Luan F. Diniz

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.

Avoiding irreversible 5-fluorocytosine hydration via supramolecular synthesis of pharmaceutical cocrystals

The antimetabolite 5-fluorocytosine (5-FC) was used to form pharmaceutical cocrystals in order to modulate its poor physicochemical stability in humid environments, which leads to the irreversible incorporation of a water molecule at the structural level under storage conditions. The anhydrous form of 5-FC is a well-known fluorinated analog of cytosine with antifungal activity and it has become one of the most used medications for cancer treatment via the gene therapy approach. In this study, novel 5-FC cocrystals were obtained from the reaction of 5-FC with three nontoxic coformers: caffeine (CAF), p-aminobenzoic acid (PABA) and caprylic acid (CA). These cocrystals, namely 5FC–CAF, 5FC–PABA and 5FC–CA, were characterized by single-crystal and powder X-ray diffraction (SCXRD and PXRD), spectroscopic (FT-IR and FT-Raman) and thermal (thermogravimetric analysis, differential scanning calorimetry, and hot-stage microscopy) techniques. The physical stabilities of 5-FC and its cocrystals were evaluated in environments with high relative humidity and the equilibrium solubility was measured in a pH 1.2 buffer medium. These studies show that the prodrug 5-FC is able to form different homo and heterosynthons that lead to cocrystal formation. Additionally, the solubility profiles of the novel multicomponent solid forms were found to be similar to the API raw material, a BCS class I drug, exhibiting a high solubility profile. The hydration stabilities of 5-FC and its cocrystals were evaluated in humid environments to confirm the irreversible hydration of 5-FC in contrast with the absence of phase transitions in its cocrystal forms. In this way all 5-FC cocrystals reported herein maintained to a large degree the API solubility and do not undergo the hydration process or phase transition under extreme storage conditions, being more stable than the parent 5-FC.

Facile Synthesis and Characterization of Symmetric N-[(Phenylcarbonyl) carbamothioyl]benzamide Thiourea: Experimental and Theoretical Investigations

A thiourea derivative, N-[(phenylcarbonyl)carbamothioyl]benzamide, was synthesized and characterized by elemental analysis, thermal analysis, spectroscopic methods (Fourier transform infrared (FTIR), UV-Vis, Raman, matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF), tandem mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR)) and quantum-chemical calculations. The synthetic route was simple and efficient, conducted just by one-step and no purification step was needed. The compound crystallizes in a non-centrosymmetric orthorhombic crystal system with a P212121 space group, with a = 5.06220(10) Å, b = 11.8623(3) Å, c = 21.9682(8) Å. The molecular conformation of the solid is stabilized by the N–H···O intramolecular hydrogen bond, which was present in the X-ray structure and was also found in the optimized geometry. The theoretical analysis showed that this strong interaction remains even when molecules are solvated, i.e., the rotation barrier and the hydrogen bond strength are greater than the solvent stabilization energy. In addition to this hydrogen bond effect, the relative position of phenyl groups has a certain influence on the chemical behavior of this thiourea and probably for other phenylthioureas.

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.