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AAPS Introductions in the Pharmaceutical Sciences

Ashlee D. Brunaugh
Daniel Moraga-Espinoza
Tania F. Bahamondez-Canas
Hugh D. C. Smyth
Robert O. Williams

Essential
Pharmaceutics
Second Edition
AAPS Introductions in the Pharmaceutical
Sciences

Volume 12

Founding Editor
Robin Zavod, Chicago College of Pharmacy, Midwestern University,
Downers Grove, IL, USA

Series Editor
Claudio Salomon, National University of Rosario, Rosario, Argentina
The AAPS Introductions in the Pharmaceutical Sciences book series is designed to
support pharmaceutical scientists at the point of knowledge transition. Springer and
the American Association of Pharmaceutical Scientists (AAPS) have partnered
again to produce a second series that juxtaposes the AAPS Advances in the
Pharmaceutical Sciences series. Whether shifting between positions, business
models, research project objectives, or at a crossroad in professional development,
scientists need to retool to meet the needs of the new scientific challenges ahead of
them. These educational pivot points require the learner to develop new vocabulary
in order to effectively communicate across disciplines, appreciate historical
evolution within the knowledge area with the aim of appreciating the current
limitations and potential for growth, learn new skills and evaluation metrics so that
project planning and subsequent evolution are evidence-based, as well as to simply
“dust the rust off” content learned in previous educational or employment settings,
or utilized during former scientific explorations. The Introductions book series will
meet these needs and serve as a quick and easy-to-digest resource for contemporary
science.
Ashlee D. Brunaugh • Daniel Moraga-Espinoza
Tania F. Bahamondez-Canas • Hugh D. C. Smyth
Robert O. Williams

Essential Pharmaceutics
Second Edition
Ashlee D. Brunaugh Daniel Moraga-Espinoza
College of Pharmacy University of Valparaíso
University of Michigan–Ann Arbor Valparaíso, Chile
Ann Arbor, MI, USA
Hugh D. C. Smyth
Tania F. Bahamondez-Canas College of Pharmacy
University of Valparaíso The University of Texas at Austin
Valparaíso, Chile Austin, TX, USA

Robert O. Williams
College of Pharmacy
The University of Texas at Austin
Austin, TX, USA

ISSN 2522-834X     ISSN 2522-8358 (electronic)


AAPS Introductions in the Pharmaceutical Sciences
ISBN 978-3-031-52519-3    ISBN 978-3-031-52520-9 (eBook)
https://doi.org/10.1007/978-3-031-52520-9

© American Association of Pharmaceutical Scientists 2019, 2024


Jointly published with American Association of Pharmaceutical ScientistsThis work is subject to
copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned,
specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,
reproduction on microfilms or in any other physical way, and transmission or information storage and
retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known
or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publishers, the authors, and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publishers nor the authors
or the editors give a warranty, express or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publishers remain neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

Editorial Contact: Charlotte Nunes

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Paper in this product is recyclable.


Contents

1 
Essential Pharmaceutics in the Flipped Classroom������������������������������    1
1.1 Overview of “Flipped Pharmaceutics” Course Format
and Structure ������������������������������������������������������������������������������������    2
1.2 Building the Required Foundation for Student Success
in “Flipped Pharmaceutics”��������������������������������������������������������������    3
1.3 Achieving Learning Objectives��������������������������������������������������������    5
1.4 Specific “Flipped Class” Structure—How to Implement ����������������    8
1.5 Flipped Pharmaceutics—A Pathway to Success������������������������������   10
Further Readings����������������������������������������������������������������������������������������   11
2 Overview of Biopharmaceutics and Regulatory Concepts
Relevant to Drug Product Design ����������������������������������������������������������   13
2.1 Introduction��������������������������������������������������������������������������������������   14
2.2 Utilization of Pharmacokinetic Data to Determine
Bioavailability and Bioequivalence��������������������������������������������������   17
2.3 Biopharmaceutics Classification System������������������������������������������   18
2.4 Overview of the Regulatory Pathways for Drug Product
Approval��������������������������������������������������������������������������������������������   18
Further Reading ����������������������������������������������������������������������������������������   21
3 
Preformulation in Drug Product Design������������������������������������������������   23
3.1 Introduction—Importance of Preformulation Studies
in Dosage Form Design��������������������������������������������������������������������   25
3.2 Preformulation Studies—Factors Affecting Drug
Bioavailability ����������������������������������������������������������������������������������   26
3.2.1 Solubility������������������������������������������������������������������������������   26
3.2.2 Dissociation Constant/pKa����������������������������������������������������   28
3.2.3 Dissolution����������������������������������������������������������������������������   29
3.2.4 Partition Coefficient��������������������������������������������������������������   29
3.2.5 Membrane Permeability��������������������������������������������������������   31
3.2.6 Biopharmaceutics Classification System (BCS)������������������   32
3.3 Preformulation Studies—Solid-State Characterization��������������������   32

v
vi Contents

3.3.1 Organoleptic Properties��������������������������������������������������������   33


3.3.2 Amorphous and Crystalline Morphologies��������������������������   33
3.3.3 Particle and Powder Characteristics��������������������������������������   38
3.3.4 Particle Size and Distribution ����������������������������������������������   39
3.4 Formulation Stability������������������������������������������������������������������������   40
3.4.1 Degradation by Hydrolysis ��������������������������������������������������   41
3.4.2 Degradation by Oxidation����������������������������������������������������   41
3.4.3 pH-Dependent Degradation��������������������������������������������������   42
3.4.4 Degradation by Photolysis����������������������������������������������������   42
3.4.5 Hygroscopicity����������������������������������������������������������������������   43
3.4.6 Epimerization������������������������������������������������������������������������   44
3.4.7 Arrhenius Equation and Kinetics������������������������������������������   44
3.5 Other Considerations in Preformulation Studies������������������������������   45
3.5.1 Prodrugs��������������������������������������������������������������������������������   45
3.5.2 Stereoisomers������������������������������������������������������������������������   45
Further Reading ����������������������������������������������������������������������������������������   46
4 
Capsule and Tablet Dosage Forms ��������������������������������������������������������   47
4.1 Introduction��������������������������������������������������������������������������������������   49
4.2 Capsules��������������������������������������������������������������������������������������������   49
4.2.1 Hard Shell Capsules��������������������������������������������������������������   49
4.2.2 Soft Gel Capsules������������������������������������������������������������������   51
4.3 Tablets ����������������������������������������������������������������������������������������������   51
4.3.1 Manufacturing Methods��������������������������������������������������������   52
4.4 Excipients Utilized in Capsules and Tablets ������������������������������������   59
4.5 Analytical Testing ����������������������������������������������������������������������������   61
4.5.1 Disintegration������������������������������������������������������������������������   61
4.5.2 Dissolution����������������������������������������������������������������������������   64
4.5.3 Weight Variation and Dose Content Uniformity������������������   64
4.5.4 Tablet Hardness��������������������������������������������������������������������   65
4.5.5 Friability��������������������������������������������������������������������������������   66
4.6 Formulating Poorly Water-Soluble Drugs����������������������������������������   66
4.6.1 Spring and Parachute Concept����������������������������������������������   67
4.6.2 Hot Melt Extrusion ��������������������������������������������������������������   69
4.6.3 Spray Drying������������������������������������������������������������������������   70
4.7 Physiology and Food Effects������������������������������������������������������������   70
Further Reading ����������������������������������������������������������������������������������������   72
5 
Modified Release Solid Oral Dosage Forms������������������������������������������   73
5.1 Introduction��������������������������������������������������������������������������������������   74
5.2 Delayed Release Solid Oral Dosage Forms��������������������������������������   75
5.3 Extended Release Solid Oral Dosage Forms������������������������������������   77
5.3.1 Hydrophilic Matrix Drug Delivery Systems������������������������   79
5.3.2 Insoluble Matrix Systems ����������������������������������������������������   81
5.3.3 Membrane-Controlled Release Systems ������������������������������   81
5.3.4 Osmotic Pump Systems��������������������������������������������������������   83
5.3.5 Compression Coating Systems ��������������������������������������������   84
Contents vii

5.4 Pulsatile Release Systems ����������������������������������������������������������������   86


5.5 USP Dissolution Testing for Modified-Release Dosage Forms��������   86
5.6 Dose Dumping and Alcohol Effects�������������������������������������������������   87
5.7 Abuse-Deterrent Technologies for Extended Release Opioid
Formulations ������������������������������������������������������������������������������������   88
Further Readings����������������������������������������������������������������������������������������   88
6 
Solution-Based Dosage Forms and Sterile Products����������������������������   91
6.1 Introduction��������������������������������������������������������������������������������������   93
6.2 Drug Solubility���������������������������������������������������������������������������������   93
6.2.1 Factors Influencing Solubility����������������������������������������������   94
6.2.2 Factors Influencing Dissolution��������������������������������������������   95
6.3 Excipients for Pharmaceutical Preparations ������������������������������������   96
6.3.1 Solvents��������������������������������������������������������������������������������   96
6.3.2 Antioxidants��������������������������������������������������������������������������   98
6.3.3 Chelating Agents������������������������������������������������������������������   98
6.3.4 Preservatives ������������������������������������������������������������������������   98
6.3.5 Complexing Agents��������������������������������������������������������������   99
6.3.6 Surfactants���������������������������������������������������������������������������� 100
6.4 Parenteral Route of Administration and Injectable Dosage
Forms������������������������������������������������������������������������������������������������ 101
6.4.1 Routes of Administration������������������������������������������������������ 101
6.4.2 Isotonicity ���������������������������������������������������������������������������� 103
6.4.3 pH������������������������������������������������������������������������������������������ 103
6.4.4 Syringeability and Injectability�������������������������������������������� 103
6.4.5 Long-Acting Injectable Formulations���������������������������������� 104
6.5 Lyophilization ���������������������������������������������������������������������������������� 104
6.6 Sterilization of Pharmaceutical Products������������������������������������������ 105
6.6.1 Heat Sterilization������������������������������������������������������������������ 106
6.6.2 Sterilization of Heat-Sensitive Drugs ���������������������������������� 106
6.6.3 Pyrogen Testing�������������������������������������������������������������������� 106
6.7 Packaging of Sterile Injections �������������������������������������������������������� 107
6.7.1 Labeling Requirements �������������������������������������������������������� 107
Further Reading ���������������������������������������������������������������������������������������� 107
7 Disperse Systems: Suspensions �������������������������������������������������������������� 109
7.1 Introduction�������������������������������������������������������������������������������������� 111
7.2 Properties of Suspensions ���������������������������������������������������������������� 112
7.2.1 Particle Settling�������������������������������������������������������������������� 112
7.2.2 Flocculation, Deflocculation, and Aggregation�������������������� 113
7.2.3 Rheology ������������������������������������������������������������������������������ 114
7.2.4 Electrical Charge and Zeta Potential������������������������������������ 115
7.3 Stability of Suspensions�������������������������������������������������������������������� 116
7.3.1 Particle Settling�������������������������������������������������������������������� 116
7.3.2 Particle Aggregation�������������������������������������������������������������� 116
7.3.3 Particle Growth (Ostwald Ripening)������������������������������������ 117
viii Contents

