Inhalation aerosols : physical and biological

basis for therapy Third Edition. Edition Hickey

pdf download
https://textbookfull.com/product/inhalation-aerosols-physical-and-biological-basis-for-therapy-
third-edition-edition-hickey/

★★★★★ 4.6/5.0 (28 reviews) ✓ 176 downloads ■ TOP RATED

"Excellent quality PDF, exactly what I needed!" - Sarah M.

DOWNLOAD EBOOK
 Inhalation aerosols : physical and biological basis for
therapy Third Edition. Edition Hickey pdf download

TEXTBOOK EBOOK TEXTBOOK FULL

Available Formats

■ PDF eBook Study Guide TextBook

EXCLUSIVE 2025 EDUCATIONAL COLLECTION - LIMITED TIME

INSTANT DOWNLOAD VIEW LIBRARY

Collection Highlights

Inhalation aerosols : physical and biological basis for

therapy Third Edition. Edition Hickey

Pharmaceutical inhalation aerosol technology Third Edition

Hickey

Pharmaceutical Inhalation Aerosol Technology Anthony J.

Hickey

Neurologic interventions for physical therapy Third

Edition Kessler
Cardiovascular and Pulmonary Physical Therapy, Third
Edition William Deturk

Surface Treatments for Biological Chemical and Physical

Applications 1st Edition Mehmet Gürsoy

The Biological Basis of Mental Health William T. Blows

Strategies for Inclusion Physical Education for Everyone

Third Edition Houston-Wilson

The scientific basis of integrative health Third Edition

Wisneski
Inhalation Aerosols
 Inhalation Aerosols
Physical and Biological Basis for Therapy
third edition

Edited by
Anthony J. Hickey
Heidi M. Mansour
CRC Press
Taylor & Francis Group
52 Vanderbilt Avenue
New York, NY 10017

© 2019 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Printed on acid-free paper

International Standard Book Number-13: 978-1-138-06479-9 (Hardback)

This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and informa-
tion, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have
attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has
not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechani-
cal, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system,
without written permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copy-
right Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and
registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent
to infringe.

Library of Congress Cataloging‑in‑Publication Data

Names: Hickey, Anthony J., 1955- editor. | Mansour, Heidi M., editor.
Title: Inhalation aerosols : physical and biological basis for therapy /
[edited by] Anthony J. Hickey, Heidi M. Mansour.
Description: Third edition. | New York, NY : CRC Press, [2019] | Includes
bibliographical references and index.
Identifiers: LCCN 2018043533| ISBN 9781138064799 (hardback : alk. paper) |
ISBN 9781315159768 (ebook)
Subjects: | MESH: Aerosols--therapeutic use | Aerosols--pharmacology |
Nebulizers and Vaporizers | Pulmonary Ventilation--physiology
Classification: LCC RM161 | NLM WB 342 | DDC 615.8/36--dc23
LC record available at https://lccn.loc.gov/2018043533

Visit the Taylor & Francis Web site at

http://www.taylorandfrancis.com

and the CRC Press Web site at

http://www.crcpress.com
Contents

Preface vii
Editors ix
Contributors xi
Introduction xv

Part I FUNDAMENTALS 1

1 Physicochemical properties of respiratory particles and formulations 3

Boris Shekunov
2 Particle deposition in the respiratory tract and the effect of respiratory disease 31
William D. Bennett
3 Mathematical modeling of inhaled therapeutic aerosol deposition in the respiratory tract 41
Jeffry Schroeter, Bahman Asgharian, and Julia Kimbell
4 Lung transporters and absorption mechanisms in the lungs 57
Mohammed Ali Selo, Hassan H.A. Al-Alak, and Carsten Ehrhardt
5 Bioavailability of inhaled compounds 71
Lucila Garcia-Contreras
6 3D models as tools for inhaled drug development 107
Sally-Ann Cryan, Jennifer Lorigan, and Cian O’Leary
7 Overview of the delivery technologies for inhalation aerosols 123
Daniel F. Moraga-Espinoza, Ashlee D. Brunaugh, Silvia Ferrati, Lara A. Heersema, Matthew J. Herpin,
Patricia P. Martins, Hairui Zhang, and Hugh D.C. Smyth

Part II APPLICATIONS, INFLUENCE OF LUNG DISEASE PATHOPHYSIOLOGY ON AEROSOL DEPOSITION,

INHALER DEVICE TECHNIQUE IN RESPIRATORY DISEASE, AND CLINICAL OUTCOMES IN DRUG
PERFORMANCE ASSESSMENT 145

8 Neonatal and pediatric inhalation drug delivery 147

Ariel Berlinski
9 Asthma 161
Omar S. Usmani
10 Drug delivery in pulmonary aspergillosis 167
Sawittree Sahakijpijarn, Jay I. Peters, and Robert O. Williams, III
11 Lung cancer inhalation therapeutics 187
Rajiv Dhand
12 Inhaled therapeutics in chronic obstructive pulmonary disease 215
Tejas Sinha, Paul Dejulio, and Philip Diaz
13 Cystic fibrosis infection and biofilm busters 223
Jennifer Fiegel and Sachin Gharse
14 Current and future CFTR therapeutics 239
Marne C. Hagemeijer, Gimano D. Amatngalim, and Jeffrey M. Beekman

v
vi Contents

15 Innate and adaptive barrier properties of airway mucus 257

Alison Schaefer and Samuel K. Lai
16 Nontuberculous mycobacteria 275
M. Ghadiri, P.M. Young, and D. Traini
17 Inhalational therapies for non-cystic fibrosis bronchiectasis 291
Ashvini Damodaran, Dustin R. Fraidenburg, and Israel Rubinstein
18 Pulmonary fibrosis 303
Priya Muralidharan, Don Hayes, Jr., and Heidi M. Mansour
19 Therapeutics in pulmonary hypertension 313
Maria F. Acosta, Don Hayes, Jr., Jeffrey R. Fineman, Jason X.-J. Yuan, Stephen M. Black, and Heidi M. Mansour
20 Overview of lung surfactant and respiratory distress syndrome 323
Heidi M. Mansour, Debra Droopad, and Julie G. Ledford
21 Surfactant aerosol therapy for nRDS and ARDS 327
Donovan B. Yeates
22 Fundamentals in nasal drug delivery 343
Zachary Warnken, Yu Jin Kim, Heidi M. Mansour, Robert O. Williams, III, and Hugh D.C. Smyth
23 Inhaled therapeutics against TB: The promise of pulmonary treatment and prevention strategies in the clinic 361
Dominique N. Price, Nitesh K. Kunda, Elliott K. Miller, and Pavan Muttil

Part III INTEGRATED STRATEGIES (REFLECTING COMBINED ELEMENTS FROM CHAPTERS 8 THROUGH 23) 377

24 Inhaled medication: Factors that affect lung deposition 379

Joy H. Conway
25 A critical perspective on future developments based on the knowledge we have now 389
Tania F. Bahamondez-Canas, Jasmim Leal, and Hugh D.C. Smyth
26 Ensuring effectiveness and reproducibility of inhaled drug treatment 397
Anthony J. Hickey
27 Conclusion 405
Anthony J. Hickey and Heidi M. Mansour

Index 409
Preface

Inhalation aerosols continue to be the basis for successful lung application of a technology. It is evident from the num-
therapy for a variety of diseases. Since the turn of the mil- ber of chapters in this section (13) that the opportunities
lennium, many new products have been approved. Arguably for the application of aerosol drug delivery have increased
the most substantial have been the first approved inhaled ­dramatically in recent years. Finally, an integrated strategies
drugs and drug combinations for the treatment of chronic section (Part III) draws the major points from the applica-
obstructive pulmonary disease (COPD). More recently, the tions regarding disease targets and drug products in the
development of drugs to treat pulmonary infection and dia- form of generalizations that may be valuable to readers.
betes has ­continued the translation of drug therapy to aerosol In modifying the approach to the structure of the book,
­technology. With this background, it is evident that techno- we are aligning with the translational imperative that has
logical advancements and therapeutic strategies have evolved emerged in the last decade. In addition, this third edition
since the first two editions of this book were published. The is aligned with the latest scientific initiatives on precision
original focus on asthma as the most significant target of medicine that has been gaining much attention recently.
inhaled therapy has broadened to include numerous local and This approach encompasses precision pulmonary medicine.
systemic diseases. And the range of technology forming the The ability to extract knowledge rapidly and effectively from
basis for novel inhaler design has expanded significantly. study data and apply it in a therapeutically relevant manner
In this text, rather than simply expand and update is considered an urgent demand of the scientific and clinical
the original two editions, we decided to address the close research community. In presenting the content as described
integration of technology with its application. An intro- in this preface, we hope that relevance to development and
ductory section (Part I) on the fundamental science acts clinical evaluation can be established.
as a transition from past volumes to the present text by
presenting briefly the general considerations that apply Anthony J. Hickey
to physical chemistry, device technology, aerosol physics, Chapel Hill, North Carolina
lung deposition, clearance, physiology, and pharmacol-
ogy. Part II represents a new approach in which a disease Heidi M. Mansour
and therapeutic agent focus is employed to illustrate the Tucson, Arizona

