COMMENTARY
Professor Stephen R. Byrn: Scientist, Educator, and Visionary
GEORGE ZOGRAFI
Edward Kremers Professor Emeritus, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705
Received 24 January 2010; accepted 26 January 2010
Published online 26 March 2010 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22114
poor wettability, and the physical instabilities of
suspended particles exhibited by many   hydrophobic 
drugs and excipients. This interest led me to try to
learn more about the surface properties of solids at
the molecular level, and in particular, those of
crystalline solids, the solid form in which most drugs
are prepared. In my opinion, most physical chemical
research in the pharmaceutical sciences dealing with
the use of solids in pharmaceutical dosage forms at
that time, with the possible exception of solid-state
chemical instability, was being approached at a fairly
macroscopic and phenomenological level, rather than
at the molecular level. Consequently, what a delight it
was in 1982 when I obtained a copy of Steve Byrn s
book,   Solid State Chemistry of Drugs,  in which he
placed major emphasis on crystal structure and its
Professor Stephen R. Byrn potential role in helping scientists to understand the
molecular basis of various solid-state physical and
chemical properties and instabilities. As my research
in the 1980 s moved in the direction of process-
induced disorder in crystalline solids and the
amorphous state, I continued to follow Steve s out-
INTRODUCTION
standing studies at the molecular level with great
interest. In 1987, I had the opportunity to meet Steve
It is a great personal pleasure to have the opportunity
personally for the first time in Boston when we shared
to provide an introduction to this special issue of the
the podium as symposium speakers for an AAPS
Journal of Pharmaceutical Sciences, honoring my
program on solids. This began a more than 22-year
good friend and research collaborator, Stephen R.
period of research collaboration and friendship that,
Byrn, the Charles B. Jordan Professor of Medicinal
for me, has been most scientifically stimulating,
Chemistry and Professor of Industrial and Physical
productive and enjoyable. With that perspective in
Pharmacy at the Purdue University, School of
mind, I am pleased to briefly share with you a little bit
Pharmacy and Pharmaceutical Sciences. Coming
about Steve, the scientist, educator and visionary,
from a background in surface chemistry in the
and to present the reasons why I believe that Steve
1960 s and 1970 s my interests in the solid state were
Byrn has been, and continues to be, a major force in
primarily focused on adsorption of surfactants and
the increasingly important area of solid-state chem-
drugs at solid surfaces, as well as problems related to
istry in pharmaceutical systems. This is also why so
many former students, postdoctoral associates,
research collaborators, and academic and industrial
Correspondence to: George Zografi (Telephone: [phone];
colleagues, have joined together to honor him by
Fax: [phone]; E-mail: [e-mail])
presenting reports of their research in this special
Journal of Pharmaceutical Sciences, Vol. 99, 3643 3647 (2010)
ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association issue of the Journal of Pharmaceutical Sciences.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 3643
3644 ZOGRAFI AND NEWMAN
EARLY EDUCATION AND RESEARCH Seeking to expand his knowledge and skills in
TRAINING THE MAKING OF A crystallography, upon graduation with his Ph.D.
SOLID-STATE CHEMIST degree in 1970, Steve made the long trek to Los
Angeles to work as a postdoctoral fellow in the
Steve Byrn was born and raised in New Albany, laboratory of Kenneth Trueblood, a pre-eminent
Indiana located in southern Indiana, not far from internationally recognized crystallographer who
Louisville Kentucky. Except for his few years as a had pioneered many experimental and computational
graduate student and a postdoctoral fellow, Steve has methods of determining the crystal structures of
spent his entire life residing in Indiana, and remains small and large molecules. Most of his time at UCLA
to this day a   true Hoosier.  In 1962, he enrolled at was spent on developing new X-ray software
DePauw University in Greencastle, Indiana majoring packages, used to carry out single crystal structure
in mathematics and chemistry, with the idea of determinations more easily and in much shorter
becoming a physician. However, by the time he times. This led to one publication, but perhaps more
graduated with his Bachelor of Arts degree in 1966, importantly, it also enabled him to very quickly
luckily for us, he had decided that the field of include such software with his X-ray equipment when
chemistry, and in particular, organic and physical he arrived at Purdue University. It was also at UCLA
chemistry, was his passion. This led him to enroll in that Steve was able to interact with a number of other
1966 at the University of Illinois at Urbana as a very talented solid-state scientists seeking to better
graduate student in organic chemistry. Initially, he understand the relationship between crystal struc-
showed a strong interest in synthetic chemistry, but ture and physical chemical properties, and to estab-
upon encountering Professor Paul Curtin, and lish long-term friendships and research interactions.
