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Remington
The Science and Practice of Pharmacy
Remington
The Science and Practice of Pharmacy

23rd Edition

Editor-in-Chief
Adeboye Adejare
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy,
University of the Sciences, Philadelphia, PA, United States
Department of Chemistry and Biochemistry, Misher College of Arts and Sciences,
University of the Sciences, Philadelphia, PA, United States

Section Editors
Purnima D. Amin
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
Grace L. Earl
School of Pharmacy and Health Sciences, Fairleigh Dickinson University, Florham Park, NJ, United States
Simon Gaisford
UCL School of Pharmacy, University College London, London, United Kingdom
Islam M. Ghazi
Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, United States
Zhiyu Li
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy,
University of the Sciences, Philadelphia, PA, United States
David J. Newman
Newman Consulting LLC, Wayne, PA, United States
Michael S. Saporito
Intervir, LLC, Philadelphia, PA, United States
Jeff Talbert
Department of Pharmacy Practice and Science, University of Kentucky, Lexington, KY, United States

Chair of the Board

Edward F. Foote
Dean, Philadelphia College of Pharmacy, University of the Sciences,
Philadelphia, PA, United States
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Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research
methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, com-
pounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others,
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A catalogue record for this book is available from the British Library
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A catalog record for this book is available from the Library of Congress

ISBN: 978-0-12-820007-0

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visit our website at https://www.elsevier.com/books-and-journals

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Publication history
First edition, 1886 Sixteenth edition, 1980
Second edition, 1889 Chairman, Editorial Board
Third edition, 1897 Arthur Osol
Fourth edition, 1905 Editors
Joseph P. Remington Grafton D. Chase Robert E. King
Fifth edition, 1907 Alfonso R. Gennaro Alfred N. Martin
Sixth edition, 1917 Melvin R. Gibson Ewart A. Swinyard
Joseph P. Remington Assisted by C. Boyd Granberg Gilbert L. Zink
E. Fullerton Cook Stewart C. Harvey
Seventh edition, 1926
Editors Seventeenth edition, 1985
E. Fullerton Cook Chairman, Editorial Board Managing editor
Charles H. LaWall Alfonso R. Gennaro John E. Hoover
Eighth edition, 1936 Editors
Editors Associated editors Grafton D. Chase Thomas Medwick
E. Fullerton Cook Ivor Griffith Ara H. DerMarderosian Edward G. Rippie
Charles H. LaWall Adley B. Nichols Stewart C. Harvey Joseph B. Schwartz
Arthur Osol Daniel A. Hussar Ewart A. Swinyard
Ninth edition, 1948
Tenth edition, 1951 Gilbert L. Zink
Eighteenth edition, 1990
Editors
Chairman, Editorial Board Managing editor
E. Fullerton Cook
Alfonso R. Gennaro John E. Hoover
Eric W. Martin
Editorial assistant
Eleventh edition, 1956
Editors Bonnie Packer
Editors Associated editors
Eric W. Martin E. Emerson Leuallen Grafton D. Chase Edward G. Rippie
E. Fullerton Cook Arthur Osol Ara H. DerMarderosian Joseph B. Schwartz
Linwood F. Tice Stewart C. Harvey Ewart A. Swinyard
Clarence T. Van Meter Daniel A. Hussar Gilbert L. Zink
Twelfth edition, 1961
Thomas Medwick
Editors Assistant to the editors
Eric W. Martin John E. Hoover Nineteenth edition, 1995
E. Fullerton Cook Chairman, Editorial Board Managing editor
E. Emerson Leuallen Alfonso R. Gennaro John E. Hoover
Arthur Osol Editorial assistant
Linwood F. Tice Bonnie Packer
Clarence T. Van Meter Editors
Grafton D. Chase Edward G. Rippie
Thirteenth edition, 1965 Ara H. DerMarderosian Joseph B. Schwartz
Editor-in-Chief Managing editor Glen R. Hanson H. Steve White
Eric W. Martin John E. Hoover Daniel A. Hussar Gilbert L. Zink
Editors Thomas Medwick
Grafton D. Chase Robert E. King
Herald R. Cox E. Emerson Leuallen Twentieth edition, 2000
Richard A. Deno Author Osol Chairman, Editorial Board Managing editor
Alfonso R. Gennaro Ewart A. Swinyard Alfonso R. Gennaro John E. Hoover
Stewart C. Harvey Clarence T. Van Meter Editorial assistant
Bonnie Packer
Fourteenth edition, 1970 Editors
Chairman, Editorial Board Managing editor Ara H. DerMarderosian Roger L. Schnaare
Arthur Osol John E. Hoover Glen R. Hanson Joseph B. Schwartz
Editors Thomas Medwick H. Steve White
Grafton D. Chase Robert E. King Nicholas G. Popovich
Richard A. Deno Alfred N. Martin
Twenty-first edition, 2006
Alfonso R. Gennaro Ewart A. Swinyard
Paul Beringer Pardeep K. Gupta
Melvin R. Gibson Clarence T. Van Meter
Ara H. DerMarderosian John E. Hoover
Stewart C. Harvey
Linda Felton Nicholas G. Popovich
Fifteenth edition, 1975 Steven Gelone William J. Reilly, Jr.
Chairman, Editorial Board Managing editor Alfonso R. Gennaro Randy Hendrickson, Chair
Arthur Osol John E. Hoover
Twenty-second edition, 2013
Editors
Editor-in-Chief Chairman, Editorial Board
John T. Anderson C. Boyd Granberg
Loyd V. Allen, Jr Lisa A. Lawson
Cecil L. Bendush Stewart C. Harvey
Editors
Grafton D. Chase Robert E. King
Adeboye Adejare Yvonne Perrie
Alfonso R. Gennaro Alfred N. Martin
Shane P. Desselle Nicholas G. Popovich
Melvin R. Gibson Ewart A. Swinyard
Linda A. Felton Kenneth M. Shermock
Anthony C. Moffat Donna S. Wall
Dedication

I would like to dedicate this book to the Philadelphia College of Pharmacy (PCP) family, including, but not limited to
students, faculty, staff, and alumni. As the first school or college of pharmacy in North America, it can be argued that
we are really the home of pharmacy and pharmaceutical sciences in North America! From great educators like Joseph
P. Remington to helping to bring the United States Pharmacopeia to fruition to industrial giants like Eli Lilly, the con-
tributions of PCP to the profession continues to be very significant. The Remington Honor Medal is the highest honor
bestowed by the American Pharmacists Association. I am extremely grateful and proud to be part of this family as a
faculty member. Finally, I would like to dedicate the book to my greatest teacher, I. Abiola Adejare, none other than
my father. Though you have moved on to where the Yorubas say “ibi agba re” (where elders go), the seeds that you
sowed continue to bear great fruits. Your grandson is now a PCP alum!

Adeboye Adejare
Professor, Philadelphia College of Pharmacy
Editor-in-Chief
Contents

List of contributors xix 2.7. Integrated approach to drug

Foreword—Remington 23rd edition xxiii nomenclature 38
Preface to the first edition xxv 2.8. Conclusion 39
Preface to the 23rd edition xxvii Acknowledgment 39
Acknowledgments xxix References 39

Section 1 Section 2
Introduction Natural Products
David John Newman
1. History of pharmacy 3
Gregory J. Higby and Benjamin Y. Urick 3. Botanical dietary products 45
1.1. The drug-taking animal 3 Esperanza J. Carcache de Blanco and
1.2. Prehistoric pharmacy 3 A. Douglas Kinghorn
1.3. Antiquity 4
1.4. The Middle Ages 5 3.1. Botanical dietary supplements 45
1.5. The Renaissance and Early Modern Europe 6 3.2. Botanicals standardization and quality
1.6. American pharmacy 8 evaluation 48
1.7. Antebellum America: Pharmacy finds 3.3. Quality control and quality assurance
its niche 10 of botanicals 50
1.8. The search for professionalism 11 3.4. Potential toxicity of botanical dietary
1.9. Legislation 11 supplements 51
1.10. Transition to a modern profession 12 3.5. Kratom (Mitragyna speciosa), a
1.11. The era of Count and Pour 13 controversial psychoactive plant 52
1.12. The emergence of clinical pharmacy 14 3.6. Concluding remarks 53
1.13. The conflicting paradigms of References 54
pharmaceutical care and managed care 15
4. Natural products and derivatives as
1.14. The promise of a new century 15
1.15. The future 16 human drugs 59
1.16. History as a discipline 16 David J. Newman
1.17. Bibliographic notes 16
1.18. A chronology of pharmacy 20 4.1. Introduction 59
4.2. Agents against pain 59
2. Integrated approach to drug 4.3. Antiinfectives (antibacterial, antiparasitic,
nomenclature 23 and antiviral) 62
4.4. Anticancer agents 70
Amos O. Abioye 4.5. Conclusion 72
2.1. Introduction 23 References 72
2.2. The changing face of drug nomenclature 25
5. Medicinal Cannabis: an overview for
2.3. Principles of drug nomenclature 26
2.4. Types of drug nomenclature 28 health-care providers 75
2.5. Global cooperation on harmonization of Jason Wallach
drug nomenclature 29
2.6. The challenges of selecting INN 5.1. History of Cannabis use 75
for biologics 32 5.2. Clinical indications 77

ix
x Contents

5.3. Cannabis subjective effects 78 7.6. In silico prediction of protein ligand

5.4. “Stimulation versus couch lock?” 78 binding affinities by free energy methods 144
5.5. Formulations 78 7.7. Machine-learning approaches 147
5.6. Routes of ingestion 78 References 150
5.7. Product labeling 81
5.8. The endocannabinoid system 81 8. Pharmaceutical profiling 155
5.9. Pharmacology of phytocannabinoids 82
5.10. Mechanisms of action 84 Taiwo Olayemi Elufioye and Adeboye Adejare
5.11. ( 2 )-trans-Δ9-Tetrahydrocannabinol 86
8.1. Introduction 155
5.12. Cannabidiol 86
8.2. Pharmaceutical profiling in drug
5.13. Cannabinol 87
discovery 155
5.14. ( 2 )-trans-Δ8-Tetrahydrocannabinol 87
8.3. Profiling of active pharmaceutical
5.15. Propyl, butyl, and heptyl
ingredients and drug products’
phytocannabinoid homologs 88
degradants 156
5.16. Phytocannabinoid acids 90
8.4. Pharmaceutical profiling in drug
5.17. Terpenes 90
development 157
5.18. Additional small molecule components
8.5. Pharmaceutical profiling in
in Cannabis 91
pharmacokinetics and
5.19. The entourage effect 91
pharmacodynamics 158
5.20. Adverse effects 93
8.6. Pharmaceutical profiling in toxicology
5.21. Pharmaceutical cannabinoid products 94
and adverse drug reactions 158
5.22. Conclusion 95
8.7. Methods in pharmaceutical profiling 159
References 95
8.8. Absorption, distribution, metabolism,
and excretion prediction models
Section 3 and methodologies 161
Pharmaceutical Chemistry 8.9. Methods in toxicity prediction 162
Adeboye Adejare 8.10. Automation in pharmaceutical profiling 162
8.11. Concluding remarks 162
References 162
6. Pharmaceutical chemistry 105
Anush Abelian, Michael Dybek, Jason Wallach, 9. Prodrugs 169
Boyenoh Gaye and Adeboye Adejare
Zeynep Ates-Alagoz and Adeboye Adejare
6.1. Introduction 105
9.1. Introduction 169
6.2. Functional groups 105
9.2. Prodrug approaches based on drug
6.3. Acids and bases 110
delivery 170
6.4. Salts 119
9.3. Prodrug approaches based on functional
6.5. Structural determinants of drug action 121
groups 171
6.6. Intermolecular forces of attraction 123
9.4. Prodrug approaches for anticancer drugs 173
6.7. Quantitative structure activity
9.5. Summary 182
relationship studies 125
References 182
6.8. Inorganic pharmaceutical chemistry 127
6.9. Drugs 127
6.10. Excipients 128 10. Fundamentals of medical
References and further reading 128 radionuclides 187
7. Structure activity relationships and Jeffrey P. Norenberg
drug design 129 10.1. Applications of radionuclides in medicine
Eleonora Gianti and Randy J. Zauhar and pharmacy 187
10.2. Radioactivity and radiation 188
7.1. Introduction 129 10.3. The atom 189
7.2. Analog approach 130 10.4. Radioactive decay 191
7.3. Chemical space 132 10.5. Production of radionuclides 195
7.4. Quantitative structure activity 10.6. Radiolabeling of compounds to prepare
relationships 139 radiotracers and radiopharmaceuticals 199
7.5. Molecular docking for virtual screening 142 Bibliography 204
 Contents xi

Section 4 14. Model-informed drug development

Pharmacokinetics/Pharmacodynamics and discovery: an overview of current
Islam M. Ghazi practices 263
Mohamed Elmeliegy and Oliver Ghobrial
11. The science of pharmacokinetics: an
overview and applications 207 14.1. Current drug-development challenges 263
14.2. Model-informed drug development:
Islam M. Ghazi and Michael J. Cawley virtual reality meets drug discovery
and development 264
11.1. Introduction 207
14.3. Model-informed drug development
11.2. Evolution of pharmacokinetics 207
tools and approaches 265
11.3. Drug-development concepts 212
14.4. Applications of model-informed drug
11.4. Clinical application 214
development tools in different phases
11.5. Future developments 215
of drug development 272
11.6. Conclusion 215
Acknowledgments 277
References 215
Disclosures 277
References 277
12. Principles of pharmacokinetics and
pharmacodynamics 219
Section 5
Brian R. Overholser and Kevin M. Sowinski Pharmaceutics
12.1. Introduction 219 Simon Gaisford
12.2. Drug concentration versus time profile 219
12.3. Rates and orders of reactions 221 15. Preformulation 283
12.4. Intravenous bolus with instantaneous
distribution 221 Simon Gaisford
12.5. Intravenous bolus with noninstantaneous 15.1. The concept of preformulation 283
distribution 224 15.2. Physicochemical properties 283
12.6. Continuous input 227 15.3. Solubility 283
12.7. Multiple-dose administration 228 15.4. Partitioning 289
12.8. Noncompartmental analysis following 15.5. Dissolution rate 291
instantaneous input 228 15.6. Powder properties 293
12.9. Statistical moments 229 15.7. Compaction 294
12.10. Pharmacokinetic parameters derived 15.8. Summary 294
from statistical moments 229 References 294
12.11. Absorption 230
12.12. Organ-specific clearance 232 16. Powder characterization 295
12.13. Protein binding 235
12.14. Dose- and time-dependent Asma Buanz
pharmacokinetics 236 16.1. Introduction 295
12.15. Stereochemical considerations 237 16.2. Particle shape 295
12.16. Kinetics of pharmacologic effect 238 16.3. Particle diameter and particle-size
References 241 distribution 296
Further reading 242 16.4. Particle size analysis methods 298
16.5. Powder properties 301
13. Therapeutic drug monitoring 243 References 304
James M. Kidd, Tomefa E. Asempa and 17. Salt selection 307
Kamilia Abdelraouf
Simon Gaisford
13.1. Rationale for therapeutic drug
monitoring 243 17.1. The need for pharmaceutical salts 307
13.2. Practical considerations for therapeutic 17.2. The chemistry of salt formation 307
drug monitoring 244 17.3. Selection of a salt former 309
13.3. Drugs for which therapeutic drug 17.4. Salt screening 311
monitoring is performed 245 17.5. Salt solubility 311
References 259 17.6. Solubility of basic salts 311
xii Contents

