Professor William I. Higuchi: Teacher and Scientist

Abstract

For those of us (103 graduate students, 91 postdoctoral students and visiting scholars) who were at universities in Madison, Wisconsin, Ann Arbor, Michigan, and Salt Lake City, Utah, and staff at Aciont, Lipocine, and Theratech, William I. Higuchi is special and inspirational. He influenced the philosophical manner in which we think and handle scientific problems. The shadow of his extraordinary stature has cast special recognition upon us as we entered into careers in academia, the pharmaceutical industry, government institutions, consultantships, and entrepreneurial ventures. This commentary highlights Bill as a teacher and scientist. Bill received his Ph.D. in physical chemistry in 1956 at the University of California‐Berkeley. His interest in pharmaceutics began when he was a postdoctoral research fellow in 1956–1958 at the University of Wisconsin School of Pharmacy, joining his older brother of 13 years, Professor Takeru (Tak) Higuchi. Tak, also a physical chemist, was the pioneer of physical pharmacy (presently known as pharmaceutics), which started in the early 1950s. Bill worked on the theoretical modeling and diffusion of the poisonous sarin gas across skin protective ointment formulations containing absorbents. Thereafter, he spent a year (1958–1959) at California Research Corporation as a research chemist and then returned to Wisconsin as Assistant Professor of Pharmaceutical Chemistry (1959–1962). He collaborated with Professors D. Wurster, A. Lemberger, and T. Higuchi on drug release from solids, diffusion through heterogeneous barriers and the kinetics of aggregation in oil‐in‐water emulsions and suspensions. He continued his distinguished professorial career at the University of Michigan in 1962 and the University of Utah in 1982 until his retirement in 2007. He is currently Professor Emeritus of Pharmaceutics and Pharmaceutical Chemistry at Utah. From a historical point of view, he is among the few evolutionary scientists, besides Tak Higuchi, who have set the tenor and established the scope and significance of pharmaceutics in academia, the pharmaceutical industry, and therapeutics. The training of Ph.D. graduate students was shaped by Bill's foundation in physical chemistry, experiences at Wisconsin and consultantships in the pharmaceutical industry. The core curriculum included Physical Chemistry I and II, Chemical Equilibria, Surface and Colloid Chemistry, Physical Organic Chemistry, Chemical Kinetics, Diffusional Kinetics, Biophysics of Macromolecules, Differential Equations and Pharmacokinetics. His students were encouraged to continue with statistical thermodynamics and advanced calculus. He believed that advanced mathematics gave one the edge to engage in problems described by partial differential equations and, foremost, to understand the fundamental literature in physical chemistry, polymer science, and biophysics. Bill was an eloquent teacher standing before his wall‐to‐wall blackboard conducting a research meeting, planning a research proposal, or developing and solving differential equations. Diagrams of physical models, predictive plots and calculations were integrated with equations. Boxes highlighted the basic framework of the subject. Additional thoughts were written on the side, circled and directed to the mainstream by arrows. After following the arrows and translating the pieces into a comprehensive whole, the final results were displays of the breadth and depth of Bill's command of physical chemistry, mathematics, scientific acumen, and organization. Watching him handle his pocket slide rule (before the advent of the electronic calculator) and deft use of algebraic approximations, which produced rather accurate results, left us in unforgettable amazement. Bill is a theoretician who understands the essence of experiments. He utilizes physicochemical and mathematical models to direct experimental strategies in seeking the quantitative and mechanistic interplay of phenomenological parameters. A remark like “the data suggests” is insufficient and means that more intensive investigations, not necessarily repetitions, are needed. Quantitative efforts are made to distinguish experimental errors from real deviations from baseline theory. Experiments of the “n + 1” kind are invariably implemented to firmly nail down mechanistic interpretations. Bill is remarkably diplomatic in scientific discussions. An introspective pause is enough to make one realize there are deeper explanations. Being self‐disciplined by nature toward achieving excellence, he is a thorough taskmaster. He motivates and challenges one, by gentle persuasion, to excel and think critically. Bill's research is diverse, entailing mass transfer, solubilization, equilibria, colloid and surface chemistry applied to pharmaceutics and biopharmaceutics and may be categorized as follows: dissolution of solids in reactive media (23 papers), diffusional transport in in vitro systems (58), colloidal