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Lian Yu, PhD

Professor
Pharmaceutical Sciences and Chemistry


grad student chats with Dr. Yu

Yu Lab Research Lab Feature Article: Designing Better Pharmaceuticals with Glass

2020 Yu Lab Research Summary


Background: We study solids of organic molecules. These soft materials are being explored for applications in pharmaceutical and electronic technologies, and exhibit properties and physical phenomena unknown for 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. Three areas of current research are polymorphism, crystallization of 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 in the manufacture of drugs and specialty chemicals because polymorphs have different properties. Our work aims to discover polymorphs and control crystallization in polymorphic systems. A polymorphic system discovered in this laboratory (ROY) has the largest number of coexisting polymorphs of solved structures. Such a system helps elucidate the origin of polymorphism and study 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?

(2) Crystallization of Organic Glasses. For many applications, amorphous solids (glasses) are preferred over crystalline solids. Organic glasses are materials for organic electronics, bio-preservation, and delivery of poorly soluble drugs. Any amorphous material must be stable against crystallization because crystallization negates its advantages. We study how organic glasses crystallize. Despite their solidity, glasses can crystallize, sometimes surprisingly fast. We are investigating fast modes of crystal growth that emerge in organic liquids as they are cooled to become glasses. The phenomenon is unknown or uncommon for hard materials. 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 fast surface 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 control how fast physicochemical changes can occur. We are studying two types of molecular mobility in organic solids: surface diffusion and moisture diffusion. The method of surface grating decay is used to measure surface molecular mobility. This property is of interest because crystal growth can occur much faster at the surface than in the bulk of organic glasses. Raman microscopy is used to measure moisture diffusion. This property is important 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.

Professional Interests: 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.

Education:

  • PhD Physical Chemistry - Ohio State University
  • BS Chemistry - Peking University
Highlighted Publications:
  1. Li, X.; Ou, X.; Rong, H.; Huang, S.; Nyman, J.; Yu, Lia Lu, M. The twelfth solved structure of ROY: Single crystals grown from melt microdroplets and a blind test of crystal structure prediction. Crystal Growth and Design 2020, in review.
  2. Yu, Lia Lu, M. A general method for cultivating single crystals from melt microdroplets. Chem Comm. 2020, published. https://doi.org/10.1039/d0cc03157g.
  3. Lu, X.; Li, M.; Huang, C.; Lowinger, M. B.; Xu, Wei; Yu, Lia Byrn, Stephen R.; Templeton, A. C.; Su, Yongchao. Atomic-level Drug Substance and Polymer Interaction in Posaconazole Amorphous Solid Dispersion from 19F Magic Angle Spinning NMR. Mol Pharm2020, 17, 2585–2598. https://doi.org/10.1021/acs.jpcb.0c02131. Cover art.
  4. Bagchi, Kushal; Deng, Chuting; Bishop, Camille; Li, Yuhui; Jackson, Nichola Yu, Lia Toney, Michael; de Pablo, Jua Ediger, Mark. Over what length scale does an inorganic substrate perturb the structure of a glassy organic semiconductor? ACS Appl. Mater. Interfaces 2020, 12, 26717–26726.
  5. Cao, Chengrong; Yu, Lia Perepezko, John. Surface dynamics measurement on a gold based metallic glass. Phys. Lett. 2020, 116, 231601. https://doi.org/10.1063/5.0007838.
  6. Li, Yuhui; Zhang, Wei; Bishop, Camille; Huang, Chengbi Ediger, M. D.; Yu, Lian. Surface diffusion in glasses of rod-like molecules posaconazole and itraconazole: Effect of interfacial molecular alignment and bulk penetration. Soft Matter 2020, 16, 5062-5070.
  7. Bishop, C.; Yu, L.; Ediger, M. D. Fytas, G. Extreme Elasticity Anisotropy in Molecular Glasses. Advanced Functional Materials 2020, 30, 2001481. Cover art.
  8. Lu, Xingyu; Huang, Chengbi Li, Mingyue; Skomski, Daniel; Xu, Wei; Yu, Lia Byrn, Stephe Templeton, Alle Su, Yongchao. Molecular Mechanism of Crystalline-to-Amorphous Conversion of Pharmaceutical Solids from 19F Magic Angle Spinning NMR. J. Phys. Chem. B 2020, 124, 5271–5283. https://doi.org/10.1021/acs.jpcb.0c02131. Cover art.
  9. Bishop, C.; Li, Y.; Toney, M. F.; Yu, L.; Ediger, M. D. Molecular orientation for vapor-deposited organic glasses follows rate-temperature superposition: The case of posaconazole. J. Phys. Chem. B 2020, 124, 2505-2513.
  10. Chen, Z.; Yu, J.; Teerakapibal, R.; Meerpoel, L.; Richert, R.; Yu, Lian. Organic glasses with tunable liquid-crystalline order through kinetic arrest of end-over-end rotation: The case of saperconazole. Soft Matter 2020, 16, 2025 – 2030. https://doi.org/10.1039/c9sm02180a
  11. Yao, X.; Huang, C.; Benson, E. G.; Shi, C.; Zhang, G. G. Z.; Yu, Lian Effect of polymer solute on crystal nucleation in glass-forming molecular liquids: Equal suppression of nucleation and growth. Cryst. Growth Des. 2020, 20, 237−244.  https://doi.org/10.1021/acs.cgd.9b01095.
  12. Bishop, C.; Delongcham Toney, M. F.; Yu, Lia Ediger, M. D. Vapor deposition of a nonmesogen prepares highly structured organic glasses. PNAS 2019, 116, 21421–21426. www.pnas.org/cgi/doi/10.1073/pnas.1908445116.
  13. Bishop, C.; Gujral, A.; Toney, M. F.; Yu, Lia Ediger, M. D. Vapor-Deposited Glass Structure Determined by Deposition Rate−Substrate Temperature Superposition Principle. J. Phys. Chem. Lett. 2019, ASAP. https://doi.org/10.1021/acs.jpclett.9b01377.
  14. Zeng, A.; Yao, X.; Gui, Y.; Li, Y.; Jones, K. J.; Yu, Lian. Inhibiting Surface Crystallization and Improving Dissolution of Amorphous Loratadine by Dextran Sulfate Nano-coating. J. Pharm. Sci. 2019, online. DOI: https://doi.org/10.1016/j.xphs.2019.02.018
  15. Gui, Y.; Chen, Y.; Yu, L. Improving Stability and Dissolution of Amorphous Clofazimine by Nano-Coating. Pharm. Res. 2019, 36:67. https://doi.org/10.1007/s11095-019-2584-9. Journal Cover.