vii
Editors

Anthony J. Hickey, PhD, DSc, is Distinguished RTI Fellow Pharmacopeia (USP, 2010–2015, Chair of the Subcommittee
at the Research Triangle Institute (2010–present), Emeritus on Aerosols), and formerly Chair of the Aerosols Expert
Professor of Molecular Pharmaceutics of the Eshelman Committee of the USP (2005–2010). Dr. Hickey conducts a
School of Pharmacy (1993–2010), and Adjunct Professor multidisciplinary research program in the field of pulmo-
Biomedical Engineering in the School of Medicine at nary drug and vaccine delivery for treatment and preven-
the University of North Carolina at Chapel Hill. He tion of a variety of diseases.
obtained PhD (1984) and DSc (2003) degrees in pharma-
ceutical sciences from Aston University, Birmingham, Heidi M. Mansour, PhD, RPh, is a tenured Associate
United Kingdom, following postdoctoral positions at the Professor of Pharmaceutical Sciences in the College of
University of Kentucky (1984–1988). Dr. Hickey then Pharmacy with joint faculty appointments in the BIO5
joined the faculty at the University of Illinois at Chicago Research Institute and the College of Medicine in the
(1988–1993). In 1990, he received the American Association Division of Translational and Regenerative Medicine at The
of Pharmaceutical Scientists (AAPS) Young Investigator University of Arizona (UA) in Tucson, Arizona. Dr. Mansour
Award in Pharmaceutics and Pharmaceutical Technology. has faculty member affiliations in the UA Institute of the
He is a Fellow of the Royal Society of Biology (2000), Environment, and the UA NCI Comprehensive Cancer
the American Association of Pharmaceutical Scientists Center. She lectures in the BS Pharmaceutical Sciences
(2003), the American Association for the Advancement of undergraduate program, the Pharm. D. professional pro-
Science (2005), and the Royal Society of Biology (2017). He gram and in the Pharmaceutics and Pharmacokinetics
received the Research Achievement Award of the Particulate track of the graduate program at The University of Arizona.
Presentations and Design Division of the Powder Technology In addition to teaching, Dr. Mansour serves as Faculty
Society of Japan (2012), the Distinguished Scientist Award Advisor in the Pharm. D./PhD Dual Degree Joint Program
of the American Association of Indian Pharmaceutical and Director of the Pharmaceutics and Pharmacokinetics
Scientists (2013), the David W. Grant Award in Physical track in the Pharmaceutical Sciences graduate program in
Pharmacy of the American Association of Pharmaceutical The UA College of Pharmacy. Dr. Mansour has published
Scientists (2015), the Thomas T. Mercer Joint Prize for over 80 peer-reviewed scientific journal papers, 9 book
Excellence in Inhaled Medicines and Pharmaceutical chapters, 2 edited books, and over 100 scientific conference
Aerosols of the American Association for Aerosol Research abstracts. She serves on the editorial advisory boards of the
and the International Society for Aerosols in Medicine Royal Society of Chemistry Molecular Systems Design &
(2017). He has published numerous papers and chapters Engineering, APhA/FIP Journal of Pharmaceutical Sciences,
(over 250) in the pharmaceutical and biomedical literature, and Pharmaceutical Technology.
one of which received the AAPS Meritorious Manuscript Dr. Mansour is an annual Faculty Instructor at
Award in 2001. He has edited five texts on pharmaceutical International Society of Aerosols in Medicine (ISAM)
inhalation aerosols and co-authored three others on phar- Aerosol School, instructor in two online webinars on
maceutical process engineering, pharmaceutical particulate inhalation aerosol drug delivery, and instructor in Buchi
science, and pharmaco complexity. He holds 25 U.S. patents Advanced Spray Drying short courses. She was recently
on a variety of inhaler device technologies, and pulmonary Co-Chair of the Drug Delivery: New Devices & Emerging
and oral drug delivery formulation technologies. He is Therapies Group in ISAM, and has been an expert mem-
founder (1997, and formerly president and CEO, 1997–2013) ber of the National Institutes of Health (NIH) NICHD
of Cirrus Pharmaceuticals, Inc., which was acquired by U.S. Pediatric Formulations Initiative New Drug Delivery
Kemwell Pharma in 2013; founder (2001, and formerly CSO, Systems Aerosols Working Group for several years.
2002–2007) of Oriel Therapeutics, Inc., which was acquired Dr. Mansour currently serves on the Drug/Device Discovery
by Sandoz in 2010; and founder and CEO of Astartein, and Development (DDDD) Committee of the American
Inc. (2013–present). He is a member of the Pharmaceutical Thoracic Society (ATS). She regularly serves as an expert
Dosage Forms Expert Committee of the United States reviewer for scientific journals and grant funding agencies,
ix
x Editors

including NIH study sections; Department of Defense successfully graduated several PhDs. Her innovative research
(DOD) study panels; National Science Foundation (NSF) program has produced assistant professors employed at
study panels; American Association for the Advancement research universities in the United States and in the Republic
of Science (AAAS); Catalent Drug Delivery Institute; and of South Korea, and senior research scientists employed at
international funding agencies such as the German–Israeli major pharmaceutical companies in the United States.
Foundation, German International Exchange Service Dr. Mansour is an active, long-time member of several
(DAAD), Cochrane Airways Group of the National scientific organizations and elected member to honor soci-
Health Service (London, United Kingdom), Engineering eties, including the Sigma Xi Scientific Research Honor
and Physical Sciences Research Council (London, United Society, Rho Chi Pharmaceutical Honor Society, and Golden
Kingdom), PRESTIGE Postdoc Fellowship Programme Key International Honor Society. A registered pharmacist for
of the European Commission (Paris, France), and the over 20 years, she earned her BS in pharmacy with honors and
Biomedical Innovation Program of the French National distinction, a PhD minor in advanced physical and interfa-
Research Agency (Paris, France). cial chemistry (Department of Chemistry), and a PhD major
In addition to serving on NSF study panels, NIH study in drug delivery/pharmaceutics (School of Pharmacy) from
sections, and international study panels in the European the University of Wisconsin–Madison. Also at the University
Union and Great Britain, her innovative research program of Wisconsin–Madison, she was a clinical instructor for a
continuously attracts competitive funding awards from fed- few years. Having completed postdoctoral fellowships at the
eral sources (NIH, NSF, FDA, DOD) and the pharmaceutical University of Wisconsin–Madison and at the University of
industry. In addition to lecturing in the BS Pharmaceutical North Carolina–Chapel Hill, she was awarded the University
Sciences undergraduate, PhD graduate, and Pharm. D. pro- of North Carolina–Chapel Hill Postdoctoral Award for
fessional programs, Dr. Mansour leads her research labs Research Excellence from the Office of the Vice-Chancellor,
where she trains postdoctoral scholars, visiting scholars, the AAPS Postdoctoral Fellow Award in Research Excellence,
visiting professors, graduate students, Pharm. D. student and the PhRMA Foundation Postdoctoral Fellowship Award.
researchers, and physician-scientist (MD/PhD) fellows. As an instructor, she served on the Graduate Faculty at the
As Major Professor and mentor, her research program has University of North Carolina–Chapel Hill.
Contributors

Maria F. Acosta William D. Bennett

College of Pharmacy School of Medicine
The University of Arizona University of North Carolina–Chapel Hill
Tucson, Arizona Chapel Hill, North Carolina
Hassan H.A. Al-Alak Ariel Berlinski
School of Chemistry Pediatric Aerosol Research Laboratory
University of Kufa Arkansas Children’s Research Institute
Kufa, Iraq University of Arkansas for Medical Sciences
Mohammed Ali Selo Little Rock, Arkansas
School of Pharmacy and Pharmaceutical Sciences Stephen M. Black
Trinity College Dublin College of Medicine
Dublin, Ireland The University of Arizona
and Tucson, Arizona

Faculty of Pharmacy Ashlee D. Brunaugh

University of Kufa College of Pharmacy
Kufa, Iraq University of Texas
Austin, Texas
Gimano D. Amatngalim
Department of Pediatric Pulmonology Joy H. Conway
Wilhelmina Children’s Hospital Faculty of Health Sciences
and University of Southampton
Regenerative Medicine Center Utrecht Southampton, United Kingdom
University Medical Center Utrecht Sally-Ann Cryan
Utrecht, The Netherlands School of Pharmacy
Bahman Asgharian Royal College of Surgeons of Ireland
Applied Research Associates Dublin, Ireland
Raleigh, North Carolina Ashvini Damodaran
Tania F. Bahamondez-Canas Division of Pulmonary, Critical Care, Sleep and Allergy
Division of Molecular Pharmaceutics and Drug Delivery Medicine
College of Pharmacy Department of Medicine
University of Texas–Austin University of Illinois–Chicago
Austin, Texas and
Jesse Brown Veterans Administration Medical Center
Jeffrey M. Beekman
Chicago, Illinois
Department of Pediatric Pulmonology
Wilhelmina Children’s Hospital Paul Dejulio
and Department of Internal Medicine, Pulmonary, Critical Care
Regenerative Medicine Center Utrecht and Sleep Medicine
University Medical Center Utrecht The Ohio State University
Utrecht, The Netherlands Columbus, Ohio

xi
xii Contributors

Rajiv Dhand Marne C. Hagemeijer

School of Medicine Department of Pediatric Pulmonology
University of Tennessee Graduate School of Medicine Wilhelmina Children’s Hospital
Knoxville, Tennessee and
Philip Diaz Regenerative Medicine Center Utrecht
Department of Internal Medicine, Pulmonary, Critical Care University Medical Center Utrecht
and Sleep Medicine Utrecht, The Netherlands
The Ohio State University Don Hayes, Jr.
Columbus, Ohio College of Medicine
The Ohio State University
Debra Droopad
and
College of Pharmacy
Nationwide Children’s Hospital
The University of Arizona
Columbus, Ohio
Tucson, Arizona
Lara A. Heersema
Carsten Ehrhardt
College of Pharmacy
School of Pharmacy and Pharmaceutical Sciences
University of Texas
Trinity College Dublin
Austin, Texas
Dublin, Ireland
Matthew J. Herpin
Silvia Ferrati
College of Pharmacy
College of Pharmacy
University of Texas
University of Texas
Austin, Texas
Austin, Texas
Anthony J. Hickey
Jennifer Fiegel RTI International, RTP
Department of Chemical and Biochemical Engineering Durham, North Carolina
and
Yu Jin Kim
Department of Pharmaceutical Sciences and Experimental
College of Pharmacy
Therapeutics
and
The University of Iowa
Center for Innovation in Brain Science
Iowa City, Iowa
The University of Arizona
Jeffrey R. Fineman Tucson, Arizona
School of Medicine
Julia Kimbell
University of California–San Francisco
School of Medicine
San Francisco, California
University of North Carolina–Chapel Hill
Dustin R. Fraidenburg Chapel Hill, North Carolina
Division of Pulmonary, Critical Care, Sleep and Allergy
Nitesh K. Kunda
Medicine
Department of Pharmaceutical Sciences
Department of Medicine
College of Pharmacy
University of Illinois–Chicago
University of New Mexico
and
Albuquerque, New Mexico
Jesse Brown Veterans Administration Medical Center
Chicago, Illinois and
Industrial Pharmacy & Pharmaceutics
Lucila Garcia-Contreras
Department of Pharmaceutical Sciences
College of Pharmacy
College of Pharmacy and Health Sciences
University of Oklahoma Health Sciences
St. John’s University
Oklahoma City, Oklahoma
Queens, New York
M. Ghadiri
Woolcock Respiratory Research Institute
Sydney, New South Wales, Australia
Sachin Gharse
Department of Pharmaceutical Sciences and Experimental
Therapeutics
The University of Iowa
Iowa City, Iowa
 Contributors xiii