choosing him as his thesis advisor, his interests An added bonus was his ability to regularly attend the
shifted to solid-state physical organic chemistry. group meetings of Professor Donald Cram, the1987
This, of course set into motion the various studies recipient of the Nobel Prize in Chemistry.
that led him to eventually focus his talents on the In 1969 Steve married his fellow DePauw Uni-
solid-state chemistry of drugs. One interesting aspect versity undergraduate student, Sally Rushmore, and
of his very early graduate studies was the time he by 1971 they had started a wonderful family that
took during the summer between his first and second ultimately became 8 children, 4 by adoption, and 13
years of graduate school to work in the Central grandchildren.
Research Division of the Monsanto Chemical Co., in
St. Louis, doing synthetic chemistry research. From
the beginning of his graduate studies Steve was sure SCIENTIFIC ACTIVITIES AND
that he wanted to be a professor. However, Professor ACCOMPLISHMENTS AT PURDUE
Curtin convinced Steve of the importance of being UNIVERSITY, SCHOOL OF PHARMACY
able to see for himself what industrial research in AND PHARMACEUTICAL SCIENCES
organic chemistry could be like before he made a final
career decision. He had a wonderful experience at In July of 1972, Steve Byrn came home to Indiana to
Monsanto that led to a 1967 paper in JACS, entitled, assume the position of assistant professor in the
  Amination of b-Dicarbonyl Compounds with Tetra- Department of Medicinal Chemistry and Pharma-
kis (dimethylamino) Titanium.  At Illinois, Steve cognosy at Purdue University in West Lafayette.
immersed himself in a number of solid-state studies Thus, began a strong career-long commitment to the
that eventually led to the publication of five papers in School of Pharmacy and the broader Purdue Uni-
JACS and J Org Chem. It was in these studies that he versity community. As a member of the Department
first encountered polymorphic crystalline forms, and of Medicinal Chemistry, Steve became very involved
in particular, the yellow and white solid polymorphic with his medicinal chemistry colleagues on a number
forms of some dihydroxyterephthalates. The focus of of synthetic and natural products projects, where he
this work was on determining crystal structures and provided significant analytical expertise using solid-
relating them to the molecular properties of these state techniques, such as X-ray diffraction and solid-
molecules in the solid state and in solution, as well as state nuclear magnetic resonance. This led to over 30
on the interconversions that occurred between one published papers. As early as 1976, Steve s recogni-
form and the other in the solid state. Ironically, it was tion of the importance of understanding the mechan-
to be about 25 years before he would return to the isms of solid-state chemical reactions that give rise
interesting properties of different colored polymorphs to various chemical instabilities of drugs, led to
with his paper   Conformational and Color Poly- the publication of a ground-breaking review in
morphism of 5-Methyl-2-[(2-nitrophenyl)amino]-3- the Journal of Pharmaceutical Sciences, entitled,
thiophencarbonitrile,  carried out in collaboration   Mechanisms of Solid- State Reactions of Drugs.  This
with scientists at Eli Lilly. was followed by a pioneering series of single crystal
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps
COMMENTARY 3645
studies in the late 1970 s on the desolvation of crystal on the manufacturing process, and this led Steve to
hydrates, as well as on a variety of solid-state take the lead in forming consortia with his Purdue
reactions involving the oxidation, dehydrochlorina- colleagues, N.S.F., other academic programs and
tion, and decarboxylation of organic molecules. This various pharmaceutical companies to develop funda-
fundamental work on solid-state chemical reactivity mental studies, that could lead to a molecular-level
has continued uninterrupted for the past 37þ years, understanding of pharmaceutical manufacturing.
as reflected in a 2007 paper entitled,   Solid State For example, in the context of the significant interest
Interconversion Between Anhydrous Norfloxacin and in such areas as Process Analytical Technology (PAT)
Its Hydrates.  Although the possibility of having and Quality By Design (QbD), Steve and his
different crystalline forms of the same drug, that is, colleagues took the lead to study the various effects
polymorphism, had been known in the 1960 s to be a of processing on solid-state chemistry and stability,
potentially important issue in drug development, as and visa versa, as well as to develop analytical
demonstrated by the reported impact of different approaches for the quantitative determination of
polymorphic forms of the antibiotic, chloramphenicol various components of solid dosage forms during the
palmitate on its dissolution and bioavailability, very manufacturing process. This approach to a most
few academic pharmaceutical laboratories appeared difficult problem is nicely reflected in his recent
to be prepared to carry out the fundamental studies paper,   Process Understanding and Control of Active
required to understand the extent to which such Pharmaceutical Ingredients.  Steve also continues to
problems might be understood at the molecular level be very active these days with his students and
and avoided. Having established a strong solid-state postdoctoral fellows on fundamental studies related
analytical capability, coupled with an ability to to the structure of liquid crystals as well as methods of
produce single crystals, and having had experience synthesis and analysis of nanocrystalline and nanoa-
working with polymorphs during his graduate morphous solids.