and thermodynamic surface interactions (44), intestinal and skin transport/metabolism (54), topical delivery by iontophoresis and with enhancing agents (128), dental/apatite dissolution and remineralization kinetics (91), and dissolution in cholesterol/bile acid systems (45). His research is systematic and programmatic. Because his papers are quantitative, mechanistic, in‐depth and modelistic, they serve as useful teaching examples of the application and integration of principles, as well as for their specific information. Besides journals in the pharmaceutical sciences, his prolific publications extend into journals related to physical chemistry, colloid and interfacial sciences, theoretical biology, membrane science, dental research, etc. A few noteworthy comments of his research are worthwhile:(1)Bill understood the essence of diffusion of solutes across the aqueous boundary layer (ABL) from a surface as in diffusion‐controlled dissolution, as well as, toward a surface of a permeable membrane as in drug absorption. Despite the lack of understanding of the ABL in the latter situation by pharmaceutical scientists in the 1960s, the ABL remained a centerpiece in his research in the intestinal and buccal absorption of drugs. He pointed out and quantitatively delineated when the governing mass transfer resistances‐in‐series was ABL‐controlled or membrane‐controlled and how the ABL played a major role in appreciating the relationship of drug molecular structure and oral drug absorption.(2)Encouraged by John Hefferren, Ph.D., Director of Research of the American Dental Association, Bill carried out studies of the dissolution kinetics of dental enamel (hydroxyapatite) in dental caries. Believing that this would be a “slam‐dunk,” his own words, because of his previous experiences in the dissolution kinetics of solids of weak electrolytes in buffer systems and his understanding of theoretical models of fluxes of all diffusible species and complex equilibria, this research, however, became an amazing 45‐year (1962–2007) odyssey. It turned out that hydroxyapatite does not behave as a classical crystalline solid, but as a meta‐stable solid with complex solubility‐equilibria. These efforts in explaining the role of solution fluoride and inhibition of dental caries resulted in the understanding of the action of fluoride in many dental products.(3)C*, the therapeutic drug concentration at x‐distance from the skin surface needed for local dermal activity, was conceived from research studies concerned with the passive absorption of the 5′‐n‐valerate ester of Ara‐A across the stratum corneum of the hairless mouse, followed by diffusion/metabolism with esterase and deaminase across the viable epidermis and dermis. Investigations into the heterogeneous distribution of esterase and deaminase led to the development of theoretical models, and novel experimental techniques and strategies, for example “go‐through” and “reflection boundary” methods using viable epidermis/dermis tissue preparations. The testing of the C* concept in an HSV‐1 infected animal model completed the template of topical delivery research for local activity. His research has shed additional light on the skin barriers and has provided a deeper understanding of the functional roles of penetration enhancers, thus expanding opportunities for transdermal/topical delivery of drugs otherwise limited by the skin barrier for such applications. His work in skin iontophoresis, which accounted for electroosmosis and pore‐induction, has become the basis for iontophoretic ocular drug delivery.(4)The dissolution kinetics of negatively charged cholesterol disks (owing to cholanic acid impurities) by bile salt micelles represent the unique example of the interfacial barrier‐controlled dissolution mechanism of highly water‐insoluble solids by charged micelles. The phenomenon is based on diffusion of micelles across the aqueous boundary layer coupled with the interplay of overlapping spherical and planar diffuse electrical double layers and interparticle dispersion forces of attraction. The addition of strong electrolytes to screen the respective electric fields or the presence of small amounts of positively charged surfactants to neutralize the negative surface charges reduced the dissolution mechanism to the limiting diffusion‐controlled case. Bill's research led to a better mechanistic understanding of gallstone dissolution and therapeutic performance of chenodeoxycholic acid and ursodeoxycholic acid products in patients.