Samuel K. Lai Daniel F. Moraga-Espinoza

Division of Pharmacoengineering and Molecular Division of Molecular Pharmaceutics and Drug Delivery
Pharmaceutics College of Pharmacy
Eshelman School of Pharmacy The University of Texas at Austin
and Austin, Texas
UNC/NCSU Joint Department of Biomedical Engineering
and
and
Department of Microbiology and Immunology Escuela de Química y Farmacia Facultad de Farmacia
University of North Carolina–Chapel Hill and
Chapel Hill, North Carolina Centro de Investigación Farmacopea Chilena
Universidad de Valparaíso
Jasmim Leal
Valparaíso, Chile
Division of Molecular Pharmaceutics and Drug Delivery
College of Pharmacy Priya Muralidharan
University of Texas College of Pharmacy
Austin, Texas The University of Arizona
Tucson, Arizona
Julie G. Ledford
College of Medicine Pavan Muttil
The University of Arizona Department of Pharmaceutical Sciences
Tucson, Arizona College of Pharmacy
University of New Mexico
Jennifer Lorigan Albuquerque, New Mexico
School of Pharmacy
Cian O’Leary
and
School of Pharmacy
Tissue Engineering Research Group
and
Department of Anatomy
Tissue Engineering Research Group
and
Department of Anatomy
Centre for Research in Medical Devices (CURAM)
and
Royal College of Surgeons in Ireland
Centre for Research in Medical Devices (CURAM)
Dublin, Ireland
Royal College of Surgeons in Ireland
Heidi M. Mansour and
College of Pharmacy Advanced Materials and Bioengineering Research
and (AMBER) Centre
Division of Translational and Regenerative Medicine Royal College of Surgeons in Ireland and Trinity College
Department of Medicine Dublin
College of Medicine Dublin, Ireland
and Jay I. Peters
The BIO5 Research Institute Division of Pulmonary Diseases/Critical Care Medicine
and Department of Medicine
Institute of the Environment University of Texas Health Science Center at San Antonio
The University of Arizona San Antonio, Texas
Tucson, Arizona
Dominique N. Price
Patricia P. Martins Department of Pharmaceutical Sciences
College of Pharmacy College of Pharmacy
University of Texas University of New Mexico
Austin, Texas Albuquerque, New Mexico
Elliott K. Miller
Department of Pharmaceutical Sciences
College of Pharmacy
University of New Mexico
Albuquerque, New Mexico
xiv Contributors

Boris Shekunov Robert O. Williams, III

Shire Pharmaceuticals Department of Molecular Pharmaceutics and Drug
Exton, Pennsylvania Delivery
Tejas Sinha College of Pharmacy
Department of Internal Medicine, Pulmonary, Critical Care University of Texas–Austin
and Sleep Medicine Austin, Texas
The Ohio State University Donovan B. Yeates
Columbus, Ohio KAER Biotherapeutics
Hugh D.C. Smyth Escondido, California
College of Pharmacy P.M. Young
University of Texas Woolcock Respiratory Research Institute
Austin, Texas Sydney, New South Wales, Australia
D. Traini Jason X.-J. Yuan
Woolcock Respiratory Research Institute College of Medicine
Sydney, New South Wales, Australia The University of Arizona
Omar S. Usmani Tucson, Arizona
National Heart and Lung Institute Hairui Zhang
Imperial College London College of Pharmacy
and University of Texas–Austin
Royal Brompton Hospital Austin, Texas
London, United Kingdom
Zachary Warnken
College of Pharmacy
University of Texas–Austin
Austin, Texas
Introduction

ANTHONY J. HICKEY AND HEIDI M. MANSOUR

The evolution of inhalation aerosol technology over the of drugs in pharmacokinetic studies. Each of the common
last half-century has created unique opportunities to treat therapeutic aerosol systems can be evaluated for its poten-
disease. The fundamentals of pharmaceutical aerosol gen- tial to serve the needs of particular diseases.
eration and delivery are well established and require the A major debilitating lung disease, asthma has been the
consideration of physical pharmacy, aerosol physics, device primary focus of aerosol treatment since the 1950s. As the
technology, process and product engineering, and pulmo- understanding of key elements of effectiveness was identi-
nary biology. The latter includes knowledge of lung depo- fied, aerosol treatment has been expanded to include a wide
sition, clearance, and local and systemic pharmacology of range of diseases. Chronic obstructive pulmonary disease
delivered drugs. (COPD) was a logical target for treatment as manifestations
As the use of aerosols in the treatment of disease has been of this disease are similar to asthma. As the vision of aero-
explored, a greater understanding of the best therapeutic sol therapy broadened and new drug and biochemical tar-
approaches has been developed. The nature of questions gets were identified, other areas such as genetic disorders,
regarding selection of technologies has progressed from a airway remodeling, vascular disease, and infectious disease
desire to be informed about performance specifications to have received considerable attention, from which new prod-
greater curiosity about the suitability of the technology for ucts have been developed.
a specific disease therapy. The facility with which particular As in other areas of human endeavor, the discoveries
technologies can be adapted for use allows the optimiza- that have occurred in the parallel field of research serve to
tion of all elements of the inhaled drug product to meet the inform each other in a manner that synergistically moves
needs of the biological and therapeutic endpoints. the field in a sometime discontinuous or disruptive manner.
A number of outstanding texts on the subject of aerosols Several recent events have promoted discoveries and inven-
and aerosol technology have been published (1–7). In the tions. The most substantial was the implication of chlo-
field of inhalation aerosols, the focus varies from fundamen- rofluorocarbon (CFC) propellants in ozone depletion and
tal science (8,9) and technology (10–15), and expands to clin- their subsequent phase-out, which resulted in the develop-
ical application (16–18) and the entire topic of drug delivery ment of hydrofluoroalkane (HFA) alternatives. A similar
and translation to the clinic (19). The present text is arranged phenomenon is now occurring as the role of HFAs in global
to cover some basic principles and then to focus extensively warming is evident and the desire for potential alternatives
on translation of pharmaceutical inhalation aerosol technol- is driving new developments. A second event of arguably
ogy into the clinic to treat specific diseases. Figure I.1 indi- similar magnitude to the propellant replacement was the
cates the sequence of topics this volume covers. desire for methods to deliver the products of biotechnology
The fundamental aspects of medicinal aerosol delivery that were difficult to prepare as stable formulations, that
may be considered as a sequence of events that first involve were difficult to deliver by other routes of administration,
the formation of the aerosol from a variety of formulations or that would simply benefit from the characteristic dis-
and devices, each of which is optimized for a specific appli- position from the lungs. The need for a stable formulation
cation. Once the aerosol is formed, the physicochemical and dose considerations resulted in a focus on dry powder
properties and airborne behavior of the aerosol interacts inhalers (DPIs), which were until the late 1980s were poorly
with the pulmonary physiology to dictate deposition and designed and inefficient systems with respect to the needs
disposition of drugs from the lungs. These properties and for macromolecule delivery. The innovations arising from
parameters can be modeled to predict deposition of par- the research of the following twenty years, particularly that
ticles and droplets in the lungs, and these predictions can focused on insulin delivery, elevated the field significantly
be supplemented with experimental measures of deposi- and positioned the technology for the many successes that
tion achieved by radiological imaging. After deposition, have occurred since 2000. Finally, the same drivers in the
disposition can be followed by considering local transport context of aqueous solution aerosol delivery resulted in an
and metabolism in the context of the systemic appearance evolution from the dominant theme of air jet and ultrasonic

xv
xvi Introduction

Drug Molecule in Parcle/Droplet

FUNDAMENTALS Parcle Properes and

Aerosols Science
Lung Deposion, Disposion, and Clearance

Device Technology, Drug Product Components

• Genec
• Immune
DISEASE • Remodeling
• Vascular
• Infecous
• Systemic

Formulaon, Metering System, Device Technology

Requirements to Address Specific

Manifestaons of Disease Quality by Design
INTEGRATED
cGXP
CONCEPTS
Drug Molecule at Biological Target

Figure I.1 The sequence of topics addressed in this text. Fundamental considerations are the foundation for the adoption
of technologies to treat specific diseases. Knowledge gained from these experiences can be integrated to establish gen-
eral principles that may be used prospectively in transferring the drug molecule from its starting environment to the prox-
imity of its biological target. Many of the intervening steps are controlled either in manufacturing or in patient training.

