Solid-State Organic Chemistry at University of Kentucky

University of Kentucky | College of Pharmacy

Tonglei Li

analyze, compute & design
	solid-state organic/drug chemistry

Organic crystalline materials play a central role in the pharmaceutical industry as well as in fine chemicals. Physicochemical properties not only affect formulation and production, but also cast a huge impact on the performance and stability of products. Because the majority of pharmaceutical materials are solid and most of the solid are molecular crystals, controlling crystal growth and consequent materials properties of drug substances and excipients has become one of essential tasks in the industry, demanding a vast amount of investment and raising significant challenges for scientists. It is well known that crystal size and shape greatly influence formulation and unit operations including flow, blending, granulation and compaction. Uncontrolled and unpredictable properties may lead to product failure such as content inconsistency (e.g., sub- and super-potency) of solid dosage forms, cited as one of top reasons for product recall by FDA, which are often caused by segregation and poor flowability. Furthermore, being unable to identify or select a right polymorphic form of a drug makes it products susceptible to phase transformation, and consequent failure of dissolution and bioavailability requirements, putting patients' life in jeopardy and throwing a company into a market crisis.

Solid-state organic chemistry is therefore an area where understanding and control of crystal properties of organic materials, including pharmaceutical substances, are carried out. Despite decades of efforts, the crystal growth mechanism is not clearly understood. In particular, how growth environment affects growth morphology and polymorphism remains to be solved.

Although limited understanding has been achieved regarding fundamental processes of crystal growth, a significant amount of experimental observations have been made, stimulating vast interests and discussions about properties, analysis, preparation and manufacture of polymorphic systems, especially drug crystals. Polymorph screening of a new drug becomes routine, not only because of the requirement by the agency (FDA), but due to the reason also that a different polymorph may give a company an extra edge to extend the patent life and protect the market of a high-profit drug. One extra year protection of a blockbuster drug can easily generate over $1 billion sale (e.g., Pfizer sold $10.3 billions from its Lipitor in 2003). It is not surprising to see high-throughput crystallization (HTC) developed in the last few years. In fact, a new form of acetaminophen was reported by one HTC company. It appears supportive to the often-cited McCrone's argument that the number of forms discovered is up to the time and energy spent for them.

Current pharmaceutical education faces critical challenges, failing to meet the demand by the drug industry for well-educated and well-trained pharmaceutical scientists. One major reason is the shift in focus from basic science to clinical practice. Basic science courses and laboratory training have been reduced while more clinical pharmacy courses have been introduced. Undergraduate students are trained as professionals and are expected to work not as scientists but as pharmacists who are responsible for "the appropriate use of medications, devices, and services to achieve optimal therapeutic outcomes." (excerpted from 1991 APhA Annual Meeting Highlights) From the year 2000, undergraduate professional programs have been increased to a minimum of six years before granting the Doctor of Pharmacy to students. The focus on clinical practice coupled with the increase in undergraduate years required takes a severe toll on the graduate education, as fewer students go on to graduate school. In 2002, about 350 U.S.-educated pharmacists were pursuing full-time Ph.D. studies, smaller than 1% of the undergraduate enrollment of 38,902 (from AACP). Meanwhile, a shortage of facutly in pharmaceutical sciences has been noticed. All these factors have resulted in a shortage of graduate students, especially those who are trained in the U.S. in pharmacy-related disciplines.

Along with the shortage of graduate students, another major challenge facing the pharmaceutical education is the growing demand for competitive pharmaceutical scientists. Because of the continuing losses of exclusivity on drug products, it is vital for drug companies to constantly develop new products. The annual R&D expenditures in the pharmaceutical industry are more than $30 billion.(C&E News) Pfizer alone spent $7.1 billion on R&D in 2003, more than the combined $4.4 billion total of 25 major U.S. chemical companies including the leaders DuPont ($1.3 billion) and Dow ($1 billion)! Even so, the drug development cycle becomes longer, more expensive, and more difficult. Conservatively estimated, it takes more than 15 years and costs over $800 million to develop a new drug.(Boston Consulting Group) As a result, drug companies rely heavily on cutting-edge technologies to grasp new drug targets and rush their products to the market. Genomics, proteomics, combinatorial chemistry, high-throughput screening, novel delivery systems, materials engineering, and process analytical technology have emerged as key drivers for drug development. The industry also faces the pressure from the consumer and regulatory agency demanding safer, more effective and cheaper drug products, having no choice but to scrutinize every physical, chemical and biological property thoroughly. It is no surprise to see those who have specific scientific or technical expertise and have the ability to focus on required research outcomes are the most sought after by industry. Still, it is estimated that less than the 2% of R&D staff of major pharmaceutical companies have an undergraduate pharmacy degree.

Because the majority of pharmaceutical materials are solid and most solids are crystalline, solid-state organic chemistry plays a crucial role in product development of pharmaceutical industry. As crystal growth and consequent characterization is needed for every drug compound that enters the development stage, a comprehensive knowledge of organic crystals is a must for anyone who aims to work in developing pharmaceutical products.

References:

S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell. Solid-State Chemistry of Drugs, 2nd edition. West Lafayette, Indiana: SSCI, Inc., 1999.

P. York and D. J. W. Grant (1987) Crystal Engineering of Pharmaceutical Particulate Solids, Acta Pharmaceutica Suecica 24:63-64

P. York (1983) Solid-State Properties of Powders in the Formulation and Processing of Solid Dosage Forms, International Journal of Pharmaceutics 14:1-28

K. R. Morris, S. L. Nail, G. E. Peck, S. R. Byrn, U. J. Griesser, J. G. Stowell, S. J. Hwang, and K. Park (1998) Advances in Pharmaceutical Materials and Processing, Pharmaceutical Science & Technology Today 1:235-245

CDER (Center for Drug Evaluation and Research) 1999 Report to the Nation. Food and Drug Administration.

A. J. Hickey. Pharmaceutical Process Engineering. New York: Marcel Dekker, 2001.

H. G. Brittain. Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate. In: H. G. Brittain (ed.) Polymorphism in Pharmaceutical Solids, pp. 279-330. New York: Marcel Dekker, 1999.

S. R. Vippagunta, H. G. Brittain, and D. J. W. Grant (2001) Crystalline Solids, Advanced Drug Delivery Reviews 48:3-26

M. D. Hollingsworth (2002) Crystal Engineering: From Structure to Function, Science 295:2410-2413

M. Lahav and L. Leiserowitz (2001) The Effect of Solvent on Crystal Growth and Morphology, Chemical Engineering Science 56:2245-2253

J. Bernstein. Polymorphism in Molecular Crystals. Oxford: Clarendon Press, 2002.

G. R. Desiraju. Crystal Design: Structure and Function. New York: John Wiley, 2003.

A. S. Raw, M. S. Furness, D. S. Gill, R. C. Adams, F. O. Holcombe, and L. X. Yu (2004) Regulatory Considerations of Pharmaceutical Solid Polymorphism in Abbreviated New Drug Applications (ANDAs), Advanced Drug Delivery Reviews 56:397-414

J. O. Henck, U. J. Griesser, and A. Burger (1997) Polymorphism of Drug Substances - an Economic Challenge, Pharmazeutische Industrie 59:165-169

A. M. Thayer (2004) Blockbuster Model Breaking Down, Modern Drug Discovery 7:23-24

W. C. Mccrone. Polymorphism. In: D. Fox, M. M. Labes, and A. Weissberger (eds.), Physics and Chemistry of the Organic Solid State, Vol. 2, pp. 725-767. New York: Wiley Interscience, 1965.

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