17.7. Solubility of acidic salts 312 21.7. Semisolids 384

17.8. The importance of pHmax 312 21.8. Biphasic semisolids 386
17.9. Dissolution of salts 313 21.9. Packaging and labeling 387
17.10. Effect of excipients on pHm 313 21.10. Other dosage forms for application to
17.11. Partitioning of salts 313 the skin and its appendages 388
17.12. Summary 314 21.11. Rectal, vaginal, and urethral routes
References 314 of administration 389
References 392
18. Physical form 315
Gareth R. Williams
Section 6
18.1. Introduction 315
18.2. Particle size and shape 316
Biopharmaceutics
Zhiyu Li
18.3. Crystalline materials 316
18.4. Amorphous materials 324
18.5. Characterization 327 22. Biotechnology and drugs 397
18.6. Summary 332
Michelle Parker and Zhiyu Li
References 332
22.1. Biotechnology 397
19. Solid oral dosage forms 333 22.2. Biopharmaceuticals 401
Atheer Awad, Sarah J. Trenfield and 22.3. Biopharmaceutical research and
Abdul W. Basit development 408
22.4. Remarks 413
19.1. Introduction 333 References 413
19.2. Tablets 333
19.3. Types of tablets 334
19.4. Tablet compression 342
23. Therapeutic antibody discovery 417
19.5. Tablet excipients 343 Jaclyn M. Hoover, Elisabeth G. Prinslow,
19.6. Tablet formulation examples 347 Jeffrey E. Teigler, Matthew D. Truppo and
19.7. Tablet characterization 349 Sherry L. La Porte
19.8. Capsules 351
19.9. Capsule characterization 356 23.1. Introduction 417
References 356 23.2. Antibody generation 419
23.3. Hit and lead generation 423
20. Liquid dosage forms 359 23.4. Antibody lead optimization 427
23.5. Lead selection 432
Atheer Awad, Christine M. Madla, 23.6. Future directions 432
Francesca K.H. Gavins, Nour Allahham, Disclosure 432
Sarah J. Trenfield and Abdul W. Basit
References 433
20.1. Introduction 359
20.2. Monophasic liquids 360
24. Therapeutic antibody development—
20.3. Biphasic liquids 367
20.4. Quality control 374 Remington chapter 437
20.5. Applications 374 Brian Geist, Songmao Zheng and Yan Xu
References 377
24.1. Introduction 437
21. Medicated topicals 381 24.2. Background of therapeutic
antibodies 437
Purnima D. Amin, Bahijja Tolulope Raimi-Abraham,
24.3. Nonclinical development of therapeutic
Devanshi S. Shah and Sharda Gurram
antibodies 444
21.1. Introduction 381 24.4. Clinical development of therapeutic
21.2. Skin as a site for drug delivery 381 antibodies 453
21.3. Drug delivery to the skin: basic 24.5. Conclusion/future direction 457
principles 382 Acknowledgments 458
21.4. Topical drug classification system 383 Disclosure 458
21.5. Formulation considerations 383 Abbreviations 458
21.6. Formulation of topical dosage forms 384 References 458
 Contents xiii

25. Gene and cell therapy 463 28.7. Intravitreal injections/implants 571
28.8. Juxtascleral injections 572
Jieni Xu, Bing Wang and Song Li 28.9. Intracameral injections 572
25.1. Preface 463 28.10. Iontophoresis 572
25.2. Gene therapy 464 28.11. Subconjunctival injections 572
25.3. Cell therapy 478 28.12. Retrobulbar injections 572
25.4. Ethical issues 485 28.13. Ophthalmic preparation characteristics 573
25.5. Marketing and funding 486 28.14. Packaging 573
25.6. Progress and perspective 487 28.15. Antimicrobial preservatives 573
References 487 28.16. Summary 574
References 574
26. Protein drug production and
29. Parenteral preparations 577
formulation 489
Mangal Shailesh Nagarsenkar and
Izabela Gierach, Jackelyn M. Galiardi, Vivek Vijay Dhawan
Brian Marshall and David W. Wood
29.1. Introduction 577
26.1. Biologics versus synthetics—basic 29.2. Advantages of parenteral route and
definitions and history 489 formulations 577
26.2. Complexity and regulatory 29.3. Concerns with parenteral route and
considerations 490 formulations 577
26.3. Biologics manufacturing processes 524 29.4. Considerations for formulation
26.4. Special notes on biosimilars 540 development of parenterals 578
References 545 29.5. Formulation components 578
29.6. Containers and closures 581
Section 7 29.7. Pyrogens (endotoxins) and
depyrogenation 586
Pharmaceutical Materials and 29.8. General considerations—production
Devices/Industrial Pharmacy facilities 587
Purnima Dhanraj Amin 29.9. Personnel 591
29.10. Environmental control evaluation 591
27. Coating of pharmaceutical dosage 29.11. Process simulation testing by media fill 592
forms 551 29.12. Manufacturing of parenteral product 592
29.13. Quality assurance and control 600
Stuart C. Porter References 602
Further reading 603
27.1. Introduction 551
27.2. Evolution of coating processes 551
27.3. Pharmaceutical coating processes 552
30. Pulmonary, Nasal, and Topical Aerosol
27.4. Film coating of oral solid dosage forms 552 Drug Delivery Systems 605
27.5. Coating procedures and equipment 557 Mala Menon, Richard N. Dalby, Isha Naik,
27.6. Coating pans 558 Hemali Savla and Kaveri Kalola
27.7. Fluidized-bed coating equipment 560
27.8. Recent trends in film-coating processes 562 30.1. Introduction 605
References 564 30.2. Modes of drug delivery to the
respiratory tract 606
28. Ophthalmic preparations 565 30.3. Important considerations in the design
of pulmonary aerosol systems 606
Furqan A. Maulvi, Ketan M. Ranch,
Ankita R. Desai, Ditixa T. Desai and 30.4. General aerosol formulation principles 607
Manish R. Shukla 30.5. Aerosol formulation components 614
30.6. Manufacture of pressurized aerosol
28.1. Introduction 565 products 618
28.2. Bioavailability 565 30.7. Product testing 619
28.3. Types of ophthalmic dosage forms 568 30.8. Human factors 620
28.4. Drug administration 570 30.9. Future of aerosols and inhaled
28.5. Irrigating solutions 571 drug therapy 622
28.6. Intraocular injections 571 Further reading 622
xiv Contents

31. Nanotechnology 623 Section 8

Varsha Pokharkar and Krutika Khanderao Sawant Topics in Translational Research
Michael S. Saporito
31.1. Introduction toward a definition 623
31.2. Types of nanomaterials 623
31.3. Manufacturing technologies 625
35. Translational research—from basic
31.4. Characterization of nanoparticles 627 science to an approved
31.5. Applications of nanoparticles in therapeutic—an overview 663
medicine 627
Michael S. Saporito
31.6. Toxicity of nanoparticles 630
31.7. Regulatory aspects of nanoparticles 630 35.1. Introduction to translational research 663
References 630 35.2. Drug discovery—hit to lead to optimized
drug candidate 666
32. Pharmaceutical excipients 633 35.3. Drug testing in humans 672
35.4. Case studies 674
Heeshma Shah, Ankitkumar Jain, 35.5. Summary 678
Geetanjali Laghate and Divya Prabhudesai References 679
32.1. Introduction to excipients 633
32.2. Solid oral dosage forms 633 36. Translation of gene therapies 683
32.3. Liquid oral dosage forms 637
Richard Thomas Layer
32.4. Parenteral dosage forms 638
32.5. Ophthalmic and otic dosage forms 639 36.1. Introduction 683
32.6. Nasal 640 36.2. Mechanisms of action 683
32.7. Inhalation 640 36.3. Delivery vector 684
32.8. Topical 641 36.4. Adeno-associated virus 685
32.9. Rectal and vaginal 642 36.5. Mode of delivery 687
32.10. Medical devices 643 36.6. Proof of concept studies 688
32.11. Conclusion 643 36.7. Preclinical safety evaluation 688
References 643 36.8. Quality and manufacturing
considerations 689
33. Hot-melt extrusion: a versatile 36.9. Clinical trials 690
36.10. Examples of successful gene therapy
technology 645
translation programs 691
Mohammed Maniruzzaman and Jaywant Pawar 36.11. Summary 696
References 696
33.1. Introduction 645
33.3. Hot-melt extrusion Instrumentation and 37. Large-scale molecular profiling
other details 646
33.4. Applications of hot-melt extrusion 648 approaches facilitating
33.5. Conclusion 652 translational medicine: genomics,
References 652 transcriptomics, proteomics, and
metabolomics 699
34. Process validation in pharmaceutical
manufacturing 655 Felix W. Frueh and Michael E. Burczynski

Pirthi Pal Singh 37.1. The concept of forward and reverse

translational medicine studies, and the
34.1. Introduction 655 relevance of OMIC technologies 699
34.2. Background 655 37.2. Drug development tools (such as
34.3. Approach to process validation 655 biomarkers) can be identified with
34.4. Documentation 659 OMIC technologies 700
34.5. Conclusion 659 37.3. Translational medicine principles for
Disclaimer 659 enhancing drug development probability
References 659 of success 701
 Contents xv

37.4. A brief introduction to OMIC technologies 40.2. Role of the medication safety leader 749
of the central dogma: 40.3. Medication safety analysis 749
DNA-RNA-protein-(metabolite) 703 40.4. Error-reduction strategies 752
37.5. Systems biology: creating context by 40.5. Medication safety practices 753
putting the “OMES” together 715 40.6. Patient Safety and Medication
37.6. A final word—considerations regarding Safety Organizations 756
publicly available OMICS data in silico 716 40.7. Conclusion 757
37.7. Summary 716 References 757
References 717
41. Substance use disorders 759
38. Neurobiologic correlates of depression:
illustration of challenges in bench-to- Daniel J. Ventricelli and Andrew M. Peterson
bedside translation 719 41.1. Introduction 759
41.2. Definitions 760
Bruce Edward Jones
41.3. At-risk populations 761
38.1. Introduction 719 41.4. Addressing the problem 762
38.2. Defining the patient population 720 41.5. Specific substance use 763
38.3. Cultural impact on defining 41.6. Pharmacists role 766
neuropsychiatric disease 720 41.7. Conclusion 767
38.4. Hurdles to basic and translational References 767
research 721
38.5. Models of neuropsychiatric disease 721 42. Global trends in pharmacy practice 769
38.6. Genomics in depression 727
Claire Anderson
38.7. Antidepressant targets beyond serotonin 729
38.8. Summary 731 42.1. Introduction 769
References 731 42.2. Primary care and universal health
coverage 770
Section 9 42.3. Prevention 775
42.4. Pharmacists role in disease management 775
Pharmacy Practice 42.5. Pharmacist prescribing 777
Grace L. Earl
42.6. Collaborating with other health
professionals 777
39. Pharmacy and patient centered 42.7. Public health roles 777
care 737 42.8. Competency and credentialing to
provide services and advance practice 778
Kimberly A. Galt 42.9. Advancing community pharmacy
39.1. What is patient centered care? 737 globally 778
39.2. Why is patient-centered care needed? 737 References 779
39.3. History of patient centered care 738 Further reading 780
39.4. Future trends in the United States 738
39.5. Considerations affecting pharmacists 43. Value-based payment models
provision of patient-centered care 738 involving pharmaceutical services 781
39.6. Barriers and gaps 741
39.7. Patients, pharmacists, and settings Jing Yuan and Laura T. Pizzi
where patient-centered care is practiced 742 43.1. Introduction 781
39.8. Education and training 746 43.2. Approaches toward improving
39.9. Conclusion 747 health-care value 781
References 747 43.3. Approaches toward improving
health-care value 784
40. Medication safety and medication References 787
error prevention 749
44. Role of the pharmacist in research 789
Michael Claro Dejos
Lisa E. Davis and Sandipan Bhattacharjee
40.1. State of medication safety and
recent advances 749 44.1. Introduction 789
xvi Contents

44.2. What constitutes research? 789 48. Specialty pharmacy services 829
44.3. Roles for pharmacists in research 790
44.4. Implementation science 796 Vivianne K. Celario and Pinal Mistry
44.5. Preparing for careers in research 796 48.1. Practice models and services 830
44.6. Tips for success in pursuing research 797 48.2. Trends and impact 832
44.7. Tips for conducting and assessing 48.3. Stakeholders 832
outcomes research 798 48.4. Technology 833
44.8. Conclusion 798 48.5. Barriers and challenges 833
References 799 48.6. Organizational oversight 834
48.7. Education and training 834
45. Trends in nutrition practice 801 48.8. Resources 835
Diana M. Solomon and Angela L. Bingham 48.9. Conclusion 835
References 835
45.1. Introduction 801
45.2. Overview 801
45.3. Nutrition practice models 802 49. Pharmacy involvement in medical
45.4. Evidence-based medicine 803 missions 837
45.5. Factors leading to transformation
and innovation 804 Mary J. Ferrill
45.6. Oversight by relevant organizations 805
45.7. Education and training 805 49.1. Introduction 837
45.8. Barriers and gaps 806 49.2. Planning logistics 837
45.9. Resources 809 49.3. Health-care logistics 839
45.10. Conclusion 809 49.4. Integrating medical missions into
References 809 pharmacy education 844
49.5. Conclusion 847
46. Medication disposal 811 References 847

Annette McFarland and Amy Sutton Peak

50. Pharmacists’ role in infectious
46.1. Introduction 811
46.2. Hazardous waste 811 pandemics: illustration with
46.3. Household disposal of medications 812 COVID-19 849
46.4. Minimization of pharmaceutical waste 814
Grace Earl, Lisa M. Cillessen,
46.5. Conclusion 814
Heather Lyons-Burney, Paul O. Gubbins,
References 815
Andrew W. Mina, David M. Silverman,
Further reading 815 Carmela M. Silvestri and Maria Leibfried
47. Pharmacist use of point-of-care testing 50.1. Introduction 849
to improve access to care 817 50.2. Pharmacists’ response to
COVID-19 850
Lisa M. Cillessen, Heather Lyons-Burney and 50.3. Pharmacy scope of practice 851
Paul O. Gubbins 50.4. Pharmacists’ response in the
community 851
47.1. Introduction 817
50.5. COVID-19 treatments and medication
47.2. Community pharmacy based
safety 853
CLIA-POCT services 818
50.6. Pharmacists’ role in point-of-care
47.3. Pharmacy-based CLIA-POCT testing in
testing for COVID-19 855
the ambulatory care setting 821
50.7. Pharmacists’ response in critical care
47.4. Cost-effectiveness of pharmacist-
and healthcare systems 860
provided CLIA-POCT testing 823
50.8. Pharmacists’ response in long-term
47.5. Future ways pharmacist-provided
care settings 867
CLIA-POCT testing can improve
50.10. Conclusion 872
access to care 824
References 873
References 826
 Contents xvii

