Issue:May 2015

THE SECOND QUADRANT – The Birth of Physical Pharma: 1920-1960

“Evolution is a process of constant branching and expansion.” – Stephen Jay Gould

Innovation can be viewed as a sort of relay race in which individuals or teams contribute to the progress of the whole. Often it’s only in retrospect when we observe that those running the different legs of the race may not have been aware of where or what the finish line really was. In this column, we continue where the last one left off, observing progress that enabled spray drying for pharmaceutical applications, and other progress that has enabled the solubilization technologies and approaches we use today.


In the mid-to-late 19th century, we observed the invention of methods, technologies, and chemistry for the preservation of food and prevention of infectious disease. Applications primarily for the agricultural, food, and manufacturing industries drove innovations to ensure the safety of the food supply, and to deliver methods for efficient processing and manufacturing in support an expanding and increasingly far-flung populace. And pharmaceutics were embraced to prevent and treat disease.

In the first half of the 20th century, progress accelerated in the three key components for spray drying: nozzles, pumps, and dust collection. Whereas fundamental innovations had been made in 1840, 1901, and 1906, respectively, for these components, the diffusion of knowledge and innovations in advancing these technologies progressed at a whirlwind pace from 1900-1960 (Figure 1). This progress – combined with rapid progression in the understanding of chemistry – would set the stage for the earliest applications of spray drying to pharmaceuticals.

Part of the momentum seen in the period between 1914 and continuing into the 1940s can be attributed to a national focus on advancing technologies in general in support of war efforts, and the emerging automotive and aeronautic industries. Innovations in spray drying itself soared during this same era, as the technologies on which its progress was critically dependent rapidly evolved. Figure 2 shows this progress based on the number of patents granted containing the term “spray drying” between 1900 and 1960.


Starting in the late 1940s, the University of Wisconsin became a hotbed for the study and development of modern spray drying. W. Robert Marshall directed comprehensive and fundamental studies that were chronicled in the publication Atomization and Spray Drying during the period 1948-1964”.2 Contemporaneous to this undertaking, Sidney Riegleman, now recognized as one of the fathers of modern physical pharmacy, was a graduate student in the University’s School of Pharmacy.

In 1950, in the last of a four-part series of articles reporting on Studies on Pharmaceutical Powders and the State of Subdivision, Riegelman and three coauthors first introduced spray drying to pharmaceutical applications. Part four, The Application of Spray-Drying Techniques to Pharmaceutical Powders, is where Riegelman and his colleagues explore the utility of the spray dry process for the modification of “physical, pharmaceutical, and pharmacological properties of medicinal substances…”3

“[Spray drying techniques] have found great application in the soap and food industries in the direct processing of various products. However, the apparatus has not found large acceptance in the handling of pharmaceutical products.”2

In this paper, the spray drying and physical properties of drug substances –sulfanilamide, colloidal and precipitated sulfur, and the excipients methyl cellulose and boric acid — were reported. It is of particular interest that the antibiotic drugs Sulfadiazine and Sulfanilamide were spray dried (Figure 3), and a sulfur/methylcellulose solid dispersion was prepared, perhaps the first precursor of a spray dried drug/excipient solid dispersion.

The inquisitive minds of these and subsequent researchers and inventors would form the foundation for today’s success with spray drying to enhance bioavailability – and today’s increasingly large acceptance of this technique. (Since 2005, spray drying has seen the fastest growth rate of any solubilization technology used for FDA-approved drugs.4) Hence, the birth of spray drying as a method to produce a solubilized form of a low solubility drug and excipients was born.

Riegelman went on to have a highly productive career as a physical pharmacist, with his work spanning three more decades until his untimely death in 1981. His accomplishments included a body of groundbreaking research in the importance of techniques to fabricate high surface area pharmaceutical powders to improve bioavailability. Riegelman also contributed pioneering work in bioanalytical chemistry, biopharmaceutics, pharmacokinetic modeling and regulatory policy.


Another ingredient that will later enable spray drying to overcome insolubility had its roots in the 19th century. The earliest patent for rubber cement was granted in 1843. During this same period, modified cellulose products, resins, and synthetic polymers were being developed, but it took another many decades before synthetic polymers emerged to commercial applications. Fueled by shortages of natural materials during WWI and later WWII (and the need for better adhesives for aircraft and other materiel), the birth of polymer science can be traced to 1922.5 This is the first known use of “soybean glue,” invented by scientists at the I. F. Laucks company and patented in 1927. US Patent No. 1,622,496 A, Cellulose-fiber product treated with a size embodying soy-bean flour and process of making the same, formed part of a body of research and innovation that sought novel ways to develop synthetics to create new, stronger and lighter materials for airplanes and other applications.6,7 These other applications would ultimately find their way to enhancing the bioavailability of poorly soluble molecules.


Up to this point in history, we’ve observed the maturation of spray drying, evolving from its earliest roots in food preservation into the beginnings of the modern pharmaceutical era. During the period from 1920-1960, this technique for enhancing the bioavailabilty of insoluble molecules starts to emerge. This diffusion of innovation of this single technology over a century evidences the circuitous path to commercial success: integration of numerous and disparate technologies, “borrowing” innovations from other fields, and the creativity, tenacity, and collaboration of the individuals involved. The next column will cover the introduction of polymers for the application of spray drying for poorly soluble drugs.


1. Thomas A. Edison.
2. Atomization and Spray Drying, William Robert Marshall, American Institute of Chemical Engineers, 1954.
3. Riegelman S, Swintosky JV, Higuchi T, Busse LW. Studies on pharmaceutical powders and the state of subdivision. IV. The application of spray-drying techniques to pharmaceutical powders. J AAPS. 1950;39(8):444-450.
4. Crew M. BIOAVAILABILITY ENHANCEMENT – Analysis of the Historical Use of Solubilization Technologies. Drug Development & Delivery. 2014;14(2):22-25.
5. Canadian Conservation Institute, Major Developments in Adhesive Manufacture. 1750-2000.
6. US Patent and Trademark Office. US Patent No. 1,622,496 A. Cellulose-fiber product treated with a size embodying soy-bean flour and process of making the same;1927.

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Marshall Crew, VP, Global PDS Scientific Excellence, Patheon