Delivery Nebulization of Liposomes Liposomal Dry-powder Inhalers Solid Lipid Microparticles in Pulmonary Drug Delivery Solid Lipid Nanoparticles in Pulmonary Drug Delivery Nanostructured Lipid Carrier (NLC) in Pulmonary Drug Delivery 88 89 92 93 93 97 99 100 101 102 103 103 106 108 110 111 114 123 124 125 126 126 128 129 131 133 viii Contents 6.9 Nanoemulsions in Pulmonary Drug Delivery 6.10 Conclusion and Perspectives References Chemical and Compositional Characterisation of Lactose as a Carrier in Dry Powder Inhalers Rim Jawad, Gary P Martin and Paul G Royall 7.1 7.2 7.3 7.4 7.5 Introduction Production of Lactose Lactose: Chemical Forms, Solid-State Composition, Physicochemical Properties Epimerisation of Lactose Analysis of Lactose 7.5.1 Powder X-ray Diffraction 7.5.2 Nuclear Magnetic Resonance 7.5.3 Infrared Spectroscopy 7.5.4 Differential Scanning Calorimetry 7.5.5 Polarimetry 7.6 The Influence of the Chemical and Solid-State Composition of Lactose Carriers on the Aerosolisation of DPI Formulations 7.7 Conclusions References Particle Engineering for Improved Pulmonary Drug Delivery Through Dry Powder Inhalers Waseem Kaialy and Ali Nokhodchi 8.1 8.2 8.3 Introduction Dry Powder Inhalers Particle Engineering to Improve the Performance of DPIs 8.3.1 Crystallization 8.3.2 Spray-drying 8.3.3 Spray-freeze-drying 8.3.4 Supercritical Fluid Technology 8.3.5 Pressure Swing Granulation (PSG) Technique 8.4 Engineered Carrier Particles for Improved Pulmonary Drug Delivery from Dry Powder Inhalers 8.5 Relationships between Physical Properties of Engineered Particles and Dry Powder Inhaler Performance 8.5.1 Particle Size 8.5.2 Flow Properties 8.5.3 Particle Shape 8.5.4 Particle Surface Texture 8.5.5 Fine Particle Additives 8.5.6 Surface Area 8.6 Conclusions References 134 135 136 143 144 145 147 150 151 152 153 156 157 158 159 163 163 171 172 172 172 173 174 177 177 178 178 182 182 184 185 187 188 188 189 189 156 Pulmonary Drug Delivery transition of lactose to undergo solid-state epimerisation to the 𝛽-anomer [88] A final ratio of 50% 𝛽:50% 𝛼 indicated that the mechanism in the solid-state is different from the epimerisation reaction pathway recorded in aqueous solution [88] A 1:1 ratio of anomers is almost never observed for spray- or freeze-dried amorphous lactose, although a broad range of anomeric ratios has been reported [36, 58–60] A key advantage of using NMR is that it allows the accurate determination of the amount of each anomer present in the lactose material [30, 80, 82] Nevertheless, there has been a lack of focus on the investigation of anomeric composition of different types of lactose commonly used in the pharmaceutical industry; therefore there is a need for a thorough assessment of the types of lactose used in pharmaceutical preparations In addition, it would appear to be important to assess whether the anomeric content can have an impact upon the stability or performance of these formulations 7.5.3 Infrared Spectroscopy Infrared (IR) spectroscopy has been extensively used in pharmaceutical research to study the physical characteristics of solid materials [82] IR provides information on polymorphism, crystallinity, drug–excipient interaction, mixing and particle sizing [82] and can also provide physical and chemical data that might be used as a control in pharmaceutical manufacturing procedures Near IR (NIR) has also been used to monitor the crystalline phase change of amorphous samples in real time The main principle of NIR is that the X–H molecular bonds of the sample absorb electromagnetic radiation between 13,000 and 4000 cm−1 depending upon the type of bond present [44] Accordingly, the frequency of radiation absorbed is specific for each type of bond Many studies have been carried out in the past using conventional IR spectroscopy employing the original ‘potassium bromide pellet method’ (Figure 7.9); however a drawback to using this method is that the sample preparation is tedious, time consuming and requires the solid material to be made into a liquid or paste With lactose as the test material, this may cause difficulties due to the epimerisation process that occurs in the liquid phase Therefore, the most recent technique of attenuated total reflection FT-IR may offer a solution to this problem The main principle of ATR involves measuring molecular vibrations and the changes that occur in a totally reflected IR beam which is in contact with the sample material [89] The major advantage is its increased speed in analysing samples and sensitivity in comparison to conventional IR methods Differences occur in the absorbance bands of the IT spectra of lactose, within the fingerprint region, particularly at 1092 and 987 cm−1 [90] These peaks are of interest, as they correlate to the hydroxyl group orientation in the 𝛼- and 𝛽-anomers of lactose [90] However, the bonds in an amorphous lactose sample absorb the radiation more strongly than its corresponding crystalline form, giving higher intensity peaks in the spectra This is due to the lack of rigid, long-range structure in the amorphous material resulting in a difference in the amount that the bonds can stretch compared to the crystal NIR also has the capacity to detect hydrates [91] and