Section 10 54. Pharmacoeconomics 915

Pharmaceutical Outcomes and T. Joseph Mattingly II
Policy 54.1. Overview 915
Jeff Talbert
54.2. Perspectives 917
54.3. Designing an economic analysis 917
51. Health policy and pharmacy 879 54.4. Measuring costs 919
54.5. Measuring health effects 919
Nathan Pauly and Amie Goodin
54.6. Analysis considerations 921
51.1. Section 1: Introduction to health policy 54.7. Reporting and interpreting results 922
in pharmacy 879 54.8. Discussion 926
51.2. Section 2: Pharmacist participation in References 926
the policy process—vaccinations and
the advancement of the profession 881 55. Laws governing the practice of
51.3. Section 3: The pharmacists’ role in pharmacy 929
substance use disorder policy 882
Karl G. Williams
51.4. Section 4: Opioid use disorder
policy levers 883 55.1. Relationship between state and
51.5. Conclusion 886 federal law 929
References 887 55.2. Definitions 931
55.3. Rules and regulations 932
52. Implementation and evaluation of 55.4. Entry-level competence: licensing
pharmacy services 889 exams 932
55.5. Transfer of an existing license:
Jacob T. Painter and Geoff Curran “reciprocity” 933
55.6. Nuclear pharmacy 933
52.1. Introduction 889
55.7. Pharmaceutical care 933
52.2. Implementation of pharmacy services 889
55.8. Remote pharmacy practices 934
52.3. Evaluation of pharmacy services 893
55.9. Prescription drug order 934
52.4. Conclusion 897
55.10. Transfer of a prescription drug order 935
References 897
55.11. Product selection by the pharmacist 935
55.12. Hypodermic needles and syringes 935
53. Pharmacoepidemiology and 55.13. Pharmacy licensing and regulation 936
pharmacovigilance 899 55.14. Pharmacy licensing and facilities 936
55.15. Pharmacy supervision 936
Chris Delcher, Daniela Moga, Yan Li, 55.16. Compounding 936
Monica Muñoz, Minji Sohn and 55.17. Outsourcing facilities 937
Jungjun Bae
55.18. Federal laws 938
53.1.Introduction 899 55.19. Historical background of the act 938
53.2.Common study types 902 55.20. Drug approval process 940
53.3.Randomized controlled trial 903 55.21. Liability under the Food, Drug, and
53.4.Cohort studies 903 Cosmetic Act 943
53.5.Case control study 905 55.22. Recordkeeping under the Food, Drug,
53.6.Cross-sectional and ecological and Cosmetic Act 944
studies 905 55.23. Prescription labeling 944
53.7. Measurements 906 55.24. Package inserts/professional product
53.8. Bias 908 labeling 944
53.9. Confounding 909 55.25. Patient package inserts or (“PPI”) 945
53.10. Communicating change 911 55.26. Unit-dose labeling 946
53.11. Summary 911 55.27. Regulation of dietary supplements 946
References 911 55.28. Drug recalls 947
Additional resources 913 55.29. Prescription Drug Marketing Act 949
xviii Contents

55.30. Misbranding and adulteration 950 56. Drug distribution system 967
55.31. Misbranded drugs 951
55.32. Poisons 952 Minji Sohn
55.33. The Comprehensive Drug Abuse 56.1. Health-care delivery and third-party
Prevention and Control Act of 1970 954 payers 967
55.34. Prescriptions 960 56.2. Drug distribution and pharmacy
55.35. Miscellaneous controlled substance reimbursement 971
issues 963 References 973
55.36. Liability for negligent acts 963
Further reading 965 Index 975
List of contributors
Kamilia Abdelraouf, Center for Anti-Infective Research
and Development, Hartford Hospital, Hartford, CT,
United States
Anush Abelian, Department of Chemistry and
Biochemistry, Misher College of Arts and Sciences,
University of the Sciences, Philadelphia, PA, United States
Amos O. Abioye, Lloyd L. Gregory School of
Pharmacy, Palm Beach Atlantic University, West Palm
Beach, FL, United States
Adeboye Adejare, Department of Pharmaceutical
Sciences, Philadelphia College of Pharmacy, University
of the Sciences, Philadelphia, PA, United States;
Department of Chemistry and Biochemistry, Misher
College of Arts and Sciences, University of the
Sciences, Philadelphia, PA, United States
Nour Allahham, UCL School of Pharmacy, University
College London, London, United Kingdom
Purnima D. Amin, Department of Pharmaceutical
Sciences and Technology, Institute of Chemical
Technology, Mumbai, India
Claire Anderson, Division of Pharmacy Practice and
Policy, School of Pharmacy, University of
Nottingham, Nottingham, United Kingdom
Tomefa E. Asempa, Center for Anti-Infective Research
and Development, Hartford Hospital, Hartford, CT,
United States
Zeynep Ates-Alagoz, Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Ankara University,
Ankara, Turkey; Department of Pharmaceutical
Sciences, Philadelphia College of Pharmacy,
University of the Sciences in Philadelphia,
Philadelphia, PA, United States
Atheer Awad, UCL School of Pharmacy, University
College London, London, United Kingdom
Jungjun Bae, Institute for Pharmaceutical Outcomes and
Policy, College of Pharmacy, University of Kentucky,
Lexington, KY, United States
Abdul W. Basit, UCL School of Pharmacy, University
College London, London, United Kingdom
Sandipan Bhattacharjee, Health Outcomes Division,
College of Pharmacy, The University of Texas at
Austin, Austin, TX, United States
Angela L. Bingham, Philadelphia College of Pharmacy,
University of the Sciences, Philadelphia, PA, United
States
Asma Buanz, School of Pharmacy, University College
London, London, United Kingdom
Michael E. Burczynski, Department of Pharmacology,
University of Pennsylvania, Philadelphia, PA, United
States
Esperanza J. Carcache de Blanco, Medicinal Chemistry
and Pharmacognosy, College of Pharmacy, The Ohio
State University, Columbus, OH, United States
Michael J. Cawley, Philadelphia College of Pharmacy/
University of the Sciences, Philadelphia, PA, United States
Vivianne K. Celario, Pharmacy, Walgreens and Rutgers
University, New Brunswick, NJ, United States
Lisa M. Cillessen, University of Missouri-Kansas City,
School of Pharmacy at Missouri State University,
Springfield, MO, United States
Geoff Curran, Center for Mental Healthcare &
Outcomes Research, Central Arkansas Veterans
Healthcare System, Little Rock, AR, United States;
Departments of Pharmacy Practice and Psychiatry,
Center for Implementation Research, University of
Arkansas for Medical Sciences, Little Rock, AR,
United States
Richard N. Dalby, Department of Pharmaceutical
Sciences, School of Pharmacy, University of
Maryland, Baltimore, MD, United States
Lisa E. Davis, Pharmacy Practice & Science, University
of Arizona, Tucson, AZ, United States; Pharmacy,
Banner University Medical Center, Tucson, AZ,
United States
Michael Claro Dejos, Department of Patient Safety,
Methodist Le Bonheur Healthcare, Memphis, TN,
United States
xix
xx List of contributors
Chris Delcher, Department of Pharmacy Practice and
Science, College of Pharmacy, University of
Kentucky, Lexington, KY, United States
Ankita R. Desai, Maliba Pharmacy College, Uka
Tarsadia University, Surat, India
Ditixa T. Desai, Maliba Pharmacy College, Uka Tarsadia
University, Surat, India
Vivek Vijay Dhawan, IPA-MSB’s Bombay College of
Pharmacy, Mumbai, India
Michael Dybek, Department of Chemistry
Biochemistry, Misher College of Arts and Sciences,
University of the Sciences, Philadelphia, PA, United States
Grace Earl, Fairleigh Dickinson University, School of
Pharmacy and Health Sciences, Florham Park, NJ,
United States
Mohamed Elmeliegy, Pfizer, Inc., San Diego, CA,
United States
Taiwo Olayemi Elufioye, Faculty of Pharmacy,
University of Ibadan, Ibadan, Nigeria; Department of
Pharmaceutical Sciences, Philadelphia College of
Pharmacy, University of the Sciences, Philadelphia,
PA, United States
Mary J. Ferrill, College of Pharmacy, Taipei Medical
University, Davenport, FL, United States
Felix W. Frueh, Opus Three, Del Mar, CA, United
States
Simon Gaisford, UCL School of Pharmacy, University
College London, London, United Kingdom
Jackelyn M. Galiardi, Department of Chemical and
Biomolecular Engineering, The Ohio State University,
Columbus, OH, United States
Kimberly A. Galt, School of Pharmacy and Health
Professions, Creighton University, Omaha, NE, United
States
Francesca K.H. Gavins, UCL School of Pharmacy,
University College London, London, United
Kingdom
Boyenoh Gaye, Department of Pharmaceutical Sciences,
Philadelphia College of Pharmacy, University of the
Sciences, Philadelphia, PA, United States
Brian Geist, Biologics Development Sciences, Janssen
Research and Development, LLC., Spring House, PA,
United States
Islam M. Ghazi, Philadelphia College of Pharmacy/
University of the Sciences, Philadelphia, PA, United States
Oliver Ghobrial, Teva Branded Pharmaceuticals R&D,
West Chester, PA, United States
Eleonora Gianti, Department of Chemistry and
Biochemistry, Swarthmore College, Swarthmore, PA,
United States; College of Science and Technology,
Temple University, Philadelphia, PA, United States
Izabela Gierach, Protein Capture Science, LLC, Dublin,
OH, United States
Amie Goodin, Department of Pharmaceutical Outcomes
and Policy, University of Florida, Gainesville, FL,
United States; Center for Drug Evaluation and Safety
(CoDES), Gainesville, FL, United States
and
Paul O. Gubbins, University of Missouri-Kansas City,
School of Pharmacy at Missouri State University,
Springfield, MO, United States
Sharda Gurram, Department of Pharmaceutical
Sciences and Technology, Institute of Chemical
Technology, Mumbai, India
Gregory J. Higby, School of Pharmacy, University of
Wisconsin-Madison, Madison, WI, United States;
American Institute of the History of Pharmacy,
Madison, WI, United States
Jaclyn M. Hoover, Biologics Discovery, Janssen
Research and Discovery, LLC., Spring House, PA,
United States
Ankitkumar Jain, Signet Excipients Pvt. Ltd, Mumbai,
India
Bruce Edward Jones, Research and Development, CSO
Score Pharma Inc., Exton, PA, United States
Kaveri Kalola, Department of Phamaceutics, Bombay
College of Pharmacy, Mumbai, India
James M. Kidd, Center for Anti-Infective Research and
Development, Hartford Hospital, Hartford, CT, United
States
A. Douglas Kinghorn, Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, The Ohio State
University, Columbus, OH, United States
Geetanjali Laghate, Signet Excipients Pvt. Ltd,
Mumbai, India
Sherry L. La Porte, Biologics Discovery, Janssen
Research and Discovery, LLC., Spring House, PA,
United States
Richard Thomas Layer, Research & Development,
Ganglion Therapeutics, New York, NY, United States
Maria Leibfried, Fairleigh Dickinson University, School
of Pharmacy and Health Sciences, Florham Park, NJ,
United States
Song Li, Center for Pharmacogenetics, Department of
Pharmaceutical Sciences, School of Pharmacy,
University of Pittsburgh, Pittsburgh, PA, United States