7.4 Methods of Particle Size Reduction for Suspensions ���������������������� 118


7.5 Colloidal Dispersions������������������������������������������������������������������������ 118
7.5.1 Light Scattering Properties of Colloids�������������������������������� 119
7.5.2 Kinetic Movement of Colloids���������������������������������������������� 119
7.5.3 Nanoparticles in Suspensions ���������������������������������������������� 120
7.6 Excipients Used in Suspension Formulations���������������������������������� 122
7.6.1 Suspending Agents���������������������������������������������������������������� 122
7.6.2 Surfactants���������������������������������������������������������������������������� 122
7.6.3 Flocculating Agents�������������������������������������������������������������� 125
7.6.4 Sweetening Agents and Flavors�������������������������������������������� 127
7.6.5 Other Excipients������������������������������������������������������������������� 127
7.7 Sterility and Sterilization of Dispersed Systems������������������������������ 128
Further Reading ���������������������������������������������������������������������������������������� 129
8 Disperse Systems: Emulsions������������������������������������������������������������������ 131
8.1 Introduction�������������������������������������������������������������������������������������� 132
8.2 Emulsion Types�������������������������������������������������������������������������������� 132
8.3 Routes of Administration������������������������������������������������������������������ 134
8.3.1 Oral Route���������������������������������������������������������������������������� 134
8.3.2 Topical Route������������������������������������������������������������������������ 134
8.4 Emulsifying Agents�������������������������������������������������������������������������� 134
8.4.1 Stabilization Theory�������������������������������������������������������������� 135
8.4.2 Hydrophile-Lipophile Balance��������������������������������������������� 135
8.4.3 Types of Emulsifying Agents������������������������������������������������ 136
8.5 Other Excipients�������������������������������������������������������������������������������� 138
8.6 Preparation of Emulsions������������������������������������������������������������������ 138
8.7 Colloidal Dispersions—Microemulsions������������������������������������������ 138
8.7.1 Liposomes ���������������������������������������������������������������������������� 139
8.8 Emulsion Stability���������������������������������������������������������������������������� 139
8.8.1 Aggregation and Coalescence���������������������������������������������� 139
8.8.2 Phase Separation ������������������������������������������������������������������ 140
8.8.3 Phase Inversion �������������������������������������������������������������������� 140
9 
Ophthalmic and Otic Drug Delivery������������������������������������������������������ 141
9.1 Introduction�������������������������������������������������������������������������������������� 142
9.2 Special Considerations in Ophthalmic Dosage Forms���������������������� 143
9.2.1 Sterility���������������������������������������������������������������������������������� 144
9.2.2 Tonicity �������������������������������������������������������������������������������� 144
9.2.3 pH������������������������������������������������������������������������������������������ 144
9.2.4 Ocular Bioavailability ���������������������������������������������������������� 145
9.2.5 Packaging������������������������������������������������������������������������������ 145
9.2.6 Administration���������������������������������������������������������������������� 146
9.3 Types of Ophthalmic Dosage Forms������������������������������������������������ 146
9.4 Special Considerations in Otic Dosage Forms���������������������������������� 148
9.5 Types of Otic Dosage Forms������������������������������������������������������������ 149
Further Reading ���������������������������������������������������������������������������������������� 149
Contents ix

10 
Topical and Transdermal Drug Delivery ���������������������������������������������� 151
10.1 Introduction������������������������������������������������������������������������������������ 153
10.2 Anatomy of the Skin—A Brief Review������������������������������������������ 153
10.3 Diffusion of Drug Through the Skin���������������������������������������������� 154
10.3.1 Application of Fick’s Law of Diffusion������������������������������ 154
10.3.2 Transport Through the Skin Layers������������������������������������ 155
10.3.3 In Vitro Analysis ���������������������������������������������������������������� 157
10.4 Mechanisms of Enhancing Drug Penetration Through Skin���������� 157
10.4.1 Diffusion Coefficient���������������������������������������������������������� 158
10.4.2 Partition Coefficient������������������������������������������������������������ 159
10.4.3 Degree of Drug Saturation in the Formulation ������������������ 159
10.4.4 Electrical and Mechanical Methods of Increasing
Drug Transport�������������������������������������������������������������������� 159
10.5 Topical Semi-Solid Formulations �������������������������������������������������� 160
10.5.1 Ointment Bases ������������������������������������������������������������������ 160
10.5.2 Ointment Manufacture/Preparation������������������������������������ 162
10.5.3 Gels ������������������������������������������������������������������������������������ 162
10.6 Transdermal Patches ���������������������������������������������������������������������� 162
10.6.1 Patch Design, Formulation, and Manufacture�������������������� 164
10.6.2 Drug Release from Transdermal Patches���������������������������� 165
10.6.3 Patient Counseling—Transdermal Systems������������������������ 166
10.7 Additional Excipients Utilized in Topical and Transdermal
Dosage Forms �������������������������������������������������������������������������������� 167
Further Reading ���������������������������������������������������������������������������������������� 169
11 Oral Transmucosal Delivery ������������������������������������������������������������������ 171
11.1 Introduction������������������������������������������������������������������������������������ 172
11.2 Barriers for Oral Mucosal Drug Delivery �������������������������������������� 173
11.2.1 Oral Mucosal Membrane Barriers�������������������������������������� 173
11.2.2 Residence Time and Dilution���������������������������������������������� 174
11.2.3 Other Barriers and Considerations�������������������������������������� 174
11.3 Methods of Oral Transmucosal Administration������������������������������ 175
11.3.1 Tablets, Lozenges, and Troches������������������������������������������ 175
11.3.2 Films and Patches �������������������������������������������������������������� 175
11.3.3 Other Oral Transmucosal Dosage Forms���������������������������� 176
11.4 Excipients Used in Oral Transmucosal Formulations�������������������� 177
Further Reading ���������������������������������������������������������������������������������������� 179
12 
Rectal and Vaginal Drug Delivery���������������������������������������������������������� 181
12.1 Introduction������������������������������������������������������������������������������������ 182
12.2 Rectal Route������������������������������������������������������������������������������������ 182
12.2.1 Rectum Anatomy���������������������������������������������������������������� 183
12.2.2 Rectal Dosage Forms���������������������������������������������������������� 184
12.3 Vaginal Route���������������������������������������������������������������������������������� 184
12.3.1 Vaginal Physiology ������������������������������������������������������������ 185
12.3.2 Vaginal Dosage Forms�������������������������������������������������������� 186
x Contents

12.4 Suppository Formulation���������������������������������������������������������������� 187


12.4.1 Suppository Base Considerations �������������������������������������� 188
12.4.2 Oleaginous Bases���������������������������������������������������������������� 188
12.4.3 Water-Soluble Bases ���������������������������������������������������������� 190
12.4.4 Other Excipients Used in Suppository Dosage Forms�������� 192
12.4.5 Particle Size and Particle Settling During
the Preparation of Suppositories ���������������������������������������� 193
12.4.6 Drug Release from a Suppository Base
and Absorption�������������������������������������������������������������������� 193
12.4.7 Storage and Handling���������������������������������������������������������� 194
12.5 Suppository Manufacture/Production �������������������������������������������� 194
Further Reading ���������������������������������������������������������������������������������������� 194
13 Pulmonary Drug Delivery ���������������������������������������������������������������������� 195
13.1 Introduction������������������������������������������������������������������������������������ 196
13.2 Lung Anatomy and Physiology������������������������������������������������������ 197
13.3 Mechanisms of Particle Deposition������������������������������������������������ 199
13.3.1 Particle Clearance and Dissolution ������������������������������������ 200
13.3.2 Influence of Disease������������������������������������������������������������ 201
13.4 Nebulizers �������������������������������������������������������������������������������������� 201
13.4.1 Jet Nebulizers���������������������������������������������������������������������� 202
13.4.2 Ultrasonic Nebulizers���������������������������������������������������������� 203
13.4.3 Vibrating Mesh Nebulizers ������������������������������������������������ 203
13.4.4 Nebulizer Formulations������������������������������������������������������ 204
13.5 Pressurized Metered Dose Inhalers������������������������������������������������ 204
13.5.1 Device Design �������������������������������������������������������������������� 206
13.5.2 Formulation Considerations of pMDIs ������������������������������ 207
13.5.3 Propellants�������������������������������������������������������������������������� 208
13.5.4 Other Excipients Used in pMDIs���������������������������������������� 208
13.6 Dry Powder Inhalers ���������������������������������������������������������������������� 209
13.6.1 Formulation������������������������������������������������������������������������ 209
13.6.2 Mechanisms of Aerosolization (Particle Fluidization
and Redispersion)��������������������������������������������������������������� 210
13.6.3 Device Design �������������������������������������������������������������������� 210
13.6.4 Device Resistance �������������������������������������������������������������� 212
13.7 Analytical Methods for Pulmonary Drug Delivery Systems���������� 212
Further Reading ���������������������������������������������������������������������������������������� 214
14 Nasal Drug Delivery�������������������������������������������������������������������������������� 215
14.1 Introduction������������������������������������������������������������������������������������ 215
14.2 Barriers for Nasal Drug Delivery���������������������������������������������������� 216
14.3 Excipients Used in Nasal Formulations������������������������������������������ 217
14.4 Methods and Devices for Nasal Administration ���������������������������� 218
14.5 Nasal Device Performance Testing ������������������������������������������������ 219
Further Reading ���������������������������������������������������������������������������������������� 220
Contents xi

