Chains or rings? Polymorphism of an isoniazid derivative derivatized with diacetone alcohol

Abstract

Isoniazid was derivated with diacetone alcohol in a Schiff-base reaction in order to yield N′-[(2E)-4-hydroxy-4-methylpentan-2-ylidene]pyridine-4-carbohydrazide. The resulting product was determined to be polymorphic, exhibiting two crystal forms: form I and form II. From the crystal structure determination using SC-XRD it was determined that form I crystalizes in the C2/c space group while form II crystalizes in the P2₁/c space group. The hydrogen bonding patterns of both forms are distinctively different from each other: form I forms a chain hydrogen bond motif by forming a hydrogen bond between the hydroxyl group and the oxygen of the amide group while form II forms dimers with a ring hydrogen bond motif forming between the hydroxyl group and the pyridine group. From DSC analysis form I and form II are enantiotropically related, with form I converting to form II at 132.3 °C before melting at 142.3 °C. Based on both experimental and computational evidence, we conclude that form I is a metastable form, with form II being the most stable form. This is another case of a “disappearing polymorph.”