(5)Bill's pioneering work in drug release mechanisms from matrices became the basis for the design of several long acting commercial products. His research on “high energy” drug forms and particle size distributions in dissolution rates proved valuable in designing products with increased bioavailability. Bill has made an impact on the life sciences industry by co‐founding and leading as Chairman of the Board of TheraTech, Lipocine, and Aciont. Each venture focused on insights generated by his extensive research in transdermal and iontophoretic delivery and intestinal absorption. The mild‐mannered Bill brings a leadership/management style, that facilitates decision‐making and engenders collegial spirit. It is a blend of demanding critical scientific analysis of multi‐dimensional cause‐effect issues in the decision‐making process, encouraging the participation and growth of colleagues, listening and displaying enthusiasm in the implementation of technological and formulation innovations. Dr. Alejandro Zaffaroni, an industry leader and co‐founder of Alza Corporation, summarizes Bill's contribution toward providing realistic solutions to challenging practical problems as follows, “I have had a passion for drug delivery for many years and drug delivery is a field I know well. There are very few people who have made as substantial an impact to the field as Bill Higuchi.” There is a human side. Bill unexpectedly bumped into Setsuko (Sets) Saito on the University of California‐Berkeley campus steps, rediscovering her from their childhood years at the Japanese‐American relocation center at Heart Mountain, Wyoming during World War II. In the tradition of the Saito and Higuchi families, Sets and Bill firmly believed that education was an essential priority and the means to overcome adversity. They were proud of the academic accomplishments and successful careers of their four children. Sets deserves special recognition. Being the bedrock of the family, shouldering responsibilities, and displaying abundant patience and encouragement, she contributed to Bill's success in building the renowned Ph.D. programs at the Universities of Michigan and Utah. Her gracious hospitalities promoted a collegial spirit among students and scientists. In 2005, after a marriage spanning 49 years, Sets passed away. In summarizing Bill's outstanding accomplishments, dedication, and the impact of his extraordinary intellect, ending this commentary on a philosophical note seems appropriate. In the 1994 D.E. Wurster Research Award in Pharmaceutics, among his other prestigious national and international awards, the “physical model approach” was attributed to Bill. This has been used in many of his publications associated with absorption.“The physical (biophysical) model approach is a basic science‐oriented approach in attacking a multivariable system. The approach strives to account for key anatomical, biochemical, physicochemical, and transport factors and to interrelate the above factors within a rigorous, mathematical and mechanistic framework of a biophysical model. The model serves as the basis for the design of appropriate experimental strategies, quantification of phenomenologic parameters, determination and delineation of rate‐determining steps and factors, and the understanding of various parts of the system. As a consequence of experimental and theoretical efforts, one should be able to accomplish the following goals: (a) lay the foundation for directing strategies and options in the manipulation of chemical, physicochemical, biophysical and formulation factors to optimize drug delivery within established boundaries; (b) define the principal parameters, rate‐determining factors and experimental methodology to judiciously interrelate animal and human studies; and (c) establish the model as a computational and predictive tool. An important attribute of the approach is that the biophysical model is built on a mechanistic template, emanating from the first principles of physical chemistry and transport kinetic theory, to enable one to accommodate the facts and new evidences as they come to the forefront.” Bill, searching for words of deep appreciation that would satisfy all of us is difficult. Therefore, we, the beneficiaries of your mentorship, counsel, friendship, and your dedication to excellence in teaching and research over five decades, simply say “thank you.” As part of this special tribute, Bill kindly agreed to answer a few questions that provide his perspective on pharmaceutical science education and research over the last half century.(1)You were trained as a physical chemist, yet you made the transition to pharmaceutical science early in your career. How did that come about and how did your training in physical chemistry help you make that transition so successfully?My transition to pharmaceutical science began when I joined my brother Takeru's laboratory at the University of Wisconsin in 1956 for a 1½‐year period. Not long after arriving in Madison, I came to realize that pharmaceutics should be a very attractive field for a physical chemist. I found it quite remarkable that essentially every identifiable important challenge in the design, development and manufacture of dosage forms needed physical chemistry for problem solving. I also found pharmaceutics particularly attractive in that, in many instances, the successful “application” of physical chemistry in solving the pharmaceutical problem would require the deeper probing of the underlying principles themselves, that is, there would be new questions at the frontiers of physical chemistry that would require investigation along with the pharmaceutical problem at hand. The thought of maintaining some balance between identifying and pursuing interesting pharmaceutical problems and trying to grow in one's original field of training was certainly quite exciting and I saw early on this would be possible in pharmaceutical science.