Yan Li, Department of Pharmaceutical Outcomes and
Policy, College of Pharmacy, University of Florida,
Gainesville, FL, United States; Division of
Pharmacovigilance I, Office of Surveillance and
Epidemiology, Center for Drug Evaluation and
Research, U.S. Food and Drug Administration, Silver
Spring, MD, United States
Zhiyu Li, Department of Pharmaceutical Sciences,
Philadelphia College of Pharmacy, University of the
Sciences, Philadelphia, PA, United States
Heather Lyons-Burney, University of Missouri-Kansas
City, School of Pharmacy at Missouri State University,
Springfield, MO, United States
Christine M. Madla, UCL School of Pharmacy,
University College London, London, United Kingdom
Mohammed Maniruzzaman, Pharmaceutical Engineering
and 3D Printing (PharmE3D) Labs, Division of
Molecular Pharmaceutics and Drug Delivery, College
of Pharmacy, University of Texas at Austin, Austin,
TX, United States
Brian Marshall, Department of Chemical and
Biomolecular Engineering, The Ohio State University,
Columbus, OH, United States
T. Joseph Mattingly II, University of Maryland School
of Pharmacy, Baltimore, MD, United States
Furqan A. Maulvi, Maliba Pharmacy College, Uka
Tarsadia University, Surat, India
Annette McFarland, College of Pharmacy and Health
Sciences, Butler University, Indianapolis, IN, United States
Mala Menon, Department of Phamaceutics, Bombay
College of Pharmacy, Mumbai, India
Andrew W. Mina, St. Michael’s Medical Center, Staten
Island, NY, United States
Pinal Mistry, Pharmacy Revenue Integrity, Corporate
Pharmacy Services, OhioHealth, Columbus, OH,
United States
Daniela Moga, Department of Pharmacy Practice and
Science, College of Pharmacy, University of
Kentucky, Lexington, KY, United States;
Epidemiology, College of Public Health, University of
Kentucky, Lexington, KY, United States
Monica Muñoz, Division of Pharmacovigilance I, Office
of Surveillance and Epidemiology, Center for Drug
Evaluation and Research, U.S. Food and Drug
Administration, Silver Spring, MD, United States
Mangal Shailesh Nagarsenkar, IPA-MSB’s Bombay
College of Pharmacy, Mumbai, India; VES College of
Pharmacy, Mumbai, India
Isha Naik, Department of Phamaceutics, Bombay
College of Pharmacy, Mumbai, India
List of contributors xxi
David J. Newman, Newman Consulting LLC, Wayne,
PA, United States
Jeffrey P. Norenberg, Chemistry, Invicro—A Konica
Minolta Company, Boston, MA, United States; Pharmacy
and Anesthesiology, University of New Mexico Health
Sciences Center, Albuquerque, MA, United States
Brian R. Overholser, Department of Pharmacy Practice,
College of Pharmacy, Purdue University, West
Lafayette and Indianapolis, IN, United States; Division
of Clinical Pharmacology, Department of Medicine,
School of Medicine, Indiana University, Indianapolis,
IN, United States
Jacob T. Painter, Division of Pharmaceutical Evaluation
& Policy, Department of Pharmacy Practice,
University of Arkansas for Medical Sciences, Little
Rock, AR, United States; Center for Mental Healthcare
& Outcomes Research, Central Arkansas Veterans
Healthcare System, Little Rock, AR, United States
Michelle Parker, Thermo Fisher Scientific, Waltham,
MA, United States
Nathan Pauly, Office of Health Affairs, West Virginia
University, Morgantown, WV, United States
Jaywant Pawar, Department of Pharmaceutical Sciences
and Technology, Institute of Chemical Technology
Mumbai, Mumbai, India
Amy Sutton Peak, College of Pharmacy and Health
Sciences, Butler University, Indianapolis, IN, United States
Andrew M. Peterson, Philadelphia College of
Pharmacy, University of the Sciences in Philadelphia,
Philadelphia, PA, United States
Laura T. Pizzi, Center for Health Outcomes, Policy, and
Economics (HOPE), Ernest Mario School of Pharmacy,
Rutgers University, Piscataway, NJ, United States
Varsha Pokharkar, Department of Pharmaceutics,
Poona College of Pharmacy, Bharati Vidyapeeth
(Deemed University), Pune, India
Stuart C. Porter, Pharmaceutical R&D, PPT Pharma
Technologies, Hatfield, PA, United States
Divya Prabhudesai, Signet Excipients Pvt. Ltd,
Mumbai, India
Elisabeth G. Prinslow, Biologics Discovery, Janssen
Research and Discovery, LLC., Spring House, PA,
United States
Bahijja Tolulope Raimi-Abraham, Institute of
Pharmaceutical Science, School of Cancer and
Pharmaceutical Sciences, King’s College London,
London, United Kingdom
Ketan M. Ranch, Maliba Pharmacy College, Uka
Tarsadia University, Surat, India
xxii List of contributors
Michael S. Saporito, Intervir, LLC, Philadelphia, PA,
United States
Hemali Savla, Department of Phamaceutics, Bombay
College of Pharmacy, Mumbai, India
Krutika Khanderao Sawant, Department of Pharmacy,
Faculty of Pharmacy, The Maharaja Sayajirao
University of Baroda, Vadodara, India
Devanshi S. Shah, Department of Pharmaceutical
Sciences and Technology, Institute of Chemical
Technology, Mumbai, India
Heeshma Shah, Signet Excipients Pvt. Ltd, Mumbai, India
Manish R. Shukla, Maliba Pharmacy College, Uka
Tarsadia University, Surat, India
David M. Silverman, Prime Healthcare, Newark, NJ,
United States
Carmela M. Silvestri, Med-Therapy Consults LLC,
Flemington, NJ, United States
Pirthi Pal Singh, Associate Vice-President & Head R&D,
Differentiated Formulations, Proprietary Products, Dr.
Reddy’s Laboratories Ltd., Hyderabad, India
Minji Sohn, College of Pharmacy, Ferris State
University, Big Rapids, MI, United States; Department
of Pharmaceutical Science, College of Pharmacy,
Ferris State University, Big Rapids, MI, United States
Diana M. Solomon, Cooper University Hospital,
Camden, NJ, United States
Kevin M. Sowinski, Department of Pharmacy Practice,
College of Pharmacy, Purdue University, West
Lafayette and Indianapolis, IN, United States; Division
of Clinical Pharmacology, Department of Medicine,
School of Medicine, Indiana University, Indianapolis,
IN, United States
Jeffrey E. Teigler, Biologics Discovery, Janssen
Research and Discovery, LLC., South San Francisco,
CA, United States
Sarah J. Trenfield, UCL School of Pharmacy,
University College London, London, United Kingdom
Matthew D. Truppo, Biologics Discovery, Janssen
Research and Discovery, LLC., Spring House, PA,
United States
Benjamin Y. Urick, Practice Advancement and Clinical
Education (PACE), University of North Carolina
Eshelman School of Pharmacy (UNC ESOP), Chapel
Hill, USA
Daniel J. Ventricelli, Philadelphia College of Pharmacy,
University of the Sciences in Philadelphia,
Philadelphia, PA, United States
Jason Wallach, Department of Pharmaceutical Sciences,
Philadelphia College of Pharmacy, University of the
Sciences, Philadelphia, PA, United States; Substance
Use Disorders Institute, University of the Sciences,
Philadelphia, PA, United States
Bing Wang, Department of Orthopaedic Surgery, School
of Medicine, University of Pittsburgh, Pittsburgh, PA,
United States
Gareth R. Williams, UCL School of Pharmacy,
University College London, London, United Kingdom
Karl G. Williams, Professor of Pharmacy Ethics
and Law, St John Fisher College, Rochester, NY,
United States; Adjunct Professor of Pharmacy
Ethics and Law, Bernard J. Dunn School of
Pharmacy, Shenandoah University, Winchester, VA,
United States
David W. Wood, Protein Capture Science, LLC, Dublin,
OH, United States; Department of Chemical and
Biomolecular Engineering, The Ohio State University,
Columbus, OH, United States
Jieni Xu, Center for Pharmacogenetics, Department of
Pharmaceutical Sciences, School of Pharmacy,
University of Pittsburgh, Pittsburgh, PA, United States
Yan Xu, Clinical Pharmacology & Pharmacometrics,
Janssen Research and Development, LLC., Spring
House, PA, United States
Jing Yuan, Center for Health Outcomes, Policy, and
Economics (HOPE), Ernest Mario School of Pharmacy,
Rutgers University, Piscataway, NJ, United States
Randy J. Zauhar, Department of Chemistry and
Biochemistry, University of the Sciences, Philadelphia,
PA, United States
Songmao Zheng, Biologics Development Sciences,
Janssen Research and Development, LLC., Spring
House, PA, United States
Foreword—Remington 23rd edition
There is arguably no textbook that has been more influen-
tial on the profession of pharmacy than Remington: The
Science and Practice of Pharmacy. First Authored by
Joseph Remington in 1885, an eminent pharmacist and
long-serving faculty member and the second dean of
Philadelphia College of Pharmacy (PCP), the textbook
has been published continuously since then and as such, I
am proud to introduce the 23rd edition of Remington. As
an alumnus of PCP (now part of University of the
Sciences) and it’s 16th dean, I am particularly delighted
that the newest edition of Remington is being edited once
again by a PCP faculty member, Dr. Adeboye Adejare
who “moved mountains” to bring Remington to fruition.
Remington: The Science and Practice of Pharmacy
will be forever tied to the legacy of PCP and the profes-
sion of pharmacy. Joseph Remington was profoundly
influenced by William Proctor Jr—another PCP faculty
member—and considered by many to be the father of
American Pharmacy. Further, Remington is being pub-
lished to coincide with the 2021 bicentennial of the
founding of PCP, the first college of pharmacy in the
nation and often considered the birthplace of American
Pharmacy. There can be no better tribute to our
profession.
I found it profound that Professor Remington, in the
Preface to the first edition (a reproduction which is
included in this edition!), wrote, “The rapid and substan-
tial progress made in Pharmacy within the last decade has
created a necessity for a work treating of the improved
apparatus, the revised processes, and the recently
introduced preparations of the age.” Even more so than
the late 19th century, the profession continues to rapidly
evolve and Remington continues to serve us as both a
valuable reference text and a record of pharmacy’s prog-
ress over the last 135 years. Our profession is unique
among the sciences and health-care arenas in that it is
truly a science and practice profession. The original sec-
tions of Remington detailing the pharmaceutical apparatus
and the listings of inorganic and organic chemical sub-
stances of the day, which may seem irrelevant and foreign
to the contemporary pharmacist, have been replaced with
chapters such as therapeutic antibodies and molecular pro-
filing. In Remington’s time (and for many years thereaf-
ter) the practice of pharmacy was much closer aligned to
a shopkeeper than a health-care provider. The ever-
changing role of pharmacists in the direct care of patients
is elucidated in chapters such as point-of-care testing and
the role of the pharmacist in the COVID-19 pandemic.
This truly is a marvelous and comprehensive textbook!
For many seasoned pharmacists, Remington was the
pharmacy textbook. We no longer carry this massive
tome under our arms, but the book (in particular the elec-
tronic version!) will continue to inspire generations of stu-
dents, pharmacists, and pharmaceutical scientists for years
to come.
Edward F. Foote
Dean, Philadelphia College of Pharmacy,
University of the Sciences,
Philadelphia, PA, United States
xxiii
Preface to the first edition
The rapid and substantial progress made in pharmacy
within the last decade has created a necessity for a work
treating of the improved apparatus, the revised processes,
and the recently introduced preparations of the age.
The vast advances made in theoretical and applied
chemistry and physics have much to do with the develop-
ment of pharmaceutical science, and these have been
reflected in all the revised editions of the pharmacopoeias
which have been recently published. When the author was
elected in 1874 to the chair of Theory and Practice of
Pharmacy in the Philadelphia College of Pharmacy, the
outlines of study which had been so carefully prepared for
the classes by his eminent predecessors, Prof. William
Proctor, Jr. and Prof. Edward Parrish, were found to be
not strictly in accord, either in their arrangement of the
subjects or in their method of treatment. Desiring to pre-
serve the distinctive characteristics of each, an effort was
at once made to frame a system that should embody their
valuable features, embrace new subjects, and still retain
that harmony of plan and proper sequence which are
absolutely essential to the success of any system.
The strictly alphabetical classification of subjects
which is now universally adopted by pharmacopoeias and
dispensatories, although admirable in works of reference,
presents an effectual stumbling block to the acquisition of
pharmaceutical knowledge through systematic study; the
vast accumulation of facts collected under each head
arranged lexically, they necessarily have no connection
with one another, and thus the saving of labor effected by
considering similar groups together, and the value of the
association of kindred subjects, are lost to the student. In
the method of grouping the subjects which is herein
adopted, the constant aim has been to arrange the latter in
such a manner that the reader shall be gradually led from
the consideration of elementary subjects to those which
involve more advanced knowledge, while the groups
themselves are so placed as to follow one another in a
natural sequence.
The work is divided into six parts. Part I is devoted to
detailed descriptions of apparatus and definitions and
comments on general pharmaceutical processes.
The Official Preparations alone are considered in Part
II. Due weight and prominence are thus given to the
Pharmacopoeia, the National authority, which is now so
thoroughly recognized.
In order to suit the convenience of pharmacists who
prefer to weigh solids and measure liquids, the official
formulas are expressed, in addition to parts by weight, in
avoirdupois weight and apothecaries’ measure. These
equivalents are printed in bold type near the margin, and
arranged so as to fit them for quick and accurate
reference.
Part III treats inorganic chemical substances.
Precedence is of course given to official preparation in
these. The descriptions, solubilities, and tests for identity
and impurities of each substance are systematically tabu-
lated under its proper title. It is confidently believed that
by this method of arranging the valuable descriptive fea-
tures of the Pharmacopoeia will be more prominently
developed, read reference facilitated, and close study of
the details rendered easy. Each chemical operation is
accompanied by equations, while the reaction is, in addi-
tion, explained in words.
The carbon compounds, or organic chemical sub-
stances, are considered in Part IV. These are naturally
grouped according to the physical and medical properties
of their principal constituents, beginning with simple bod-
ies such as cellulin and gum and progressing to the most
highly organized alkaloids, etc.
Part V is devoted to extemporaneous pharmacy. Care
has been taken to treat the practice that would be best
adapted for the needs of the many pharmacists who con-
duct operations upon a moderate scale, rather than for
those of the few who manage very large establishments.
In this, as well as in other parts of the work, operations
are illustrated, which are conducted by manufacturing
pharmacists.
Part VI contains a formulary of pharmaceutical pre-
parations which have not been recognized by the pharma-
copoeia. The recipes selected are chiefly those which
have been heretofore rather difficult of access to most
pharmacists, yet such as are likely to be in request. Many
private formulas are embraced in the collection, and such
preparations of the old pharmacopoeias, that have not
been included in the new edition, but are still in use, have
been inserted.
xxv
xxvi Preface to the first edition
In conclusion the author ventures to express the hope
that the work will prove an efficient help to the pharma-
ceutical student as well as to the pharmacist and the phy-
sician. Although the labor has been mainly performed
amidst the harassing cares of active professional duties,
and perfection is known to be unattainable, no pains have
been spared to discover and correct errors and omissions
in the text. The author’s warmest acknowledgments are
tendered to Mr. A B Taylor, Mr. Joseph McCreery, and
Mr. George M Smith for their valuable assistance in revis-
ing the proof sheets and to the latter especially for his
work on the index. The outline illustrations, by Mr. John
Collins, were drawn either from the actual objects or from
photographs taken by the author.
JPR
Philadelphia, October, 1885
Preface to the 23rd edition
The 200th year anniversary of the founding of the
Philadelphia College of Pharmacy edition
It is indeed an honor and a career high to be able to lead
the development of the 200th year anniversary of the
founding of the Philadelphia College of Pharmacy (PCP)
edition of Remington: The Science and Practice of
Pharmacy. It is also the 23rd edition of Remington. This
fruition did not come without significant challenges and
obstacles. The first challenge was to truly examine
whether or not there is need for a compilation of this
nature and what such might look like, especially given the
easy access to information for free on the internet.
Another task was to carefully examine reasons why the
22nd edition was not well received. After consulting with
appropriate stakeholders, the findings were clear and
pointed to marching forward with this edition and we
decided to do so. A major development along the way
was ability to recruit one of the largest publishers,
Elsevier, Inc. to partner with us on the new Remington.
This fact is significant not just in the global availability of
the book but also in ability to utilize modern publishing
technologies, giving access to the whole book or just a
chapter, electronic or hard copy. The resulting book is
indeed true to Remington!
The Preface to the first edition in 1885 is reproduced
above for historical and relevance purposes. It is impor-
tant to note that while there have been many develop-
ments in the profession of pharmacy and the underlying
sciences in over a century between then and now, the
fundamentals remain same. To quote the first paragraph
of the 1885 Preface, “The rapid and substantial progress
made in Pharmacy within the last decade has created a
necessity for a work treating of the improved apparatus,
the revised processes, and the recently introduced pre-
parations of the age.” That statement is true of the new
Remington and topics of this “age” are “treated.” There
are indeed chapters dealing with new formulation and
manufacturing techniques, translational research, and nat-
ural products including medicinal cannabis. There are
also chapters dealing with modern issues including phar-
maceutical chemistry, prodrugs, biotechnology, protein
formulation, therapeutic antibody, specialty pharmacy,
substance use disorders, and health policy. As the work
was rounding up, the pandemic of 2020 [Coronavirus
SARS-CoV-2, Coronavirus Disease 2019 (COVID-19)]
became a reality and is thus addressed.
With PCP as anchor, we have been able to recruit edi-
tors and authors from all over the world consistent with
the mission of Remington. I indeed hope that you find the
compilation useful.
Adeboye Adejare
Philadelphia College of Pharmacy,
University of the Sciences, Philadelphia,
Pennsylvania, United States
October 2020
xxvii
Acknowledgments

I would like to gratefully acknowledge all those who have played roles in making this edition possible. I thank the edi-
tors and authors for a phenomenal job in spite of dealing with the current pandemic (COVID-19) and many other duties.
I thank the Dean of PCP, who also happens to be an alum of PCP, Dr. Edward Foote who has been very encouraging
on this journey; as well as my colleagues. I would also like to thank Kristine Jones for bringing me to the Elsevier fam-
ily as an author. With the success of the book “Drug Discovery Approaches for the Treatment of Neurodegenerative
Disorders: Alzheimer’s Disease,” there was no doubt in my mind as to where to go once deliberations about the new
edition of Remington began. I would like to thank the many colleagues at Elsevier, especially Barbara Makinster, Erin
Hill-Parks, and Sreejith Viswanathan. It has been great working with you and I hope that we get to do it again!
I would like to acknowledge the support for my career in academia and for this book granted by my family, starting
from my lovely wife, Adekemi, to our children Adeboye Jr. (AJ), Adekunle (PCP alum), Aderonke, and Adeola. I
would also like to thank many people who have been helpful in one way or another, with special thanks going to my
mother, Ayoola Adejare.

