Cristiane C. de Melo

Mechanochemistry applied to reformulation and scale-up production of Ethionamide: Salt selection and solubility enhancement

Ethionamide (ETH), a Biopharmaceutics Classification System class II drug, is a second-line drug manufactured as an oral dosage form by Pfizer to treat tuberculosis. Since its discovery in 1956, only one reformulation was proposed in 2005 as part of the efforts to improve its solubility. Due to the limited scientific research on active pharmaceutical ingredients (APIs) for the treatment of neglected diseases, we focused on the development of an approachable and green supramolecular synthesis protocol for the production of novel solid forms of ETH. Initially, three salts were crystal engineered and supramolecular synthesized via slow evaporation of the solvent: a saccharinate, a maleate and an oxalate. The crystal structures of all salts were determined by single crystal X-ray diffraction. In sequence, mechanochemical protocols for them were developed, being the scale-up production of the maleate salt successfully reproducible and confirmed by powder X-ray diffraction. Finally, a more complete solid-state characterization was carried out for the ETH maleate salt, including thermal analysis, infrared spectroscopy, scanning electron microscopy and equilibrium solubility at different dissolution media. Although ETH maleate is thermodynamically less stable than ETH, the equilibrium solubility results revealed that this novel salt is much more soluble in purified water than ETH, thus being a suitable new candidate for future formulations.

Supramolecular synthesis and thermochemical investigations of pharmaceutical inorganic isoniazid salts

In multiple-drug therapy, isoniazid (INH) is considered one of the most important antibiotics for the treatment of tuberculosis. Beyond its pharmacological importance, INH is also a versatile compound that can be combined with several other molecules to produce salts and co-crystals. In this study, novel salts of INH, obtained from the reaction with pharmaceutically accepted inorganic acids (HBr, HNO3 and H2SO4), were investigated. The reaction of INH with H2SO4, gives rise to two forms: an INH sulfate and an INH sulfate hemihydrate salt. The four salts feature a supramolecular assembly quite different from the one described for INH hydrochloride. INH hydrobromide and INH nitrate adopt a head-to-tail assembly, where the cations (INH+) are directly connected to each other. However, this is not the case for the sulfate forms, where the cations appear surrounded by the anions, being connected to them through their pyridinium and hydrazide groups. Interestingly, an unexpected homodimer is observed in the INH sulfate salt. Hirshfeld surface analysis was used to highlight and quantify the contributions of the main interactions. The relative thermal stability of these salts was studied by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and hot-stage microscopy (HSM). Although the melting points of both sulfate forms are practically the same, the four INH salts have distinct thermal profiles.

Reaching Biocompatibility with Nanoclays: Eliminating the Cytotoxicity of Ir(III) Complexes

Cyclometalated IrIII complexes are promising candidates for biomedical applications but high cytotoxicity limits their use as imaging and sensing agents. We herein introduce the use of Laponite as carrier for triplet-emitting cyclometalated IrIII complexes. Laponite is a versatile nanoplatform because of its biocompatibility, dispersion stability and large surface area that readily adsorbs functional nonpolar and cationic molecules. These inorganic-organic hybrid nanomaterials mask cytotoxicity, show efficient cell uptake and increase luminescent properties and photostability. By camouflaging intrinsic cytotoxicity, this simple method potentially extends the palette of available imaging and sensing dyes to any metal-organic complexes, especially those that are usually cytotoxic.

Crystal engineering of multicomponent crystal forms of antituberculosis drugs

Tuberculosis (TB) is one of the major causes of mortality in developing countries. Its high incidence and prevalence turns TB a global health problem. The TB treatment is based on the use of drugs as a fixed-dose combination (FDC) tablet which can simplify the TB treatment. However, one of the main concerns about the use of anti-TB drugs lies in the high hygroscopicity of Ethambutol (ETB) and limited solubility of Ethionamide (ETH). The development of multicomponent crystal forms, e.g. salts and cocrystals, represents an important branch of pharmaceutical sciences as alternative route to improve drug’s physicochemical properties (aqueous solubility, hygroscopicity and thermal stability). Salt or cocrystal formation is a process strictly governed by the acidity/basicity of the ionizable groups in the drug and in the salt coformers. In general, pharmaceutical acceptable strong acids are used to protonate a basic drug, such as ETB and ETH and thereby convert it into salts. For ionizable drugs, salt formation is still the most effective low-cost method and consequently the preferential one to increase the low solubility and bioavailability of the parent drug. Based on the crystal engineering approach, we developed novel pharmaceutical salts of Isoniazid (INH), ETH and ETB anti-TB drugs. These salts were crystal engineered and supramolecular synthesized using a series of inorganic and carboxylic acids formers (maleic, nitric, sulfuric and oxalic) in order to overcome the undesirable effects of these drugs. The new salts obtained were study by single crystal X-ray diffraction as well as thermal and spectroscopy analysis. These studies showed that the assembly of ETH maleate salt is dominated by a cyclic tetramer arrangement where two ETH+ cations are alternately linked to two counterions. ETH nitrate crystallized with four independent ionic pairs in the asymmetric unit being the first ETH structure with Z’>1 reported. Each ionic pair is stabilized by a strong pyridinium...NO3Hbond. Solubility studies show that ETH nitrate salt is about 240-fold more soluble than ETH commercial API. In the INH sulfate salt, the INH+ cations form a rather unexpected R(_2^2)(10) homodimers. The sulfate anions, in turn, bridge these homodimers into a 1-D chain via a R(_2^2)(10) motif formed by pyridinium...SO4H-bonds. Due to the presence of a much stronger anionINH+ H-bonds, this salt presents a high melting point (204 oC) when compared than INH parent form (m.p 170 oC). Analysis of the crystal structure and packing of ETB oxalate salt revealed that min this case the ion-pairs (ETB+/OXA-) are stabilized by the expected NH+... COOsynthons. Hygroscopicity tests of the ETB oxalate salt showed that this salt is non-hygroscopic making a suitable candidate for the anti-TB multiple-drug therapy formulation.