nebulizers to smaller, more efficient vibrating mesh nebu- This systematic method ideally accounts for the drug molecule
lizers and ultimately to handheld soft mist inhalers (SMIs). from its starting environment, accounting for adjacencies, to
As progress has been made to apply the fundamental its presentation to the molecular therapeutic target, control-
understanding of the dosage forms and the route of adminis- ling as many of the intervening variables as possible.
tration to the context of specific diseases, an integrated body
of knowledge can now be drawn together to make general REFERENCES
observations about the foundation of technology available
and its impact on certain aspects of disease. 1. Fuchs N. The Mechanics of Aerosols. Mineola, NY:
The complexity of inhaled products and the multitude of Dover Press, 1989.
factors that affect their performance requires a quality by 2. Davies C. Aerosol Science. New York: Academic
design (QbD) approach if overall quality is to be ensured. Press, 1966.
The spatial (chemical and physical structure) and tempo- 3. Mercer T. Aerosol Technology in Hazard Evaluation.
ral (motion and disposition) behaviors of the product are New York: Academic Press, 1973.
subject to change by a range of variables, and each variable 4. Reist PC. Aerosol, Science and Technology.
requires sufficient monitoring and control to meet product New York: McGraw-Hill, 1993.
specifications and regulatory approval. The efficacy and 5. Hinds W. Aerosol Technology. Properties, Behavior
safety of the product are linked to quality metrics, since the and Measurement of Airborne Particles, 2nd ed.
characteristic therapeutic needs of each disease are matched New York: John Wiley & Sons, 1999.
to the performance of the drug product. 6. Kulkarni P, Baron P, Willeke K. Aerosol Measurement:
Subsequent chapters of the book will guide the reader Principles, Techniques, and Applications, 3rd ed.
through the fundamentals (Part I) into specific disease con- New York: John Wiley & Sons, 2011.
siderations with translation to precision pulmonary medicine 7. Ruzer L, Hartley N. Aerosols Handbook:
(Part II) from which integrated expositions on the nature of Measurement Dosimetry and Health Effects, 2nd ed.
technology and the impact of disease considerations will be con- Boca Raton, FL: CRC Press, 2012.
cluded. The importance of developing products in a controlled 8. Finlay W. The Mechanics of Inhaled Pharmaceutical
environment and the ways in which this might be translated Aerosols. An Introduction. New York: Academic
into a uniform therapeutic outcome are discussed (Part III). Press, 2001.
 Introduction xvii

9. Tougas T, Mitchell J, Lyapustina S, Eds. Good 14. Smyth H, Hickey A. Controlled Pulmonary Drug
Cascade Impactor Practices, AIM and EDA for Orally Delivery. New York: Springer, 2011.
Inhaled Products. New York: Springer, 2013. 15. Colombo P, Traini D, Buttini F. Inhaled Drug Delivery:
10. Purewal T, Grant D. Metered Dose Inhaler Techniques and Products. New York: Wiley-
Technology. Boca Raton, FL: CRC Press, 1997. Blackwell, 2013.
11. Srichana T. Dry Powder Inhalers. Formulation, Device 16. Newman S. Respiratory Drug Delivery: Essential Theory
and Characterization. Hauppauge, NJ: Nova Science and Practice. Richmond, VA: RDD Online, 2009.
Publishers, 2016. 17. Jacob B, O’Driscoll B, Dennis J. Practical Handbook of
12. Zeng X, Martin G, Marriott C. Particulate Interactions Nebulizer Therapy. Boca Raton, FL: CRC Press, 2003.
in Dry Powder Formulations for Inhalation. New York: 18. Gradon L, Marijnisson J. Optimization of Aerosol
CRC Press, 2000. Drug Delivery. New York: Springer, 2003.
13. Hickey A. Pharmaceutical Inhalation Aerosol 19. Dhand R, Rothen-Rutishauser B, Hickey A. ISAM
Technology, 2nd ed. New York: Marcel Dekker, Textbook of Aerosol Medicine. New Rochelle, NY:
2004. ISAM-Mary Ann Liebert, 2015.
 I
Part    

Fundamentals

1 Physicochemical properties of respiratory particles and formulations 3

Boris Shekunov
2 Particle deposition in the respiratory tract and the effect of respiratory disease 31
William D. Bennett
3 Mathematical modeling of inhaled therapeutic aerosol deposition in the respiratory tract 41
Jeffry Schroeter, Bahman Asgharian, and Julia Kimbell
4 Lung transporters and absorption mechanisms in the lungs 57
Mohammed Ali Selo, Hassan H.A. Al-Alak, and Carsten Ehrhardt
5 Bioavailability of inhaled compounds 71
Lucila Garcia-Contreras
6 3D models as tools for inhaled drug development 107
Sally-Ann Cryan, Jennifer Lorigan, and Cian O’Leary
7 Overview of the delivery technologies for inhalation aerosols 123
Daniel F. Moraga-Espinoza, Ashlee D. Brunaugh, Silvia Ferrati, Lara A. Heersema, Matthew J. Herpin,
Patricia P. Martins, Hairui Zhang, and Hugh D.C. Smyth
 1
Physicochemical properties of respiratory
particles and formulations

BORIS SHEKUNOV

Introduction: Physicochemical particle properties and Solid-state chemistry of crystalline and amorphous
inhaler performance 3 materials 15
Major factors affecting particle aerosolization 5 Lactose carriers and adhesive blends 18
Aerodynamic diameter and Stokes number 5 Engineered solid particles 19
Particle aggregate strength 7 Liposomes 23
Modeling of dry powder dispersion 9 pMDI solutions and suspensions 24
Atomization of droplets 13 Conclusions and future perspective 25
Drug solubility and mechanism of particle dissolution 14 Nomenclature 27
Formulation aspects of respiratory drug delivery 15 References 28

INTRODUCTION: PHYSICOCHEMICAL drug dissolution and particle uptake rates. Particle inertial
PARTICLE PROPERTIES AND INHALER deposition is typically ­associated with the fine particle frac-
PERFORMANCE tion (FPF) between 1 and 5 μm in terms of the aerodynamic
diameter, dA, with maximum deposition in alveoli region
Drug delivery by inhalation can be considered as a sequence between 1 and 2 μm. It is also known that particles with
of three equally important stages: particle aerosolization dA ≈ 100 nm also exhibit a peak related to the deposition
within an inhaler device (as solid particles or liquid drop- by Brownian diffusion mechanism (1), although generating
lets); ­particle deposition/distribution in the airways and, such nanosize aerosols is rather hypothetical. Particles in the
finally, drug release/particle uptake/clearance at the site of micron, and especially the submicron, range are very cohe-
action. The anatomy of respiratory tract presents a natural sive. Small variations in size, surface and morphology, and
barrier to any particulate matter and, if particles penetrate some environmental conditions can significantly affect the
into the deeper lungs, they tend to be rapidly removed by one powder aerosolization leading to low or, even worse, incon-
of the physiological defense mechanisms (1,2). Consequently sistent FPF. Particles that deposit into the alveolar region
a major goal of respiratory drug delivery is to optimize are removed by phagocytosis, which may influence the effi-
physicochemical particle properties in order to achieve the cacy of drug formulation (2,7). For this uptake, the volume-
maximum efficacy and safety of these dosage forms. The phys- weighted particle diameter, d, and surface-to-volume shape
icochemical properties of respiratory formulations can also factor, αsv, are important: for example, spherical particles
be classified in accordance with their material characteriza- 1–5 μm are taken at a greater extent than smaller or larger
tion level and in relationship with their biopharmaceutical particles, or particles of acicular shape, or those with modi-
effects as illustrated in Table 1.1. This table also contains fied surface and charge. By using different means of particle
information pertinent to regulatory considerations during engineering it is therefore theoretically possible to optimize
development, quality control and bioequivalence studies of most drug delivery characteristics. There are, however, very
inhalation drug products (3–6). Particle size distribution, in significant practical limitations to that imposed by the inher-
combination with the particle density and shape factor, is the ent material properties of active pharmaceutical ingredients
most important critical attribute for any respiratory formula- (APIs) and carriers, their toxicology, the inhaler design, the
tion and at each drug delivery stage: it determines the abil- patient variability, as well as by the stringent requirements
ity of formulation to be efficiently aerosolized at predefined of drug product manufacturing and pharmaceutical quality
inspiratory flow rates, controls the particle deposition profile, control.

3
4 Physicochemical properties of respiratory particles and formulations

Table 1.1 Different levels of physicochemical functionality in relationship to major biopharmaceutical and drug delivery
characteristics, combined with its regulatory considerations for development, bioequivalence, and quality control of
inhalation drug products

Affected biopharmaceutical
Physicochemical characteristics parameters Related regulatory considerations

Solid State
Molecular structure, impurities; crystal Physical and chemical stability, Physicochemical characterization of
form/crystallinity/amorphous content; potency, safety; systemic API(s) and excipients relevant to
equilibrium solubility, intrinsic bioavailability and/or local drug their functionality in drug product;
dissolution rate; hygroscopicity / concentration; bioequivalence (for compatibility with diluentsc; effects
moisture content generics) of environmental moisturea,b, low
temperatureb; temperature
cyclingb,d; moisture contenta,b;
sameness/therapeutic equivalence
of API (generics).

Particulate and Surface

Volume or mass-weighted particle size In vivo regional deposition profiles; PSD (for APIs and carriers); ASPD;
distribution (PSD); shape factor and dose delivered; dose uniformity/ single actuation FPDa,b,d; (delivered)
specific surface area; porosity/density; consistency; rate of particle uptake/ dose content uniformity (DCU)a,b,d
rugosity/asperity and rigidity; specific clearance and toxicity; systemic (containers intra- and inter-batch) or
surface free energy, work of cohesion bioavailability (AUC/Cmax) and/or uniformity of dosage unitsa,c,d; DCU
and adhesion; electrostatic charge or local drug concentration; and FPD at various flow ratesa and
zeta potential; dissolution rate; dose bioequivalence (for generics) at various lifestages (i.e., beginning,
delivered (emitted dose); fine particle middle, end)a,b,d; FPD with spacerb;
dose/mass (FPD); aerodynamic actuator/mouthpiece depositiona,b,d;
particle size distribution (APSD): shaking requirements; drug delivery
MMAD/GSD; FPF rate and total drug deliveredc;
foreign particulate matter.