studies, Steve Byrn was in an excellent position to Steve Byrn s outstanding contributions to so many
take on this interesting and important area of scientific and technological aspects of the pharma-
research. Although he was called upon by many ceutical sciences have led to the publication of over
pharmaceutical companies to assist them with such 150 scientific papers, a number of book chapters and
problems early in his career, his first published study two editions of his widely used classic book   Solid
on polymorphs, besides his thesis work, was reported State Chemistry of Drugs,  He has given hundreds of
in 1985 in the paper,   Analysis of Solid-State Carbon- invited lectures and short courses all over the world in
13 NMR Spectra of Polymorphs (Benoxaprofen and academic and industrial institutions, and his scien-
Nabilone) and Pseudopolymorphs (Cefaolin).  From tific expertise and accomplishments have brought
that point on there have been innumerable studies him recognition and awards from many scientific
from his laboratory at Purdue that have set the tone organizations. He was elected a Fellow of the
for what is now a very active area of pharmaceutical American Association of Pharmaceutical Scientists
research and development around the world. Indeed, in 1989, was elected to the United States Pharma-
the current strong emphasis on screening for various copeia Committee of Revision from 1990 to 2000, and
solid forms, including polymorphs, very early in, and served as a member of its Council of Experts in 2000
throughout, the drug development process, in my 2005. In 2001, the Food and Drug Administration
opinion, was very much influenced by the 1995 presented him with its FDA Advisory Committee
seminal paper, written by Steve in conjunction with Service Award, and in 2009, Steve became the first
Dr. Ralph Pfeiffer and various FDA scientists, recipient of the AAPS David Grant Memorial
  Pharmaceutical Solids: A Strategic Approach to Research Award for distinguished contributions to
Regulatory Considerations.  the field of Physical Pharmacy. In 1991 his alma
Steve Byrn s innovative research activities in the mater, DePauw University presented him with its
1980 s and early 1990 s, clearly had a very significant Distinguished Alumni Citation.
impact on the fields of pharmaceutics, pharmaceu-
tical technology and drug development, in addition to
medicinal chemistry, chemical processing, and drug STEPHEN BYRN DISTINGUISHED EDUCATOR
discovery. Therefore, it is not surprising that in 1994 AND ACADEMIC ADMINISTRATOR
the School of Pharmacy administration called on
Steve, then the Head of the Department of Medicinal From the beginning of his days as a graduate student,
Chemistry and Pharmacognosy, to assume the same Steve Byrn wanted to be a university professor, and,
position in the Department of Industrial and Physical indeed, he has had an active and distinguished career
Pharmacy. His work in the Department brought him devoted to the educational mission of Purdue Uni-
in closer contact with many solid-state physical versity as both a teacher and administrator. As a
chemical and analytical issues that impact directly classroom teacher, despite his significant commit-
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
3646 ZOGRAFI AND NEWMAN
ments to research and administrative duties, as well STEPHEN BYRN THE VISIONARY
as much professional service outside of the Univer-
sity, Steve has maintained a steady involvement in I hope that the comments that I have made so far will
classroom teaching for professional pharmacy stu- leave no doubt as to why we are honoring Steve Byrn
dents and graduate students. The diversity of courses with this special issue of the Journal of Pharmaceu-
taught over the years includes: analytical medicinal tical Sciences. However, there is one final element of
chemistry; computers in pharmacy; advanced medic- Steve Byrn s life and career that we should briefly
inal chemistry analysis; pharmaceutical solids; drug consider. In my opinion, what makes Steve so special
development; and good regulatory practice. Over the is the fact that he is a visionary. There are many
years, he has been the major thesis advisor of 9 definitions of the word, visionary, but the ones that I
Masters students; 37 Ph.D. students, and 11 post- feel best apply to him are: (1) a person given to
doctoral associates. He currently is supervising 4 innovative speculations and enthusiasms with little
Ph.D. students and one postdoctoral associate. regard for what is thought to be actually possible; (2) a
Having collaborated for many years with Steve Bryn person with unusual powers of foresight; and (3) a
and his research group within a joint industrially person of strong and creative imaginative power and
sponsored consortium focused on fundamental stu- the ability to inspire others.