(2)Pharmaceutical science itself seemed to go through a transformation in the 1950s and early 1960s. How did that come about?It is quite interesting that there were two major developments over a brief period of 10–15 years (1950s to early 1960s) that were to define pharmaceutics as it exists today. The first of these was physical pharmacy and the other that followed within about a 10‐year period was biopharmaceutics. In the wisdom of the senior scientific leadership (mostly pharmaceutical scientists in their 20s and 30s), it was clear to them that with physical pharmacy alone there was a major deficiency in the field of pharmaceutics. The integration of biopharmaceutics into pharmaceutical science occurred quite rapidly and it became quite clear that the combination of physical pharmacy and biopharmaceutics truly made possible the rational approach to dosage form design.(3)What are your thoughts about the transition of graduate pharmaceutical science education from a focus on physical chemistry to a focus on biological systems?This is a very complex question and it is difficult to construct a simple response. There may be more questions than answers. First of all I am assuming that this question refers only to those pharmaceutics graduate programs that, in the past, had strongly emphasized physical chemistry but, in recent years, have moved away from this focus. I do find this situation to be a matter of some concern as, in my mind, the Ph.D. pharmaceutics graduate going into industry, government, academia, or another setting to be the scientific leader in dosage form design issues must have the strongest possible background in physical and physical organic chemistry. The more thoroughly and more deeply the pharmaceutical scientist investigates a dosage form design problem, physical chemistry would seem to become increasingly more important. For this reason, I personally do believe that physical chemistry should be the focus in graduate education for Ph.D.'s in this area of pharmaceutical science for those programs emphasizing dosage form design.Not too long ago, the Ph.D. pharmaceutics graduates of those graduate programs strongly emphasizing physical chemistry were clearly the first choice among industry recruiters for positions in the area of dosage form design because these graduates not only had the strong physical chemistry background but, at the same time, understood the expectations of the role of pharmaceutics in pharmaceutical R and D. In today's market, the pharmaceutics Ph.D. may be competing with top‐notch Ph.D. graduates of chemical engineering and bioengineering programs and we can wonder whether many of our new pharmaceutics Ph.D.'s will be able to successfully compete with such other Ph.D.'s with strong physical chemistry backgrounds.When biopharmaceutics became part of pharmaceutics (around the early 1960s), some of the departments of pharmaceutics began to emphasize biopharmaceutics as the core area of study. In these programs, both the department research and the course work did de‐emphasize physical chemistry to varying extents. The Ph.D. graduates of many of these programs, however, have been in high demand from the beginning by industry, but primarily for positions in the area of biopharmaceutics (pharmacokinetics, drug metabolism) and not in the area of dosage form design.Those pharmaceutics Ph.D. programs that had physical chemistry as a focus, until rather recently (into the 1980s or longer in some cases), were able to emphasize physical chemistry via the department research with research projects in areas of physical pharmacy or, quite often, the physical chemistry of biopharmaceutics (i.e., drug release mechanisms; transport of drug molecules across biomembranes). In addition, the core courses in these programs were comparable to those of the 1950s–1960s with regard to the rigor of the physical chemistry. As a side note, the advanced courses in physical and physical organic chemistry were taken in the chemistry department along side of the graduate students in chemistry and physics with the thought that it is important for the pharmaceutical science graduate students to have both the rigor and the broader foundation in physical chemistry along with knowing that their background in physical chemistry was favorably competitive with the best and that they can be critical thinkers as well as good doers. The ideal Ph.D. graduate from this program could then become a “generalist” that understood the expected role of pharmaceutics in pharmaceutical R and D but at the same time