polymorphs of lactose Crystallisation and transitions have also been analysed for wholly amorphous and crystalline lactose, where an experimental detection limit of 5%w/w amorphism was reported for a study involving spray-dried lactose mixes [92] Furthermore, spray-dried lactose mixes between 0% and 10% amorphism were analysed by NIR spectroscopy and the data used to produce a calibration curve with the ability to analyse amounts of ≥1%w/w [93] In summary, NIR is a non-invasive, non-destructive technique with a rapid analysis method It also requires no reagents/solvents, and minimal sample preparation and size (though the sample must be homogeneous) Moreover, as the absorption of radiation by water, alcohol and amine bonds are high in comparison to other bonds, they are resolved from the spectra of the molecule under investigation A disadvantage of NIR is sometimes that the overlap of spectral features can occur, and this must be resolved before identification or quantification can be achieved [83] Chemical and Compositional Characterisation of Lactose 157 (a) (b) Transmittane (%) (c) (d) (e) 4000 3000 2000 1500 1000 500 Wave number (cm−1) Figure 7.9 Infrared spectra of 𝛼-lactose monohydrate (a), 𝛽-lactose (b) and anhydrous 𝛼-lactose (c) and the molecular compounds of lactose 5𝛼-/3𝛽-lactose (d) and 3𝛼-/2𝛽-lactose (e) (Source: Reproduced from [45], with permission from Elsevier) 7.5.4 Differential Scanning Calorimetry DSC is a thermoanalytical technique that is widely used in pharmaceutical industry for characterising and quantitating mixtures of polymorphs and amorphous solids and is the principal technique for determining the glass transition temperature (Tg ) of a material [73, 75, 94] It has been prominently used to investigate the change in physical and chemical properties of lactose [95–97] It has also been extensively employed in the characterisation of phase transitions of lactose, such as glass transition, re-crystallisation, melting point, oxidative/thermal stability and exothermic decomposition [31, 73, 95, 96, 98–100] 158 Pulmonary Drug Delivery −1.1 Heat Flow (W/g) −1.3 −1.5 −1.7 −1.9 −2.1 −2.3 −2.5 25 Exo Up 75 125 Temperature (°C) 175 Universal V4 5A TA Figure 7.10 A DSC trace of 𝛼-lactose monohydrate (Source: Reproduced with permission from [23]) Information on thermal behaviour plays an important role in identifying the crystalline or amorphous forms in lactose, which has a dramatic effect on stability of medicines Several studies have been conducted in regards to assessing the thermal behaviour of lactose; however the majority focus solely on amorphous lactose samples [28, 101,102] DSC offers several advantages, which include the use of a relatively small sample size and also that during analysis the samples can be crimped within an assay pan, which provides shielding from any external effect from the atmosphere Furthermore, sample preparation is not complicated and the time needed for analysis is less than h as the scans can range from to 500∘ C/min [103] DSC has specific advantages for its application to analyse crystalline and amorphous lactose, since the DSC traces of crystalline 𝛼-lactose monohydrate contain a hydrate loss peak at 140∘ C, which is absent for the amorphous forms (Figure 7.10) Therefore, this peak may be used as a defining parameter to indicate the absence of crystallinity [31] Amorphous lactose is a fragile glass former and so will produce a relatively large step change in the signal for the glass transition [38, 104] Furthermore, such lactose has a tendency to re-crystallise after the glass transition [31, 105] Thus, both these features may be used to judge whether spray-dried, freeze-dried or milled lactose is amorphous However, the disadvantage of DSC to determine the amorphous lactose content is that the melting peak contains a contribution from degradation, which complicates the interpretation of the signals [106] 7.5.5 Polarimetry Polarimetry is an analytical technique which can measure the tendency of molecules to rotate a plane of polarised light and determine their concentration in solution Molecules which rotate the plane of polarised light to the right (or clockwise) will produce a positive (+) specific rotation [𝛼]D , while molecules which rotate the plane of polarised light to the left will have a negative (−) [𝛼]D [107–109] The observed optical rotation depends on many variables such as the nature of the sample, the concentration of the optical active components of the sample, the pathlength of the flow cell, the wavelength of the light source and the temperature of the sample The specific rotation [𝛼]D is calculated as follows: [𝛼]D = OR − 100 1∗C (7.1) Chemical and Compositional Characterisation of Lactose 159 Where [𝛼]D is the specific rotation in degrees at a wavelength of sodium lamp light source 𝜆= 589 nm, OR is the observed optical rotation in degrees, l is the pathlength in dm and C is the concentration in % (g/100 mL) The specific rotation of a lactose solution changes as a function of time after initial preparation until a constant value is obtained where the anomer ratio is in equilibrium (Figure 7.11), and is reported as being 63% 𝛽:37% 𝛼 [1] The experimentally derived data can be