Published: June 01, 2011 r2011 American Chemical Society 3489 dx.doi.org/10.1021/cg200334m | Cryst. Growth Des. 2011, 11, 3489–3503 ARTICLE pubs.acs.org/crystal Co-Crystals of Sulfamethazine with Some Carboxylic Acids and Amides: Co-Former Assisted Tautomerism in an Active Pharmaceutical Ingredient and Hydrogen Bond Competition Study Published as part of a virtual special issue on Structural Chemistry in India: Emerging Themes Soumyajit Ghosh, Partha Pratim Bag, and C. Malla Reddy* Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741252, India b S Supporting Information ’ INTRODUCTION The crystal engineering approach has generally been a suc- cessful design strategy for obtaining new co-crystal forms of active pharmaceutical ingredients (APIs) for desired physico- chemical properties without affecting the pharmacological beha- vior of the drug. 1,2 In recent times, this has been utilized successfully to modify the API stability, solubility, bioavailability, mechanical properties, etc. 3 Particularly, crystal engineering, based on the synthon approach is an effective route that provides the basis for the selection of co-formers to achieve predetermined structures, thus properties, with a higher success rate. 4 Hence, it is important to understand the precise role of functional groups, especially in the presence of other competing functionalities. 5 Sulfa drugs have been interesting in this context and studied to understand the hydrogen bond preferences of the strong hydrogen bonding groups such as SO 2 , NH (sulfonamide) , NH 2 , etc. present on them. 5d Sulfamethazine (SFZ; Scheme 1) is a sulfonamide drug, some- times known as sulfadimidine or sulfadimethylpyridine, that is used to treat a variety of bacterial diseases in human and veterinary medicine. 6 Sulfamethazine is an anti-infective agent that has a spectrum of antimicrobial actions similar to that of other sulfa- drugs. 7 Sulfamethazine is used for veterinary purposes to treat a variety of infections, as well as being utilized in the management of diseases in herds. It is also used to treat urinary tract infection, chlamydia, rheumatoid fever, toxoplasmosis, and malaria in hu- mans. Sulfamethazine is primarily used as an antibacterial drug and growth promoter in food animals, such as cattle, pigs, and poultry. The usage of SFZ in high dosages has side effects, such as hypersensitivity, photosensitivity, vomiting, etc. Sulfamethazine has two types of donors (amine NH 2 , and a sulfonamide NH) that in total bear three acidic protons. And, there are three types of acceptors, namely, two sulfoxy O atoms, one amine N, and two pyrimidine N atoms that are capable of forming hydrogen bonds in the co-crystal. Sulfamethazine is Received: March 16, 2011 Revised: May 7, 2011 ABSTRACT: Ten new co-crystals of an antibacterial drug sulfamethazine (SFZ) with various carboxylic acid and amide co-formers have been synthesized. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Crystal structures with 4-hydro- xybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic acid (DCB), sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydroxybenzamide (HBEN), and 3-hydroxy-2-naphthoic acid (3HNA) are determined. The SFZ molecule displays co-former assisted amidine to imidine tautomerism in the co-crystals in that the sulfonamide NH proton moves to one of the pyrimidine N atoms. In all the cases, the SFZ forms a robust hydrogen bonded synthon with a carboxylic acid (amidine (SFZ) 333 acid/imidine - (SFZ) 333 acid) or amide (imidine (SFZ) 333 amide) group from the co-former. The SFZ molecule, in all the carboxylic amide and carboxylic acids, HBA and 3HNA co-crystals, exists in the imidine tautomeric form while it exists in amidine tautomeric form in the rest of the acid co-crystals. Density functional theory (DFT) calculations revealed that the amidine tautomer in free SFZ is much more stable than its imidine tautomeric form, while when it is hydrogen bonded to the co-formers via acid or amide groups, the difference is greatly minimized. But the synthon formation between the stable amidine (SFZ) and amide co-former is sterically hindered; hence the SFZ tautomerizes itself to the imidine (SFZ) form to facilitate the formation of a robust imidine (SFZ) 333 amide synthon in all the amide based co-crystals in this study. Solubility properties of some of the new co-crystal forms are also studied. The crystal structures are analyzed in the context of hydrogen bond competition between various acceptors and donors, in the presence of other competing functional groups, in the active pharmaceutical ingredient (API) co-crystals.