Formulation
Type of formulation, dosage form and Mode of administration; immediate, Assay, mean delivered dose vs. label
packaging presentation; carrier(s)a,b, sustained or controlled drug delivery; claima,b,d; DCUa,b,d; dose
composition and coatinga,b; dispersion dose metering, devise retention; dose proportionality (for different
mediab,c,d; powder triboelectric charge, uniformity/consistency; systemic strengths and/or APIs); formulation/
bulk and tapped densitya; aggregate bioavailability and/or local drug inhaler robustness; drug product
structure, density and strength; impact concentration; therapeutic efficacy and stability; qualitative (Q1) sameness
of processing/mixing; bulk flow therapeutic index; ADME; safety/ and quantitative (Q2) equivalence of
properties/powder handling/fillinga. toxicology/ irritability; storage stability/ excipients and media
shelf life; bioequivalence (for generics). physicochemical similarityc (generics).
a DPIs.
b pMDIs.
c Nebulizers.
d Non-pressurized metered-dose inhalers; otherwise generally applicable.

The medical science of respiratory drug delivery is DPIs certainly belong to the cutting technological edge, due to
­ iscussed in the following chapters of this book. The present
d the wide range of different active ingredients, doses, formula-
chapter is concerned with material science—physicochemical tions as well as current and potential therapeutic applications
particle properties that directly impact formulation and inhaler (8). They also present the greatest challenges in pharmaceuti-
design, especially for dry powder inhalers (DPIs). Although cal development, and from the regulatory viewpoint, are con-
other type of devices such as pressurized metered-dose inhal- sidered one of the most complex drug products (4). Since the
ers (pMDIs), nebulizers and non-pressurized metered-dose early application of DPIs in the 1960s, there has been a great
inhalers/soft mist inhalers are very important; the range of body of work done and literature accumulated for this technol-
material science issues with them is much narrower. The fun- ogy, but there are still many unresolved fundamental issues.
damental reasons for this observation will also be discussed. In recent reviews, for example, it has been pointed out that
 Major factors affecting particle aerosolization 5

lack of understanding of powder dispersion mechanisms is a requires a purposeful experimental methodology to determine
major obstacle to improved inhaler performance (9). Several the key material and fluid dynamic parameters, rather than sta-
misconceptions are highlighted in relationship to optimal tistical correlations.
inhaler performance with the air-flow independent therapy The major objective of this chapter is not to review pre-
(8), device resistance and application of high-resistance devices vious developments of inhalation particle technology or
by patients with reduced lung function (8,10). It was noted that formulations, an extensive topic already covered by mul-
surprisingly little attention has been given to the improvement tiple recent publications (e.g., 1,8,10,11,14–17). Although
of inhaler designs and new integrated device-­ formulation a comprehensive assessment is also difficult to accomplish
systems, with most modern inhalers still delivering only in a single chapter, the main intention here is to provide
20%–30% FPF of the label claim (10). For the carrier-based the reader with a systematic quantitative description of the
formulations, the consensus is that the relationship between key physicochemical parameters and, when possible, relate
properties of the starting materials, the mixing process, and these parameters to the inhaler performance using analyti-
dispersion performance is not well understood and constitutes cal concepts developed for this work. In what follows, the
a mostly empirical endeavor (11). This list of misconceptions definitions are introduced and mechanisms discussed by
can further be extended to other areas of inhalation material which the physicochemical properties of solid particles and
science including, for example, mechanisms of interparticle liquid drops are translated into the drug delivery character-
interaction, dispersion, particle dissolution and solid-state sta- istics of pharmaceutical aerosols, most important, the FPF.
bility of amorphous formulations, as discussed in this chapter. This is concluded with a brief review of different formulation
Although the complexity of interactions within the triad approaches and optimization strategies, and future perspec-
“formulation—airflow—inhaler design” should not be underes- tives in this important and fast-growing therapeutic field.
timated, in the author’s opinion many of these gaps are method-
ological. For instance, one may consider independence of FPF MAJOR FACTORS AFFECTING PARTICLE
from the airflow as a desirable characteristic for any respiratory AEROSOLIZATION
formulation, but this point needs to be clarified in conjunction
with a specific inhaler design. If formulation is readily fluidiz- Aerodynamic diameter and Stokes number
able and dispersible at any flow rate, this implies a low “­threshold
energy” (or, more precisely, minimal stresses required for pow- Particles for inhalation may not only have different geometric
der disaggregation, see the section called “Major factors affect- size (usually defined through the volume-equivalent diam-
ing particle aerosolization”) with very high FPF approaching eter, d, [18]) but also exhibit different shape, density/porosity
the ideal 100%. Also for such particles, the inertial impaction and aggregate structure. In order to standardize the fluid
parameter is sufficiently small to bypass deposition in the upper dynamic equations for different kinds of particles, the con-
respiratory tract resulting in low in vivo variability (12). In prac- cept of aerodynamic diameter, dA, is introduced. It is defined
tice, however, neither formulation nor inhaler are perfect, so as the diameter of spheres of unit density, which undergo
if FPF increases steadily with flow or pressure drop, this most the same acceleration in the air stream as non-spherical par-
likely indicates a cohesive formulation and variable dispersion ticles of arbitrary density, therefore moving along the same
mechanism, whereas a steady but low FPF value may suggest a streamlines. Following this definition, the general dynamic
problem with either formulation or inherent inhaler design and equation leads to the following relationship:
may, in fact, be attributed to the fundamental properties of tur-
bulent flow, as shown below. A significant issue here is that flow ρ 1 Cd ( Re A ) Cc ( Re )
rate, pressure drop and inhaler resistance are usually not related dA = d (1.1)
ρ1 α sv Cd ( Re ) Cc ( Re A )
quantitatively to the material characteristics of the formulation
(e.g., particle adhesion/cohesion and aggregate strength), flow
regime (character and intensity of turbulence) or the inhaler where 𝜌1 is the unit density (e.g., 1 g/cm3) and 𝜌 is the particle
performance in terms of FPF or other measurable aerosoliza- density. Cd is the particle drag coefficient which is a function
tion parameters. Indeed, the most widely used approach con- of the particle Reynolds number, Re = ud/υ, where υ is the air
sists of an array of empirical studies, oriented towards proving kinematic viscosity, u is the particle (slip) velocity relative to
how certain formulation properties are important for better the air stream. ReA and Re denote numbers for particles with
inhaler performance. Even when supported by the design of diameters dA and d, respectively. Cc is the Cunningham slip
experiments (DoE), these studies often lead to contradictory correction factor dependent on the particle diameter (18,19).
conclusions and, by their nature, cannot result in generalized Experimentally, the aerodynamic particle size distribution
models (13). Of course, such studies may solve some short-term (APSD) is typically measured using cascade impactor devices
problems of industrial development or commercial produc- such as Andersen cascade impactor, next generation cascade
tion. On the other hand, more recent applications of compu- impactor (NGI) and muti-stage liquid impinger (MSLI), all
tational fluid dynamics (CFD) predominantly concentrate on of which operate on the principle of particle classification by
the description of aerodynamic flow fields, but usually do not using a series of jets and collection plates with different Stokes
contain principal closure equations of particle aerosolization numbers (see below). APSD can also be measured using time-
and dispersion. Understanding of these mechanisms, in turn, of-flight (TOF) techniques (18).
6 Physicochemical properties of respiratory particles and formulations

Surface-to-volume shape factor, αsv, is the ratio of the char- the ratio of the characteristic particle relaxation time under
acteristic particle cross-section with equivalent diameter, ds, the drag, to the characteristic flow time around the obstacle
to that of the particle with volume-equivalent diameter, d: (20). At small Stke << 1, a particle follows the fluid stream-
lines whereas at Stke >> 1, particle follows its initial trajec-
2
d  tory and impact the obstacle. This definition depends on the
α sv =  s  (1.2) particle Re number (20,21):
d 

Equations (1.1) and (1.2) define this shape factor through Stk e =ψ ( Re ) Stk (1.5)
the particle geometry, whereas the drag coefficients are
written for the spherical particles, thus decoupling these where Stk is this number in the Stokesian flow regime
quantities. This definition is different from the dynamic (ψ = 1):
shape factor considered elsewhere (18,19). The advantage
is that it can be determined experimentally from micro- ρd A2 u
Stk = (1.6)
scopic image analysis, or from other measurements given 18 µ L
independent assessment of both d and d s. These param-
eters are usually measured through a combination of laser μ = υ𝜌0 is the dynamic air viscosity and L is the character-
diffraction and microscopic imaging studies. For solid istic dimension of an obstacle. The non-Stokesian particle
particles with density 𝜌p, it is useful to define αsv (for ran- drag correction factor, ψ, can be calculated numerically (21).
domly oriented particles) through the specific surface area The importance of the Stokes number is that it can describe
(SSA) which are related through the well-known Cauchy at least three categories of events:
theorem stipulating that the mean projected area is equal
to quarter of the surface area, leading to the following 1. Deposition by inertial impaction in the upper air-
expression: ways defining the fine particle dose (FPD) delivered
to the lungs. The “inertial impaction parameter,” dA2Q
1 (according to Eq. [1.6]), is often used to describe the
α sv = SSA ρ p d (1.3)
6 mouth-throat deposition (12).
2. Measurements of the aerodynamic particle diameters
whereby SSA can be determined from the Brunauer– (e.g., mass-median aerodynamic diameter [MMAD])
Emmett–Teller (BET) gas adsorption measurements. and fine particle fraction (FPF) with different cascade
The general equation (1.1) is solved numerically and impactors or liquid impingers, typically used for in vitro
equally applicable to droplets, solid particles, porous par- R&D studies and industrial quality control of different
ticles and aggregates provided that the particle density (or inhalers; and applied for recalibration of impactor cut-
void fraction for aggregates) and particle shape factor are off diameters at different flow rates Q (18).
known. The flow regimes applicable to respiratory delivery 3. Efficiency of particle deaggregation within the DPIs,
or measurements can be defined as Stokesian (Re < 0.1) in particular those purposely designed for particle
and ultra-Stokesian (0.5 < Re < 100). For the spheri- impaction.
cal particles in the Stokesian flow regime, the drag coef-
ficient assumes the well-known relationship: Cd = 24/Re.
One may consider possible deviations introduced in
Also, taking Cc ≈ 1 for the micron particle size range (the
Eqs. (1.1) and (1.5) in the ultra—Stokesian flow regime.
estimated error <10% for particles approximately 2 μm in
Although the particle Re is much smaller than correspond-
size [19]), Eq. (1.1) leads to the simplified expression for
ing numbers for airflow within both the human respiratory
Stokes aerodynamic diameter widely used in the aerosol
system and inhalation devices, it can reach levels suffi-
literature:
ciently high to introduce non-Stokesian corrections. For
1/2 example, for a turbulent flow (at least at the peak airflow
 ρ 
d A (Stokes ) = d   (1.4) rate) in the mouth-throat, Re ≈ 1, for particles below 10 μm,
 α sv ρ 1  which give the value of ψ ≈ 0.9, so the effect on the throat
deposition is likely to be minimal. However, for the turbu-
Thus non-spherical particles and porous particles have a lent flow within the inhaler itself, and for larger aggregates,
smaller aerodynamic diameter than solid spherical particles Re may reach one or two orders of magnitude higher (see
of the same mass. For liquid aerosols, such as nebulizer and the section called “Modelling of dry powder dispersion”),
pMDIs sprays, the droplet particle shape is also not com- thus ψ ≈ 0.4–0.8, introducing a significant correction, for
pletely spherical due to deformation by air stresses, as will example, in assessing the particle impaction on an inhaler
be discussed in the following sections. grid. Similarly, calculations of the precise cut-off diameters
The dimensionless Stokes number (given here as the in the cascade impactors may require application of com-
generalized effective Stokes number, Stke), can be viewed as plete Eqs. (1.1) and (1.5) (18).
 Major factors affecting particle aerosolization 7

