Željko Petrovski

Ionic Liquids as Active Pharmaceutical Ingredients

Ionic liquids (ILs) are ionic compounds that possess a melting temperature below 100 °C. Their physical and chemical properties are attractive for various applications. Several organic materials that are now classified as ionic liquids were described as far back as the mid‐19th century. The search for new and different ILs has led to the progressive development and application of three generations of ILs: 1) The focus of the first generation was mainly on their unique intrinsic physical and chemical properties, such as density, viscosity, conductivity, solubility, and high thermal and chemical stability. 2) The second generation of ILs offered the potential to tune some of these physical and chemical properties, allowing the formation of “task‐specific ionic liquids” which can have application as lubricants, energetic materials (in the case of selective separation and extraction processes), and as more environmentally friendly (greener) reaction solvents, among others. 3) The third and most recent generation of ILs involve active pharmaceutical ingredients (API), which are being used to produce ILs with biological activity. Herein we summarize recent developments in the area of third‐generation ionic liquids that are being used as APIs, with a particular focus on efforts to overcome current hurdles encountered by APIs. We also offer some innovative solutions in new medical treatment and delivery options.

Development of novel ionic liquids based on ampicillin

Novel ionic liquids containing ampicillin as an active pharmaceutical ingredient anion were prepared with good yields by using a new, efficient synthetic procedure based on the neutralization of a moderately basic ammonia solution of ampicillin with different organic cation hydroxides. The relevant physical and thermal properties of these novel ionic liquids based on ampicillin were also evaluated.

Evaluation of solubility and partition properties of ampicillin-based ionic liquids

In order to overcome the problems associated with low water solubility, and consequently low bioavailability of active pharmaceutical ingredients (APIs), herein we explore a modular ionic liquid synthetic strategy for improved APIs. Ionic liquids containing L-ampicillin as active pharmaceutical ingredient anion were prepared using the methodology developed in our previous work, using organic cations selected from substituted ammonium, phosphonium, pyridinium and methylimidazolium salts, with the intent of enhancing the solubility and bioavailability of L-ampicillin forms. In order to evaluate important properties of the synthesized API-ILs, the water solubility at 25 °C and 37 °C (body temperature) as well as octanol-water partition coefficients (Kows) and HDPC micelles partition at 25 °C were measured. Critical micelle concentrations (CMCs) in water at 25 °C and 37 °C of the pharmaceutical ionic liquids bearing cations with surfactant properties were also determined from ionic conductivity measurements.

Antibacterial activity of Ionic Liquids based on ampicillin against resistant bacteria

Antibacterial activities of novel Active Pharmaceutical Ingredient Ionic Liquids (API–ILs) based on ampicillin anion [Amp] have been evaluated. They showed growth inhibition and bactericidal properties on some sensitive bacteria and especially some Gram-negative resistant bacteria when compared to the [Na][Amp] and the initial bromide and chloride salts. For these studies were analysed the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBIC) against sensitive Gram-negative bacteria Escherichia coli ATCC 25922 and Klebsiella pneumoniae (clinically isolated), as well as sensitive Gram positive Staphylococcus Aureus ATCC 25923, Staphylococcus epidermidis and Enterococcus faecalis and completed using clinically isolated resistent strains such as E. coli TEM CTX M9, E. coli CTX M2 and E. coli AmpC MOX. From the obtained MIC values of studied API–ILs and standard [Na][Amp] were derived RDIC values (relative decrease of inhibitory concentration). High RDIC values of [C16Pyr][Amp] especially against two resistant Gram-negative strains E. coli TEM CTX M9 (RDIC >1000) and E. coli CTX M2 (RDIC >100) point clearly to a potential promising role of API–ILs as antimicrobial drugs in particular against resistant bacterial strains.

Synthesis of ferrocenyldiimine metal carbonyl complexes and an investigation of the Mo adduct encapsulated in cyclodextrin

Cr and Mo tetracarbonyl complexes bearing the diimine ligand N,N′-bis(ferrocenylmethylene)ethylenediamine (FcNN) have been prepared from the ligand and M(CO)6. Two isomeric forms of (FcNN)Mo(CO)4, corresponding to the cis,cis and cis,trans geometries with respect to the CN bonds of the free ligand, were shown to exist in a 1∶12.5 ratio by 1H NMR (NOE experiments). By contrast, only the trans,trans isomer is observed for the Cr complex (FcNN)Cr(CO)4. The compounds (FcNN)M(CO)4 show ferrocene-based irreversible oxidation processes that lead to the deposition of a film at the electrode surface. (FcNN)Mo(CO)4 was immobilised in permethylated β-CD (TRIMEB) by addition of the guest to a solution of TRIMEB in dichloromethane. Removal of the solvent led to the isolation of an inclusion compound with a 2∶1 host∶guest stoichiometry, as evidenced by powder X-ray diffraction, thermogravimetric analysis, FTIR and 13C CP MAS NMR spectroscopy. The electrochemical properties of (FcNN)Mo(CO)4 upon encapsulation are discussed.

Antitumor Activity of Ionic Liquids Based on Ampicillin

Significant antiproliferative effects against various tumor cell lines were observed with novel ampicillin salts as ionic liquids. The combination of anionic ampicillin with appropriate ammonium, imidazolium, phosphonium, and pyridinium cations yielded active pharmaceutical ingredient ionic liquids (API‐ILs) that show potent antiproliferative activities against five different human cancer cell lines: T47D (breast), PC3 (prostate), HepG2 (liver), MG63 (osteosarcoma), and RKO (colon). Some API‐ILs showed IC50 values between 5 and 42 nM, activities that stand in dramatic contrast to the negligible cytotoxic activity level shown by the ampicillin sodium salt. Moreover, very low cytotoxicity against two primary cell lines—skin (SF) and gingival fibroblasts (GF)—indicates that the majority of these API‐ILs are nontoxic to normal human cell lines. The most promising combination of antitumor activity and low toxicity toward healthy cells was observed for the 1‐hydroxyethyl‐3‐methylimidazolium–ampicillin pair ([C2OHMIM][Amp]), making this the most suitable lead API‐IL for future studies.