Adeboye Adejare
Professor, Philadelphia College of Pharmacy
Editor-in-Chief

xxix
Chapter 1
History of pharmacy
Gregory J. Higby1,2 and Benjamin Y. Urick3
1
School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States, 2American Institute of the History of Pharmacy, Madison, WI,
United States, 3Department of Practice Advancement and Clinical Education (PACE), University of North Carolina Eshelman School of Pharmacy
(UNC ESOP), NC, United States
1.1 The drug-taking animal
Among the several characteristics unique to Homo sapiens
is our propensity to treat ailments, physical and mental with
medicines. From archeological evidence, this urge to soothe
the burdens of disease is as old as humanity’s search for
other tools. Like the nodules of flint used to make knives
and axes, medicines rarely occur in nature in their most use-
ful (or palatable) form. First, the active ingredients or drugs
must be collected, processed, and prepared for incorporation
into medicaments. This activity, done since the dawn of
humanity, is still the central focus of the practice of phar-
macy. Put another way, pharmacy is, and has been, the art
(and later science) of fashioning one of our most important
tools—medicines.
For today’s pharmacists it is imperative that this deep-
seated role of medicines in human history is understood.
As with other tools, drugs have been used to gain
increased control over our lives, to make them better and
longer. Over the millennia the understanding of how
drugs work has changed dramatically, in part influencing
how they are used (and abused). As is often the case with
knowledge, however, common wisdom about medicines
is a mixture of myth and science, folklore, and demon-
strated fact. Old ideas meld with new concepts to produce
a faulty jumble that can lead patients into trouble.
A basic introduction to the development of ideas con-
cerning drugs, as well as the evolution of the profession,
increases the ability of pharmacists to adjust to the chal-
lenges presented as professional roles expand. Pharmacists
have much to gain from a basic appreciation of the com-
plex role that drugs and medicines have played in the past
and of pharmacy’s part in this development.
A complete world history of how drug knowledge,
medical progress, commerce, technology, and professional
development came together to produce modern pharmacy
Remington. DOI: https://doi.org/10.1016/B978-0-12-820007-0.00001-5
Copyright © 2021 University of the Sciences in Philadelphia. Published by Elsevier Inc. All rights reserved.
would fill an entire volume. Instead, this short chapter
will tell two parallel stories: how the concept of drug
evolved over time and how a separate profession arose to
prepare drugs into medicines in the West.
Throughout history, drugs have held a special fascination.
Beyond sensational stories of the part drugs have played in
exploration, commerce, political intrigue, scientific discovery,
and the arts, they have directly influenced the lives of billions.
Drugs such as insulin have kept millions alive, and antibiotics
and chemotherapeutic agents have saved millions more. The
simple fact that all drugs become useful through pharmacy
bears repeating, and the safe and effective use of such medi-
cines has developed recently into a primary concern for this
relatively young profession. Although pharmacy as a skill is
perhaps as old as the making of stone implements, the prac-
tice of this singular art by a recognized specialist is only
about 1000 years old. For this specialization to occur a need
had to arise—but that is getting a bit ahead of the story.
1.2 Prehistoric pharmacy
Since humanity’s earliest past, pharmacy has been a part of
everyday life. Excavations of some of mankind’s oldest
settlements, such as Shanidar (c.30,000 BCE), support the
contention that prehistoric peoples gathered plants for
medicinal purposes. By trial and error the folk knowledge
of the healing properties of certain natural substances
grew. Although tribal healers or shamans often guarded
this healing knowledge closely, the recognition of medici-
nal plants, which were sometimes used as food, spices, or
charms, apparently was so widespread that it hindered any
necessity for a special class of drug gatherers and keepers.
The arts of primitive pharmacy probably were mastered by
all who practiced the domestic medicine of the household.
When healers at Shanidar or other prehistoric settle-
ments approached disease, they placed it within the
3
4 SECTION | 1 Introduction
context of their general understanding of the world around
them, which was alive with good and evil spirits. Early
peoples explained illness in supernatural terms, as they
did the other changes and disasters surrounding them.
Treatments followed suit, in which beneficial medicines
worked through supernatural means. The spells of sor-
cerers, sometimes cast with the aid of magical substances,
could be combated with the same remedies.
The magical potions for curing were part of the duty
of the shaman. Usually in charge of all or most things
supernatural in a tribe, the shaman diagnosed and treated
most serious or chronic illness. He or she compounded
the remedies needed to stave off the influences of evil
spells or spirits. This basic pattern, common among
ancient peoples, held sway over nearly the full span of
human existence. The substances of healing potions, con-
nected for thousands of years with the supernatural world,
continue to hold a special place, a fascination for all.
Thus out of these origins a dual heritage has been derived:
drugs as both simple tools and substances with nearly
supernatural powers.
The discovery that certain natural substances such as
opium or myrrh could ease the suffering of human exis-
tence, however, should not be trivialized. Even though
early peoples discovered only a small number of effective
drugs, the very concept of influencing bodily functions
via an outside force must be considered one of humanity’s
greatest advances. The further development of this con-
cept required the environment of civilization. To flourish,
rational medical therapy needed the tools provided by set-
tled cultures—writing, systems of exchange, and weights
and measures.
1.3 Antiquity
When organized settlements arose in the great fertile
valleys of the Nile, the Tigris and Euphrates, the Yellow
and Yangtze, and the Indus Rivers, changes occurred
that gradually influenced the concepts of disease and
healing. As men and women learned how to control
aspects of nature through farming, permanent shelter,
and large-scale building projects, the powers of the gods
in day-to-day life started to decline. These changes are
evident among the remains of the great civilizations of
Mesopotamia and Egypt of the second millennium BCE,
whose clay tablets and papyri document the beginnings
of rational drug use.
An examination of these ancient records reveals a
gradual separation of empirical healing (based on experi-
ence) from the purely spiritual. For the Babylonians, med-
ical care was provided by two classes of practitioners: the
asipu (magical healer) and the asu (empirical healer). The
asipu relied more heavily on spells and used magical
stones far more than plant materials; the asu drew upon a
large collection of drugs and manipulated them into sev-
eral dosage forms that are still basic today, such as sup-
positories, pills, washes, enemas, and ointments. The
asipu and the asu were not in direct competition and
sometimes cooperated on difficult cases. Apparently the
ill often went back and forth between the two types of
healers looking for a cure.
The extensive records that survive of Egyptian medi-
cal practices demonstrate a high level of pharmaceutical
sophistication with a wider range of dosage forms com-
pounded from detailed recipes. The Egyptian medical
texts, like those from Babylon, show a close connection
between supernatural and empirical healing. Suggested
recipes usually began with a prayer or incantation. Plant
drugs, of which laxatives and enemas were the most
prominent, were the main vehicle of healing power. As
was the case with healing practices in Mesopotamia, cer-
tain individuals specialized in the preparation and sale of
drugs. Were these early medicine makers the forebears of
today’s pharmacists? No, because physicians and other
healers again took on the duties of medicine preparation
as these two great river civilizations declined. A fully sep-
arate pharmaceutical calling would be centuries away.
During the millennium that followed, the roots of the
modern medical profession in the West arose out of the
flowering of Greek civilization in the basin of the Aegean
Sea. In the earliest records of ancient Greece, one finds a
similar mixed concept of drug or pharmakon, a word that
meant magic spell, remedy, or poison. In the Odyssey,
Homer (c.800 BCE) refers to the esteemed medical wis-
dom of Egypt, thus illustrating the ebb and flow of
ancient knowledge long before the printed word. The
early Greek physicians described by Homer, the demiour-
goi, had advanced to where they diagnosed natural causes
for illness, while still not rejecting the use of supernatural
healing in conjunction with empirical remedies. Some
people beset with persistent afflictions traveled to a tem-
ple of the god Asklepios, where they would sleep with the
hope of being visited during the night by the god or his
daughter Hygeia, who carried a magical serpent and a
bowl of healing medicine.
The rational tradition within Greek medicine that was
evident in Homer’s work was refined and codified in the
body of literature connected with the name of Hippocrates
of Cos (c.425 BCE). Building on the foundations laid by
previous natural philosophers such as Thales (c.590 BCE),
Anaximander (c.550 BCE), Parmenides (c.470 BCE), and
Empedocles (c.450 BCE), the Hippocratic writers con-
structed a rational explanation of illness. They accom-
plished this by forging a conceptual link between the
environment and humanity by connecting the four elements
of earth, air, fire, and water to four governing humors of
the body: black bile, blood, yellow bile, and phlegm. The
Greek physician (iatros) who followed the Hippocratic

method favored dietary and life-style adjustments over
drug use. If these conservative methods failed, the physi-
cian prepared his own medicines or left prescriptions
behind for family members to compound and administer.
Most Greek medicines were prepared from plants, and
the first great study of plants in the West was accom-
plished by Theophrastus (c.370 285 BCE), a student of
Aristotle. His example of combining information from
scholars, midwives, root diggers, and traveling physicians
was emulated 300 years later by Dioscorides (CE c.65).
The latter Greek physician’s summary of the drug lore of
his times, the Materia Medica, became, in its various
forms, the standard encyclopedia of drugs for hundreds of
years to follow.
Through the teachings and writings of Galen, a Greek
physician who practiced in Rome in the CE 2nd century,
the humoral system of medicine gained ascendancy for
the next 1500 years. Setting aside the conservative drug
use of the orthodox Hippocratists, Galen devised an elab-
orate system that attempted to balance the humors of an
ill individual by using drugs of a supposedly contrary
nature. For example, to treat an external inflammation, a
follower of Galen might apply cucumber, a cool and wet
drug. The same Galenist also might have tried bleeding, a
favorite treatment to remove the apparent excess of blood
that caused the illness. In addition to the practice of
bleeding, Galen advocated the use of polypharmaceutical
preparations (what would later be termed “shotgun pre-
scriptions”). He argued that a patient’s body pulls out the
substances that it needs to restore humoral balance from a
complex prescription.
Medicine in classic antiquity reached its pinnacle with
Galen, and the writers who followed tended to be compi-
lers and commentators on his work, not original thinkers.
Galen’s influence was so pervasive among medical practi-
tioners that the basics of his healing approach—the bal-
ance of the body’s four humors through contrary drugs—
mixed with folklore and superstition to guide common
people in their own treatment of ailments. In the Western
half of the Roman Empire, such medical knowledge
became especially valuable as civilization crumbled in the
years following CE 400.
1.4 The Middle Ages
Traditionally, the Middle Ages are defined as the period
from the first fall of Rome (CE c.400) to the fall of
Constantinople (1453). The first half of this millennium
was once referred to as the “Dark Ages” by historians
because of the political and social chaos that existed in
the lands that had once been part of the western half of
the Roman Empire. Modern historians have revealed,
however, that many advances were made during the cen-
turies between 400 and 900, including a new, independent
History of pharmacy Chapter | 1 5
calling that emerged out of the flourishing Islamic civili-
zation—pharmacy.
The story of how Greco-Roman philosophy, science,
and art returned to Western Europe and sparked the crea-
tive period known as the Renaissance is one of the most
fascinating of human history. It began with the crumbling
of civil authority in the western half of the Roman
Empire during the 4th and 5th centuries. Greco-Roman
culture survived in the Eastern (Byzantine) half of the
empire, but with less creative energy. With Roman
authority gone in the West, the Church became the stabi-
lizing cultural force, and local feudalism arose to replace
centralized government.
The use of drugs to treat illness underwent another
shift, as pagan temples, some of which had operated in
conjunction with Greco-Roman healing methods, were
closed. Rational drug therapy declined in the West, to be
replaced by the Church’s teaching that sin and disease
were related intimately. The stories of miracles connected
with Saints Cosmas and Damian, twin brothers who
healed the sick CE c.300, exemplifies this attitude.
Monasteries became centers for healing, both spiritual
and corporal, because the two were not viewed as essen-
tially separate. Cast to their own devices, monks put
together their own short versions of classical medical
texts (epitomes) and planted gardens to grow the medici-
nal herbs that were no longer available after the collapse
of trade and commerce. Strong in their faith, these ama-
teur healers tended to ascribe their cures to the will of
God, rather than to their meager medical resources.
As Western Europe struggled, a new civilization arose
among those who followed the teachings of Mohammed
(570 632). The formerly nomadic peoples who united
into the nations of Islam conquered huge areas of the
Middle East and Africa, eventually expanding into Spain,
Sicily, and Eastern Europe. Because their faith taught
them to respect the written word and those who studied it,
they tolerated the scholarship of the Christian sectarians
who had fled persecution in the Eastern Roman Empire;
the Nestorians, for example, established a famous school
in Gondeshapur in the 6th century.
At first the Arabs accepted the authority of Greek
medical writings totally, especially those of Galen and
Dioscorides. But as their sophistication grew, Islamic
medical men like Rhazes (860 932) and Avicenna
(980 1063) added to the writings of the Greeks. The
far-flung trading outposts of the conquering Arabs also
brought new drugs and spices to the centers of learning.
Moreover, Arab physicians rejected the old idea that
foul-tasting medicines worked best. Instead, they devoted
a great deal of effort to making their dosage forms elegant
and palatable through the covering of pills with gold or
silver leaf (gilding or silvering) and the use of sweetened
vehicles.
6 SECTION | 1 Introduction
The new, more sophisticated medicines required elab-
orate preparation. In the cosmopolitan city of Baghdad of
the 9th century, this work was taken over by specialists,
the occupational ancestors of today’s pharmacists. In
places such as Spain and southern Italy where the Islamic
world interacted most with recovering western Europe,
several of the institutions and developments of the more
highly developed Arabic culture—such as the separation
of pharmacy and medicine—passed over to the West.
By the mid-13th century, when Frederick II, the ruler of
the Kingdom of the Two Sicilies, codified the separate prac-
tice of pharmacy for the first time in Europe, public pharma-
cies had become relatively common in southern Europe.
Practitioners of pharmacy had joined together within guilds,
which sometimes included dealers in similar goods, such as
spicers or grocers or physicians. These protopharmacists
usually called themselves “apothecaries” after the Latinized
Greek term “apotheca,” which meant storehouse or reposi-
tory. Like bakers (bakeries) and grocers (groceries), apothe-
caries were identified closely with their shops.
Arabic culture had returned classical scientific and
medical knowledge to Europe. At centers such as Toledo
and Salerno, the writings of the Greeks, which had been
translated into Arabic centuries before on the fringes of
the old eastern half of the Roman Empire, were translated
into Latin for the use of European scholars. Thus at the
emerging universities of Europe such as Paris (1150),
Oxford (1167), and Salerno (1180), scholars discussed the
works of medical authorities such as Dioscorides, Galen,
and Avicenna.
However, the debates on medicine among European
academics were based on speculation, not observation.
Theirs’ was a philosophical pursuit, with no great impact
on medical practice. For significant change to occur in
the use of drugs, the scholastic approach had to be set
aside and a more skeptical, observational methodology
adopted. This new, experimental age we now call the
Renaissance.
1.5 The Renaissance and Early Modern
Europe
The Renaissance, simply put, was the beginning of the
modern period. Changes that had begun during the
European Middle Ages, and were stimulated further by
contacts with other cultures, gained momentum. The burst
of creative energy that would result in our present shared
culture of the West stemmed not from a single episode
but from a series of events.
In 1453 Constantinople (current Istanbul) fell to the
conquering Turks, and the remnants of the Greek schol-
arly community there fled west, carrying their books and
knowledge with them. About that same time, Johann
Gutenberg began printing with movable type, starting an
information revolution. Within a half century, Columbus
arrived in the New World, Vasco da Gama found the sea
route to India that Columbus had sought, commerce based
on money and banking was established, and syphilis raged
through Europe. It was a time for new ideas through rein-
terpretation of the old classical themes, and through
exploration on the high seas and in the laboratory.
The time was ripe for casting off the old concepts of
diseases and drugs of Galen. The new drugs that were
arriving from far-off lands were unknown to the ancients.
Printers, after fulfilling the demand for religious books
such as bibles and hymnals, turned to producing medical
and pharmaceutical works, especially those that could
benefit from profuse and detailed illustrations. On the
medical side, for example, this trend is exemplified in the
anatomical masterworks of Andreas Vesalius (1514 64).
For pharmacy, printing had a profound effect on the
study of plant drugs, because illustrations of the plants
could be reproduced easily. Medical botanists such as Otto
Brunfels (1500 34), Leonhart Fuchs (1501 66), and John
Gerard (1545 1612) illustrated their works with realistic
renditions of plants, allowing readers to do serious field
work or to find the drugs needed for their practices.
Among the most gifted of these investigators was Valerius
Cordus (1515 44), who also wrote a work in another pop-
ular genre—formula books. His Dispensatorium (1546)
became the official standard for the preparation of medi-
cines in the city of Nuremberg and generally is considered
the first pharmacopeia.
Although they were critical to the advancement of med-
ical science, the nearly modern, precise works of Fuchs
and Vesalius did not influence the treatment of disease as
much as the speculative, mystically tinged writings of an
itinerant Swiss surgeon who dubbed himself “Paracelsus.”
Born Philippus Aureolus Theophrastus Bombastus von
Hohenheim in 1493, the year Columbus went on his sec-
ond trip, this medical rebel represents well the combined
attitudes of the common man, the scholarly physician, the
practical surgeon, and the alchemist. The battles of
Paracelsus against the static ideas of Galen, Avicenna, and
other traditional authorities opened a window into the com-
plicated mind of the Renaissance. As Erwin Ackerknecht
observed in A Short History of Medicine.
Paracelsus is one of the most contradictory figures of a
contradictory age. He was more modern than most of his
contemporaries in his relentless and uncompromising drive
for the new and in his opposition to blind obedience to
authoritarianism and books. On the other hand, he was
more medieval than most of his contemporaries in his all-
pervading mystic religiosity. His writings are a strange mix-
ture of intelligent observation and mystical nonsense, of
humble sincerity and boasting megalomania.
Another random document with
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 It must be noted that Salamanca’s name was not in the list of
Ministers suggested by Narvaez. The Queen wished it to be added,
but Narvaez declined to follow suit, as he knew that this statesman
was supported by Bulwer, whose dislike of the King was well known;
and the way he had spoken of Francisco before his wedding
naturally made the King averse to seeing him.
Bulwer worked with Bermejo against Isabella during the
premiership of Salamanca, and the publication in The Times of a
demand for the royal divorce was due to him.
At last Francisco and Isabella were reconciled. It was on October
13 that the King returned to the capital. He entered the gate of the
palace in a carriage drawn by six horses, with a mounted escort of
the Guardia Civil. He was dressed quietly in black, and Brunelli, the
Pope’s Legate, was seated on his left. Narvaez, Count Alcoy, Count
Vistahermosa, rode by the coach, and two carriages followed with
the high dignitaries of the palace.
The King looked pleased. General Serrano, whom he hated so
cordially, had left Madrid, and the Queen was waiting for him at the
window. Brunelli was about to follow the royal couple as they walked
away after their first meeting, but Narvaez said: “Whither away, Your
Eminence? Let them be alone with their tears and kisses. These
things are done better without witnesses.”
The Queen arrived that day at her dwelling in the Calle de las
Rejas. There was a family dinner-party in the evening at the palace,
and, in a private interview with her daughter, Maria Cristina begged
her to be more discreet in future; and she reminded her that although
she had, as a widow, allowed herself to be captivated by a
commoner, whilst she was the wife of the King she had never
allowed her thoughts to wander beyond the circle of her rank and her
duty.
 The reckless extravagance of the Queen excited much remark.
Courtiers are still living who recollect seeing Isabella give her
bracelets to the beggars who sometimes infest the courtyard of the
palace.
When Miraflores, who was considered the soul of truth, received
a reckless order from the Queen to dispense a certain amount of
money on some petitioner, he had the sum put in pieces on a table,
and it was only the sight of the large sum which was thus laid before
the Queen which showed her the extravagance of her command.
A great influence was soon found to be at work in the palace in
the person of Sister Patrocinio, whose brother, Quiroga, was one of
the gentlemen-in-waiting.
 CHAPTER XI
ATTEMPT ON THE LIFE OF QUEEN ISABELLA—THE OVERTHROW OF THE
QUEEN-MOTHER, MARIA CRISTINA