  16. Li, Yuhui; Yu, J.; Hu, S.; Chen, Z.; Sacchetti, M.; Sun, C. C.; Yu, Lian. Polymer nanocoating of amorphous drugs for improving stability, dissolution, powder flow, and tabletability: The case of chitosan-coated indomethacin. Mol. Pharm. 2019, 16, 1305−1311.  https://doi.org/10.1021/acs.molpharmaceut.8b01237.
  17. Ediger, M. D.; de Pablo, J. J.; Yu, Lian. Anisotropic vapor-deposited glasses: Hybrid organic solids. Acc. Chem. Res. 2019, 52, 407-414.  https://doi.org/10.1021/acs.accounts.8b00513.
  18. Bagchi, K.; Jackson, N. E.; Gujral, A.; Huang,; Toney, M. F.; Yu, Lia de Pablo, J. J.; Ediger, M. D. Origin of Anisotropic Molecular Packing in Vapor-Deposited Alq3 Glasses. J. Phys. Chem. Lett. 201910, 164–170. https://doi.org/10.1021/acs.jpclett.8b03582.
  19. Zhong, Z.; Xiaotong Yang, X.; Wang, B.-H.; Yao, Y.-F.; Guo, B.; Yu, Lia Huang, Y.; Xu, J. Solvent-Polymer Guest Exchange in Carbamazepine Inclusion Complex: Structure, Kinetics and Implication for Guest Selection. CrystEngComm 2019, 21, 2164. https://doi.org/10.1039/C8CE01766B.
  20. Chen, Yinsha Chen, Zhenxuan.; Tylinski, Michael.; Ediger, M. D.; Yu, Lian. Effect of molecular size and hydrogen bonding on three surface-facilitated processes in molecular glasses: Surface diffusion, surface crystal growth, and formation of stable glasses by vapor deposition. J. Chem. Phys. 2019, 150, 024502. https://doi.org/10.1063/1.5079441 Editor’s Pick.
  21. Amidon, G. E.; Anderson, B. D.; Balthasar, J. P.; Christel Bergstrom, C.; S.-M. Gerald Kasting, G.; Kesisoglou, F.; Khinast, J.; Mager, D.; Roberts, C. J.; Yu, Lian Fifty-eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-based Modeling. J. Pharm. Sci. 2019, 108, 2-7. https://doi.org/10.1016/j.xphs.2018.11.002.
  22. Su, Yua Yu, Lia Cai, Ting. Enhanced Crystal Nucleation in Glass-Forming Liquids by Tensile Fracture in the Glassy State. Crystal Growth and Design 201919 (1), 40–44. https://doi.org/10.1021/acs.cgd.8b01427.
  23. Nyman, J.; Yu, Lia Reutzel-Edens, S. M. Accuracy and reproducibility in crystal structure prediction: The curious case of ROY. CrystEngComm 2019, 21, 2080–2088. https://doi.org/10.1039/C8CE01902A.
  24. Huang, C.; Chen, Z.; Gui, Y.; Shi, C.; Zhang, G. G. Z.; Yu, Lian. Crystal nucleation rates in glass-forming molecular liquids: D-sorbitol, D-arabitol, D-xylitol, and glycerol. J. Chem. Phys. 2018, 149, 054503. https://doi.org/10.1063/1.5042112. Editor’s Pick.
  25. Stan F.S.P. Looijmans, S. F. S. P.; Dario Cavallo, D.; Yu, Lia Peters, G. W. M. Cross-nucleation between polymorphs: Quantitative modeling of kinetics and morphology. Crystal Growth and Design 2018, 18, 3921−3926. https://doi.org/10.1021/acs.cgd.8b00254.
  26. Teerakapibal, R.; Huang, C.; Gujral, A.; Ediger, M. D.; Yu, L. Organic glasses with tunable liquid-crystalline order. Phys. Rev. Lett. 2018, 120, 055502. https://doi.org/10.1103/PhysRevLett.120.055502.
  27. Su, Yua Xu, Jia; Shi, Qi Yu, Lia Cai, Ting. Polymorphism of Griseofulvin: Concomitant Crystallization from the Melt and Single Crystal Structure of a Metastable Polymorph with Anomalously Large Thermal Expansion. Chem. Commun. 2018, 54, 358-361. https://doi.org/10.1039/c7cc07744k.
  28. Zhen, C.; Yang, K.; Huang, C.; Zhu, A.; Yu, L.; Qian, F. Surface enrichment and depletion of the active ingredient in spray dried amorphous solid dispersions. Pharm. Res. 2018, 35(2), 38. https://doi.org/10.1007/s11095-018-2345-1.
  29. Gujral, A.; Yu, L.; Ediger, M. D. Anisotropic organic glasses. Current Opinion in Solid State Materials Science 2018, 22, 49-57. https://doi.org/10.1016/j.cossms.2017.11.001.