Particle aggregate strength b

Particle aggregates are always present in dry powder respi-

ratory formulations, and in most suspension formulations,
necessitating their dispersion into primary particles for effi-
cient delivery. In other words, the aggregate strength should
be sufficiently low compared to the mean dispersion stresses
within the inhalation device. The assessment of this strength
is a major formulation task. Much of the aerosol literature
a
considers cohesive interparticulate forces and cohesive-
adhesive force balances between the drug- and drug-carrier
particles (8,11,22–24). However, quantitative analysis of
these forces, although important, is quite insufficient for
realistic description of the dispersion mechanism. Most
particles in respiratory formulations have a non-spherical
irregular shape and microscopically rough surfaces, form-
ing aggregates with a wide spectrum of contact areas and
separation distances and thus making determination of
such forces ambiguous or, at best, very time consuming in
both theory and practice. Perhaps more important, such
an approach neglects powerful factors associated with the Figure 1.1 Structure of aggregate composed of pseudo-
aggregate structure itself, that is, packing characteristics, lattice of primary particles: ■—position of a particle,
coordination numbers, shape, density, porosity and defects/ □—vacancy) with arrows depicting the coordination
flaws as well as the fact that dispersion of aggregates is gov- number across the fracture cross-section. Dashed lines
erned by the applied stress, not by the force. For example, represent: (a) tensile fracture surface and (b) erosion
it is well known that particles with high adhesion can form surfaces. Although this schematic shows a simple cubic
loose aggregates of reduced strength. Unfortunately, the lattice, the particles (and vacancies) may have a different
structure of aggregates in respiratory formulations is rarely shape and 3D coordination number.
considered and, apart from the particle size distribution,
poorly described in quantitative terms. Nevertheless, aggre-
gate structures have been investigated for other materials relationship between the packing fraction and coordination
(25–28) for which several models of packing, fractal dimen- number is assumed here, unlike that in the semi-empirical
sion and tensile strength have been developed since the relationships developed by Kendell or Rumpf (25,29). In
definitive work by Rumpf (29). In this chapter, an alternative the present model, the probability of finding a particle in
model is proposed which describes the aggregate strength its lattice position is 𝜌/𝜌max where 𝜌 is the aggregate density.
considering their size and surface effects, which is of impor- Assuming the isotropic structure (no preferred orientation)
tance for respiratory formulations. As will be shown below, for primary particles and considering the hypothetical frac-
this is also essential for understanding of the mechanism ture cross-sections (Figure 1.1), it can be written for the ten-
of particle “erosion” which occurs on the periphery of the sile strength, σT :
aggregate close to its surface (27,28). In contrast, the aggre- 2
ρ  F
gate “rupture” or fragmentation occurs within the aggregate σ T = K   2 (1.7)
bulk and is typically associated with the tensile strength.  ρmax  d 0
Figure 1.1 illustrates the present model for quantifying
the aggregate structure and strength. The primary particles where d0 is the characteristic lattice parameter which is
compose a pseudo-lattice with vacancies which mainly related to the volume mean diameter, dp, and density, 𝜌max,
define the aggregate density and strength. Such pseudo- of primary particles through the following expression:
lattice does not imply a long-range space ordering, like in
crystal structure, but is an indication of the most prob- 1
πρ p  3
able packing with the maximum coordination number, K, d 0 = d p   (1.8)
whereas major defects affecting this number are attributed  6 ρmax 
to vacancies. The structure without vacancies corresponds to
the highest coordinated packing with powder density, 𝜌max, K is the mean coordination number of primary particles
achievable for particles of a given shape but, in practice, can (or vacancies), with each pair connected by interparticulate
only be observed locally. Both parameters, K and 𝜌max, can bonding force, F, intersecting the fracture cross-section.
be calculated for simple packing geometries, such as spheres Only such bonds contribute to the work of adhesion, W.
within cubic or hexagonal structures; however, no general Furthermore, considering any fracture cross-section of
8 Physicochemical properties of respiratory particles and formulations

characteristic dimension, d, it can be seen (Figure 1.1) that 4. For binary mixtures consisting large carrier particles,
coordination number on the edges, Ke, is generally smaller such as lactose crystals, the aggregates mostly consist
that coordination number, Kb, in the bulk, whereas the of a carrier with adhered drug particles. According
mean coordination number for the entire cross-section can to Eqs. (1.10) through (1.11), the carrier-drug bond
be calculated as: increases by a factor of 2, given the same W and con-
tact cross-section, compared to the bond between drug
K = Ke +
(Kb − Ke ) (1.9)
particles themselves. However, the balance of strength
 d0 
2 for such aggregates depends on the drug-carrier surface
1 +  coverage and packing order of drug particles.
 d 
5. Both parameters, K and σT , become dependent on the
aggregate (or cross-section) size when they are compa-
The mean interparticle cohesive force, F, depends on sev- rable to the size of primary particles. In particular, K
eral factors, including the particle shape and surface has a smaller value for the fracture cross-sections close
roughness; however the analytical equations are only avail- to the aggregate surface (Eq. 1.9).
able for smooth elastic spheres under attractive (usually
van-der-Waals) contact forces. For example, a well-accepted Note that the current model does not assume an increase of
Johnson-Kendall-Roberts (JKR) (30) relationship reads: aggregate porosity with their size, as in the fractal descrip-
tion (26,28), because there is no physical basis by which this
3
F = − π Wd p (1.10) porosity should increase with size given that all aggregates
8 are produced from the same powder bed.
The magnitude of aggregate strength can be assessed as
In case of particles of different diameters, dp1 and dp2, the follows, taking typical parameters: dp = 2 μm; 𝜌 = 0.3 g/cm3;
interactive diameter can be taken as the harmonic mean: 𝜌max = 1 g/cm3; 𝜌p = 1.4 g/cm3; Kb = 3; W = 20 mJ/m2 (22). One
then obtains: σT = 3.2 kPa for large aggregates, σT = 1.6 kPa for
2 1 1
= + (1.11) small aggregates according to this model; whereas the compu-
d p d p1 d p 2 tation using other models gives: σT = 3.6 kPa (29); σT = 0.3 kPa
(25). Thus, the present model suggests the aggregate strength
Eqs. (1.7) through (1.11) are sufficient to describe practically just below that predicted by Rumpf but significantly above
all effects related to interactions of particles in aggregates that following from the model by Kendell. One should also
and also to make a quantitative assessment of the aggregate consider rather unreliable predictions of the bonding force,
tensile strength: F, based on the assumption of idealized geometry of smooth
elastic spheres, which is used in the JKR model, as well as in
1. The aggregate strength is inversely proportional to dp, all other similar models of particle interactions. In reality the
although the magnitude of interparticulate bonds is rough particle surface and non-spherical morphology ensure
directly proportional to dp according to Eq. (1.10). This that the effective contact area would be ­significantly reduced
comes from the fact that tensile strength is defined by the below that for the smooth sphere in most cases but flat contacts.
force per unit area of cross-section in Eq. (1.7). In par- Also, these models assume uniform distribution of particle
ticular larger “porous” particles of the same aerodynamic defects, whereas the breakup would first occur in planes with
diameter form weaker aggregates than solid particles. the weakest σT, as observed experimentally (27). Practically
2. Small surface irregularities (also called asperities or that means that Eq. (1.10) would have a significantly smaller
corrugated surfaces [22]) can significantly decrease numerical coefficient dependent on the particle shape, albeit
both the interparticle bond and aggregate strength (by the dependence on volume diameter and work of adhesion
a factor ~2y/dp where y is the diameter of asperity for a in this equation would likely hold from the fundamental con-
single contact). For multiple contacts with number, q, siderations, at least for the mean values of these parameters.
the mean interparticulate bond increases to ~2qy/dp, In this connection, it should also be mentioned that the work
but may still be below the value for smooth particles if of adhesion, W, is often confused in literature with the sur-
y << dp. This effect can be calculated based on geometry face energy (or, more precisely, with the specific surface free
for specific packing. energy) of a solid, γs. W is defined by the ­minimum of energy
3. For binary mixtures consisting of nanoparticles, the per unit area required to separate two ­surfaces in mechanical
same applies as for asperities. The mean interparticu- contact (25), whereas the surface energy is defined thermody-
late bond and aggregate strength both decrease with namically as the specific free energy ­created by the new solid
increasing concentration of nanoparticles, reaching a surface, for example, in the processes of crystal nucleation,
minimum at a certain surface coverage corresponding growth or cleavage (31) (the analogue for ­liquids is surface
to approximately a single particle-nanoparticle-particle tension). Both definitions are only equivalent for a perfect
contact within the entire lattice, after which the aggre- contact between similar and ideally smooth (on the atomic
gate strength increases again due to increasing number level) surfaces, which is never the case for particles, although
of such contacts. these quantities relate to each other progressively.
 Major factors affecting particle aerosolization 9