1850–1854

There was much variety of feeling when it was known that an heir to
the throne was expected. On the day of the birth, July 12, 1850, the
clerics, Ministers, diplomats, officers, and other important
personages of the realm, assembled at the palace to pay their
respects to the expected infant. But the bells and cannon had hardly
announced to the nation the birth of the girl-child when it expired. So
the dead form of the infant, which had only drawn breath in this world
for five minutes, was brought into the assembly of dignitaries, and
after this sad display the gathering dispersed in silence. The kind-
heartedness of the Queen was shown in her thoughtful generosity to
the nurses who were disappointed of their charge.
“Poor nurses, they must have felt it very much!” she exclaimed.
“But tell them not to mind, for they shall be paid the same as if they
had had my child.”
In February, 1852, an heir to the throne was once more expected,
and the birth of the Infanta Isabella was celebrated by the usual
solemn presentation. When the King showed the infant to his
Ministers, he said to the Generals Castaños and Castroterreño:
“You have served four Kings, and now you have a Princess who
may one day be your Sovereign.”
 It was on February 2, 1852, that the dastardly attempt was made
on the life of the Queen, just before leaving the palace for the
Church of Atocha, where the royal infant was to be baptized. The
Court procession was passing along the quadrangular gallery, hung
with the priceless tapestries only displayed on important occasions,
when Manuel Martin Merino, a priest of a parish of Madrid, suddenly
darted forward from the spectators lining the way, with the halberdier
guard. The petition in the cleric’s hand and his garb of a cleric led to
his step forward being unmolested, and the Queen turned to him,
prepared to take the paper. But the next moment the other hand of
the assassin appeared from under his cloak with a dagger, which he
swiftly aimed at the royal mother. Fortunately, the Queen’s corset
turned aside the murderous weapon, and, although blood spurted
from her bodice, the wound was not very deep; but she was at once
put to bed and placed under the care of the royal physicians.
The royal infant was promptly seized from the arms of its mother
at the moment of the attack, by an officer of the Royal Guard, and for
this presence of mind the soldier was afterwards given the title of the
Marquis of Amparo.
With regard to the assailant, the Queen said to her Ministers:
“You have often vexed me by turning a deaf ear to my pleas of mercy
for criminals, but I wish this man to be punished immediately.” And,
with the outraged feeling of the object of such a dastardly deed,
Isabella turned to the would-be murderer, and said: “What have I
ever done to offend you, that you should have attacked me thus?”
During the trial in the succeeding days the Queen softened to the
criminal, and said to her advisers: “No, no! don’t kill him for what he
did to me!”
However, justice delivered the man to the hangman five days
after his deed.
 The efforts to discover Merino’s accomplices were fruitless, and it
was thought that the deed had been prompted more by the
demagogue party than by the Carlists.
The cool, cynical manner of the cleric never left him even at the
moment of his execution.
When the priest’s hair was cut for the last time, he said to the
barber: “Don’t cut much, or I shall catch cold.”
The doomed man’s request to say a few words from the scaffold
was refused. When asked what he had wished to say, he replied:
“Nothing much. I pity you all for having to stay in this world of
corruption and misery.”
The ovation which the Queen had when she finally went to the
Church of Atocha to present the infant surpasses description.
Flowers strewed the way, and tears of joy showed the sympathy of
the people with the Queen in her capacity as mother, and at her
escape from the attempt on her life.
From 1852 to 1854 Isabella failed to please her subjects, and the
outburst of loyalty which had followed the attempt on her life
gradually waned. Curiously indifferent to what was for her personal
interest, as well as for the welfare of the country, Isabella turned a
deaf ear to the advice of her Ministers to dissolve a Cabinet which
was under the leadership of the Count of San Luis, who was known
to be the tool of Queen Maria Cristina, now so much hated by the
Spaniards. Miraflores wrote a letter to Isabella, advising the return of
Espartero, the Count of Valencia, but the letter never reached its
destination.
Remonstrances which had been made upon the Government
were now directed straight to the Throne.
“You see,” said her advisers, “how the persons whom you have
overwhelmed with honours and favours speak against you!”
 The Generals O’Donnell and Dulce finally took an active part
against the Ministry, supported by the Queen-mother and Rianzares.
The Count of San Luis was a man of fine bearing and charming
manners. He had been conspicuous in his early days for his
banquets and gallantries, but he had also been known for many a
generous deed to his friends; and it was noticeable that when the
tide of favour left him he was deserted by all those to whom he had
been of service.
The birth of another royal infant in 1854 excited little or no
interest in the capital, where discontent with the reigning powers was
so evident. General Dulce was accused in the presence of the
Queen and San Luis of having conspired against the Throne. This
the officer indignantly denied on the spot, declaring that never could
he have believed in the perfidy which had prompted the report.
At last the storm of revolution broke over Madrid, and the parties
of the Generals O’Donnell and Dulce came into collision with those
of the Government. Insulting cries against the Queen-mother filled
the streets, and during the three days’ uproar the house of Maria
Cristina, in the Calle de las Rejas, was sacked, as well as those of
her partisans. The furniture was burned in the street, and Maria
Cristina took refuge in the royal palace.
After the Pronunciamento of Vicalvaro and O’Donnell to the
troops, it was evident that the soldiers of the Escorial would also
revolt against the Government.
It was then that Isabella was filled with the noble impulse to go
alone to the barracks of the mutinous regiments and reason
personally with them. With her face aglow with confidence in her
soldiers and in herself, she said: “I am sure that the generals will
come back with me then to Madrid, and the soldiers will return to
their barracks shouting ‘Vivas’ for their Queen.”
 But this step, which would have appealed with irresistible force to
the subjects, was opposed by the Ministers, who objected to a
course which would have robbed them of their portfolios by the
Sovereign coming to an understanding with those who were
opposed to their opinions.

T H E C O U N C I L O F M I N I S T E R S O F I S A B E L L A I I . D E C L A R E S WA R
AGAINST MOROCCO

From a Painting by R. Benjumea

At this time Isabella received from the Infanta Josefa, daughter of

the Infanta Louisa Carlota and Francisco de Paula, a letter which
showed that the Princess had inherited her mother’s hatred of the
Queen-mother, Maria Cristina; for she wrote:
 “Your Majesty should distrust the artificial and partial counsels of
the Queen-mother. This lady, to whom you owe your birth, is
sacrificing you to her insatiable greed of gold. Beyond your life you
do not owe anything to Maria Cristina. She has done nothing for
Spain that you should give her submission and obedience in your
conduct as Queen. Hardly had Your Majesty’s father gone down to
his grave than his widow gave you the pernicious example of an
impure love, which began in a scandal, and ended, ten years later, in
a morganatic marriage, to the incalculable harm of the country.
“Maria Cristina is lax in the principles of morality, which ought to
be the foundation of the education of Princes, and she knew not how
to inculcate them in the mind of Your Majesty. Whilst you were a
child, she did nothing but accumulate money and arrange for her
future booty.
“The disinterestedness and the generous sentiments which
enrich Your Majesty’s heart, and the high tendencies which have
shone in your mind, and which have only been suffocated by the
pettiness of your entourage, are exclusively a gift from Heaven, and
under favourable circumstances they would have developed into
great and glorious deeds. When the time arrived for the marriage of
Your Majesty—an event of such import to your destiny—Your
Majesty knows that the Queen-mother only used her influence to
make you marry a man whose sole merit lay in his power of
ministering to her omnivorous nature. Never did a mother behave in
such a self-interested way in what concerned her daughter’s
domestic happiness! And now she continues the soul of the
Government, counselling Your Majesty for her own ends, and with
utter disregard of the wishes of the people.”
This letter, which gives an idea of the dissensions of the Royal
Family, and the expression of feeling against Maria Cristina, was
shared by the people. Indeed, the hatred of the Queen-mother was
publicly shown after she took refuge in the royal palace. The Plaza
de los Ministros resounded with the cries from the townsfolk of
“Death to Cristina!” A storm of stones broke all the windows of the
palace. The soldiers fired on the people. The palace gate of El
Principe had to be guarded by two cannon commanding the Plaza
de Oriente. Twelve guns were stationed in the great courtyard called
the Plaza de las Armas, and all the cavalry at Madrid was
summoned to the defence of the royal abode; and during the siege
there was serious anxiety that the provisions would not last long.
Queen Isabella sought to encourage and support her mother, but
she saw that the stream of public hatred was now too strong to be
stemmed.
The arrival of Espartero in Madrid, on July 29, raised the siege of
the palace, and the people, delighted at the sight of their favourite
leader, gave a loyal ovation to Queen Isabella when she appeared at
a window of the palace.
The days from July 17 to August 28 were fraught with anxiety for
the Queen of Spain. The cries for the dismissal of the Queen-mother,
and for her trial for the appropriation of State moneys, could no
longer be silenced, and the day came when the royal lady found that
her personal safety demanded her departure from the country. So,
accompanied by a mounted escort, Maria Cristina submitted to the
decision of Espartero, as the mouthpiece of the people, and she
finally bade farewell to her weeping daughter at the palace door, and
left the country, never more to return.
Espartero made a crusade against the undue priestly influence at
Court. The weak-minded King was quite under the power of “the
bleeding nun,” as Patrocinio was called, and his constant visits to her
apartments in the palace were said to have been in search of
spiritual counsel, with which she was supposed to be miraculously
endowed by reason of the wounds in her forehead and hands, which
refused to be healed, as they were said to be illustrative of those of
the Saviour. The Queen and all the Royal Family became
hysterically hypnotized by this phenomenon.
But Espartero soon put an end to the matter by having the lady
put under the authoritative care of a doctor, who had her hands tied
so as to prevent her irritating the wounds; and thus in a short time
the supposed miracle was over, and the power of the religieuse and
her brother, the Archbishop Claret, was at an end.
Espartero had O’Donnell as his Minister of War. Dissensions
broke out again in the Cabinet, and O’Donnell reaped the success of
his camarilla influence at the midnight Council meeting held before
the Queen in July, 1856. For when Espartero found that his
measures for the new Constitution were rejected, he offered his
resignation; and then, to his surprise, the Queen, by a prearranged
concert, turned to his colleague with her sweetest smile, saying, “I
am sure you won’t abandon me, will you?” and he was sworn in as
Prime Minister the following day.
But O’Donnell had a powerful rival for favour at the palace in the
person of Narvaez, a General of some fame, whose alert, dapper
little figure, said to have been improved by corsets, made him
popular at Court as a dancer.
This officer was extremely arrogant, and noting that the
grandees, by right of their special prerogative, stood covered in the
royal presence during the ceremony of the King washing the feet of
the poor, and feeding them in the historical Hall of Columns, he
promptly put his own cocked hat on his head, and bade his officers
do the same.
O’Donnell, who was of a heavier, clumsier build than his rival,
suffered much at the sight of the success of Narvaez in the arts of
society. One day at a state ball at the palace the two Generals stood
in readiness to conduct the Queen through the mazes of the rigodon.
As Prime Minister, O’Donnell considered that the distinction of taking
Isabella’s hand for the figures was his by right, but Isabella could not
resist the temptation of having for a partner a man distinguished as a
follower of Terpsichore, and she therefore singled out Narvaez as
her partner.
In a fury at what he considered a public slight, O’Donnell gave in
his resignation the next day as President of the Council, and General
Narvaez was chosen to fill the vacant place.
It was well known at Court that the British Ambassador, Bulwer
Lytton, was working against the Court of Spain in England, and
consequently he was an object of great aversion to the military
leader of the Government.
Irritated at the Englishman’s assumption of authority, Narvaez
said one day to Bulwer Lytton that Spain did not interfere with the
affairs of Queen Victoria like England did with those of Isabella II. To
this remark the British diplomat returned that Victoria did not owe her
throne to foreign intervention, as Isabella did.
One day Narvaez was in his bureau in a great state of irritation
about some action of the British Ambassador, when Bulwer Lytton
was announced. He drew a chair close to Narvaez, and, although
the Spaniard pushed his back, drew his seat still closer. Upon this
Narvaez jumped up in his excitable manner, and then, wishing to
seat himself again, he missed the place and found himself lower
than he wished.
Upon this the Ambassador made some remark which added fuel
to the fire of the General’s wrath, and, advancing to the Englishman,
he made him rise from his seat, took him by the neck, and kicked
him so that he nearly fell to the ground. The Ambassador took his
papers for England that day, and this incident doubtless added to the
bitterness with which Bulwer reported on the affairs of Spain.
 The incident just related, of this last interview of Sir Bulwer Lytton
with the Spanish Premier, was evidently never reported in all its
bearings, but enough was known for it to be seen that the
Ambassador was apt to embroil matters. For in “The Letters of
Queen Victoria,” vol. ii., p. 207, Her Majesty writes:

“May 23, 1848.

