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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. Wu, H.; Yao, X.; Hao, H.; Yu, Lian. Surface Enhancement of Crystal Nucleation in Amorphous Acetaminophen. Crystal Growth and Design, in press.
  2. Li, Y.; Yu, J.; Tan, X.; Yu, Lian. Influence of moisture and surfactants on surface dynamics of amorphous drugs: A concentration-temperature superposition principle. Mol. Pharm., in press.
  3. Xin Yao, Qitong Liu, Bu Wang, Ilia Guzei, Michael M Aristov, Chenyang Shi, Geoff G. Z. Zhang, Lian Yu. Anisotropic Molecular Organization at a Liquid/Vapor Interface Promotes Crystal Nucleation with Polymorph Selection. J. Am. Chem. Soc. 2022, 144, 26, 11638–11645. https://doi.org/10.1021/jacs.2c02623
  4. Hernández Espinell, José; Toro, Veronica; Yao, Xi Yu, Lia López-Mejías, Vilmalí; Stelzer, Torsten. Solvent-mediated Polymorphic Transformations in Molten Polymers: The Account of Acetaminophen. Mol. Pharm. 2022, in press
  5. Yao, X.; Benson, E. G.; Stelzer, T.; Zhang, G. G. Z.; Yu, Lian. Effect of Surfactants on Crystal Nucleation and Growth of Amorphous Nifedipine. Mol. Pharm. 2022, in press. Special Mol. Pharm and Crystal Growth Des. Issue “Crystallizing the Role of Solid-State Form in Drug Delivery”. https://doi.org/10.1021/acs.molpharmaceut.2c00156
  6. Yu, J.; Yao, X.; Que, C.; Huang, L.; Hui, H.-W.; Gong, Y.; Yu, Lian. Kinetics of Surface Enrichment of a Polymer in a Glass-Forming Molecular Liquid. Mol. Pharm., in press.
  7. Gui, Y.; Huang, C.; Shi, C.; Stelzer, T.; Zhang, G. G. Z.; Yu, Lian. Polymorphic Selectivity in Crystal Nucleation. J. Chem. Phys. 2022, 156, 144504. https://doi.org/10.1063/5.0086308
  8. Ajay Annamareddy; Manel Molina-Ruiz; Donez Horton-Bailey; Frances Hellma Yuhui Li; Lian Yu; Dane Morgan. Compositional Trends in Surface Enhanced Diffusion in Lead Silicate Glasses. Computational Materials Science 2022, 206, 111304. https://doi.org/10.1016/j.commatsci.2022.111304
  9. Li, Y.; Bishop, C.; Ediger, M. D.; Yu, Lian. Surface diffusion of a glassy discotic organic semiconductor and the surface mobility gradient of molecular glasses. J. Chem. Phys. 2022, 156, 094710. https://doi.org/10.1063/5.0079890
  10. Yu, Junguang; Chen, Zhenxua Teerakapibal, Rattavut; Benmore, Chri Richert, Ranko; Yu, Lian. Structure of Glasses Created by Multiple Kinetic Arrests. J. Chem. Phys. 2022, 156, 084504.  https://doi.org/10.1063/5.0080846
  11. Yu, J.; Li, Y.; Yao, X.; Que, C.; Huang, L.; Hui, H.-W.; Gong, Y.; Qian, F.; Yu, Lian. Surface Enrichment of Surfactants in Amorphous Drugs: An X-Ray Photoelectron Spectroscopy Study. Mol. Pharmaceutics 2022, 19, 654−660. https://doi.org/10.1021/acs.molpharmaceut.1c00786
  12. Li, Y.; Annamareddy, A.; Morgan, D.; Cao, C.; Perepezko, J.; Ediger, M.D.; Voyles, P.; Yu, L. Surface diffusion is controlled by bulk fragility across all glass types. Phys. Rev. Lett. 2022, 128, 075501. https://doi.org/10.1103/PhysRevLett.128.075501.