dies of the properties and stability of crystalline and Much of this visionary behavior has been demon-
amorphous solids, and meeting together at least twice strated by Steve in the manner in which he has
a year, my research group and I were able to see first chosen to initiate scientific studies in certain research
hand how dedicated he was to the quality of education areas before they became main stream, and to develop
and research training that his students received. This courses and other educational programs where an
sense of quality and the accomplishments of these unmet need existed. Excellent examples also include,
scientists certainly attest to his strong commitment to his leadership in establishing the Purdue University
the educational process. As another element of his Center for AIDS Research, the Chao Manufacturing
interest in education, in recent years, sensing a real Center in the Purdue Research Park, the Purdue
need in the pharmaceutical industry, Steve has University Molecules to Market Program, and the
devoted a significant amount of time and energy to joint Purdue Kilimanjaro program in industrial
the development of a graduate certificate and Masters pharmacy, the first of its kind in East Africa. One
Program in Regulatory and Quality Compliance, other visionary activity initiated and nurtured by
wherein 7 courses taught by various academic and Steve that stands out in our field was his recognition
industrial scientists have been made available of a real void within the pharmaceutical industry in
through Purdue University to industrial scientists not always being able to connect a fundamental
on a part-time basis. To date, there have been over 90 understanding of the solid-state chemistry of drugs to
graduates of the certificate program and 3 who have the task of taking an API from discovery to market.
graduated with a Masters degree. More recently, Such fundamental topics include crystallization,
Steve has actively participated in establishing a crystal structure, selection of the most suitable solid
graduate certificate program in industrial pharmacy form, analysis of solid mixtures, process-induced
and manufacturing at the Kilimanjaro School of disorder in crystals, and how they affect solid-state
Pharmacy in Tanzania, going there for various 2- chemical and physical instability, and ultimately,
week periods to conduct manufacturing laboratory dissolution and bioavailability. His response to this
exercises, as well as presenting a course on Drug need was to establish in 1991, together with his wife,
Regulatory issues. Sally, SSCI, Inc., which stands for Solid State
In reviewing Steve Byrn s years at Purdue Chemical Information. Here, in addition to regularly
University, one is struck by the extent to which, providing innumerable industrial short courses on
when called upon, he has provided administrative the solid-state chemistry of drugs, Steve and Sally set
service in so many ways. He served as Associate up a 400 sq.ft laboratory with two technicians to
Head and Head of the Department of Medicinal provide a variety of analytical services focused
Chemistry and Pharmacognosy from 1984 to primarily on crystallization, crystal structure deter-
1994, and Head of the Industrial and Physical mination, and crystal form selection. The positive
Pharmacy Department from 1994 to 2009. His response of the pharmaceutical industry to this
leadership in both of these departments led to greater service is demonstrated by the fact that by 1999
levels of financial support from the University, SSCI had moved into its own building and eventually
increased extramural research funding and an employed a full-time staff of about 100. In 2006,
expansion of the number of full-time faculty appoint- SSCI was sold to Aptuit, Inc. a general pharmaceu-
ments. He also served as Assistant Dean of the tical CRO. I believe that it is safe to say, that as the
Purdue University, Graduate School from 1984 to first of its kind, SSCI, especially through its own
1988. R&D activities, short courses and research publica-
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps
COMMENTARY 3647
tions, has had an enormous impact on the current CONCLUSION
active state of solid-state chemistry in the pharma-
ceutical sciences and in the pharmaceutical I hope in this brief commentary that I have been able to
industry. More recently, Steve became the illustrate the key factors that went into the develop-
technical founder of Andara, now owned by Cyber- ment ofSteve Byrn asa scientist and educator, and how
kinetics,Inc., a company specializing in devices through his talents, energy, and vision, he has been
and drugs for the treatment of spinal cord injury able to have an outstanding impact on the pharma-
and CNS disease states. For all of these most ceutical sciences, and in particular, on solid-state
successful entrepreneurial activity, Purdue Univer- pharmaceutics. I know many will join me in wishing
sity awarded Steve with its 2008 Outstanding Steve and his family the very best in the coming years,
Commercialization Award for Purdue University as he continues,   full speed  , to contribute to all aspects
Faculty. of our field in new ways.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010