“The sending away of Sir H. Bulwer[17] is a serious affair, which

will add to our many embarrassments. The Queen, however, is not
surprised at it, from the tenor of the last accounts of Madrid, and
from the fact that Sir H. Bulwer has, for the last three years, been
sporting with political intrigues. He invariably boasted of being in the
confidence of every conspiracy, though he was taking care not to be
personally mixed up in them; and, after their various failures,
generally harboured the chief actors in his house under the plea of
humanity. At every crisis he gave us to understand that he had to
choose between a revolution and a palace intrigue, and not long ago
he wrote to Lord Palmerston that if the Monarchy with the
Montpensier succession was inconvenient to us, he could get up a
Republic.”

[17] “Lord Palmerston had written a letter to Bulwer (which the

latter showed to the Spanish Premier) lecturing the Spanish Queen
on her choice of a Minister. This assumption of superiority, as Sir
Robert Peel calls it, led to a peremptory order to leave Spain in
twenty-four hours.—Editor.”

But Isabella’s realm was still torn by insurrections. In January,

1860, the Prefect of the Police reported that a rebellion was being
prepared in Spain against the throne by the Carlist party, under Don
Carlos Luis de Bourbon y de Braganza, Count of Montemolin. When
justice was prepared to take its course against the insurrectionists,
Don Carlos wrote to Isabella, saying:
“I am certain that your compassionate heart, which has always
shown pity for the unfortunate, will not fail to have mercy on your
cousins, and not deny the pardon that we crave.”
This mercy was also eloquently pleaded for by the unhappy
mother of the delinquents. So, obedient to the impulse of her kind
heart, Isabella said to the weeping parent: “Be at rest; your son shall
not die.”
However, the Carlist family soon forgot the clemency of the
Queen, and the letter of Juan de Bourbon, son of Don Carlos,
Ferdinand’s brother, showed that the spirit of animosity burnt as
powerfully as ever in the breast of the claimant to the throne.
“Twenty-seven years you have reigned,” ran the Prince’s letter to
his royal cousin, “and you must confess that the hand of God has not
helped you. I know the country; I know equally well that your heart is
good, and that you do good when you can, and you regret the evils
which afflict Spain. But you try in vain. You cannot fight against
Providence, which never wills that evil should prosper. Be assured,
dear cousin, that God did not choose you to make the happiness of
Spain, and that Divine Providence has denied you the lot of being a
great Queen. Descend, Isabella—descend from the throne! Show
yourself great in this matter, and take the place to which you have a
claim in my family as my dear cousin, and as having occupied the
throne for so many years, and do not expose yourself to final
disaster and bring ruin on the family.”
 CHAPTER XII
COURT INTRIGUES

