Chameleon Behavior of a New Salt of 3-(Aminocarbonyl) Pyridinium Malonate and Implications for Polymorphism on the Salt/Cocrystal Continuum

Abstract

This contribution presents a previously unreported example and comparative study of a binary crystalline adduct which exhibits a salt form in a 1:1 stoichiometry. Specifically, a new salt form of a novel 1:1 form of 3-(aminocarbonyl) pyridinium malonate is reported, and the route to isolating it from aqueous solution and the crystal chemistry of the system are characterized. Structurally, the nicotinamide dimer motif present in the polymorphic cocrystals is absent in the salt, allowing an equimolar structure arising from a singly donated proton from one malonic acid carboxylic acid group. A comparative study of the solid form landscape is presented against its known polymorphic forms I and II, which form in a 2:1 ratio of bis(nicotinamide) malonic acid, wherein computational mapping reveals the order or stability as a 1:1 salt, 2:1 cocrystal polymorph II, and 2:1 cocrystal polymorph I, the latter being the metastable form. Intriguingly, on the basis of periodic DFT-D calculations, we also propose two tentative 2:1 salt forms of cocrystal polymorph II which would be of higher stability than both the hitherto explored 2:1 cocrystalline forms and linked crystal packing/interactions with crystal growth outcomes. This study demonstrates the importance of computational studies to explore the salt/cocrystal continuum and could highlight subtle isostructural changes that could yield novel solid forms and impact physiochemical properties and morphology, providing further impetus for screening activities/characterization.