could think about and deal with pharmaceutical science issues in considerable depth.During the time frame of the 1970s, NIH began to become a source of significant research funding for faculty members in departments of pharmaceutical science. Today many of the leading departments of pharmaceutics are those that are well‐funded by NIH. As a consequence of the nature of the mission of NIH, the NIH funded research project is usually multidisciplinary in nature in which pharmaceutical science may play a role but often not necessarily the major role. Quite often the necessity to demonstrate important biological or therapeutic outcomes in the NIH project is so great that the P.I. cannot find the time in the research project for investigating interesting aspects of the pharmaceutical science. Herein lies the problem because this situation impacts importantly upon the research training of the graduate student. Also, during the past 10–15 years, the trend toward the more biological in research has influenced the required course work as well, and physical chemistry has been de‐emphasized to varying extents in many of these programs that were previously characterized as being comprehensive and rigorous in physical chemistry. I do find it very difficult to judge and to quantify how much de‐emphasis of physical chemistry is too much, leading to serious negative consequences in the long run. For a pharmaceutical science graduate student, is there a minimum “dwell” time for physical chemistry topics during graduate studies, below which the student may suffer some long term penalty? I for one believe that even a modest amount of de‐emphasis may have a proportionate negative effect, because physical chemistry is so ubiquitous in pharmaceutical science and it is especially important in solving the toughest problems.(4)What were the most significant changes you have witnessed in pharmaceutical sciences in the past five decades?I would say there were two major events and/or changes in pharmaceutical science in the past half century. One of these is the integration of biopharmaceutics into pharmaceutics (late 1950s through the 1960s). This defined pharmaceutics and made it into a truly rational area of study and a very significant component of pharmaceutical research and development. The second is the founding of the ALZA Corporation and the many changes in pharmaceutical science and the development of new technologies that followed from it.(5)Who were the most influential people in your life?There have been many individuals that have been important in my life. Their advice and/or their deeds at particular time points have influenced the directions I have taken in my career. If I made a list of the names of such individuals, it may fill a couple of pages, but at the top of the list would be my own family members, especially my three brothers: James, a medical doctor; Kiyoshi, a biochemist Ph.D.; and Takeru, a physical chemist Ph.D. Early on, their collective influence without doubt was quite important in my going into a scientific field. Around the time I was nearing graduation from San Jose State College where I was majoring in chemistry, I began to have more serious conversations with Takeru who by then was established on the faculty at the University of Wisconsin. Takeru suggested I apply for graduate study in physical chemistry at Berkeley where Chester O'Konski had just recently joined the faculty (Takeru, Chester O'Konski, and Joseph Swintosky were roommates in Madison around 1939). A few years later, more discussions with Takeru led me to thinking about joining him after completing my Ph.D. work. Takeru had introduced to me his view that the need and the opportunities for physical chemistry in the field he was now in (pharmaceutics) was great and that physical chemistry could make immense contributions in the field. I did join Takeru as a postdoc (1956–1958). Then I was invited back to Wisconsin as an assistant professor a year later. During my years at Wisconsin I learned first hand of the great opportunities in pharmaceutics. I also became involved in some research (dissolution rates of solids; transport of drug molecules through membranes) in collaboration with Takeru and Dale Wurster that has continued to this day.(6)What are the accomplishments you look back upon with great pride?I feel that I have been very fortunate in having had the opportunity to (a) contribute to the education of many graduate students, (b) to collaborate with many faculty colleagues and others in this endeavor, and (c) in doing so to also participate in a number of interesting research projects over the years. I do take great pride particularly in those research projects where graduate students have played major roles. These include the achievements of the “physical model approach” due largely to Norman Ho's creative insights regarding how to attack the complex problem of in vivo biomembrane drug transport employing physical chemical concepts and methods. This approach and its modifications have been used in the mechanistic studies of intestinal membrane, dermal/transdermal, and other biomembrane transport studies with highly rewarding results. Another research project that I am quite proud of and worthy of mention is our 45‐year research effort aimed toward the understanding of apatite solubility and dissolution kinetics where Jeff Fox's talents and abilities have made the difference in unraveling some of the mysteries of this complex system. Thirty‐seven Ph.D. graduate students have been involved in this research program since 1962.