1864–1868

On November 28, 1857, “the birth of Alfonso XII.,” as Martin Hume

says, “added another thong to the whip which the King-Consort
could hold over the Queen for his personal and political ends, and it
also had the apparently incongruous effect of sending Captain Puig
Moltó into exile.”
Of course there were the usual rejoicings at the birth of a Prince,
but things were far from satisfactory at the Court. The Queen had
now a taste of personal power and a higher notion of her own
political ability. The Congress was in slavish servitude to the palace,
and, acting in accordance with this sentiment, it had managed to get
rid of the men in the Senate who had been working for the
constitutional privileges of the country which would have led to the
indispensable protection of the prerogative of a true suffrage; and
freed from these patriots, the press was silenced and Parliament
was suspended.
The return of Maria Cristina, the Queen’s mother, was another
step which added to the unpopularity of Isabella II. Once more
wearied out with waiting for the realization of constitutional rights, the
people’s exasperation was voiced by the soldiers at the barracks of
San Gil, within view of the royal palace of Madrid. O’Donnell at once
took steps for the suppression of the insurrection.
 The cries of “Viva Prim!” “Viva la Libertad!” showed that the spirit
of republicanism was rampant.
Swiftly as O’Donnell went to the scene of action, Narvaez was
before him, and so the Prime Minister had the mortification of seeing
his rival carried into the palace to be tended for the slight wound he
had received in the conflict.
The rebellion was soon quelled, and the insurgents were shot;
but disinterested advisers of the Queen might have shown her that
such émeutes proved that the fire of discontent was smouldering,
and with a strong Government for the constitutional rights for which
the country was clamouring the revolution of 1868 would have been
avoided.
On the day following the San Gil insurrection a man of influence
at the Court went to plead pardon for two of the insurgents from Her
Majesty herself.
The interview was characteristic of the kind-heartedness of the
Queen.
After waiting for half an hour in the antechamber, the gentleman
was shown into the royal presence.
“You have been quite lost,” said Isabel graciously, as her visitor
bent over her hand. “It is a thousand years since you have been to
see me.”
Whilst excusing himself with courtly grace, Tarfe noticed that
during the two years in which he had been absent from the palace
the Queen had grown much stouter, and had thus lost some of her
queenly dignity. She seemed distrait and troubled, and the red lids of
her limpid blue eyes gave her an expression of weariness. They
were, moreover, the eyes of a woman who had been brought in
contact with the encyclopædic array of the various forms of the
despoilers of innocence.
 The petitioner submitted his plea for mercy for his friends by
saying that his request was backed by a letter from the holy Mother,
begging her to write two letters to General Hoyos for their release. To
the delight of the intercessor, the Sovereign at once wrote the letters.
When this was done, the surprise of the courtier was increased when
the Queen, who was generally mañanista, said in a quick, nervous
tone: “Do not delay giving these letters; do not wait till to-morrow; do
it to-day!”
Before leaving the royal presence, Tarfe ventured to say that
O’Donnell was much upset by the events of the preceding day, and
the Queen replied in a tone curiously devoid of feeling: “Yes, I like
O’Donnell very much.” This she said three times in the same
passionless voice, and then, seeing that he was dismissed, Tarfe
took leave of Her Majesty; and after fulfilling the mission to Hoyos,
he went to see O’Donnell at his palace of Buenavista.
The General declined to believe the reports of his friends, of the
intrigues which were to compass his fall.
The victor at Tetuan was more able to repel the open advance of
an enemy than the underhand plots of a palace.
But when Ortiz de Pinedo suddenly came in, and said, “Gonzalez
Brabo has left San Juan de Luz to-day, and he is coming to form a
Ministry with Narvaez,” the General was somewhat taken aback.
On the following morning, after finishing a long despatch for the
royal signature, he repaired to the palace, and, anxious to know the
real state of affairs, he submitted to Her Majesty the list of
appointments to the Senate-house, many of which had been
suggested by Isabel herself.
To the surprise of the Minister, the list was rejected by the Queen
in a cold, disdainful way, so O’Donnell found himself forced to offer
his resignation. This was accepted with the usual meaningless
smiles and compliments.
Then O’Donnell returned to his house, where his friends were
waiting for him. His face betrayed his rage and mortification, and,
throwing his gloves on the table with an angry gesture, he
exclaimed:
“I have been dismissed just as you would dismiss one of your
servants.”
“My General,” exclaimed one of the partisans of the ex-Minister,
“the camarilla delayed the change of Ministry for two days after the
mutiny; why was that? And Ayala returned because it was better for
Narvaez that we should have the odium of shooting the insurgents.
Now he can take his place in Parliament with all the airs of
clemency.”
O’Donnell, who could not deny the truth of this remark, took
General Serrano by the arm into another room, but they could plainly
hear their indignant followers saying: “Eso, señora, es imposible!”
The Marquis of Miraflores says that a General Pierrad, the head
of the Pronunciamento, told a chief of the halberdiers that he had
better tell the Queen that there were no means of putting down
meetings, and this for two reasons: Prim and his friends only wanted
a change in the power by a disciplined Pronunciamento, but the
artillery, through some strange influence, would not recognize
military chiefs. He who said this was to have been shot down by
them; he saw them drunk and faithless to their commands. This
communication was made to the Queen. In 1867 an important
interview took place in the Palace of Madrid between Isabel II. and
her sister, the Duchess of Montpensier.
It will be remembered that, after the adventures of the royal
couple in the revolution of 1848, the Duke and Duchess retired to
Seville, where they lived in the Palace of San Telmo with all the state
dignity of sovereigns. The Queen had made the Duke an Infante of
Spain, and he had also been appointed Captain-General.
The Duke decided to take his wife to Madrid to counsel her sister
to adopt a more liberal policy. The Duchess was expecting another
child, but she was advised not to postpone her visit to the royal
palace of Madrid. The interview was far from satisfactory, for Isabella
had no intention of allowing Montpensier to have an active part in the
Government. So the Princess returned to Seville, and Isabella
afterwards wrote her a letter, in which she expressed displeasure at
her aims. This letter received an angry reply, first from the husband,
and then from the wife. So a coldness grew up between the sisters,
and, indeed, Isabella’s want of confidence in Montpensier was
proved by the subsequent events in 1868, when Prim himself
rejected the Duke’s offer to raise forces in his favour.
During all this time the little Prince of Asturias, who was nine
years old when the insurrection broke out in the barracks of San Gil
for Prim, was pursuing his education in the palace. The style of the
Prince’s education is given in the remark of the royal child’s playmate
to his father, when he had been to spend a day at the palace.
“Papa,” said the boy, “Alfonso does not know anything. He is
taught nothing but religion and drilling. After the religious lesson,
which was very dull,” the child continued, “Alfonso was given a spear
and a sword, and he waved them about so much that Juanito and I
were afraid he would hurt us.”
A record was kept of the little Prince’s doings during the day. His
frequent colds, his coughs, his acts of devotion, his appetite at
meals, his games, his toys, his little tempers, his deeds of
obedience, were all entered in the register as signs of his
temperament and as indications of his future character as a man.
 The Prince’s apartments were dreary. The windows were high up
in the thick walls, the ceilings were low, and, as a grandee says
when speaking of this fact, it seemed strange that the light and air so
essential for a child should be insufficiently supplied to a future King.
General Pavia, who was gentleman-in-waiting to Alfonso, only
shrugged his shoulders at this remark, but Señor Morphy ventured to
say: “That is our opinion, but she who commands, commands.”
When the grandee was introduced to the little Prince, he returned
the salutation with the manner of one accustomed to it, but with a
pretty smile which was very attractive.
“Yes,” said his attendant, “His Royal Highness is better to-day. He
only has a little cough now, but the doctor says he is not to be tired
with lessons to-day; he is only to rest.”
“Last night,” said the General, “His Highness asked for his lead
soldiers to play with in bed. He did not want to say his prayers. So I
had to fetch the new prayer-book which Her Majesty sent a few days
ago, and I read the prayers whilst he repeated them after me. So in
this way he said his prayers, but not willingly.”
Hereupon Alfonso protested, saying: “But this morning, Marquis, I
said my prayers without your reading anything.”
“Yes, yes,” returned the gentleman; “but Your Highness did not
want to get up, so I had to read stories to you until the doctor came.”
A few pages from the diary of the young Prince of Asturias gives
some insight into the dreary daily life of the delicate child:
“October 1, 1866.—His Highness breakfasted at 11 o’clock. At 1
o’clock he had drilling till 1.40. At 2 o’clock a writing lesson with
Señor Castilla; at 3 o’clock religion with Señor Fernandez; 4.30, rice
soup as usual; 4.50 he went up to the rooms of Her Majesty to go for
a drive with her.
 “October 4.—His Highness played about till 2.15. He had no
lessons to-day, as being Her Majesty’s saint’s day. At 2.43 he went
up to the Queen’s apartments to assist at the reception. He wore the
uniform of a sergeant, with the Cross of Pelayo. The ceremony over
at 6.15, when His Highness came down with Señor Novaliches, as a
boot hurt him (not the Marquis, but His Highness). The said Marquis
took off the boot, and carefully examined the foot, but he found
nothing to account for the pain. Mention is made of this circumstance
as the Chief of the Chamber of His Highness thinks it fitting to do
so....
“October 6.—My Lord Prince lunched at 12 o’clock. I gave him
his lessons. He went to the Church of Our Lady of Atocha. He went
to bed at 10 o’clock, and slept ten hours. He took some chocolate,
made his confession at 9.30, and Father Fernandez celebrated
Mass.
“October 9.—He breakfasted with appetite. He had his lessons at
the marked hours, and he was somewhat restless. At 4 o’clock he
took some soup, and went out for a walk with the Mayordomo, Señor
Marquis de Novaliches, Professor Sanchez, and Juanito. He had
supper at 8 o’clock, and played till 10 o’clock with Juanito, but left off
when he knocked his left leg against a table. He slept from 10
o’clock till 9 o’clock in the morning. He got up at 9.30 without feeling
any pain in his leg from the blow. He did his orisons, assisted at the
Mass in his room; he went out for a walk with his Mayordomo,
returned at 11 o’clock, and assisted at the Mass with Their Majesties
and the Princesses; and at 11.45 he had his hair cut.”
As Perez Galdos says in his works, the long hours of religious
instruction every day would have qualified the little Prince for the
Council of Trent. When any Bishops came to visit Isabella, they were
sent to the apartments of her little son; and thus Morphy writes in the
register: “I gave the lesson to His Highness in the presence of the
Bishops of Avila, Guadix, Taragona, and of other dioceses whose
names I do not remember.” And Losa wrote: “He opened his eyes at
8.30; he dressed and gave thanks to God; he took his chocolate with
appetite, and at 10 o’clock had his religion lesson in the presence of
the Cardinal of Burgos, who was pleased with his progress, and
noted that His Highness was ‘magnificent in everything.’”
Courtiers who were true of heart saw with apprehension the
artificial character of the Prince’s education.
“Ah!” said a man who would gladly have been frank with the
Queen, but he felt he was powerless against her crowd of flatterers,
“Alfonso is a very intelligent child. He has qualities of heart and mind
which would give us a King worthy of the people, were they only
properly cultivated; but we shall never see this ideal realized,
because he is being brought up like an idiot. Instead of educating the
boy, they are stultifying him; instead of opening his eyes to science,
life, and nature, they blind them so that his sensitive soul remains in
darkness and ignorance.”
The same courtier implored the Prince’s educators to give the lad
a chance. “Take him out of this atmosphere of priests and nuns, and
devotional books by Father Claret. If you want Alfonso to be a great
King, let him breathe the pure air of fine deeds. Take him away from
the gloomy atmosphere of the royal palace; let him inhale the fresh
breezes of liberty. His talents will develop, and he will become a
different boy.”
It was indeed true the little Prince was in an unnatural
atmosphere in the palace, where the tunic of the nun Patrocinio had
become an object of worship, and where the King, in his stuffy
apartments, gave himself over to the study of relics which were
brought to him at a high price by the priestly folk, who made harvest
out of his credibility.
The situation of Queen Isabella is graphically given by the
historian Galdos in the reflections of a loyal courtier whilst having,
with his wife, an audience of Isabella II.:
“Oh, your poor Majesty!” he said to himself. “The etiquette
invented by the set-up gentlemen of the Court to shut you off from
the national sentiment prevents me telling you the truth, because it
would hurt you to hear it. Even those on the most intimate terms with
you shut you out from the truth, and they come to you full of lies. So,
kind-hearted Isabella, you receive the homage of my gilded untruths.
All that I have said to you this afternoon is an offering of floral
decorations, the only ones received on royal altars.... You, who are
more inclined to the ordinary and the plebeian than other Kings—you
let the truth come to you in external decorative, and verbal matters,
but in things of public consequence you like nothing but lies,
because you are educated in it, and falsity is the religious cloak, or
rather the transparent veil, which you like to throw over your political
and non-political errors. Oh, poor neglected, ill-fated Queen...!”
The reflections of the courtier were here interrupted by Isabella
saying to his wife: “Maria Ignacia, I want to give you the ribbon of
Maria Luisa.... I shall never forgive myself for not having done it
before. I have been very neglectful—eh?”
The Marchioness was eloquent in her thanks, and Beramendi
could only say: “Señora, the kindness of Your Majesty is
unbounded.... How can we express our gratitude to Your Majesty?”
But the Marquis said to himself: “We take it, because even as you
accept our lying homage, so we receive these signs of vanity. King
and people we deceive each other; we give you painted rags of
flattery, which look like flowers, and you bestow honours on us which
take the place of real affection.”
Isabella continued: “I must give you a title of Count or Viscount,
which your son can take when he comes of age.”
 The Marquis’s wife returned: “Our Queen is always so good; that
is why the Spaniards love her so.”
“Ah, no, no!” exclaimed Isabella in a melancholy tone, “they do
not love me as they did.... And many really hate me, and yet God
knows I have not changed in my love for the Spaniards.... But things
have got all wrong.... I don’t know how it is ... it is through the heated
passions of one and the other. But, Beramendi, it is not my fault.”
“No, indeed,” returned the courtier; “you have not caused this
embroiled state of affairs. It is the work of the statesmen, who are
moved by ambition and egoism.”
This indeed was true, for even as Serrano used the Queen’s
favour to his own ends, and had his debts twice paid by Her Majesty,
he was the first to lead the country against her.
“Do you think that matters will improve, and that passions will
calm down?” asked Isabella anxiously.
“Oh, señora, I hope that the Government will confirm your
authority, and that those that are in rebellion will recognize their
error.”
“That is what they all say,” said Isabella, with a little satirical
smile. “We shall see how things will turn out. I trust in God, and I
don’t believe He will forsake me.”
“Ah!” said Beramendi to himself, whilst his royal mistress
continued in the same strain of religious trust to his wife, “do not
invoke the true God whilst you prostrate yourself before the false
one. This god of thine is an idol made of superstition, and decked in
the trappings of flattery; he will not come to your aid, because he is
not God. I pity you, blind, generous, misled Sovereign.... Those who
loved you so much now merely pity you.... You have been silly
enough to turn the love of the Spaniards to commiseration, if not to
hatred. I see your goodness, your affection, but these gifts are not
sufficient to rule a nation. The Spanish people have got tired of
looking for the fruit of your good heart.”
When Isabella gave the sign of dismissal of the courtier and his
wife by rising to her feet, he said to himself sadly:
“Good-bye, Queen Isabella; you have spoilt your life. Your reign
began with the smiles of all the good fairies, but you have changed
them into devils, which drag you to perdition.... As your ears are
never allowed to hear the truth, I cannot tell you that you will reign
until O’Donnell will permit the Generals to second Prim’s plans. Oh,
poor Queen! you would think me mad if I said such a thing to you;
you would think I was a rebel and a personal enemy, and you would
run in terror to consult with your devilish nuns and the odious set
which has raised a high wall between Isabella II. and the love of
Spain. Good-bye, lady of the sad destiny; may God save your
descendants, as He cannot save you!”
The good-heartedness of the Queen was, indeed, seen by all
about her, and there are people still at the Palace of Madrid who
remember seeing Her Majesty take off her bracelets and give them
to the beggars which infest the royal courtyard. All the best impulses
of Isabella were turned to her own ruin for the want of true patriots,
who by supporting the constitutional rights of the nation would have
secured the sovereignty to the Queen. The self-interested conduct of
the generals and statesmen, whose command in the camarilla of the
palace meant rule over the heart of Her Majesty, tended naturally
only to the overthrow of personal rivals, and to the neglect of the
welfare of the land.
Prim therefore became the hope of the nation. With his return to
the capital, thought the people, crushed down by taxation and
deprived of constitutional liberty, there will be an end to the camarilla,
Narvaez, and Patrocinio, and we shall have the pure fresh air of
disinterested policy.
 The death of O’Donnell at Biarritz relieved Narvaez of the fear of
his rival’s return, but the General had the mortification of seeing his
royal mistress utterly in the hands of Marfori, who had been raised
from the position of Intendente of the Palace to the position of
supreme personal favour.
When the Queen heard of O’Donnell’s death, she is reported to
have said: “He determined not to be Minister with me again, and now
he can never be.”
The Queen now committed the suicidal act of making Gonzalez
Brabo Prime Minister in the place of Narvaez. The poor lady seemed
quite to have lost her head, and there was no one to put her on the
right path, surrounded as she was with harpies.
According to a letter from Pius IX., found in the Princess’s prayer-
book in the royal palace after the Queen had taken flight, the Pope
counselled the marriage of the Infanta Isabella with a Neapolitan
Prince. Even whilst the fêtes of the marriage were going on,
Gonzalez Brabo was concerting with the revolutionary Generals, and
the name of “Prim and Liberty!” was heard on all sides, and
messengers were sent to consult with the leader of the Republican
party in London.
The supporters of the Montpensier party hoped that the
dethronement of Isabella would mean the acceptance of the
Duchess of Montpensier as Queen, and her husband as Prince-
Consort. But this idea was soon nipped by Monsieur de Persigny, the
President of the Privy Council of the Emperor of the French, saying
to Olozaga, who was then Spanish Ambassador at Paris, that he
would never consent to the crown of Spain being on the head of
either the Duke or the Duchess of Montpensier.
After the historic day of September 29, 1868, when Prim made
his successful coup at Cadiz, the Royal Family fled to San
Sebastian.
 The haste with which the flight was made could be seen in the
collections of jewels and money which had been thrust into bags
which were after all left behind.
In the Hôtel d’Angleterre of the seaside resort Isabella still
seemed to expect a miracle to take place in her favour. A throne
does not fall every day, and a crowd hovered about the hotel to see
how the Queen would accept her overthrow.
A murmur of satisfaction broke out among the bystanders when
the loyal-hearted Marquis de Beramendi was seen entering the
hotel. “That is a good thing,” they said, “for Isabella will listen to his
advice, which is certain to be wise.”
The courtier’s remarks to the Lady-in-Waiting were short and to
the point.
“I have come to tell you,” he said, “that, if the Queen keeps to the
good idea of abdicating, certain infatuated people ought to be kept
from opposing it. I have had direct news from Serrano, and he says
that, if Doña Isabella will abdicate in favour of Don Alfonso, he will
save the dynasty, and she herself will be saved. The Duke of Torres
will not put obstacles in the way of this course.”
“Better than that,” returned the Lady-in-Waiting, in a voice which
a cold rendered almost inaudible, “I thought that Her Majesty had the
same idea, ‘that she had better go to Logroño, and abdicate in
favour of the Prince of Asturias in the presence of Espartero.’”
“That’s admirable!” said Beramendi.
“And then, after abdicating, the Queen will depart immediately for
France, leaving the new King in the power of the Regent Espartero.”
“Admirable! splendid!” cried Beramendi; “but there is not a minute
to lose.”
“The departure will be arranged this evening.”
 “But, my God, I fear delays will be fatal; I am afraid that some bad
friend, some plotting courtier of the camarilla, will spoil this saving
step——”
“Well, I must go upstairs now,” returned the lady. “The Señora,
Don Francisco, and Roncali, are busy with manifestoes for the
nation.”
“And Spain will say, ‘Manifestoes to me!’ Now is the time to show
the country fine deeds, and not empty rhetoric.”
On the following morning, when Beramendi went to the hotel, he
came upon Marfori; and although he had had little to do with this
nephew of Narvaez since royal favouritism had raised him to such
undue importance, he said, in a tone of assumed respect: “So Her
Majesty is going direct to France? Something was said about her
travelling to Logroño?”
Upon this Marfori frowned angrily, saying: “You don’t understand,
my dear Marquis, that it would be very humiliating for the Queen of
Spain to ask protection from a General, although he bear the name
of Espartero. All concert with Progressists is dangerous. The Queen
is leaving Spain under the conviction that she will soon be recalled
by her people.”
“I knew it was useless to say more. Don Carlos Marfori was busy
giving orders to the servants. I regarded him with resentment,
because he was the personification of the evil influence which
brought the Queen to her ruin.
“His Arab type of handsomeness, with his large mouth and heavy
jaw, was eloquent of sensuality, and his obesity robbed him of the
attraction which he had possessed in earlier days. He was
impetuous, overbearing, and wanting in the courtesy common to a
superior education.”
 The Marquis was then taken into the presence of the Queen, and
as he bent over her hand she whispered: “You know we have given
up the idea of going to Logroño. No more humiliations! I am going
away so as not to aggravate matters, and to prevent bloodshed; but I
shall be recalled, shall I not?”
“I had to console Her Majesty with one of the usual Court lies,
and the Royal Family soon took its departure, the Queen leaning on
the arm of Don Francisco, the little Infantas with their Ladies-in-
Waiting, and the Prince of Asturias, in a blue velvet suit, led by
Señora de Tacon. The poor little fellow looked pale and sad; his
great eyes seemed to express the royal and domestic sadness of the
scene, and nothing was now wanting but the order for departure.”
Marfori was always much disliked by people at Court. It was in
the summer of 1867. Many courtiers and ladies of high rank were
promenading in the beautiful gardens of La Granja. The soft, well-
kept turf of the shady alleys by the countless sparkling fountains set
off the beauty of the dresses, when, with his usual courtly grace,
General Narvaez advanced to meet the Countess of Campo Alange.
This illustrious lady, whose salons in Madrid were graced by the
highest in the land, was soon to give a ball.
“I have received your invitation,” said the General, after he had
greeted the Countess.
“It is almost the first that I have sent,” returned the lady.
“I have just met Marfori,” said the Duke of Valencia, “and he tells
me he has not received his.”
“Neither will he,” replied the lady sharply.
“And why, being a Minister?” queried the General in surprise,
knowing how the slight to the Queen’s favourite would be resented at
Court.
 “Simply because Cabinet Councils are not held at my house,”
returned the lady caustically, firm in her decision to show her dislike
of the man.
General Narvaez, whose dapper figure and perfect dancing made
him always a welcome guest at the Spanish Court, was still
unmarried when he had to withdraw to Paris as an exile. He had
always been fond of feminine society, but, gay butterfly as he was,
he did not fix his affections upon any one lady.
The beautiful Leocadia Zamora had been once the object of the
officer’s attention, and, indeed, the charming way she accompanied
herself on the harp fascinated other admirers beside the Count of
Valencia. She was a constant visitor in the salons of the Countess of
Montijo, where the lovely Eugénie shone with the brilliance and
charm which were so soon to be transported to the Court of France.
But fate did not reserve the joy of a happy marriage for the lovely
Leocadia, and the sweet spirit, disillusioned by an unhappy love,
retired to a convent in Oviedo, where she passed the rest of her life
performing the duties of a Lady Abbess.
It was said that it was the gallant Don Salvador de Castro who
had taken Leocadia’s heart captive, when she was young; and,
indeed, it is not surprising if this report be true, for he was a typical
courtier of his time, and when he was home from his duties as
Ambassador in Italy he seemed to dwarf all the attractions of the
lady’s other admirers. Leocadia was, in truth, a star of the Court of
Spain, and the beautiful picture by Frederick Madrazo shows the
perfection of her charms, with no other ornament than a white rose
to adorn her simple white dress. Salvador de Castro was honoured
by the friendship of King Francis II. and Queen Maria Sophia when
the Italian Revolution robbed them of the throne of the Two Sicilies,
and he was able to render them marked services and prove himself
as loyal a friend as he was perfect a gentleman. After the
capitulation of Gaeta, the King and Queen rewarded his loyalty by
granting him the title of Prince of Santa Lucia, with the gift of the
beautiful palace on the banks of the Tiber which is known by the
name of the Farnesina, whilst the gardens were sold to the Emperor
Napoleon. The place was deserted, and so near to its ruin that
sheep and goats fed in its grounds, and the custodian took his meals
in the beautiful hall of the frescoes of Sodon.
It was in this palace that Michael Angelo painted a head on the
wall, which is known by the name of “The Visiting Card,” as he left it
as a sign of his call on Raphael when the artist was out.
The Prince of Santa Lucia had the palatial dwelling restored, and
he gave magnificent entertainments in this palace, of which it was
not destined that the lovely Leocadia should be mistress. Indeed, the
lady abandoned all thoughts of love and pomp when she entered a
convent in Oviedo, where she ended her days as Lady Abbess;
whilst the daughter of her old admirer wedded the Marquis of Bey,
and made a mark in Court society of Madrid.
But to return to the gallant little General. His affections were at
last taken captive by another friend of the young Empress of the
French, the beautiful daughter of the Count of Tacher. The Empress
Josephine had belonged to this family, and her parents, the Duke
and Duchess de Tacher de la Pogerie, were much beloved by Queen
Marie Amélie, wife of King Louis Philippe.
It was General de Cordova, who had played such an important
part during the Regency of Queen Maria Cristina, who first took him
to the house of the Tachers. When Narvaez paid a second visit to the
palace on the Boulevard Courcelles, he found that nobody was at
home; and he was waiting in the drawing-room for the return of the
lady of the house, when the daughter came in, looking beautiful in a
white dress, but with her face tied up.
“Are you ill?” asked the General, with concern.