Co-crystal engineering of N-heterocyclic active pharmaceutical ingredients with nitrobenzoic acid derivatives

Abstract

The pharmaceutical industry continues to face challenges with properties of drugs like poor solubility, limited bioavailability and insufficient stability of active pharmaceutical ingredients (APIs), which collectively hinder drug development. Co-crystallization has been shown to be an effective strategy to improve these physicochemical properties of drugs without altering their chemical properties. In this study, fifteen novel crystalline structures were obtained using both solution-based crystallization (slow evaporation) and mechanochemistry methods. A series of N-heterocyclic APIs were co-crystallized with selected nitro-substituted aromatic co-formers, enabling the evaluation of multiple co-former families across diverse APIs. 3,5-Dinitrosalicylic acid (DNSA) formed crystalline phases with seven APIs, nitroterephthalic acid (NTPA) with six APIs, and 2-(nitrophenyl)methanol with two APIs. The crystalline structures formed included neutral co-crystals, salt co-crystals, hydrated forms and solvates, reflecting the structural diversity of outcomes possible with carefully selected co-formers and varied crystallization techniques. Notably, an unexpected esterification product was structurally identified in one of the crystalline systems, highlighting the potential for solid-state or solution-mediated transformations during crystallization. Structural characterization was performed using single-crystal X-ray diffraction, with structure solution and refinement carried out using SHELXT and SHELXL respectively. Findings on some of the crystalline structures were supported by complementary analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) spectroscopy, and Hirshfield surface analysis. Overall, the findings of this study provide valuable insight into the structural diversity in co-crystallization, supramolecular interaction driving successful co-crystallization and how different crystallization methods affect co-crystallization. Furthermore, the study introduces a series of novel co-crystals which contribute to the knowledge of pharmaceutical crystal engineering and provides a strong foundation for future research aimed at improving drug performance.