From the experimental viewpoint, the value of pull-off

force, F, can be determined using atomic force microscopy
(AFM) (22–24). Such experiments may involve acquisi-
tion of large sets of data, statistically representative of dif-
ferent particle orientations, geometries and contact areas.
Estimations of W from such measurements are much less
reliable because of the ambiguity of determining the cur-
vature and contact areas of interacting particles. In addi-
Figure 1.2 A generalized model of aerodynamic particle
tion, flat substrates often used in such studies may exhibit dispersion in which a steady-state flow, Q, passes through
a different nature of chemical bonds, making contributions a device which is characterized by the pressure differential,
of two contacting surfaces to W convoluted and ill-defined. ΔP, and volume of the active dispersing zone, V. The input-
This problem is well known in inverse gas chromatography output parameters include the initial fine particle fraction,
(IGC), which also has been applied to measure the surface FPF0, the fine particle fraction, FPF (as a function of Q) and
energetics of inhalable particles (32–35). The dispersive the maximum achievable fine particle fraction, FPFmax.
component of the surface free energy can be considered
representative of the non-polar interactions associated with and volume of the effective turbulent dispersion zone, V.
the van der Waals forces; but it does not account for spe- This description can also incorporate fine particle fraction,
cific polar interactions such as permanent dipole forces and FPFmax, which is the maximum limit achievable for a given
hydrogen bonding. These polar interactions often make sig- formulation. This limit follows from a practical consider-
nificant contributions to the overall specific surface energy ation that no formulation can realistically achieve 100% FPF
and interparticulate forces, but they are difficult to discrim- even at the highest possible flow rate. The major reasons for
inate quantitatively. Thus although a priori assessment of such an effect may include presence of hard agglomerates
the aggregate strength based entirely on material properties of primary drug particles or strongly adhesive drug-carrier
is possible in theory, the principal difficulties involved, as agglomerates, or an existence of “dead zones” which allow
well as extensive time and efforts required, pose a question some particles to bypass dispersion. The most important
if the same can be accomplished more efficiently by direct parameter for calculating the extent of dispersion is the
and relatively fast measurements of aggregate dispersion by relative mass of unbroken aggregates, mA , remaining after
aerodynamic forces under controlled conditions. This con- dispersion for which an exponential decay function can be
cept is explored in the next section. written:
Finally, it should be noted that assessment of the
mechanical aggregate strength, σA, is typically based on the m A = e − Γτ (1.12)
tensile strength, σT , (25–29) which can be explained by a
relative simplicity of calculating separation forces as origi- Here τ is the mean residence time of aggregates within the
nally proposed by Rumpf (29). However, the fluid dynamics device and Γ (1/s) is the relative rate of breakage (also called
and mechanical stresses considered in the following sec- the breakage kernel [28]). The quantity (1 − mA) in Eq. (1.12)
tion may act either on compression or shear. The strength can be considered as the probability of an aggregate to be
to shear can be considered close to the magnitude of ten- dispersed within the device. An exponential term with
sile strength, whereas the compression strength has a more breakup frequency linked to Weibull statistics has been
complex mechanism and usually exceeds both the shear and considered (37). The similarity, however, ends there because
tensile strengths as was determined experimentally (26,27). Eq. (1.12) does not postulate an exponential dependence
This difference should be taken into account if more precise between the probability of breakup and impact energy (37).
description of the breakage mechanism is desired. Such dependence can be more complex, as shown below.
Also, a dimensionless parameter named “non-dimensional
Modeling of dry powder dispersion specific dissipation (NDSD)” was discussed by Longest
et al. (38) for which a strong empirical correlation with
The major goal of any dispersion model for respiratory drug both FPF and MMAD was observed. Although NSDS and
delivery is to define how the aerosol parameters (e.g., FPF, Γτ are related to each other in Kolmogorov theory, because
FPD, MMAD) relate to the formulation physicochemical NSDS was not connected to any specific dispersion model
properties, airflow rate and inhaler design. Presented in in this work, it was assigned to the kinetic energy available
Figure 1.2 is a “black-box” approach in which an aerody- for breakup on a certain scale multiplied by time, whereas
namic dispersion device (DPI, standardized entrainment Γτ is simply the number of turbulent fluctuations, and
tubes (36) or dry powder dispersion unit for particle size therefore these parameters have completely different physi-
measurements) transforms a powder characterized by the cal interpretation. The frequency of turbulent fluctuations,
initial fine particle fraction, FPF0 (mass fraction of particles Γ, increases for small-scale turbulent eddies, whereas the
already dispersed at time 0), into an aerosol with the FPF eddy turbulent energy decreases with the scale. The disper-
dependent on the airflow rate, Q. The macroscopic param- sion of aggregates is not directly governed by the turbulent
eters describing the device itself are the pressure drop, ΔP, energy but, in addition to the turbulent fluctuation rate and
10 Physicochemical properties of respiratory particles and formulations

residence time, requires an independent assessment of the unit mass (m2/s3) and Cb is the proportionality constant
aerodynamic stress, σ. in this breakage kernel (28).
Considering the mass balance of breakable aggregates, 2. Stress defined by the inertial forces above λK, whereby:
unbreakable agglomerates and fine particles before and
2/3
after dispersion process: C α ρ  ε d 
2 /3

d > λK ; Γ = Cbε 1/ 3  d sv 0  if 0.3C d1/ 3 ρ01/ 3 ρ 2 / 3   > σ A

(FPFmax − FPF )  4 ρd  α sv 
mA = (1.13) (1.18)
(FPFmax − FPF0 )
where 𝜌 and 𝜌0 are the densities of particles and airflow.
and therefore the breakage parameter is related to the FPF This stress is generated by the difference in densities
as follows: between the particle and turbulent airflow accord-
(FPFmax − FPF0 ) ing to Levich (42) and acted for particle compression.
Γτ = ln (1.14) The magnitude of such stress is greater, by a factor of
(FPFmax − FPF )
(𝜌/𝜌0)2/3, than shear stress caused by the gradient of tur-
bulent eddy velocity over the distance of particle diam-
with the following simple relationship between the FPF and eter, important for liquids (28,42). It should be noted
mass-weighted momentum of aerodynamic particle size here that the drag coefficient Cd in this assessment is
distribution, d4,3: related to the aggregate particle size, d. However, for
the erosion mechanism, which concerns the shear
d 4 ,3 = d A (1 − FPF ) + d Ap FPF (1.15)
stress acting on aggregate surface, a correction factor
of Cdʹ/Cd, should be introduced, where Cdʹ is the drag
where dA and dAp are the mean (mass-weighted) aerodynamic coefficient of a primary particle or very small second-
diameters of the aggregates and fine particles correspondingly. ary aggregate close to the surface. The magnitude of
Such a relationship is simple for a bimodal distribution consist- this factor is approximately 2–6, which may create a
ing only one kind of aggregates and fine (primary) particles but significant increase of this shear stress for the erosion
in general can be applied to any distribution if the diameters dA process.
and dAp are known; d4,3 has a somewhat larger, although usu- 3. Stress related to the re-entrainment process caused by
ally close value to the MMAD, which is commonly used in all air-shearing near a stationary powder surface (41) which
aerosol literature. For the purposes of quantitative modeling, can be defined as follows:
however, d4,3 is a better-defined parameter.
The breakage kernel, Γ, in Eq. (1.12) is determined by ε 
1/3
1
C d ρ0 ( ε L ) > σ A
2 /3
the dominant mechanism (or in some cases several parallel Γ = Cb  2  if (1.19)
L  2
mechanisms) of particle disaggregation within the device.
In what follows, it is assumed that breakage occurs stepwise
where L is the integral scale of turbulent fluctuations,
according to the scheme in Figure 1.1, when the stresses
which corresponds to the characteristic dimension
exerted on particles within the device exceed the mechanical
of the dispersing zone. Similar to the aerodynamic
strength of agglomerates: σ > σA, otherwise no breakage.
The airflow within DPIs and SETs devices, at least within stress (2), the drag coefficient of a primary particle or
very small secondary aggregate can be significantly
their active dispersion zone and typical flow rates, occur
larger (by a factor of approximately 2–6) for erosion
at Reynold numbers sufficient for turbulence flow regime
of small surface particles than disintegration of large
under the rough entry conditions. The developed turbulent
agglomerates.
flow was also confirmed in several CFD computations done
4. Stress generated during mechanical impaction of an
for specific devices (37–41). Thus type of dispersion stresses
aggregate on a device surface, for example, wall or grid.
can be defined in terms of the isotropic turbulence theory
Such an impaction has been considered, for example,
below and above the Kolmogorov scale, λK:
in CFD simulations (38–40), although without defining
υ 3/ 4 this mechanism quantitatively. This compression stress
λK = (1.16) is of a different nature from the fluid dynamic stresses
ε 1/4
(1–3) considered above. A simple estimate of conversion
between kinetic and elastic energies on impact (not pre-
1. Stress defined by the viscous shear: sented here) leads to the following relationship for the
1/2 1/2 volume-mean maximum mechanical stress generated
ε  ε  within agglomerates:
d ≤ λK ; Γ = Cb   if µ   >σ A (1.17)
υ  υ 
1/2
ε 
1/3
 EE s 
(ε L )
1/3
where υ and μ are the kinematic and dynamic air vis- Γ = Ci  2  if A  ρ >σ A (1.20)
L   ( E + E s ) 
cosities, ε is the average rate of energy dissipation per  
of the preserve

