School of Pharmacy at University of Wisconsin-Madison - Research Homepage

Navigation Options

 

Pharmaceutical Sciences Division

photo

Lian Yu, Ph.D.

Professor of Pharmaceutical Sciences and Chemistry

4119 Rennebohm Hall
Phone: 608-263-2263

lyu@pharmacy.wisc.edu
Email Lian Yu

Education:

  • Ph.D. Physical Chemistry - Ohio State University
  • B.S. Chemistry - Peking University

Overview

Lian Yu joined the School of Pharmacy in 2004. Before then he was a research scientist in Eli Lilly and Company. His honors include Elected Fellow of the American Association of Pharmaceutical Scientists, Lilly Research Laboratories President's Award, and Invited Visiting Professorship at the University of Manchester, and David Grant Research Achievement Award in Physical Pharmacy from American Association of Pharmaceutical Scientists. He has an affiliate appointment in the Department of Chemistry.

Solids of organic molecules are increasingly being explored for applications in pharmaceutical, biomedical, and electronic technologies. These soft materials exhibit properties and physical phenomena unknown for traditional hard materials. In this laboratory, physical measurements and crystallization experiments are performed to understand the formation, properties, and transformation of molecular solids. Our major techniques are crystallography, calorimetry, spectroscopy, and microscopy. The key areas of research are polymorphism, organic glasses, and molecular motions in solids.

(1) Polymorphism of Organic Materials. Polymorphism, the ability of the same molecule to crystallize in different structures, is important to the makers of pharmaceuticals and specialty chemicals. Our work aims to discover unusual polymorphs, understand how polymorphic systems crystallize, and use polymorphs as a tool to understand the process of crystallization. A polymorphic system discovered in this laboratory (ROY) has the largest number of coexisting polymorphs of solved structures (Figure 1). Such a system helps elucidate the origin of polymorphism and structure-property relations. Some questions being investigated include: Why do some molecules have many polymorphs and others seemingly none? Why do polymorphs grow from the same liquid at rates orders of magnitude different? What determines the probability of one polymorph nucleating on another during crystallization (Figure 2)?

(2) Crystallization of Organic Glasses. For many applications, amorphous solids (glasses) are preferred over crystalline solids. Amorphous drugs, for example, are more soluble than crystalline drugs, a property useful for delivering the increasing number of highly potent but poorly soluble drugs. Any amorphous material must be stable against crystallization for crystallization negates its advantages. We are interested in how organic glasses crystallize. It is remarkable that despite the freezing of liquid-like molecular mobility, a glass can still crystallize, even at rates faster than permitted by diffusion. We are studying two mechanisms leading to fast crystal growth: transition from diffusion-controlled to "diffusionless" crystal growth and surface-enhanced crystal growth. To our knowledge, these phenomena have been observed only for organic glass formers. Some questions being investigated include: Is crystal growth from glasses controlled by crystal/liquid structural similarity? How does crystal growth from glasses differ from diffusion-controlled growth in low-viscosity liquids? Is surface-enhanced crystal growth caused by high surface molecular mobility? Can surface crystallization be suppressed with a coating? How does surface-enhanced crystallization differ from bulk crystallization?

(3) Molecular Motions in Organic Solids. Molecular motions in a solid controls how fast it undergoes physical and chemical changes. We are studying two types of molecular mobility in organic glasses: surface diffusion and moisture diffusion. The method of surface grating decay is used to measure the surface molecular mobility of organic glasses. This property is of interest because crystal growth can occur orders of magnitude faster at the surface than in the bulk of organic glasses. Raman microscopy is used to measure moisture diffusion in sugar glasses. This property is of interest because the interaction with water is a major mechanism for the degradation of pharmaceutical and food products.

Figure 1. The simple molecule ROY forms at least ten polymorphs with different colors and molecular conformations; the structures of seven polymorphs (shown) have been solved.

Figure 2. Crystal seeds in a supersaturated medium are expected to grow in the same lattice. We found, however, that seeds of one polymorph can nucleate another polymorph. D-mannitol crystallized first as the delta polymorph and then as the alpha polymorph, with alpha nucleating on delta. This phenomenon is relevant to understanding and controlling crystallization in polymorphic systems.

