Pharmaceutical cocrystals: a comparison of sulfamerazine with sulfamethazine

Although there has been much debate about its definition among scientists, a cocrystal may be defined as a crystalline material that consists of two or more electrically neutral molecular species held together by non-covalent forces, and meanwhile all components are solids at room temperature. Obviously it is great to introduce predictable structural motifs to an active pharmaceutical ingredient (API) by design. One widely used approach to cocrystal design is based on the consideration of ΔpKa, which can represent the propensity of molecular species to form a cocrystal or a salt. In this work, p-aminobenzoic acid (PABA) was mixed with sulfamerazine (SMZ) or sulfamethazine (STH) by use of neat cogrinding and solvent-drop cogrinding. It was found that PABA and SMZ with a ΔpKa of 2.13 would form a binary eutectic, while PABA and STH with a larger ΔpKa of 2.59 can form a cocrystal in the ratio of 1:1. The phenomenon indicates that not only the ΔpKa but also the stereo-hindrance effect (geometric fit) should be considered during the design of pharmaceutical cocrystals.

► We firstly compare the reactivity of sulfamerazine and sulfamethazine with p-aminobenzoic acid.
► We find that sulfamethazine and p-aminobenzoic acid can form a cocrystal while sulfamerazine and p-aminobenzoic acid will form a binary eutectic.
► We attribute the stereo-hindrance effect caused by intramolecular hydrogen bonding to the different reactivity above.