  30. Zhu, M.; Yu, L. Isomerization energies of azopyridines. J. Therm. Anal. Calorimetry 2017, 132, 463-469. https://doi.org/10.1007/s10973-017-6913-0.
  31. Teerakapibal, R.; Gui, Y.; Yu, L. Gelatin Nano-coating for Inhibiting Surface Crystallization of Amorphous Drugs. Pharm. Res. 2017, 35, 23. https://doi.org/10.1007/s11095-017-2315-z.
  32. Roque Flores, Roxana L.; Ilia A. Guzei, Ilia, A.; do Rosario Matos, Jivaldo; Yu, Lian. Polymorphs of the Antiviral Drug Ganciclovir polymorph I. Acta Crystallographica Section C 2017, C73, 1-5.
  33. Huang, C.; Ruan, S.; Cai, T.; Yu, L. Fast Surface Diffusion and Crystallization of Amorphous Griseofulvin. J. Phys. Chem. B 2017, 121, 9463–9468. https://doi.org/10.1021/acs.jpcb.7b07319.
  34. Chen, Yinsha; Zhu, Me; Laventure, Audrey; Lebel, Olivier; Ediger, Mark; Yu, Lian. Influence of Hydrogen Bonding on the Surface Diffusion of Molecular Glasses: Comparison of Three Triazines. J. Phys. Chem. B 2017, 121, 7221–7227. https://doi.org/10.1021/acs.jpcb.7b05333.
  35. Zhu, M.; Yu, L. Polyamorphism of D-manntitol. J. Chem. Phys. 2017, 146, 244503. http://dx.doi.org/10.1063/1.4989961
  36. Shi, C.; Teerakapibal, R.; Yu, Lia Zhang, G. Pair distribution functions of amorphous organic thin films from synchrotron X-ray scattering in transmission mode. IUCrJ 2017, 4, 555–559. https://doi.org/10.1107/S2052252517009344.
  37. Cavallo, D.; Francesca Galli, F.; Yu, L.; Alfonso, G. C. Cross-nucleation between concomitantly crystallizing α- and γ-phases in polypivalolactone: secondary nucleation of one polymorph on another. Crystal Growth & Design 2017, 17, 2639–2645.
  38. Gómez, J.; Gujral, A.; Huang, C.; Bishop, C.; Yu, L.; Ediger, M. D. Nematic-like stable glasses without equilibrium liquid crystal phases. J. Chem. Phys. 2017, 146, 54503.
  39. Gujral, A.; Gómez, J.; Jiang, J.; Huang, C.; O’Hara, K. A.; Toney, M. F.; Chabinyc, M. L.; Yu, L.; Ediger, M. D. Highly organized smectic-like packing in vapor-deposited glasses of a liquid crystal. Chem. Mater. 2017, 29, 849–858. https://doi.org/10.1021/acs.chemmater.6b04877.
  40. Huang, C.; Powell, C. T.; Sun, Y.; Cai, T.; Yu, L. Effect of Low-Concentration Polymers on Crystal Growth in Molecular Glasses: A Controlling Role for Polymer Segmental Mobility Relative to Host Dynamics. J. Phys. Chem. B 2017, 121, 1963−1971. https://doi.org/10.1021/acs.jpcb.6b11816.
  41. Ruan, S.; Musumeci, D.; Zhang, W.; Gujral, A.; Ediger, M. D.; Yu, L. Surface Transport Mechanisms in Molecular Glasses Probed by the Exposure of Nano-particles. J. Chem. Phys. 2017, 146, 203324. http://dx.doi.org/10.1063/1.4978667.
  42. Chen, Y.; Powell, C. T.; Yu, L. Tensile Fracture of Molecular Glasses Studied by Differential Scanning Calorimetry: Reduction of Heat Capacity by Lateral Constraint. J. Phys. Chem. B. 2017, 121, 444−449.
  43. Chen, Y.; Zhang, W.; Yu, L. Hydrogen Bonding Slows Down Surface Diffusion of Molecular Glasses. J. Phys. Chem. B 2016, 120 (32), 8007–8015.
  44. Ruan, S.; Zhang, W.; Sun, Y.; Ediger, M. D.; Yu, L. Surface Diffusion and Surface Crystal Growth of tris-Naphthyl Benzene Glasses. J. Chem. Phys. 2016, 145, 064503.
  45. Zhang, W.; Teerakapibal, R.; Yu, L. Surface Mobility of Amorphous ο-Terphenyl: A Strong Inhibitory Effect of Low-Concentration Polystyrene. J. Phys. Chem. B 2016, 120, 6842–6847.
  46. Musumeci, D.; Hasebe, M.; Yu, L. Crystallization of Organic Glasses: How Does Liquid Flow Damage Surface Crystal Growth? Crystal Growth and Design 2016, 16, 2931−2936.
  47. Gomez, J.; Jiang, J.; Gujral, A.; Huang, C.; Yu, L.; Ediger, M. D. Vapor deposition of a smectic liquid crystal: Homogeneous, highly anisotropic glasses with tunable molecular orientation. Soft Matter 2016, 12, 2942-2947.