15 
Drug Product Design and Delivery of Biologics������������������������������������ 221
15.1 Introduction������������������������������������������������������������������������������������ 222
15.2 Production of Biologics������������������������������������������������������������������ 222
15.3 Formulation of Biologics���������������������������������������������������������������� 223
15.4 Devices for Administration of Biological Products
and Performance Testing���������������������������������������������������������������� 224
15.5 Characterization and Performance Testing of Biologics���������������� 228
15.6 Biosimilars�������������������������������������������������������������������������������������� 229
Futher Reading������������������������������������������������������������������������������������������ 230

Index�������������������������������������������������������������������������������������������������������������������� 231
About the Authors

Ashlee D. Brunaugh is an assistant professor at the University of Michigan


College of Pharmacy in the Department of Pharmaceutical Sciences. She is also the
President/CEO of CloXero Therapeutics Inc and a scientific advisor for Via
Therapeutics LLC. Dr. Brunaugh holds both a Pharm.D. and a Ph.D. degree in
Pharmaceutical Sciences from the University of Texas at Austin. Upon completing
her education, she worked as a senior scientist and later Director of Strategy and
Operations at Via Therapeutics, a pharmaceutical start-up located in Austin, TX,
focused on the bridging of novel drug delivery systems from the preclinical to clini-
cal stages of development. In 2021, she joined the faculty at the University of
Michigan. Dr. Brunaugh’s research is focused on the elucidation of the underlying
mechanisms for respiratory disease progression to determine appropriate therapeu-
tic targets and develop novel formulation and drug delivery approaches to improve
patient outcomes. In addition to her research experience, Dr. Brunaugh is a regis-
tered pharmacist and has experience practicing in hospital, community, and clinical
trial settings. She has several years of experience in teaching pharmaceutical sci-
ence courses at the undergraduate and graduate level, including the development
and implementation of a flipped-classroom basic pharmaceutics course with Drs.
Smyth and Williams at the University of Texas at Austin College of Pharmacy.

Daniel Moraga-Espinoza is a pharmacist from Universidad de Valparaíso, Chile


(2010), and completed a Ph.D. in Molecular Pharmaceutics and Drug Delivery
(MPDD) at the University of Texas at Austin, USA (2018). Presently, Dr. Moraga-
Espinoza holds the position of Assistant Professor at Universidad de Valparaíso,
serves as an adjunct professor at the University of Texas at Austin, and works as an
associate researcher at the Chilean Pharmacopeia Research Center. His primary
research focus lies in the field of drug delivery into the lungs and the nasal cavity
through controlled release systems. He has published multiple research articles,
reviews, book chapters, and patent applications. Additionally, he is member of the
editorial boards of the scientific journals Drug Development and Industrial
Pharmacy (DDIP) (2018) and AAPS PharmSciTech journal (2018). Dr. Moraga was
the recipient of the Grant FONDECYT de iniciación 11190987 for young

xiii
xiv About the Authors

researchers, honored as one of the leading research innovators by BRAIN Chile


(2023), and serves as a regulatory consultant for the Chilean regulatory agency,
contributing to the development of guidelines for the evaluation of orally and nasally
inhaled drug products.

Tania F. Bahamondez-Canas is a pharmacist from Universidad de Valparaiso,


Chile (2010), and holds a Ph.D. from the University of Texas at Austin, USA (2018).
She is an associate professor at Universidad de Valparaiso, Chile, an academic posi-
tion sponsored by the Chilean Agency of Research and Development (ANID) with
the grant PAI 77190010 (2019). She is also an adjunct professor of the Ph.D. pro-
gram in Molecular Pharmaceutics and Drug Delivery at the University of Texas at
Austin, USA. She has teaching experience in various programs from the College of
Pharmacy of Universidad de Valparaíso, including undergraduate pharmacy, mas-
ter's, and continuing education programs. She is the Director of the Chilean
Pharmacopeia Research Center (CIFAR) at Universidad de Valparaíso and PI of the
Antimicrobial Pharmaceutics laboratory focusing on novel drug delivery systems to
effectively fight bacterial biofilm infections. She has published multiple research
articles, reviews, book chapters, and patent applications. Her work on biofilm infec-
tions and tissue engineering in chronic wounds was funded by the ANID grants for
young researchers FONDECYT 11190348 (2019) and applied sciences FONDEF
ID19I10028 (2019) and FONDEF ID21I10153 (2021), and was recently awarded
by the Chilean regulatory agency (ISP).

Hugh D. C. Smyth is the Alcon Centennial Professor, with tenure, in the Division
of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of
Texas at Austin. Dr. Smyth oversees multidisciplinary laboratory funded by NIH,
FDA, and industry that focuses on engineering new drug delivery systems with an
emphasis on drug delivery to the airways. He has over 350 published works. Dr.
Smyth is editor of four books and is an inventor on numerous patents or patent
applications. He has a Pharmacy and a Ph.D. degree from the University of Otago,
New Zealand. Dr. Smyth has worked as a practicing pharmacist and a scientist in
industry and has received training in several academic settings. He has been faculty
at the University of North Carolina at Chapel Hill and the University of New
Mexico. He was the American Association of Pharmaceutical Scientists (AAPS)
New Investigator award winner for Pharmaceutics and Pharmaceutical Technologies
in 2007. He also received the PhRMA Foundation New Investigator Award in phar-
maceutics in 2007. He gave the DDL Annual Lecture in 2022. He was the Editor-in-­
Chief of Drug Development and Industrial Pharmacy from 2014 to 2022. Dr. Smyth
has started several companies resulting from technologies discovered in his labora-
tory which are now advancing these technologies for clinical use.

Robert O. Williams Bill Williams is the Johnson & Johnson Centennial Chair
and Professor of Pharmaceutics and the Division Head of Molecular Pharmaceutics
and Drug Delivery at the College of Pharmacy, University of Texas at Austin. He
earned a B.S. in Biology from Texas A&M University, a B.S. in Pharmacy from the
About the Authors xv

University of Texas at Austin, and Doctor of Philosophy in Pharmaceutics in 1986


from the University of Texas at Austin. Dr. Williams was elected Fellow of the
American Association of Pharmaceutical Scientists in 2006, Fellow of the American
Institute of Medical and Biological Engineering in 2008, and Fellow of the National
Academy of Inventors in 2019. He was named the Inventor of the Year by the
University of Texas at Austin in 2017. He has been a member of the American
Association of Pharmaceutical Scientists (AAPS) since its inception, as well as
other professional societies including the American Association of Colleges of
Pharmacy. He is the co-founder of several pharmaceutical companies. He has pub-
lished over 500 peer-reviewed research articles, reviews, abstracts, and book chap-
ters and co-edited four books in the field of pharmaceutical technology and drug
delivery, including Formulating Poorly Water-Soluble Drugs, Third Edition (AAPS
and Springer). He is an inventor on over 60 patents and patent applications. Dr.
Williams is the Editor-in-Chief of AAPS PharmSciTech since 2014. He is on the
Editorial Advisory Board of Journal of Drug Delivery Science and Technology, and
he serves as a reviewer for numerous other journals.
Chapter 1
Essential Pharmaceutics in the Flipped
Classroom

Abstract This chapter provides a guide on how to implement a flipped classroom


model into a pharmaceutics course. Course design, daily class organization, strate-
gies for student success, and how to implement prereading materials (specifically
this text) are discussed in detail.

Keywords Case studies · Pharmaceutical education · Flipped classroom ·


Problem-based learning · Teaching methods · Active learning · Information literacy

“Essential Pharmaceutics,” as the name implies, provides students in clinical and


research areas of the pharmaceutical sciences, including PharmD and PhD students,
with the critical concepts and knowledge foundation as a part of their pharmaceutics
training. These essential concepts are complemented by additional materials and
applications in our “flipped” pharmaceutics course, the design and implementation
of which is explained below.
The first edition of this book was developed over several years as an accompaniment
to the flipped-classroom pharmaceutics course taught by Professors Hugh D. C. Smyth
and Robert O. (Bill) Williams III at the University of Texas at Austin College of
Pharmacy (UTCoP). Following 2 years of planning and preparation, and with input
from educational and instructional experts, in the Spring of 2014, the “Pharmaceutics”
course within the UTCoP PharmD curriculum was restructured from a conventional
lecture-based content delivery to a flipped instruction, team-­based, classroom model.
This second edition of Essential Pharmaceutics has now incorporated nearly 10 years
of experience and valuable feedback received during the delivery of the course to over
one thousand PharmD and graduate students in the pharmaceutical sciences.
So, what does a “flipped class” mean in terms of a pharmaceutics course? In
short, it emphasizes the application of facts, foundational knowledge, information
literacy skills, and team-based learning to the solving of real-world drug delivery
and formulation science problems. Students leave our course with an understanding
of pharmaceutics that goes beyond rote memorization of facts and in parallel
develop the critical thinking and communication skills necessary to become leaders
in pharmacy practice, clinical, industry, and academic settings.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 1


A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the
Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9_1
2 1 Essential Pharmaceutics in the Flipped Classroom

This textbook, Essential Pharmaceutics, provides the cornerstone of our flipped


classroom approach and provides the basis of students’ preclass readings, which
prepares them for in-class applications and in-depth utilization of these basic con-
cepts and principles. This approach can be applied successfully in universities
around the world. In our own experience, we have found that the incorporation of
this text has been an invaluable asset in promoting student understanding of key
concepts and ensuring the success of the flipped classroom model as applied to
pharmaceutics.

