Cocrystal Formation by Compression

Introduction and Background

While significant progress has been made in the field of cocrystals, relatively few methods are available to prepare cocrystals. Traditional methods include crystallization from solution1, solvent-assisted grinding2, Kofler contact method3, and reaction crystallizations4. While most laboratory screening methods for preparing cocrystals are carried out under atmospheric pressure, high-pressure can be encountered during the manufacturing steps, such as tableting and roller compaction5. Little has been published concerning cocrystal formation under high-pressure, especially non-solution based preparations of cocrystals by compression.


  • Develop a method for preparing binary and ternary cocrystals using unilateral based compression. 
  • Determine if stresses generated during manufacturing conditions can impact cocrystal formation by using pressures to mimic those found in unit operations6. 
  • Determine if the addition of a solvent plays a role in cocrystal formation by compression. 
  • Determine if an increase in temperature by friction and particle deformation during compression impacts cocrystal formation.


  • Cocrystal systems were chosen against known systems that were not successfully generated by grinding 7,8,9,10,11,12,13  
  • Powdered mixtures of components were lightly ground separately using mortar and pestle to reduce particle size. Stoichiometric amounts of the powdered components were thoroughly mixed to achieve a homogenous mixture.
  • Cocrystallization by Direct Compression
    • Components were compressed overnight using a 13 mm circular stainless steel punch and die at 0.3 GPa. 
    • In some experiments, a drop of solvent was used to facilitate cocrystal formation. 
    • Discs were removed from pellet dies and analyzed by X-ray powder diffraction for composition.
  • Control Experiments to Study Solvent Effect 
    • Solvent was added to starting components to form a paste. 
    • Samples were left in a closed, glass vial overnight under ambient conditions. Samples were washed with heptane, air dried and analyzed by X-ray powder diffraction.

Results and Discussion

Results of compression and control experiments are presented in Tables 1 and 2, respectively.


  • Cocrystals were generated through dry and solvent drop compression with both binary and ternary cocrystal systems tested although most contained large amounts of starting materials.
  • Yield of cocrystal by compression was generally increased by addition of a small amount of solvent during compression. Complete conversion was achieved for thiamine HCl:glycolic acid system.
  • Choice of solvent appears critical. When compressed dry or with DMSO, cocrystal formation occurred for the resorcinol: tetramethylpyrazine system, but not when using water although both components are soluble in water.
  • Cocrystal formation occurred upon direct compression in the case of acetylsalicylic acid: carbamazepine in the presence of solvents but not in the control experiments involving the same solvents.


  • A method was developed to screen for cocrystals by uniaxial compression of powdered components and is applicable to both binary and ternary cocrystals. 
    • Uniaxial compression may generate cocrystals not produced by other methods. 
    • Choice of solvent may be critical for cocrystal formation for certain systems. 
    • Compression can be a useful technique to generate seeds of cocrystals, which may not be produced by other methods. 
  • The results indicate that unintentional cocrystal formation during unit operations involving pressure (e.g. roller compaction) is possible and should be taken into consideration when working with actives and excipients prone to cocrystal formation.


  • PANalytical X’Pert Pro MPD, Bruker D8 DISCOVER, Shimadzu XRD 6000, and Inel XRG-3000, Cu Kα radiation diffractometers


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  2. A.V. Trask, W. Jones, Top. Curr. Chem., 2005, 254, 41-70.
  3. D.J. Berry, et al., Cryst. Growth Des. 2008, 8(5), 1697–1712.
  4. S.J. Nehm, B. Rodriguez-Spong, N. Rodriguez-Hornedo, Cryst. Growth. Des., 2006, 6, 592-600.
  5. E Hadzovic et al., Int. J. Pharm., 2010, 396, 53-62.
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  9. Pickering M, Small R.W.H, Acta Cryst., Sect.B: Struct. Crystallogr. Cryst. Chem. 1982, 38, 3161.
  10. S.Harkema, J.W.Bats, A.M.Weyenberg, D.Feil, Acta Crystallogr., Sect.C: Cryst. Struct. Commun., 1972, 28, 1646.
  11. S.Harkema, J.H.M.ter Brake, Acta Crystallogr., Sect.B: Struct. Crystallogr. Cryst. Chem. 1979, 35, 1011.
  12. R.D. Bailey Walsh, et al., Chem. Comm, 2003, 186.
  13. T. Friščić, et al., Chem. Comm., 2006, 5009.