Work-Related Interests/Research:

Crystallization, polymorphism, amorphous solids, solid-state chemistry.

Awards:

  • David Grant Research Achievement Award in Physical Pharmacy, American Association of Pharmaceutical Scientists, 2011
  • Invited Visiting Professor, University of Manchester, UK, 2009.
  • Elected Fellow, American Association of Pharmaceutical Scientists, 2006.
  • Lilly Research Laboratories President's Award, 2003.

Highlighted Publications:

  • Yu, L. Inferring Thermodynamic Stability Relationship of Polymorphs from Melting Data. J. Pharm. Sci. 1995, 84, 966.
  • Yu, L.; Stephenson, G. A.; Mitchell, C. A.; Bunnell, C. A.; Snorek, S. V.; Bowyer, J. J.; Borchardt, T. B.; Stowell, J. G.; Byrn, S. R. Thermochemistry and Conformational Polymorphism of a Hexamorphic Crystal System. J. Am. Chem. Soc. 2000, 122, 585-591.
  • Yu, L. Amorphous Pharmaceuticals - Preparation, Characterization and Stabilization. Adv. Drug Delivery Rev. 2001 48, 27-42.
  • Mitchell, C. A.; Yu, L.; Ward, M. D. Selective Nucleation and Discovery of Organic Polymorphs through Epitaxy with Single Crystal Substrates. J. Am. Chem. Soc. 2001, 123, 10830-10839.
  • Yu, L. Red, Orange and Yellow Polymorphs of a Conformationally Flexible Molecule: Single-Crystal Spectroscopy, Optical Crystallography and Computational Chemistry. J. Phys. Chem. A 2002, 106, 544-550.
  • Yu, L. Nucleation of One Polymorph by Another. J. Am. Chem. Soc. 2003, 125, 6380-6381.
  • Chen, S.; Guzei, I. A.; Yu, L. New Polymorphs of ROY and New Record for Coexisting Polymorphs of Solved Structures. J. Am. Chem. Soc. 2005, 127, 9881-9885.
  • Yu, L.; Huang, J.; Jones, K. J. Measuring Free-Energy Difference between Crystal Polymorphs through Eutectic Melting. J. Phys. Chem. B 2005, 109, 19915-19922.
  • Chen, S.; Xi, H.; Yu, L. Cross Nucleation between ROY Polymorphs. J. Am. Chem. Soc. 2005, 127, 17439-17444.
  • Wu, T.; Yu, L. Surface Crystallization of Indomethacin below Tg. Pharm. Res. 2006, 23,2350-2355.
  • Wu, T.; Yu, L. Origin of Enhanced Crystal Growth Kinetics near Tg Probed with Indomethacin Polymorphs. J. Phys. Chem. B 2006, 110, 15694-15699.
  • Huang, J.; Chen, S.; Guzei, I. A.; Yu, L. Discovery of a Solid Solution of Enantiomers in a Racemate-Forming System by Seeding. J. Am. Chem. Soc. 2006, 128, 11985-11992.
  • Zhu, L.; Brian, C.; Swallen, S. F.; Straus, P. T.; Ediger, M. D.; Yu, L. Surface Diffusion of an Organic Glass. Phys. Rev. Lett. 2011, 106, 256103
  • Sun, Y.; Zhu, L.; Kearns, K. L.; Ediger, M. D.; Yu, L. Glasses Crystallize Rapidly at Surfaces by Growing Crystals Upward. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 5990.
  • Zhu, L.; Cai, T.; Huang, J.; Stringfellow, T. C.; Wall, M.; Yu, L. Water Self Diffusion in Glassy and Liquid Maltose Measured by Raman Microscopy and NMR. J. Phys. Chem. B 2011, 115, 5849.
  • Cai, T.; Zhu, L.; Yu, L. Crystallization of Organic Glasses: Effects of Polymer Additives on Bulk and Surface Crystal Growth in Amorphous Nifedipine. Pharm. Res. 2011, 28, 2458?2466.
  • Gunn, E.; Ilia Guzei, I. A.; Yu, L. Does Crystal Density Control Fast Surface Crystal Growth in Glasses? A Study with Polymorphs. Crystal Growth & Design 2011, 11, 3979