1.1 Overview of “Flipped Pharmaceutics” Course Format


and Structure

Team-based learning and the development of effective communication skills are


critical components to the flipped pharmaceutics course. Prior to the beginning of
the semester, students enrolled in the pharmaceutics course are randomly assigned
to five-member permanent teams, with whom they continue working through the
duration of the course. These teams are encouraged and expected to operate in a
format similar to a project team meeting or board meeting, in which students are
expected to respectfully acknowledge the input and differences of opinion from
other team members, challenge teammates in a professional manner, and engage in
concise and compelling communication, with the expectation that their position is
backed with facts, not opinions.
Our course is structured as a series of modules, each of which is focused on an
aspect of pharmaceutics and dosage form design. The chapters of this book are
based upon these modules and are intended to provide students with an understand-
ing of the foundational concepts that they will need in order to successfully com-
plete the real-world case studies assigned in the classroom. Generally, the semester
proceeds in the following manner:
1. Preclass reading assignment: Students are assigned factual-based content 1 week
before attending class (referred to as the “Pre-class Reading Assignment”). The
prereading assignment consists of reading a prescribed chapter from this book
and answering specific questions on key concepts. Occasionally, other assigned
relevant peer-reviewed original research and review papers from the literature
are also included in the preclass reading assignment to supplement the book and
also introduce students to a diverse range of information sources relevant to
pharmaceutics. Accordingly, the purpose of this book is to provide the essential
facts related to dosage form design and drug delivery that provide the necessary
foundational knowledge for students to successfully engage in the in-class real-­
world case study assignments.
2. Readiness assessment quiz: Once the students have completed the Pre-Class
Reading Assignment, they should have acquired foundational knowledge prior
to class. Student readiness assessment quizzes are administered at the beginning
1.1 Overview of “Flipped Pharmaceutics” Course Format and Structure 3

of class and assess the students’ knowledge of the key concepts covered by these
preclass readings. Grades obtained by students in these assessments count
toward their final grade, which provides an incentive to complete the prereading
assignment prior to the class.
3. Cumulative exam assessments: Instead of having two or three high-stake major
exams during the semester, we have recently implemented an innovative assess-
ment tool. In our class, the Cumulative Exam is made up of a series of 11 indi-
vidual tests covering each module (e.g., each technical chapter in this book) and
made up of questions covering only the prior week’s case studies. The Cumulative
Exam is administered by electronic exam software and is given at the beginning
of each class period. These 11 Cumulative Exams represent 100% of the stu-
dent’s grade for their major exam, which the student has accumulated along the
way (Explanation: Each one of the 11 Cumulative Exams represents 9.09% of
the total Cumulative Exam, so 11 × 9.09% = 100%). We also implemented an
alternative assessment strategy in which students can individually choose to take
an Optional Final Exam for any reason at the end of the semester, which replaces
their Cumulative Exam grade. The Optional Final Exam is cumulative and made
up of questions that cover all materials from the entire semester, including pre-
readings, mini-lectures, and case studies.
4. In-class team based learning: Class time is then focused on the strategic applica-
tion of the pre-class reading assignments through practical, hands-on activities.
All teams are required to complete two research-based drug product design
assignments (referred to as “case studies”). Fifty-five minutes are allotted for
each assignment, and a 55-min countdown clock helps keep the teams aware of
the time remaining. To successfully complete the assignment, groups are required
to utilize a variety of online information resources in order to answer a series of
analytical questions. During the time allotted for each case study, faculty, gradu-
ate student teaching assistants, and experienced PharmD student assistants (these
are PharmD students who already passed the course and are funded through an
Academic Assistant position) continuously interact and engage the teams to
facilitate learning (our student:instructor ratio is typically no more than 15:1). At
various points during the case study, the countdown clock is stopped and faculty
deliver two or three mini-lectures consisting of 2–3 slides each on different tech-
nical/scientific aspects of the case study, thus linking the student’s prereading
class assignments (facts) to the case study (applying facts to concepts).

1.2 Building the Required Foundation for Student Success


in “Flipped Pharmaceutics”

Implementation of our model required input and coordination with faculty across
the PharmD curriculum at the University of Texas at Austin. Incoming students to
our flipped pharmaceutics course are in the second semester of their first year of the
4 1 Essential Pharmaceutics in the Flipped Classroom

Fig. 1.1 The flipped pharmaceutics course is strategically placed in the PharmD curriculum to
ensure students have the necessary foundational knowledge and critical thinking skills to achieve
success in class. The source for foundation facts, information literacy skills, and communication
skills is color coded according to the prerequisite courses offered in the immediately preceding
Fall semester of the PharmD first year

PharmD program. By this point in the curriculum, students have completed a num-
ber of foundational courses that are crucial in laying the groundwork for the topics
covered in the flipped pharmaceutics course (Fig. 1.1). We mapped each of these
prerequisite courses to confirm that students would have the necessary background
before beginning our flipped class. We also note that the placement of our course in
the curriculum is such that the students have not yet completed their second semes-
ter of Physiology/Pathophysiology and Pharmaceutical Biochemistry, which take
1.2 Building the Required Foundation for Student Success in “Flipped Pharmaceutics” 5

place concurrently with this pharmaceutics course in the spring semester of year
one of the PharmD program. We, thus, strategically structure our flipped course
content such that the students are assured to have covered a specific topic before it
is used in class (e.g., we ensure that anatomy of the eye is covered outside our
course prior to the introduction of ophthalmic drug products).
As the flipped pharmaceutics course has evolved over the past 10 years, we have
come to understand that student acquisition of the necessary information literacy
skills prior to beginning our course is a key component to ensuring student success.
In-class activities require extensive utilization of primary literature, patents, data-
bases, etc. This information is analyzed by students in teams, already armed with the
knowledge obtained from concepts provided in this book. Extensive work conducted
by PharmD/MSc student Natalia Malesa as part of her master’s thesis revealed that
integration of information literacy training in coursework prior to the start of flipped
pharmaceutics increased student performance of the course, as student perception of
their own information literacy abilities. In response to these findings, faculty have
incorporated an introduction to these information literacy skills in the “Introduction
to Pharmacy Practice” course that students complete in the first Fall semester of
their first year. Through this course, students gain experience using bibliographic
databases for biomedical research, including Google Scholar, PubMed/MEDLINE,
ScienceDirect, and Web of Science. With assistance from a pharmacy subject spe-
cialist librarian, students learn optimal search strategies for these databases, such as
the utilization of Medical Subject Headings (MeSH). Students are also instructed in
how to locate tertiary resources and how to appropriately cite references. In our
flipped pharmaceutics course, we continue to build these information literacy skills
by introducing search strategies that are more specific to drug products, including
the use of patents, the US Pharmacopeia/National Formulary Online, drug substance
databases (e.g., TOXNET, Reaxys), medication package inserts, and FDA resources
including the Orange Book and the Inactive Ingredients Database. With assistance
from The University of Texas at Austin library system, we have designed a course
web portal that contains links to each of these resources, in addition to guides on
how to use each database, how to read US patents, and how to appropriately cite
references, and it is located here: https://guides.lib.utexas.edu/pharmacy/pharma-
ceutics. Students utilize these resources in class and beyond, with many students
reporting years later to us how helpful the web portal is throughout the PharmD
curriculum. Overall, the information literacy skills that are developed in flipped
pharmaceutics become invaluable to our students as they progress through the cur-
riculum and begin work in clinical and industry settings.

1.3 Achieving Learning Objectives

Learning objectives for the flipped pharmaceutics course at UTCoP were initially
designed and are regularly updated to reflect PharmD accreditation standards in the
United States. For example, learning objectives in our course were recently updated
6 1 Essential Pharmaceutics in the Flipped Classroom

to reflect the American Association of Colleges of Pharmacy (AACP) Curriculum


Outcomes and Entrustable Professional Activities (COEPA) 2022 document.
In designing this “flipped class” course, the following learning objectives are
communicated to students through our syllabus:
1. Identify and explain the physicochemical and formulation properties of a drug
that influence its absorption and stability.
(a) Identify and describe the factors that influence the aqueous solubility and
partition coefficient of a drug. Explain the importance of appropriate aque-
ous solubility and partition coefficient in the formulation design and absorp-
tion of drugs.
(b) Understand and explain the ionization of weak acidic and weak basic drugs
and calculate the fraction of a drug in its ionized and unionized forms as a
function of pH.
(c) Describe how pKa and pH influence the observed solubility and partitioning
of a drug.
(d) Identify, evaluate, and explain the factors that affect the chemical stability of
a drug under various environmental and packaging conditions.
(e) Identify and explain the factors that control the physical and microbiological
stability of a drug product under various environmental and packaging
conditions.
(f) Identify and explain the unique pharmaceutical challenges posed by con-
temporary biotechnology-based drug products (biopharmaceuticals).
2. Identify and explain the properties of a drug that influence dosage form design
and its route of administration.
(a) Describe the various routes of administration available for drug delivery,
and discuss the advantages and disadvantages of each delivery system.
(b) Describe the characteristics of an ideal drug delivery system. Identify the
various types of liquid, solid, and semisolid dosage forms available.
(c) Discuss how the physicochemical properties of a drug influence the design
of various dosage forms, including biotech drugs.
(d) Explain the various formulation approaches taken to improve the in-vitro
dissolution, solubility, stability, and absorption of drugs from different dos-
age forms.
(e) Identify physical-chemical and formulation properties that make a drug suit-
able for modified release/controlled release, and explain the various formu-
lation approaches available for modifying drug release from dosage forms.
(f) Discuss the methods/techniques used for establishing the performance and
quality of dosage forms.
3. Identify and explain the dosage form features that influence therapeutic
outcomes.
(a) Describe the role and functions of inactive/inert ingredients in different
types of dosage forms.
1.3 Achieving Learning Objectives 7

