Crystal Engineering: Effects of Amide/Lactam Containing Additives on the Crystallization Behaviour of Nitrofurantoin Monhydrate

Abstract

Introduction: Crystal engineering is of great interest for many drug manufacturers in order to improve their products. A large number of active pharmaceutical ingredients (APIs) are poorly water soluble affecting the bioavailability, likewise they can have challenging physical properties such as unfavourable particle shape (e.g. needles) and surfaces affecting powder flowability and mixability. By designing crystals with optimized particle size and shape the API performance can be improved. Objective: To investigate the modified crystallization behaviour of nitrofurantoin monohydrate in presence of amide/lactam containing additives. Method: Nitrofurantoin was chosen as a model API as it is poorly water soluble and it forms needle-shaped crystals in aqueous environment. Nitrofurantoin was crystallized using evaporate crystallization from acetone/water mixtures on glasslides in presence of additives. Following polymers and monomers were used as additives: poly(N-isopropyl acrylamide) (PNIPAM), polyvinylpyrrolidone (PVP), Soluplus® (SOL), N-isopropyl acrylamide (NIPAM), dimethylacetamide (DMAA) and N-methylpyrrolidone (NMP). Optical microscope was used to analyse the crystals. Results: The crystal morphology of nitrofurantoin monohydrate can be significantly modified when it is crystallized in presence of PNIPAM, PVP and SOL, resulting in crystals with significant smaller particle size and intense branched growth compared to the needle-shaped crystals achieved without additives. Presence of SOL results in smaller crystals than presence of PNIPAM and PVP. Presence of NIPAM, DMAA and NMP were not found to affect the crystal morphology. The molecular size of the additive seems to have a key role in modifying the crystal morphology, indicating the dentrictic crystal growth could be related to steric hindrance or to the decreased diffusion in solution. The polymers also has the amide/lactam moiety in common, enabling possible hydrogen bond formation to nitrofurantoin. Conclusion: Small dendritic nitrofurantoin monohydrate crystals were achieved using amide/lactam containing polymeric as additives, whereas amide/lactam containing monomers didn't resulted in morphological changes.