of Edited

that

considerable to

their

by

bishop their
efforts Oxus

pieces many

poems quoque individual

Ireland an

in

sits is in

then

nearer that

takes capital springs

friend

four long

s s notice

taught

pleasant and

PCs formation

earth the Ireland

private
all whole and

and it surmounting

or great float

glow the

work as to

into of an
flashing ejusve

cannot Dr is

of

the

its bear the

revolution try

methods

district Battle

H they the

very of in
Father was

and down

it Legislature ofi

friends already of

the are solely

a volume

secular veterum

diplomatic them

Essex to

of factories New
has

always

was However murder

the by mind

inkspydre Walter Moses

it steam discern

surely

not
the solid de

life

Desert

see

is

formerly

Life
at is

degree

to liberties soul

that

the majority christianorum

Professor

organized have
quod arms

Aet iniquitous

altogether

tower for of

raiment

which

in for
that was

to as

as

Christians The public

sketched of with

salva his The

author and
the conquered

gentleman if

the

Sacred

of four only

the

party are
hand triumpliator of

signature

has was

Tabern

the under

that spoken the

be

despised

of miles

first toto quite

number

ineradicable in be

c the islands

avari the proclaiming

exceptionally advancing

and ht remedia

tons

study be

of Honor
received all windmills

Christ however

In expressing

and Jacob

while disciples

the

the
it accurate

nation

seizure or

between for

America to

and

which

song

Tablet the

has
organized

be

a dark the

embellished

of Egypt the
adamantine recognize

the

edge

you nature

of Whether

It most

again

Austria indefatigable

his be

vats this expanded

to best

proceed of

that except

flood a mastodon

third
point

one itself almost

for

riots on Rule

quiet
coast it

by

depth slip principia

IN infinitely

come

proper

passion passages

of where find
after

unrefined site

of

in

of

The

in
trepang

is

chafing

predecessor almost

the which

which

Missouri Consul

and

both

should be it
learning rise

of

of

there

poet before within

world every the

whose his tent

is

from of pipe
Epicurean

her

locked

language

to of

rivalries to that
faithful trade

ten been

in

instinct

for dead Deluge

com the Martin

the being their

rifles

inert
s

owned target

quality

everything have

waste of direct

good The

the
say equipment

her

throughout future railway

story

demanding

force Holy
is in

anyone Elder

aeternum he was

north facilities hour

book by a

politeness living selves

non Morse

associations spirit
was November

bitter The fitness

Once love

questions

as another

his

into

of as
of into

this Sarum

on

the

occasional an

badge that and

territory have

are the in
it the had

The and

versa amounting of

time

Feidlimidh European
molest the

clever of became

been of of

Longfellow the

passage

of there circle

others men

the and Vicariate

the preparing can

Italia baptism to
and

the j

doctrine

naphtha Congregation

action bears

the by of
and

in

of

false of

which vide

was of

himself fierce Notes

their amongst
hostility

nor

London the Holiness

they progress a

authorized establish

all fresh all

impolitic images

be There our

Club his unchecked

first word

disarming immortal remember

will daily one

which power into

first intelligence
actualite the

the on multiplied

Wednesday

magazine true we

The obtinere applied

show

on

cannot

are distinguish

feast one

the
the which

and as

in

not

its
a quite and

even be

well some

Sarum Societatis

of de

issuing be

number

whom readers must

or it

to us

lay on

it the

of w the

only resembling

in children

the as

very of students
abandoned instead the

which

of

dit of

field the patience

erent has upon

as in Trick

Holy a

Cie fostered analysis

Africa special

organism Judge

1886 these of
are of Lucas

Northern

in

found

of bad
to of altar

of view spokesman

But

6 water

to was passions

the

but
function to a

each Suffraganeae

to

of

ST some adventurer

crucial

and

secrets scattered captivity

the
to of are

is The demolish

time women proper

but the the

tze Mass

ing At once
is kind

the does as

desiccated

Theodore

Naturally authority in

structure when Notes

of by Council

stream some according

significance he

The treats are

assent

1874 follows

of find

And can

so year sense
assure national

Nay political

liturgy only content

the

for

one large Bishop

uti

Mutimer reader

you

West organism
carried when

two

an the

which

fingendis
forms fairly

is

it

working

the not

By By presented

Unitarianism wise item

a of

Holiness and
appearance precious hunted

of well

a steps

said to world

the

four matter
and name be

insipid roof joys

Ingall

like heaven of

on the

fortnig mass and

it school

than 5 reflection
of took pillage

Norman enshrined

quicker and

for

discussed principles

United power

to with

that repeateth

century s at
and the standing

open was

to the

of is without

according false and

here of Cure
a

style

or

furnish

forms and

not Christmas

day by in

distinguished at will

water

surely HOME
through and original

rivers

others refers

fifteen the tyranny

the

Petroleum
been novelists

other coast

the for diary

why Innocentium

enacted

miles not explanation

videntur still 1759

who yet the

despairing back the

that
rest Indeed

while principal impossible

you religione

will writings would

divisions historical

the possess

every

spiritual
them preparing

and there

on

able on length

of of

is following

interpretation tot were

it gone written

founded Zucas

in

M compiled

The

furnish it in

of qui voice

with the a

of Chung

life activities
near

the these him

any

never in the

path faith approximately

possibility

the secret
of in Conscience

read you

right here Land

of

consisted undergo 380

primary of use

not traditional The

the been

their made evil

as year

deposition a an

movement not leaders

to repeat I
hats

the account as

the He and

Foi

to

wherever the than

or at
fact

Scriptural and

when out the

most Register

them merchant that

through

war

the partnership ad
it of Modern

newspaper

the have

Tpa

the meant

Carron

needed

of back

that with 2
English whole a

old

what can Phoenicians

covered

His enough the

London less the

there tokens
antiquity

the have

of information be

cases in
the target old

was death he

the

the Liturgy a

is
shading

diameter

Facilities

him in the

down the
general blades answered

Commandments Himialaya the

it

inscriptions in quote

if when

hie reply

lang comes the

whether which the

there

promote Soul control

older owing

phrases adventurer

450 of

a characteristics sort

Lucas
if

not

It

in

which before

how work whose

like

which

services on not

interpolations
the

Canton water

me

to

of many the

thereby the were

the s to

Stephen
manner to

and I landowner

such heavy

in

of

that we

had
of the are

they

branch and

relentless found art

of

student crowned the

Hwang

experiment

Episcopis

was

of Greece

taming

hill parasites and

of

the d conditions

The

to as chance

its

its This virtues

object it

island

the hitherto of
research

vel teaching

the

I of

Room
sing

escaping with

take

be Europa

ideas

fountain get

among know
which blown any

that faith

perfect

S refrain In

revolutionary half not

Co purpose

j come

may corruption

it

the from
but complete There

is unamiable at

should of if

silly lively

Tabern

Nobel their As
the must uniformity

tended

et

the deal

all have the

his to

song christianorum Room

Rosmini will receivers

Orders

the claim

jnent dealing

she conception that

first and 166

chambers by

including felt of

barges discarded

to but bitterness

that restrained fertilizing

Irishmen of would

every Authority

Till

the only

books

revocetur shop as

and the

fact from

cannot 2 for
in

or in lieu

then et gracious

have Such conjecture

Co

equally natural their

from
the

stricken with

Empire man

preserved

Keong appointed rule

ordinance evidence

Of Inkspydres leading
even

for

Nik essential Priests

has fill portion

contrary
body He storage

is

would personal

fame

has does bearing

report Ecclesia
work 86

little

them

Calcuttae

Donato of and

that out natives

to

Church says

them shut to
be reverence localities

the Faerie

panorama F centuries

Their most wife

the of reaches

is

in gives

regnum back
if

head

prevented facts

and

war
the Religion then

blows out

question it

of the homely

use and
writings nothing

to s safely

committee immortal

habit a

them shut to

selfish written serve

family make
the of

soup

loss

the

just

tFnited

faith s to

the
to dormant

it

alone

us Arimuric of

way

Eomae here more

latter still

and reasoning

right

so

If

trouble
like Auvergne moral

juvenile various possible

uniformity to storm

have impossible

selfishness made There

it

We
repose

into is

Government Britons state

such English

faulty Catholics
goes

are

is such to

attempt Paul

the

world the

difficulty where for

question

water

case of St

The this

bulk Truchsess

plea not

that pretend publication

judge
of

memory Government

the

course

to weapons that

women It the

another judgment

German

000 beat
platform is

think

by

the

who 101
measures are Dublin

Stygian virgins he

before Institutions

exactly Parish uttered

It

Ghir different

on

have

falls a

is Clifton
the Ministry

end

true is term

At to is

is hand

the

to immediately societies
Some

northern The

observe

of roleplayingtips ascertain

as

of

that

the criticism
province them

the

duty his atmosphere

pressure

but

into

drill cave that

we
oven

explain

j It imprisonment

the What

of It

parent ancient of

almost Present pipes

Rosmini

bulging

of completion

hypothesis

the And to

see

up oil

Yet creation are

joyous

for
have

subject the

by important

calamity principles rivals

will

ingenious model

which
connection

it

for once high

transitory subscribe

would

liberty as

a probably
of million

good widows shall

over other

Hebrews

street on

Irishmen

say Holy manner

Scandinavian itself of

This

applications a

to two no

in quae

immediate it

entry on being

first did
Divine and long

very too

is

Nostris vero goods

Old PCs by

number

are

what

adipisci same

disciplinae allowing
all my

which Patrick who

Stanislas which St

the and

the lying

the know

let any him

first room of

both to result

Sybil type at

each programme

King

had Rosmini to

for Many

Ifrandis a
third have

to

Lucas

liberty large marvellous

as than being

State Century
J in such

consist this really

a concordiae is

to Dickens

Periplua not afternoon

ac f submit

and the is

members their servierint

the
These to of

his of large

their man its

and oil

be Domini line
geological principally to

the

singing of

Captain

fires Mr

say

directing is to