(b) Describe the various methods of compounding and/or manufacture of differ-


ent types of dosage forms.
(c) Explain the importance of packaging and storage conditions in expiration
dates and drug product quality and assurance.
(d) Select an appropriate packaging container based on the physicochemical
properties of the drug, which meets a patient’s need.
(e) Explain principles underlying the proper use of dosage forms, and their
influence on bioavailability and therapeutic outcome.
(f) Determine the importance of selection of appropriate dosage form in drug
therapy.
(g) Explain the influence of formulation, physiological, and anatomical factors
on drug absorption from dosage forms.
(h) Discuss how compliance and adherence can be improved by appropriate
dosage form selection.
(i) Select and recommend the best route of administration and dosage form for
a patient.
(j) Identify and prevent drug interactions and incompatibilities based on the
presence of active and inactive pharmaceutical ingredients.
(k) Identify, solve, and prevent drug therapy problems related to dosage form,
delivery system, and route of administration.
4. Make appropriate selection decisions for multisource drug products.
(a) Explain and understand the concepts of pharmaceutical equivalence, bio-
equivalence, and therapeutic equivalence. Understand the basis for thera-
peutic equivalence or nonequivalence.
(b) Use the Orange Book appropriately to select and recommend a drug.
(c) Select and recommend appropriate drug products according to scientific,
legal, and economic guidelines where appropriate.
5. Compound safe and effective extemporaneous pharmaceutical products.
(a) Apply relevant standards of practice (including ethical guidelines) to pre-
pare safe and effective dosage forms and perform in-process quality control.
(b) Search and apply the most accurate and standardized information on extem-
poraneous compounding.
(c) Evaluate the suitability of an extemporaneously compounded dosage form
for the administration of a drug for a patient.
(d) Identify physical and chemical incompatibilities among active and inactive
pharmaceutical ingredients of a formulation; recommend and follow
approaches to avoid incompatibilities and unwanted interactions.
(e) Calculate and measure the correct quantity of active and inactive pharma-
ceutical ingredients.
(f) Use correct laboratory measuring procedures to obtain the desired quantity
of all formulation ingredients.
(g) Use good extemporaneous compounding practices in the preparation of a
patient-specific drug product.
8 1 Essential Pharmaceutics in the Flipped Classroom

(h) Design and maintain an adequate operational facility for compounding


pharmaceutical products.
6. Preparing safe and effective sterile dosage forms and enteral nutrition products.
(a) Apply relevant standards of practice (including ethical guidelines) to pre-
pare safe and effective sterile dosage forms and perform in-process quality
control.
(b) Calculate and measure the correct quantity of ingredients for preparing a
sterile product.
(c) Use proper aseptic techniques to prepare sterile products.
(d) Identify physical and chemical incompatibilities among active and inactive
components of sterile formulations; recommend and follow approaches to
avoid unwanted interactions and incompatibilities.
(e) Use sterilization methods that are appropriate for the drug and product.
(f) Calculate the rate of drug administration based on the prescription order and
the type of infusion pump used.
(g) Determine a patient’s fluid, electrolyte, and nutritional needs, and calculate
the composition of parenteral or enteral nutrition sources to meet their needs.
(h) Apply appropriate quality control procedures for sterile products.
(i) Evaluate the impact of physical and chemical stability on a sterile product.
(j) Design and maintain an adequate operational facility for compounding ster-
ile pharmaceutical products.
7. Maintain professional competence by identifying and analyzing emerging issues
in pharmaceutical dosage forms and compounding.
This is accomplished in the flipped classroom course by assigning real-life prob-
lems that the students must strategically evaluate and solve using the pharmaceutics-­
related knowledge acquired through their independent reading or team research
conducted during class. Students must master the “Pharmaceutics” portal and gain
the skills to effectively use and cite the literature to support their answers.

1.4 Specific “Flipped Class” Structure—How to Implement

In the first class of flipped pharmaceutics, we introduce discipline-specific informa-


tion resources during an interactive tutorial session. Students participate in an
instructor-guided case study, in which they are provided hands-on training and
opportunities to practice accessing and retrieving specialized scientific information
from a variety of online resources (e.g., United States Pharmacopeia/National
Formulary Online), drug substance databases (e.g., TOXNET, Reaxys), package
inserts (e.g., DailyMed), and patents (e.g., US Patent and Trademark Office, US
Food and Drug Administration Orange Book, US Food and Drug Administration
Purple Book, Google Patents). At this point, students are introduced to the
Pharmaceutics Web Portal, which consolidates these various drug product resources
1.4 Specific “Flipped Class” Structure—How to Implement 9

Fig. 1.2 Cycle of a typical flipped pharmaceutics class

into a student-friendly course guide. Figure 1.2 provides a graphic overview of how
the typical flipped pharmaceutics class is conducted after this initial introductory
session.
One week prior to the class meeting time, students are given a pre-reading assign-
ment consisting primarily of reading and understanding a specific chapter from this
book. Most individual chapters serve as a separate module. Students gain additional
experience in accessing drug information and related resources by occasionally
accessing and reading research articles and review papers relevant to the topic of the
upcoming case study. A list of relevant papers is included at the end of each chapter
of this book to provide examples of possible “prereading assignments” for instruc-
tors who wish to implement their own flipped-classroom model. Additionally, a list
of learning objectives is provided to guide at-home study, which are incorporated
into each chapter of this text.
For example, at the start of the class, students are given two assessments, the
Cumulative Exam (explained above) and the Readiness Assessment quiz. These
assessments ensure that students are motivated to review their last week’s case stud-
ies and to complete the prereading assignments. Based on the results of the Readiness
Assessment quiz, the instructors can determine which concepts require further
10 1 Essential Pharmaceutics in the Flipped Classroom

review and explanation before starting the case studies. Following these tests, a
mini-lecture is typically given to students to provide context to the products featured
in the case studies.
The teams then begin work on the product case study, which was provided in the
form of a structured worksheet, typically with six to seven multipart questions cov-
ering various aspects of the drug product design and key pharmaceutical concepts.
Each case study is focused on a marketed drug product that students will likely
encounter in their professional careers. These case studies are designed in the fol-
lowing general topics based on real-world examples:
• Question 1—Understanding the problem that existed and needed to be solved for
this particular drug substance or disease state using pharmaceutics approaches.
• Questions 2 and 3—Gathering data on physicochemical properties and charac-
teristics of the drug and excipients.
• Questions 4 and 5—Synthesize foundational knowledge and new information to
understand formulation and drug delivery system properties.
• Questions 6 and 7—Applying new pharmaceutics understanding to answer clini-
cal pharmacy questions related to pharmaceutics principles.
During the course of the case study, instructors meet individually with teams to
provide guidance through areas of difficulty. Structured and ad hoc breaks are taken
to review concepts with the entire class. During these breaks, teams are regularly
called upon to provide answers to questions regarding their drug product design
assignments. Finally, drug product design assignment questions are formatted to
emphasize keywords that can be helpful for students when optimizing search strate-
gies. As the semester progresses, this format is dropped to allow students to deter-
mine their own keywords.

1.5 Flipped Pharmaceutics—A Pathway to Success

The first PharmD cohort to participate in our flipped-classroom model graduated in


