Quantifying Homo‐ and Heteromolecular Hydrogen Bonds as a Guide for Adduct Formation

Abstract

An investigation into the predictability of molecular adduct formation is presented by using the approach of hydrogen bond propensity. Along with the predictions, crystallisation reactions (1a-1j) were carried out between the anti-malarial drug pyrimethamine (1) and the acids oxalic (a), malonic (b), acetylenedicarboxylic (c), adipic (d), pimelic (e), suberic (f), azelaic acids (g), as well as hexachlorobenzene (h), 1,4-diiodobenzene (i), and 1,4-diiodotetrafluorobenzene (j); seven (1a to 1g) of these successfully formed salts. Five of these seven salts were found to be either hydrated or solvated. Hydrogen bond propensity calculations predict that hydrogen bonds between 1 and acids a-g are more likely to form rather than the H bonds involved in self-association, providing a rationale for the observation of the seven new salts. In contrast, propensity of hydrogen bonds between 1 and h-j is much smaller as compared to other bonds predicted for self-association/solvate formation, in agreement with the observed unsuccessful reactions.

The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine

“…In particular, though they deposited the crystallographic data for this phase at the CSD (refcode XEGJEA), no description of the structure, morphology, thermodynamic properties or solubility profile were presented in their manuscript. The present account in part, serves to elaborate on the physicochemical properties of PyrMeOH, being distinctly unrelated to the study by Delori et al (7). We found that recrystallization may not only risk the alteration of the toxicity of anhydrous pyrimethamine, but also its manufacturability.…”

“…The focus of the work done by Delori et al (7) was completely different to that which is presented herein. The work of Delori et al (7) focused on the formation of co-crystals and salts of pyrimethamine, with the formation of Pyr-MeOH as a mere by-product of their study, being allocated, in passing, only two sentences in their manuscript (7). In particular, though they deposited the crystallographic data for this phase at the CSD (refcode XEGJEA), no description of the structure, morphology, thermodynamic properties or solubility profile were presented in their manuscript.…”

“…In our work, we found it possible to prepare the methanol solvatomorph (hereinafter referred to as Pyr-MeOH) as first described by Delori et al (7) from recrystallisation, as opposed to their technique of liquid assisted grinding. The focus of the work done by Delori et al (7) was completely different to that which is presented herein.…”

“…In our work, we found it possible to prepare the methanol solvatomorph (hereinafter referred to as Pyr-MeOH) as first described by Delori et al (7) from recrystallisation, as opposed to their technique of liquid assisted grinding. The focus of the work done by Delori et al (7) was completely different to that which is presented herein. The work of Delori et al (7) focused on the formation of co-crystals and salts of pyrimethamine, with the formation of Pyr-MeOH as a mere by-product of their study, being allocated, in passing, only two sentences in their manuscript (7).…”

“…Pyrimethamine ( Figure 1) has been used in the treatment of uncomplicated malaria for more than 30 years (3,4). Different solid forms of pyrimethamine have been described as early as 1976 (5), and yet the discovery of new solid forms in 2011 and 2012 (6,7) revealed that its solid state chemistry has still not yet been exhaustively elucidated.…”