Toxicity Caused by Co-crystal Formation

There is some evidence demonstrating the advantages of altering/controlling the solid form by co-crystal formation. However, co-crystallization of otherwise non-toxic molecules can sometimes also prove to be fatal. One such case, involving the unexpected co-crystallization of melamine and cyanuric acid has acted as an eye-opener in this field. It further underlines the importance of detailed studies of the solid state characteristics of not only the individual components in a formulation but also their different combinations. 

Melamine (2,4,6-triamino-l,3,5-triazine) is a relatively non-toxic compound with acute toxicity observed in rodents, with oral lethal doses (LD50) of 3100 mg kg and 3900 mg kg in male rats and male mice, respectively. In another study, a 125 mg kg oral dose of melamine showed only diuretic effects in dogs. Toxicity studies of cyanuric acid derivatives (e.g. sodium cyanurate) at 700 mg kg and 2200 mg kg doses in rats and mice, respectively, resulted in bladder calculi and bladder epithelial hyperplasia, with no other adverse effects. In other studies, it was observed that dietary monosodium cyanurate administered in dogs for 6 months at 0.8% concentration produced no adverse effects, although at 8% for a longer period of 16 to 24 months it produced kidney fibrosis and fical dilation. This was attributed to the low solubility of sodium cyanurate, due to which it precipitated at higher concentrations in urine, leading to renal dysfunction.  

Kerns and L. Di, Drug-Like Properties Concepts, Structure Design and Methods from ADME to Toxicity Optimization, Academic Press, Burlington, MA, 2008. 

Stahl and C.G. Wermuth, Handbook of Pharmaceutical Salts Properties, Selection and Use, ed. P.H. Stahl and C.G. Wermuth, Wiley-VCH, Zurich and Weinheim, 2008. 

Variankaval, R. Wenslow, J. Murry, R. Hartman, R. Helmy, E. Kwong, S-D. Clas, C. Dalton and I. Santos, Cryst. Growth Des., 2006,6, 690. 

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