(723e) Thermodynamics of Co-Crystal Systems

Dipali. Ahuja,¹ and Åke. C. Rasmuson¹

¹Synthesis and Solid State Pharmaceutical Centre, Bernal Institute, Department of Chemical Sciences, University of Limerick, Limerick, Ireland

Introduction.

The pharmaceutical industry has a significant interest in co-crystals for their ability to alter the physical properties of the active pharmaceutical ingredient (API) without affecting its chemical structure [1]. Co-crystallization may enhance a wide range of pharmaceutical properties like hygroscopicity, thermal stability, solubility and bioavailability. Most research in this field has been focused towards discovering new co-crystals. Much less work has been done on studying the co-crystal thermodynamic properties and manufacturing techniques. Ternary phase diagrams are crucial for the design of the manufacturing process [2] as they highlight the stability regions for various solid crystalline phases. Factors like solvent and temperature significantly affect the shape of the phase diagram and the solubility differences between the co-crystal components can cause a system to be congruent or incongruent [3]. It is most likely that a large solubility difference causes a system to show incongruent dissolution. The main interest in the ternary phase diagram is the size of the region where co-crystal is the most stable solid phase.

Methods and Experiments.

For this work, thermodynamic studies for 1:1 sulfamethazine (SMT)-salicylic acid (SA) co-crystal system were carried out. SMT is a sulfonamide drug and is used an antibacterial and anti-infective agent; SA is used to relieve pain and fever and is used for anti-acne treatments. Ternary phase diagrams were constructed in three solvent systems (methanol, acetonitrile and DMSO-methanol) at three temperatures. The methodology behind the phase diagram construction involved determination of the pure component solubilities by gravimetric technique. The invariant points were determined by mixing the solid and solvent and allowing sufficient time for equilibration. Solids were then analysed by PXRD (Powder X-ray Diffraction) or DSC (Differential Scanning Calorimetry) and the solution composition was determined by HPLC (High Performance Liquid Chromatography).

Results and Discussion.

Solvent dependent congruent and incongruent dissolution was observed, highlighting how solvent choice can affect the phase diagram. The co-crystal system showed congruent dissolution in acetonitrile but showed an incongruent behavior in methanol and DMSO-methanol. The effect of temperature over the range studied was found to be weak. Based on the solubility data for the pure components and the co-crystal, the Gibb’s free energy of co-crystal formation was determined, and ranged from -5.5 to -7.7 kJ/mol, changing with temperature. The negative values reveal the thermodynamic stability of the co-crystal and spontaneity of the co-crystal formation from SMT and SA. The enthalpy and entropy associated with co-crystallization were determined to be +23 kJ/mol and +0.1 kJ/mol, ℃, respectively. From this data, co-crystal formation seems to be an entropy driven process. A relationship between the solubility ratio between API and coformer and the size of the region where the co-crystal is the most stable phase has been observed. In addition, it was found that the solubility ratio between the pure components does not allow for confident prediction of whether a system will show congruent or incongruent behaviour. The co-crystal yields and volumetric productivities in the three solvent systems were determined using the slurry crystallization technique.

References:

[1] J. Urbanus, C. P. M. Roelands, D. Verdoes, P.J. Jansens, J.H. ter Horst, Co-Crystallization as a Separation Technology: Controlling Product Concentrations by Co-crystals, Cryst. Growth Des., 10, 1171 (2010).

[2] D.M. Croker, M. E. Foreman, B. N. Hogan, N. M. Maguire, C.J. Elcoate, B. K. Hodnett, A.R. Maguire, Ã…. Rasmuson, Understanding the p-Toluenesulfonamide/Triphenylphosphine Oxide Crystal Chemistry: A New 1:1 Cocrystal and Ternary Phase Diagram, Cryst. Growth Des., 12, 869 (2012).

[3] S. Zhang, Å. Rasmuson, Cryst. Thermodynamics and Crystallization of the Theophylline–Glutaric Acid Cocrystal, Cryst. Growth Des., 13, 1153 (2013).