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Department of Chemistry

Research Focus

The role of co-crystals in pharmaceutical science.

Figure

Figure. Representative examples of pharmaceutical co-crystals: (a) carbamazepine: saccharin; (b) ibuprofen: 4,4'-bipyridine.

Pharmaceutical co-crystals, i.e. crystal forms that consist of a stoichiometric ratio of an active pharmaceutical ingredient (API) and one or more pharmaceutically acceptable co-crystal formers, are being targeted for study by number of groups in academia and industry. Although co-crystals are known since the 1840’s, they have newly recognized potential in the pharmaceutical industry because they are amenable to control and design (crystal engineering) in a manner that is not inherently present in other forms of API's such as salts, polymorphs, and solvates. Furthermore, they represent new compositions of matter and as such they are patentable and will exhibit different physical properties when compared to their parent cocrystal formers.

Research activities in our group are both fundamental and applied and cover all aspects of crystal engineering of co-crystals and their potential usage in the pharmaceutical industry. Examples of research activities include the following:

  • Datebase mining. The Cambridge Structural Database (CSD) is a key database for analysis of crystal packing, identification of hydrogen bonded supramolecular synthons, statistical surveys, polymorph searches. Most crystal engineering studies start with a detailed CSD survey.
  • Synthesis/processing of co-crystals can be accomplished via a number of methods, including crystallization from solution, solvent-reduced (e.g. slurrying, solvent-drop grinding) and solvent-free (e.g. grinding, melt) techniques.
  • Characterization of co-crystals involves both structure (spectroscopy, single crystal x-ray crystallography and powder x-ray diffraction) and physical properties (e.g. DSC, TGA). Published examples of pharmaceutical co-crystals are presented in the Figure.
  • Applications of co-crystals including drug discovery (e.g. new molecule synthesis, nutraceutical co-crystals), drug delivery (solubility, bioavailability) and chiral resolution are being investigated. The relevance of co-crystals in API formulation is particularly salient since it includes the ability to fine-tune physical properties, identification of novel or more robust forms of polymorphic API's, and the opportunity to generate intellectual property. Other applications of co-crystals that might be of broad interest to the pharmaceutical industry include green chemistry and drug design.

Researchers

Dr. Kapildev Arora
E-mail: karora@cas.usf.edu
Personal Page: http://chemistry.usf.edu/faculty/karora/
Dalia Aboarayes
E-mail: daboaray@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/aboarayes/
Miranda Cheney
E-mail: mcheney@cas.usf.edu
Personal Page: http://chemistry.usf.edu/grad/mcheney/
Heather Clarke
E-mail: hdclarke@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/hclarke/
Catherine Geiser
E-mail: cgeiser@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/cgeiser/
Tien Teng Ong
E-mail: tong2@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/tong/
Jason Perman
E-mail: perman@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/jperman/
John J. Perry
E-mail: jjperry@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/jperry/
Twarita Pujari
E-mail: tpujari@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/tpujari/
David Weyna
E-mail: dweyna@mail.usf.edu
Personal Page: http://chemistry.usf.edu/grad/dweyna/
Sandra Zoccali
E-mail:
Personal Page: http://chemistry.usf.edu/grad/szoccali/

Our recent publications in this area include the following:

  1. Fleischman, S.; Morales L.; Moulton, B.; Rodríguez-Hornedo, N; Bailey Walsh, R.; Zaworotko, M.J., "Crystal Engineering of the Composition of Pharmaceutical Phases", Chem. Commun., 186-7, 2003.
  2. Fleischman, S.G.; Kuduva, S.S.; McMahon, J.A.; Moulton, B.; Walsh, R.B.; Rodriguez-Hornedo, N.; Zaworotko, M.J. "Crystal Engineering of the Composition of Pharmaceutical Phases. 2. Multiple Component Crystalline Solids Involving Carbamazepine", Crystal Growth & Design, 3, 909-919, 2003.
  3. McMahon, J.A.; Zaworotko, M.J.; Remenar, J.F. "Polymorphism in butylated hydroxy anisole (BHA)", Chem. Commun., 278-279, 2004.
  4. Almarsson, Ö.; Zaworotko, M.J. "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Chem. Commun., 1889-1896, 2004.
  5. McMahon, J.A..; Bis, J.A.; Vishweshwar, P.; Shattock, T.R.; McLaughlin, O.L.; Zaworotko, M.J."Crystal Engineering of the Composition of Pharmaceutical Phases 3. Primary Amide Supramolecular Heterosynthons and Their Role in the Design of Pharmaceutical Co-Crystals." Zeit. Fur Krist., 220, 340-350, 2005.
  6. Bis, J.; Zaworotko, M.J. "The 2-aminopyridinium-carboxylate supramolecular heterosynthon: a robust motif for generation of multiple component crystals." Crystal Growth & Design, 5, 1169-1179, 2005.
  7. Vishweshwar, P.; McMahon, J.A.; Peterson, M.L.; Hickey, M.B.; Shattock, T.R.; Zaworotko, M.J. "Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients." Chem. Commun., 4601-4603, 2005.
  8. Vishweshwar, P.; McMahon, J.A.; Oliveira, M.; Peterson, M.L.; Zaworotko, M.J. "The predictably elusive form II of aspirin." J. Amer. Chem.. Soc., 127, 16802-16803, 2005.
    Also featured in Chemical & Engineering News as a concentrate, November 2005.
  9. Vishweshwar, P.; McMahon, J.A.; Bis, J.A.; Zaworotko, M.J. "Pharmaceutical Co-crystals." J. Pharm. Sci., 95, 499-516, 2006.
  10. Bis, J.A.; Vishweshwar, P.; Middleton, R.A.; Zaworotko, M.J. "Concomitant and conformational polymorphism, conformational isomorphism, and phase relationships in 4-cyanopyridine•4,4'-biphenol co-crystals." Crystal Growth & Design, 6, 1048-1053, 2006.
  11. Bis, J.A.; McLaughlin, O.L.; Vishweshwar, P.; Zaworotko, M.J. "Supramolecular heterocatemers and their role in co-crystal design." Crystal Growth & Design, 6, 2648-2650, 2006.
  12. Peterson, M.L.; Hickey, M.B.; Zaworotko, M.J.; Almarsson, O. "Expanding the scope of crystal form evaluation in pharmaceutical science." J. Pharm. Pharmaceut. Sci., 9, 317-326, 2006.
  13. Zaworotko, M.J. "Molecules to crystals, crystals to molecules… and back again?" Crystal Growth & Design, 7, 4-7, 2007.
  14. Hickey, M.B.; Peterson, M.L.; Scoppettuolo, L.A.; Morrisette, S.L.; Vetter, A.; Guzman, H.; Remenar, J.F.; Zhang, Z.; Tawa, M.D.; Haley, S.; Zaworotko, M.J.; Almarsson, O. "Performance Comparison of a Co-crystal of Carbamazepine with Marketed Product." Eur. J. Pharmaceutics Biopharmaceutics, 67, 112-119, 2007.
  15. Cheney, M.L.; McManus, G.J.; Perman, J.A.; Wang, Z.; Zaworotko, M.J. "The role of co-crystals in solid-state synthesis: co-crystal controlled solid-state synthesis of imides." Crystal Growth & Design, 7, 616-617, 2007.
  16. Bis, J.A.; Vishweshwar, P..; Weyna, D.; Zaworotko, M.J. "Hierarchy of Supramolecular Synthons: Persistent Hydroxyl∙∙∙Pyridine Hydrogen Bonds in Co-Crystals that Contain a Cyano Acceptor." Molecular Pharmaceutics, 4, 401-416, 2007.
  17. Shan, N.; Zaworotko, M.J. "The role of co-crystals in pharmaceutical science." Drug Discovery Today, 13, 440-446, 2008.