(7)How has the pharmaceutical industry changed in your lifetime?Here I can comment only with regard to how pharmaceutical science has changed in the pharmaceutical industry in my lifetime. When I joined Takeru in 1956, pharmaceutics (physical pharmacy) was enjoying a glorious period. Many would represent the period of the late 1940s into the mid‐1950s as the period of transition in which pharmaceutical product development in the pharmaceutical industry was undergoing a major change from the “art and science” of pharmacy to the rigorous science of physical pharmacy. The physical pharmacy Ph.D. graduates were receiving multiple offers from Big Pharma and the new science the graduates brought with them to the companies was rapidly integrated into practice.The founding of ALZA (1968) by Alex Zaffaroni stimulated an irreversible change in the pharmaceutical industry. Until the arrival of ALZA upon the scene, pharmaceutical industry, especially “Big Pharma”, had been comfortable with the belief that pharmaceutical science should be basically a support service in pharmaceutical research and to be mainly concerned with developing traditional dosage forms in product development. ALZA brought to the fore the concept that there were many new drug delivery opportunities to be explored and new products based on new drug delivery technologies to be developed. The changes in pharmaceutical science that followed resulted in the influx of many top‐notch scientists from outside of traditional pharmaceutics, start‐ups of many new drug delivery companies, and many superior drug products based upon the principles of controlled release.(8)What is the future of pharmaceutical science?Pharmaceutical science will always be a challenging and exciting field, as long as there are people suffering from diseases and other conditions. It is also a field that is very attractive for scientists of many disciplines. There will be challenges not only with newly discovered drugs but also with improving the performance of old drug molecules such as in improving the therapeutic index of drugs through methods of pharmaceutical science. Better understanding of the various biological barriers to drug delivery and methods to overcome them safely for the patient will continue to offer important challenges. I cannot see anything in the foreseeable future but great opportunities for pharmaceutical science.(9)The students and colleagues who worked with you soon found themselves to be a part of the “Higuchi family”. Your wife, Sets, was such an important part of that. What are your thoughts on the role Sets played in your life?I am grateful for this question. Sets indeed played a very important role. I would definitely not have achieved many of my professional goals and objectives in life without her. Most characteristic of Sets was that she always made special effort to get to know the students and other members of the laboratory and considered it very high priority to be involved with them. She is well‐remembered by many of the former students and colleagues for her warmth and kindness.(10)Numerous students and post doctoral scientists trained under you have had tremendous impact worldwide in academia and industry. In your opinion, what training attributes may have played a role in their success?I believe that I have been fortunate to have had a good number of very good, and some outstanding, graduate students and post‐doctoral scientists and many of them have had extremely successful careers. To be candid, I have not given a great deal of thought to the question of what factors during graduate studies would best correlate with the student's later success in his/her career in pharmaceutical science. I offer the following thought. I do believe that a student's desire to succeed (for whatever reasons) which translates into being well‐focused on the objectives of the graduate studies, working hard, and not giving up when set‐backs occur—that these may correlate with success in later life. This desire to succeed should be aided by the student's own strong belief that the graduate education program should make a difference in attaining his/her career goals. If then, at the time of graduation, the student still feels positive about the experience, he/she can embark upon a career with a high degree of self‐confidence. Norman Ho acknowledges assistance from Dr. Gregory Amidon, Dr. Gene Fiese, Dr. Robert Lipper, and Dr. Mahesh Patel.