2017. North American Pharmacist Licensure Examination (NAPLEX) first-time
attempt pass rate for UTCOP that year was 95%, compared to a national average of
88%. We have worked to improve our course each year it is taught, and this is
reflected in the 2022 first-attempt NAPLEX pass rate for UTCOP, which was 87%,
compared to a national average of 80%.
In addition to providing a solid foundation for prospective clinical pharmacists,
we have also had great success in utilizing our course to teach first-year PhD stu-
dents in the University of Texas at Austin’s Molecular Pharmaceutics and Drug
Delivery program. Our students have reported that the integration of information
literacy skill building in the course has improved their confidence and performance
in effectively and efficiently solving patient-health-related and pharmaceutics-­
related problems.
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cautioned me against talking too much here in Leadville; especially
against giving any hint of the locality. You’ll look out for that?”
Bromley laughed. “I’m deaf and dumb—an oyster—a clam. Where
can I find this Mr. Stephen Drew who is going to help us transmute
our hard rock into shiny twenty-dollar pieces next spring?”
Philip gave him Drew’s Leadville address, and then went to climb the
ladder-like stair to the room with the dirty window, where he flung
himself upon the unmade bed without stopping to undress, and fell
asleep almost in the act. When next he opened his eyes the room
was pitchy dark and Bromley was shaking him awake.
“What’s happened?” he gasped, as Bromley struck a match to light
the lamp; and then: “Good God, Harry!—have you let me waste a
whole day sleeping?”
“Even so,” was the cheerful reply. “I’ll tell you about it while you’re
sticking your face into a basin of cold water. To make it short—the
way you did this morning—the cat’s out of the bag. This whole town
knows that there has been a big gold strike made on the other side
of the range. What it hasn’t found out yet is who made the strike, or
where it is located. Mr. Drew put me on.”
“Good Lord!” Philip groaned. “And we’ve lost hours and hours!”
“They’re not lost; they’ve only gone before. Friend Drew is
responsible. He said, since the news had got out, we would better
wait until after dark to make our start, and then take the road as
quietly as we could; so I let you sleep. So far, as nearly as Mr. Drew
could find out, we haven’t been identified as the lucky discoverers.”
“That will follow, as sure as fate!” Philip predicted gloomily.
“Maybe not. While there’s life there’s hope. I’ve paid our bill here at
the hotel, and we’ll go to a restaurant for supper. Everything is done
that needed to be done; claim recorded, grub-stake bought, jacks
packed and ready to move, and a couple of tough little riding
broncos, the horses a loan from Mr. Drew, who pointed out, very
sensibly, that we’d save time and shoe-leather by riding in, to say
nothing of leg weariness. Drew has one of his hired men looking out
for us at the livery stable where the horses and jacks are put up, and
this man will give us a pointer if there is anything suspicious in the
wind. If you are ready, let’s go.”
As unobtrusively as possible they made their way down the steep
stair to pass out through the office-bar-room. As they entered the
smoky, malodorous public room Philip thought it a little odd that there
were no card players at the tables. A few of the evening habitués
were lined up at the bar, but most of them were gathered in knots
and groups about the rusty cast-iron stove in which a fire had been
lighted. With senses on the alert, Philip followed Bromley’s lead.
There was an air of palpitant excitement in the place, and, on the
short passage to the outer door, snatches of eager talk drifted to
Philip’s ears; enough to make it plain that the new gold strike was
responsible for the group gathering and the excitement.
“I’ll bet a hen worth fifty dollars that Hank Neighbors—that big cuss
leanin’ up ag’inst the bar—knows who struck it, and whereabouts it’s
located,” was one of the remarks that he overheard; and, glancing
back from the door, he saw the man to whom the reference was
made—a tall, loose-jointed man, with deep-set, gloomy eyes and a
curling brown beard that masked something more than half of his
face.
Upon leaving the hotel, Bromley led the way down Harrison Avenue
toward a restaurant not far from the stable where their outfit waited
for them. With the mining excitement now at its most populous
height, and the sidewalks filled with restless throngs of men, there
was curiously little street disorder; this though the saloons, dance-
halls and gaming rooms of a wide-open mining-camp city were
running full blast, their garishly lighted entrances lacking even the
customary slatted swing doors of concealment. For the greater part,
the crowds were good-natured and boisterously hilarious; and where
the not too infrequent drunken celebrator came weaving along, the
sidewalk jostlers gave him room, shouting such encouragements as
“Walk a chalk, old boy!” or “Go it while you’re young—when you’re
old you can’t!” One of the staggerers who bumped against Philip and
his partner was repeating monotonously: “’Rah for Jimmie Garfield—
canal boy, b’gosh—nexsht presh’dent!” an exotic injection of the
politics of a campaign year into an atmosphere as remote as that of
another planet from matters political or governmental.
In the side-street restaurant Philip chose a table in a corner and sat
with his back to the wall so that he could see the length and breadth
of the room. The hour was late, and the tables were no more than
half filled; but where there were groups of two or more, there was
eager talk.
“It’s here, too,” Philip commented in low tones, indicating the eager
and evidently excited groups at the other tables.
“It is everywhere, just as I told you. The town is sizzling with it. When
I was a little tad I used to sit goggle-eyed listening to the tales of a
cousin of ours who was one of the returned California Forty-niners. I
remember he said it was that way out there. A camp would be
booming along fine, with everybody happy and contented, until word
of a new strike blew in. Then the whole outfit would go wild and
make a frantic dash for the new diggings. It’s lucky nobody has
spotted us for the discoverers. We’d be mobbed.”
“I wish I could be sure we haven’t been spotted,” said Philip, a wave
of misgiving suddenly submerging him.
“I think we are safe enough, thus far,” Bromley put in, adding: “But it
was a mighty lucky thing that we came in after dark last night with
those sacks of samples. If it had been daytime——”
The Chinese waiter was bringing their order, and Bromley left the
subjunctive hanging in air. Philip sat back while the smiling Celestial
was arranging the table. As he did so, the street door opened and
closed and he had a prickling shock. The latest incomer was a tall
man with sunken eyes and a curly brown beard masking his face;
the man who had been leaning against the bar in the Harrison
Avenue hotel, and who had been named as Hank Neighbors.
“What is it—a ghost?” queried Bromley, after the Chinaman had
removed himself.
“It is either a raw coincidence—or trouble,” Philip returned. “A fellow
who was in the bar-room of the hotel as we passed through has just
come in. He is sitting at a table out there by the door and looking the
room over ... and trying to give the impression that he isn’t.”
“Do you think he has followed us?”
“It is either that or a coincidence; and I guess we needn’t look very
hard for coincidences at this stage of the game.”
“Don’t know who he is, do you?”
“No, but I know his name. It’s Neighbors. Just as we were leaving
the hotel, one of the bar-room crowd named him; pointed him out to
his fellow gossips as a man who probably knew who had made the
new gold strike, and where it is located.”
“Well,” Bromley began, “if there is only one of him——”
“If there is one, there will be more,” Philip predicted. Then, at a
sudden prompting of the primitive underman: “I wish to goodness we
had something more deadly than that old navy revolver we’ve been
lugging around all summer.”
Bromley’s smile was cherubic.
“As it happens, we are perfectly well prepared to back our judgment
—at Mr. Drew’s suggestion. Our arsenal now sports a couple of late
model Winchesters, with the ammunition and saddle holsters
therefor. I bought ’em and sneaked ’em down to the stable this
afternoon.”
Philip looked up with narrowed eyes. “Would you fight for this chance
of ours if we’re pushed to it, Harry?”
Bromley laughed.
“I’ll shoot any man’s sheep that’ll try to bite me. Have you ever
doubted it?”
“I didn’t know.”
“How about you?”
“I have never fired a rifle in my life; not at anything—much less at a
man. But if I had to——”
“I know,” said Bromley with a grin. “You’re a chip off the old Puritan
block. If the occasion should arise, you’d tell your New England
conscience to look the other way, take cold-blooded aim, pull trigger
and let the natural law of expanding gases take its course. But we
mustn’t be too blood-thirsty. If we are followed to-night it needn’t be a
foregone conclusion that the trailers are going to try to take our mine
away from us. It is much more likely they’ll be tagging along to do a
little hurry stake-driving of their own, after we’ve shown them the
place.”
Philip had drained his second cup of coffee. “If you are through?” he
said; and as they left the restaurant he shot a quick glance aside at
the man who either was, or was not, a coincidence. To all
appearances, suspicion had no peg to hang upon. The Neighbors
person was eating his supper quietly, and he did not look up as they
passed him on their way to the street.
At the stable they found Drew’s man; a young fellow who looked like
a horse-wrangler, and who dressed the part, even to a pair of jingling
Mexican spurs with preposterous rowels, and soft leather boots with
high heels.
“Everything lovely and the goose hangs high,” he told them; and as
they were leading the loaded jacks and the saddle animals out: “The
big boss said I was to ride herd on yuh till yuh got out o’ town. He
allowed it’d be safer if yuh didn’t go pee-radin’ down the Avenoo.”
In silence they followed their mounted guide through the lower part
of the town and so came, by a rather long and dodging detour, into
the rutted stage road at some distance beyond the last of the
houses. Here their pace-setter turned back and they went on alone.
It was a moonless night, but they had no trouble in following the well-
used road over the hills and down to the valley of the Arkansas.
At the river crossing, however, the difficulties began. Though hardly
more than a mountain creek at this short distance from its source,
the river still held hazards in places for a night crossing with loaded
pack animals, and it was some little time before they found the
shallows through which they had led the burros the previous
evening. Just as they reached and recognized the crossing place
they heard the sound of galloping hoofs, and Philip jerked his rifle
out of its saddle scabbard and began to fumble the breech
mechanism.
“Don’t shoot!” Bromley warned; and when the single horseman
closed up they saw that he was the guide who had piloted them out
of Leadville.
“Sashayed out to tell yuh there’s a bunch a-trailin’ yuh,” he
announced laconically. “Five of ’em, with Hank Neighbors headin’ the
procession. Must’ve got onto yuh, some way.”
“Did you see them?” Philip asked.
“Passed ’em as I was goin’ back, and circled round to get ahead of
’em.”
“What sort of a man is this Neighbors?”
“Minin’ man, is what he lets on to be.”
“Straight or crooked?”
“You can’t prove nothin’ by me. But if I was you-all, I’d try to make
out to lose him and his pardners in the shuffle somewheres betwixt
here and wherever it is you’re a-headin’ for. I shore would.”
“Have they horses?” Bromley inquired.
“Yep; and three jacks, packed same as yourn.”
“Then they can’t make any better time than we can,” Philip put in.
“That depends on how much time yuh make and how much yuh lose.
But that don’t make no difference. They can trail yuh, if yuh don’t
figger out some trick to throw ’em off.”
“Are they armed?” Philip asked.
The horse-wrangler chuckled at the tenderfoot naïveté of the
question.
“Folks don’t trail round much in this neck o’ woods without totin’ their
artillery. Leastways, a hombre like Hank Neighbors don’t. Far as that
goes, you-all seem to be pretty well heeled yourselves.”
“We’ll try to hold up our end of the log,” Philip boasted. Then: “If
they’re chasing us, I guess we’d better be moving along. Much
obliged for your trouble—till you’re better paid. Get hold of that
canary’s halter, Harry, and we’ll pitch out.”
The river crossing was made in safety, and, to their great relief, they
had little difficulty in finding their way to the high basin. Since the trail
