Solubility and Thermodynamic Stability

Co-crystal-solution phase interactions have a major impact on our ability to understand and engineer co-crystal solubility. Recent advances in crystal engineering, in combination with the pioneering work of the 1950s and 1960s on molecular complexes in solution, provide the opportunity to develop scientific concepts that link how molecules interact in the solid phase with how a collection of molecules behave in the (liquid) solution phase in order to tailor systems for specific purposes. 

This chapter focuses on the applications of fundamental concepts. The interested reader is referred to the original literature for development of the theoretical framework upon which this chapter is based. 

Solubility is of great importance in pharmaceutical systems since a drug must be dissolved before it is absorbed. When the drug absorption process is limited by dissolution, enhancing solubility can increase dissolution rate and in this way improve bioavailability.In addition to the dissolution rate, the ability to dissolve the therapeutic dose of the drug and the selection of solubilization techniques are critical for product development. 

Reduced aqueous solubility of many molecules is a major problem to overcome in order to achieve the desired therapeutic response. The underlying causes of low solubility are captured by colloquial terms used to describe such molecules as grease balls when the resistance to solubility is hydrophobicity and as brick dust when solubility is limited by high lattice energies. This means that the strategies for improving solubility require a combination of technologies to influence solvent-solute and solute-solute interaction forces. 

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May H.M., Kinniburgh D.G., Helmke P.A. and Jackson M.L. (1986) Aqueous dissolution, solubilities and thermodynamic stabilities of common aluminosilicate clay minerals Kaolinite and smectites. Geochim. Cosmochim Acta 50, 1667-1677. 

We found that the studied micelles containing long PEO chains, which should assure their solubility and thermodynamic stability, are surprisingly apt to a secondary aggregation and formation of micellar clusters. We suspected that the secondary aggregation of the PEO sheU is caused by a hindered and incomplete solvation. Therefore, we supplemented the LS study of micellar solutions by SRM, with the aim of obtaining detailed information on the solvation of micellar shells. 

Eutectic concentration measurements are essential for understanding why and under what conditions co-crystal solubility and thermodynamic stability will change. The experiments have important advantages as they (a) require little material and time, and (b) guide the rational seleetion of formulation aids and dissolution media that will best capture the eo-erystal drug release behavior. 

The study of pharmaceutical co-crystals is also a re-emerging and exciting field of academic research in the context of crystal engineering and rational design of molecular assemblies. Most, if not all, fundamental aspects have been reviewed in this book, from the role of weak interactions in co-crystals to mechanochemical methods of synthesis, including insights into solubility and thermodynamic stability or phase diagrams of co-crystals. 

Valetti, N.W., Boeris, V., Pico, G. Characterization of chymotrypsin-i — carrageenan complex in aqueous solution a solubility and thermodynamical stability study. Int. J. Biol. 

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