  13. Gui, Y.; Jin, Y.; Ruan, S.; Sun, G.; López-Mejías, V.; Yu, Lian. Crystal energy landscape of nifedipine by experiment and computer prediction. Cryst. Growth Des. 2022, 22, 1365−1370. https://doi.org/10.1021/acs.cgd.1c01317
  14. Zhenxuan Chen, Chengbin Huang, Xin Yao, Chris J. Benmore, Lian Yu. Structure of supercooled glycerol, xylitol, and D-sorbitol by synchrotron X-ray scattering and relation to dynamic fragility. J. Chem. Phys. 2021, 155, 244508. https://doi.org/10.1063/5.0073986
  15. Xin Yao, Amy Neusaenger, Lian Yu. Perspective: Amorphous Drug-Polymer Salts. Pharmaceutics 2021, 13 (8), 1271. https://doi.org/10.3390/pharmaceutics13081271
  16. Xin Yao, Soojin Kim, Yue Gui, Zhenxuan Chen, Junguang Yu, Lian Yu. Amorphous drug-polymer salt with high stability under tropical conditions and fast dissolution: The case of lumefantrine-PAA. J. Pharm. Sci. 2021, 110, 3670−3677. https://doi.org/10.1016/j.xphs.2021.07.018.
  17. Zhenxuan Chen, Yue Gui, Kai Cui, J. R. Schmidt, and Lian Yu. Prolific Polymorph Generator ROY in Its Liquid and Glass: Two Conformational Populations Mirroring the Crystalline-State Distribution. J. Phys. Chem. B 2021, 125, 10304−10311. https://doi.org/10.1021/acs.jpcb.1c05834
  18. Chen, Zhenxua Bishop, Camille; Thoms, Erik; Bock, Harald; Ediger, Mark; Richert, Ranko; Yu, Lian. Controlling columnar order in a discotic liquid-crystal by kinetic arrest of disc tumbling. Chem. Mater. 2021, 33, 12, 4757–4764. https://doi.org/10.1021/acs.chemmater.1c01331     
  19. Ajay Annamareddy, Yuhui Li, Lian Yu,  Paul M. Voyles, and  Dane Morgan. Factors correlating to enhanced surface diffusion in metallic glasses. J. Chem. Phys. 154, 104502 (2021); https://doi.org/10.1063/5.0039078           
  20. Yue Gui, Xin Yao, Ilia A. Guzei, Michael M. Aristov, Junguang Yu, and Lian Yu. A Mechanism for Reversible Solid-State Transitions Involving Nitro Torsion. Chem. Mater. 2020, 32, 18, 7754–7765.
  21. Yue Gui, Erin C. McCann, Xin Yao, Yuhui Li, Karen J. Jones, and Lian Yu. Amorphous Drug–Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Case of Clofazimine and Poly(acrylic acid). Mol. Pharmaceutics 2021, 18, 1364–1372.  https://doi.org/10.1021/acs.molpharmaceut.0c01180
  22. Barták, J.; Málek, J.; Bagchi, K.; Ediger, M. D.; Li, Y.; Yu, L. Surface mobility in amorphous selenium and comparison with organic molecular glasses. J. Chem. Phys. 154, 074703 (2021). https://doi.org/10.1063/5.0041273
  23. Changlin Yao, Ilia A Guzei, Yingdi Jin, Lian Yu. Polymorphism of Piroxicam: New Polymorphs by Melt Crystallization and Crystal Structure Prediction. Cryst. Growth Des. 2020, 20, 12, 7874–7881. DOI: https://doi.org/10.1021/acs.cgd.0c01165.
  24. Xiao Ou, Xizhen Li, Haowei Rong, Lian Yu, and Ming Lu. A general method for cultivating single crystals from melt microdroplets. Chem. Commun. 2020, 56, 9950-9953. https://doi.org/10.1039/d0cc03157g.
  25. Yue Gui, Xin Yao, Ilia A. Guzei, Michael M. Aristov, Junguang Yu, and Lian Yu*. A Mechanism for Reversible Solid-State Transitions Involving Nitro Torsion. Chem. Mater., 32, 18, 7754–7765.
  26. Xizhen Li, Xiao Ou, Haowei Rong, Siyong Huang, Jonas Nyman, Lian Yu, Ming Lu. The Twelfth Solved Structure of ROY: Single Crystals of Y04 Grown from Melt Microdroplets. Cryst. Growth Des. 2020, 20, 11, 7093–7097. https://doi.org/10.1021/acs.cgd.0c01017.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. Bishop, C.; Yu, L.; Ediger, M. D. Fytas, G. Extreme Elasticity Anisotropy in Molecular Glasses. Advanced Functional Materials 2020, 30, 2001481. Cover art.
  32. 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.
  33. 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.
  34. 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
  35. 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.
  36. 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.
  37. 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.
  38. 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
  39. 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.
  40. 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.
  41. 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.