threaded a dry gulch for the greater part of the ascent, there were
only a few stretches where they had to dismount and lead the
horses, so not much time was lost. Nevertheless, it was past
midnight when they reached the easier travelling through the basin
toward the pass of the crusted snowdrifts. Riding abreast where the
trail permitted, they herded the jacks before them, pushing on at
speed where they could, and slowing up only in places where haste
threatened disaster.
“What’s your notion, Phil?” Bromley asked, when, in the dark hour
preceding the dawn, they found themselves at the foot of the
precipitous climb to the pass. “Don’t you think we’d better camp
down and wait for daylight before we tackle this hill?”
Philip’s reply was an emphatic negative. “We can make it; we’ve got
to make it,” he declared. “If those people are chasing us, they can’t
be very far behind, and if we stop here they’ll catch up with us. And if
we let them do that, we’d never be able to shake them off.”
“As you like,” Bromley yielded, and the precipitous ascent was
begun.
With anything less than tenderfoot inexperience for the driving
power, and the luck of the novice for a guardian angel, the perilous
climb over a trail that was all but invisible in the darkness would
never have been made without disaster. Convinced by the first half-
mile of zigzagging that two men could not hope to lead five animals
in a bunch over an ascending trail which was practically no trail at all,
they compromised with the necessities and covered the distance to
the summit of the pass twice; once to drag the reluctant broncos to
the top, and again to go through the same toilsome process with the
still more reluctant pack animals. It was a gruelling business in the
thin, lung-cutting air of the high altitude, with its freezing chill; and
when it was finished they were fain to cast themselves down upon
the rocky summit, gasping for breath and too nearly done in to care
whether the animals stood or strayed, and with Bromley panting out,
“Never again in this world for little Henry Wigglesworth! There’ll be a
railroad built over this assassinating mountain range some fine day,
and I’ll just wait for it.”
“Tough; but we made it,” was Philip’s comment. “We’re here for
sunrise.”
The assertion chimed accurately with the fact. The stars had already
disappeared from the eastern half of the sky, and the sharply
outlined summits of the distant Park Range were visible against the
rose-tinted background of the coming dawn. In the middle distance
the reaches of the great basin came slowly into view, and in the first
rays of the rising sun the ground over which they had stumbled in the
small hours of the night spread itself map-like below them. Far down
on the basin trail a straggling procession of creeping figures revealed
itself, the distance minimizing its progress so greatly that the
movement appeared to be no more than a snail’s pace.
“You see,” Philip scowled. “If we had camped at the foot of this hill it
would have been all over but the swearing.”
Bromley acquiesced with a nod. “You are right. What next?”
“We have our lead now and we must hold it at all costs—get well
down into the timber on the western slope before they can climb up
here. Are you good for more of the same?”
“A bit disfigured, but still in the ring,” said the play-boy, with his
cheerful smile twisting itself, for very weariness, into a teeth-baring
grin. Then, as the sunlight grew stronger, he made a binocular of his
curved hands and looked back over the basin distances. As he did
so, the twisted smile became a chuckling laugh. “Take another look
at that outfit on the trail, Phil,” he said. “It’s my guess that they have
a pair of field-glasses and have got a glimpse of us up here.”
Philip looked, and what he saw made him scramble to his feet and
shout at the patient jacks, lop-eared and dejected after their long
night march. The group on the distant trail was no longer a unit.
Three of the dots had detached themselves from the others and
were coming on ahead—at a pace which, even at the great distance,
defined itself as a fast gallop.
VI
With the vanguard of the army of eager gold-hunters fairly in sight,
the two who were pursued cut the summit breathing halt short and
resumed their flight. Avoiding the sand-covered snowdrifts in which
they had come to grief on the journey out, they pushed on down the
western declivities at the best speed the boulder-strewn slopes and
craggy descents would permit, postponing the breakfast stop until
they reached a grassy glade well down in the foresting where the
animals could graze.
After a hasty meal made on what prepared food they could come at
easily in the packs, and without leaving the telltale ashes of a fire,
they pressed on again westward and by early afternoon were in the
mountain-girt valley of the stream which had been their guide out of
the western wilderness two days earlier. Again they made a cold
meal, watered and picketed the animals, and snatched a couple of
hours for rest and sleep. Scanting the rest halt to the bare necessity,
mid-afternoon found them once more advancing down the valley,
with Philip, to whom horseback riding was a new and rather painful
experience, leading his mount.
One by one, for as long as daylight lasted, the urgent miles were
pushed to the rear, and after the sun had gone behind the western
mountains they made elaborately cautious preparations for the night.
A small box canyon, well grassed, opened into the main valley on
their left, and in this they unsaddled the horses and relieved the
jacks of their packs and picketed the animals. Then, taking the
needed provisions from one of the packs, they crossed the river by
jumping from boulder to boulder in its bed, and made their camp fire
well out of sight in a hollow on the opposite bank; this so that there
might be no camp signs on the trail side of the stream. But in the
short pipe-smoking interval which they allowed themselves after
supper, Bromley laughed and said: “I guess there is a good bit of the
ostrich in human nature, after all, Philip. Here we’ve gone to all sorts
of pains to keep from leaving the remains of a camp fire in sight,
when we know perfectly well that we are leaving a plain trail behind
us for anybody who is even half a woodsman to follow. That’s a
joke!”
“Of course it is,” Philip agreed; and for a time before they
extinguished the fire and recrossed the river to roll up in their
blankets in the box canyon where the animals were grazing, they
discussed the pressing matter of trail effacement without reaching
any practical solution of the problem.
The next morning they were up and on their way in the earliest dawn
twilight. As yet, there were no signs of the pursuit. The mountain
silences were undisturbed save by the drumming thunder of the swift
little river and the soft sighing of the dawn precursor breeze in the
firs. Convinced that all the haste they were making was clearly so
much effort thrown away unless they could devise some means of
throwing their followers off the track, they resumed the camp-fire
discussion, falling back in the end, not upon experience, which
neither of them had, but upon the trapper-and-Indian tales read in
their boyhood. In these, running water was always the hard-pressed
white man’s salvation in his flight, and, like the fleeing trapper, they
had their stream fairly at hand. But the mountain river, coursing
along at torrent speed, and with its bed thickly strewn with slippery
boulders, was scarcely practicable as a roadway; it was too
hazardous even for the sure-footed broncos, and entirely impossible
for the loaded jacks.
Next, they thought of cutting up one of the pack tarpaulins and
muffling the hoofs of the animals with the pieces, but aside from the
time that would be wasted, this expedient seemed too childish to
merit serious consideration. In the end, however, chance, that sturdy
friend of the hard-pressed and the inexperienced, came to their
rescue. Some seven or eight miles beyond their night camp they
came upon a place where, for a half-mile or more, the left-hand bank
of the stream was a slope of slippery, broken shale; the tail of a slide
from the mountain side above. Bromley was the first to see the
hopeful possibilities.
“Wait a minute, Phil,” he called to his file leader; “don’t you
remember this slide, and how we cursed it when we had to tramp
through it coming out? I’ve captured an idea. I believe we can delay
this mob that’s chasing us, and maybe get rid of it for good and all. Is
the river fordable here, do you think?”
Philip’s answer was to ride his horse into the stream and half-way
across it. “We can make it,” he called back, “if we can keep the jacks
from being washed away.”
“We’ll take that for granted,” said Bromley. “But we don’t need to go
all the way across. Stay where you are, and I’ll herd the rest of the
caravan in and let it drink.”
This done, and a plain trail thus left leading into the water, Bromley
explained his captured idea. While they couldn’t hope to make a
roadway of the stream bed for any considerable distance, it was
quite possible to wade the animals far enough down-stream to
enable them to come out upon the shale slide. After they had been
allowed to drink their fill, the expedient was tried and it proved
unexpectedly successful. On the shale slide the hoof prints vanished
as soon as they were made, each step of horse or burro setting in
motion a tiny pebble slide that immediately filled the depression.
Looking back after they had gone a little distance they could see no
trace of their passing.
“This ought to keep the mob guessing for a little while,” Bromley
offered as they pushed on. “They’ll see our tracks going down into
the creek, and think we crossed over. They’ll probably take a tumble
to themselves after a while—after they fail to find any tracks on the
other side; but it will hold ’em for a bit, anyway. Now if we could only
scare up some way of hiding our tracks after we get beyond this
slide——”
Though the continuing expedient did not immediately suggest itself,
the good-natured god of chance was still with them. Before they
came upon ground where the tracks of the animals would again
become visible, they approached the mouth of one of the many side
gulches scarring the left-hand mountain, and in the gulch there was
a brawling mountain brook with a gravelly bottom.
“This looks as if it were made to order, don’t you think?” said Philip,
drawing rein at the gulch mouth. “If we turn up this gulch we can
walk the beasts in the water.”
“But that isn’t the way we want to go,” Bromley objected.
“I’m not so sure about that. The map shows our valley lying on the
other side of this southern mountain range. The route we took,
coming out, was along two sides of a triangle, following the streams
—which is the long way around. I’m wondering if we couldn’t cut
straight across and save a lot of time. We’ve climbed worse
mountains than this one looks to be. And there’s another thing: we
can take the water trail up this gulch for a starter, and the chances
are that we’d lose the hue and cry that’s following us—lose it
permanently. What do you say?”
“I’m good for a try at it, if you are,” was the prompt reply; and so,
without more ado, the route was changed.
For the first half-mile or so through the windings of the gulch they
were able to hide their tracks in the brook bed, but the farther they
went, the rougher the way became, until finally they had to drag the
horses and pack animals up out of the ravine and take to the
mountain slopes, zigzagging their way upward as best they could
through the primeval forest. Luckily, though there were craggy
steeps to be climbed with shortened breath, perilous slides to be
avoided, and canyon-like gulches to be headed at the price of long
detours, they encountered no impassable obstacles, and evening
found them far up in the forest blanketing of the higher slopes, with
still some little picking of grass for the stock and with plenty of dry
wood for the camp fire which they heaped high in the comforting
assurance that its blaze would not now betray them.
It was after they had cooked and eaten their first hearty meal of the
toilsome day, and had stretched themselves luxuriously before the
fire for the evening tobacco-burning, that Bromley said: “How about
it, Philip?—are you getting a bit used to the millionaire idea by this
time?”
Philip shook his head slowly.
“No, Harry; I can’t fully realize it yet. For a little while after I saw the
figures of those assays I thought I could. But now it seems more like
an opium dream. It doesn’t seem decently credible that after only a
short summer’s knocking about in these hills, two raw green-horns
like ourselves could stumble upon something that may change the
entire scheme of things for both of us for the remainder of our lives.
It’s fairly grotesque, when you come to think of it.”