fitted to a first-order exponential decay and the data extrapolated to zero time after mixing, i.e to the theoretical point where optical rotation might have been measured on the freshly prepared solution The fitted data can then be employed to determine the fraction of anomer present at any time point by employing a series of equations based on mass balance [30] Therefore both NMR and polarimetry can be employed to determine the chemical purity of lactose, including the measurement of the anomeric ratio of both 𝛽- and 𝛼-anomers 7.6 The Influence of the Chemical and Solid-State Composition of Lactose Carriers on the Aerosolisation of DPI Formulations The aerosolisation performance of a DPI is typically measured by the in vitro deposition that results using inertial apparatus, for example, in the next-generation impactor (NGI) (Figure 3.6), multiplestage cascade Andersen impactor (ACI) and twin- (or multi-) stage impingers [14, 110, 111] These techniques apply an air stream that is drawn through the device using an appropriately calibrated pump, during and post-actuation to mimic, in part, the process of inhalation by the patient Actuation typically involves the piercing of a capsule, or a blister, that contains the powdered formulation while air is drawn through the mouthpiece of the device [110] Turbulence within the device allows detachment of the API from the carrier particles and creates an aerosol within the air stream that is being drawn through mouthpiece The aerosolisation performance is then measured by separating 90 85 80 [α]D (degrees) 75 70 65 60 55 50 45 100 200 Time (min) 300 400 Figure 7.11 An optical rotation plot of 4% w/v 𝛼-lactose monohydrate in water (fitted to exponential decay), experimental parameters are 𝜆= 589 nm, 10 cm path length and 25∘ C; single hatch time frame when spray-drying took place; cross hatch time frame when equilibrium ratio is attained (Source: Reproduced from [30] with kind permission from Springer Science and Business Media) 160 Pulmonary Drug Delivery the API particles from this airflow on the basis of inertia and then assaying the content of the various stages and components of the apparatus and device For example, impactors use an array of nozzles at right angles to collection surfaces that induce an abrupt change in the direction of the air stream to allow separation on the basis of particle size and velocity Particles with sufficient inertia continue along their trajectory, as they are unable to follow the sudden change in airflow direction, allowing these particles to be collected on a surface or plate The smaller particles with less inertia continue to follow the air stream and pass through to the next stage of the impactor These arrays of holes or stages are arranged in descending aperture size allowing separation of the particles into different size fractions Liquid impingers operate on a similar mechanism but obviate the potential disadvantage of particle-bounce on a solid interface Thus throughout the literature, the fine particle fraction (FPF) of the API (the fraction of the emitted dose that is collected in the later impactor stages) is one of the parameters most commonly used to describe in vitro deposition and thus characterise DPI efficacy [12, 53, 112] The method used to calculate the FPF does vary, depending on the impaction technique used to measure the particle deposition and obtain the emitted dose [113] For example, in one study the FPF was defined as the ratio of the amount of API collected on stages 1–8 expressed as a fraction of the cumulative total of the API collected in the inhaler device, throat piece and all eight stages of the impactor [12] If the dimensions of the holes or nozzles are known and the method has been suitably validated, then the stages within the impactor may be directly related to the aerodynamic diameters of the particles collected The aerodynamic diameter of a particle is defined as the diameter of an equivalent spherical particle with unit density that has the identical settling velocity as the particle under investigation [114] So for a simple twin or two-stage impinger, the stage at which the FPF is determined represents a cut off in aerodynamic diameter of usually (i.e., at a flow rate of 60 L min−1 ) of 6.4 μm Particles collected downstream of this cut off, with an aerodynamic diameter equal to, or below 6.4 μm, represent the respirable dose of the API Cascade impactors and NGIs as a result of their multiple-stage construction permit the determination of particle size distributions, with the largest particles separated first followed sequentially by the smaller particles If the particle size is normally distributed then it is possible to determine the mass median aerodynamic diameter and the geometric standard deviation for the distribution of particle sizes within the aerosol generated by the DPI using log-probability plots of the cumulative mass undersize measured within the impactors’ stages [113] Particles with aerodynamic diameters below 6.4 μm or more usually, if using impactors particles within the 1–5 μm size range, have been traditionally considered as fulfilling the size requirement for inhalation therapy [12, 49] Clinical research has