“Well, I guess it isn’t a dream, at any rate. Mr. Drew gave me a good
bit of his time day before yesterday; went with me to the land office,
and afterward helped me in the horse market where I bought the
extra burro. He asked a lot of questions; about the width of the vein,
how far we had traced it, and how fair or unfair we’d been to
ourselves in picking the samples; and after I had answered him as
well as I could, he said, in effect, that we had the world by the neck,
or we would have, if the ‘Little Jean’ pans out anywhere near as
good as it promises to.”
Again Philip shook his head. “I’m not at all sure that I want to grab
the world by the neck, Harry. That doesn’t seem like much of an
ambition to me.”
“All right; say it doesn’t. What then?”
“Oh, I don’t know. If the miracle had happened a year or so ago ...
but it didn’t; so what’s the use?”
“Go on and turn it loose,” Bromley encouraged. “Set the clock back a
year or so and let us see what it strikes.”
“I had a few ideals then; modest ones, I guess you’d call them. I’d
had to break my college course in the third year—family matters. At
that time I wanted nothing so much as to go back and finish; and
perhaps have a try for a Ph.D. degree afterward.”
“And past that?”
“More of what you’d call the modesties, I guess: a teaching job in
some college back home, or something of that sort; a job in which I’d
have some leisure for reading, thinking my own thoughts, living my
own life.”
“No wife and kiddies in the picture?” Bromley asked, with his most
disarming smile.
“No; not then.”
The play-boy laughed softly. “No sentimental foolishness for the
austere young student and pedagogue, of course. But the ‘not then’
tells a different story. You’ve met the incomparable ‘her’ in your later
avatar?”
It was some measure of the distance he had come on the road to
freer human expression that Philip did not at once retreat into the
speechless reticences.
“Yes,” he said: “I’ve met a girl.”
“The ‘angel’ you spoke of, the night you fed a hungry hold-up?”
“Don’t get it wrong. She is not so angelic that she can’t be perfectly
human.”
“But didn’t you say you’d met her only twice?”
“I did; and the saying still holds true.”
“Bowled you over like a shot, did she? I’d never have believed it of
you, Philip.”
“You needn’t believe it now. There was no ‘bowling over’ about it. I
first met her on the train coming to Denver—with her family; sat with
her for part of an afternoon. She isn’t like any other girl I’ve ever
known.”
“And that is as far as you’ve gone? You are a cold-blooded fish,
Philip, dear. But we were talking about futures. I take it the teaching
job in a New England college doesn’t appeal to you now; or won’t if
our mine keeps its promise?”
“Honestly, Harry, I can’t see very far ahead. I’m not at all sure that I
want to go back and finish my college course. There is nothing truer
than the saying we have hurled at us all the time out here—that the
West lays hold of a man and refuses to let go; that you may be as
homesick as the devil, but you’ll never go home to stay. But this is all
dream stuff—this talk. We haven’t got the millions yet. Even if the
mine is as rich as it seems to be, we may find jumpers in
possession, and so many of them that we can’t get away with them.”
“That’s so. ‘There’s many a slip,’ as we read in the copy-books.”
For a time the high-mountain silence, a silence curiously bereft of
even the small insect shrillings of the lower altitudes, enveloped
them. The cheerful fire was beginning to fall into embers when Philip
began again.
“A while back, you thought the money fever was getting hold of me,
Harry, but I hope you were wrong. Of course, there are things I want
to do; one in particular that money would help me to do. It was my
main reason for heading west from New Hampshire a little less than
a year ago.”
“Is it something you can talk about?”
“I guess so—to you,” and, breaking masterfully through whatever
barrier of the reticences remained, he told the story of his father’s
disappearance, of the cloud which still shadowed the Trask name, of
his own unshakable belief in his father’s innocence, and, lastly, of his
determination to find the lost man and to clear the family name.
“You see how the money will help; how I couldn’t hope to do much of
anything without money and the use of my own time,” he said in
conclusion. Then, the ingrained habit of withdrawal slipping back into
its well-worn groove: “You won’t talk about this, Harry? You are the
only person this side of New Hampshire who knows anything about
it.”
“It is safe enough with me, Phil; you ought to know that, by this time.
And here is my shy at the thing: if it so happens that the ‘Little Jean’
is only flirting with us—that we get only a loaf of bread where we’re
hoping to hog the whole bakery—you may have my share if your
own isn’t big enough to finance your job. I owe you a good bit more
than the ‘Little Jean’ will ever pan out on my side of the partnership.”
“Oh, hell,” said Philip; and the expression was indicative of many
things not written down in the book of the Philip who, a few months
earlier, had found it difficult and boyishly embarrassing to meet a
strange young woman on the common ground of a chance train
acquaintanceship. Then, “If you’ve smoked your pipe out, we’d better
roll in. There is more of the hard work ahead of us for to-morrow.”
But the next morning they found, upon breaking camp and emerging
from the forest at timber line, that the blessing of good luck was with
them still more abundantly. With a thousand and one chances to
miss it in their haphazard climb, they had come upon an easily
practicable pass over the range; and beyond the pass there was a
series of gentle descents leading them by the middle of the
afternoon into a valley which they quickly recognized as their own.
Pushing forward at the best speed that could be gotten out of the
loaded pack animals, they traversed the windings of the valley with
nerves on edge and muscles tensed, more than half expecting to
find a struggle for re-possession awaiting them in the treasure gulch.
At the last, when the more familiar landmarks began to appear, Philip
drew his rifle from its holster under his leg and rode on ahead to
reconnoitre, leaving Bromley to follow with the jacks. But in a few
minutes he came galloping back, waving his gun in the air and
shouting triumphantly.
“All safe, just as we left it!” he announced as he rode up. And then,
with a laugh that was the easing of many strains: “What a lot of
bridges we cross before we come to them! Here we’ve been
sweating blood for fear the claim had been jumped—or at least I
have—and I don’t suppose there has been a living soul within miles
of it since we left. Kick those canaries into action and let’s get along
and make camp on the good old stamping ground.”
VII
The autumn days were growing perceptibly shorter when the
discoverers of the “Little Jean” lode began to make preparations to
be snowed in for the winter in the western mountain fastnesses. By
this time they had heard enough about the mountain winters to know
what they were facing. With the first heavy snowfall blocking the
passes they would be shut off from the world as completely as
shipwrecked mariners on a desert island. But hardships which are
still only anticipatory hold few terrors for the inexperienced; and with
the comforting figures of the assays to inspire them, they thought
more of the future spring and its promise than of the lonely and
toilsome winter which must intervene.
Since there was still sufficient grass in sheltered coves and forest
glades to feed the stock, they postponed the journey which one of
them would have to take to find winter quarters for the animals. The
delay was partly prudential. Though each added day of non-
interference was increasing their hope that their ruse at the shale
slide had been completely successful in throwing their pursuers off
the track, they had no reason to assume that the Neighbors party
would turn back without making an exhaustive search for the new
“rich diggings”; and Philip was cannily distrustful of the Neighbors
purpose.
“It may be just as you say: that they are merely hungry gold-chasers,
breaking their necks to be the earliest stake-drivers in a new district;
but then, again, they may not be,” was the way he phrased it for the
less apprehensive Bromley. “If they happen to be the other sort—the
lawless sort—well, with both of us here to stand up for our rights,
they’d be five to our two. We can’t afford to make the odds five to
one. I’d rather wait and take the horses and jacks over the range in a
snow storm than to run the risk of losing our mine.”
“Meaning that we needn’t lose it if we can muster two to their five?”
said Bromley, grinning.
“Meaning that if anybody tries to rob us there’ll be blood on the
moon. Get that well ground into your system, Harry.”
“Ho! You are coming on nicely for a sober, peaceable citizen of well-
behaved New England,” laughed the play-boy. “But see here, didn’t
you tell me once upon a time that you had never fired a gun? If you
really believe there is a chance for a row, you’d better waste a few
rounds of ammunition finding out what a gun does when you aim it
and pull the trigger. It’s likely to surprise you. I’ve shot ducks in the
Maryland marshes often enough to know that pretty marksmanship
is no heaven-born gift.”
“Thanks,” returned Philip grimly. “That is a sensible idea. Evenings,
after we knock off work, we’ll set up a target and you can give me a
few lessons.”
Making the most of the shortening days, they had become pioneers,
felling trees for the building of a cabin, and breaking the two broncos,
in such primitive harness as they could contrive out of the pack-
saddle lashings, to drag the logs to a site near the tunnel mouth. Like
the drilling and blasting, axe work and cabin building were unfamiliar
crafts, to be learned only at a round price paid in the coin of aching
backs, stiffened muscles and blistered palms. Nevertheless, at the
end of a toiling fortnight they had a one-room cabin roofed in,
chimneyed and chinked with clay, a rude stone forge built for the drill
sharpening and tempering, and a charcoal pit dug, filled and fired to
provide the forge fuel. And though the working days were prolonged
to the sunset limit, Philip, methodically thorough in all things, did not
fail to save enough daylight for the shooting lesson, setting up a
target in the gulch and hammering away at it until he became at least
an entered apprentice in the craft and was able to conquer the
impulse to shut both eyes tightly when he pulled the trigger.
They were bunking comfortably in the new cabin when they awoke
one morning to find the ground white with the first light snowfall. It
was a warning that the time had come to dispose of the animals if
they were not to be shut in and starved. In his talk with Bromley,
Drew, the Leadville mine owner, had named a ranch near the mouth
of Chalk Creek where the borrowed saddle horses could be left, and
where winter feeding for the jacks might be bargained for; and after a
hasty breakfast Philip prepared to set out on the three-days’ trip to
the lower altitudes.
“I feel like a yellow dog, letting this herding job fall on you, Phil,”
protested the play-boy, as he helped pack a haversack of provisions
for the journey. “I’d make you draw straws for it if I had the slightest
idea that I could find the way out and back by myself.”
“It’s a stand-off,” countered the potential herd-rider. “I feel the same
way about leaving you to hold the fort alone. If that Leadville outfit
should turn up while I’m away——”
“Don’t you worry about the Neighbors bunch. It’s been three full
weeks, now, with no sign of them. They’ve lost out.”
“I’m not so sure of that. Better keep your eye peeled and not get too
far away from the cabin. If they should drop in on you——”
“In that case I’ll man the battlements and do my small endeavors to
keep them amused until you put in an appearance,” was the
lighthearted rejoinder. “But you needn’t run your legs off on that
account. They’ve given us up long ago.” Then, as Philip mounted
and took the halter of the horse that was to be led: “Are you all set?
Where’s that old pistol?”
“I don’t need the pistol. If I’ve got to walk back, lugging my own grub
and blankets, I don’t want to carry any more weight than I have to.”
“Just the same, you’re going prepared to back your judgment,”
Bromley insisted; and he brought out the holstered revolver and
made Philip buckle it on. “There; that looks a little more shipshape,”
he approved. “Want me to go along a piece and help you start the
herd?”
“Nothing of the kind,” Philip refused; and thereupon he set out,
leading the extra horse and driving the jacks ahead of him.
It was his intention to back-track over the trail by which they had first
penetrated to their valley in the late summer, and being gifted with a

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