modified this hypothesis, by providing evidence that inhaled particles with aerodynamic diameters less than μm are likely to deposit in the alveoli and peripheral airways which is ideal for API delivery to the systemic system; this has been exploited for drugs such as insulin and nicotine [115, 116] The abundance and complex nature of the critical attributes associated with lactose carrier particles that affect the FPF and thus the APIs availability from a DPI make studying each attribute in isolation extremely difficult However, there are a number of overarching solid-state properties of lactose particles that have been clearly resolved that influence the adhesion of API particles to its surface [12] Typically, the adhesion of an API to the surface of a lactose carrier particle is related to the surface energies of both the lactose and the API [43] On a molecular scale, this is likely to be attributable in part to the orientation of the hydrogen-bonding groups at the surface of the lactose particles This in turn will be influenced by the orientation of the groups at the surface (among other factors) and therefore the 𝛼- and 𝛽-anomer content of the lactose carrier particles might be expected to affect the aerosolisation performance of a DPI [8, 13] Thus it is very clear that the forces of adhesion between the API particles and the lactose carrier are extremely important [14] The API particles must be attracted to and ‘stick’ on the carrier’s surface; however, the adhesion must not be too strong or the API will not be removed upon actuation Chemical and Compositional Characterisation of Lactose 161 and inhalation Therefore, carrier particle size is an obvious attribute to consider because a change in surface area will affect the number of available sites for API adherence For example, it has been reported that as the size of the lactose particles increased, the FPF decreased from a number of DPI formulations [117] Therefore, one possible strategy for improving DPI efficiency might be to mill the lactose carrier particles in order to reduce their size and thus increase the FPF of the emitted API However this has the potential complication of the unintentional introduction of amorphous regions [49], and as discussed earlier in this chapter the anomer ratio may also be disrupted by communition [88] Particle sizing of the lactose carrier particles, in contrast to the emitted API, is generally carried out using more conventional techniques that typically not include impactor methods, for example, scanning electron microscopy (SEM), optical microscopy, laser diffraction and time of flight spectroscopy have all be used to determine carrier particle size [118] Such characterisation cannot identify any changes in the amorphous content or the anomeric ratio even if they can determine the consequences of any changes; and thus careful characterisation of processed lactose is required A clear demonstration of the complexity and knowledge gaps associated with the processes occurring within DPI devices can be found in a more recent article [119], where it was argued that the impact of carrier physical properties on the performance of DPI devices with different dispersion mechanisms remains under-reported The latter study took account of the turbulence and collisions between carrier particles and the inhaler within the DPI devices by coupling in vitro aerosol performance and computational fluid dynamics (CFD) measurements It was concluded that the DPI device type had a major influence on the manner in which the lactose carriers performed, with respect to carrier particle size For example, using budesonide as the test API, it was shown that the Aerolizer® generated an increased number of collisions, and thus conferred a better performance, as the particle size of the lactose carrier was increased Whereas in contrast, the Handihaler® was found to induce fewer collisions overall and no change was determined in the performance as a function of lactose carrier size [119] Therefore, it is clear that both the physical properties of the carrier and also the geometry of the inhalation device must be taken into account when characterising DPI performance and that more research work is required in this field The influence of lactose particle size on DPI performance should not be considered just in terms of particles with a normal distribution of diameters, since polydisperse powders are a key feature of DPI research and medicines [120] The heterogeneity in terms of particle size of commercial grade lactose has been attributed to its success in API–carrier blends, as the inclusion of fine lactose particles appears to be required for an optimum FPF [121] The significance of lactose fines is concisely shown in one study where compressed air was employed to remove some of the fine lactose particles from the surface of larger lactose carrier particles [122] When tested using a conventional DPI device after blending with salbutamol (albuterol) sulphate, the observed FPF for the API was significantly less when compared to an identical blend containing the original commercial lactose carrier that still contained the lactose fines (defined as particles of the sugar having diameters