María M. de Bertorello

Solubilization of naphthoquinones by complexation with hydroxypropyl-β-cyclodextrin

Abstract The effects of the hydroxypropyl- β -cyclodextrin (HPCD) on the solubility of 2-hydroxy- N -(5-methyl-3-isoxazolyl)-1,4-naphthoquinone-4-imine ( I ) were investigated. I is an experimental drug for the treatment of cancer which exhibits low water solubility and it is therefore difficult to prepare the solutions for biological tests. The presence of an ionizable hydroxyl moiety (p K a =5.80) increases the solubility via pH adjustment, but only a solubility of 0.124 mg/ml was obtained at pH 8.00. I was found to form inclusion complexes in either its neutral or its anionic form with HPCD. Although the stability constant of the I complex is larger in the neutral form, a greater overall solubility is obtained when I is in its ionized form. A 270-fold solubility enhancement is possible by using a combined approach of pH adjustment and complexation with HPCD.

Second-derivative UV spectrophotometric assay for determining the degradation kinetics of 3-bromo-N-bromo-N-(3,4-dimethyl-5-isoxazolyl-4-amine)-1,2-naphthoquinone

The application of the second-derivative UV spectrophotometry for determining the stability of 3-bromo-N-bromo-N-(3,4-dimethyl-5-isoxazolyl-4-amine)-1,2-naphthoquinone in ethanolic solutions is described. The validity of this method was evaluated using synthetic mixtures of the intact drug and its degradation products and by statistical analysis of the calibration data. In order to verify the usefulness of this method for stability studies, recovery experiments by the standard addition method were also carried out.

Solubility profiles of some isoxazolyl–naphthoquinone derivatives

Water, ethanol and n-hexane solubility and pH-solubility behavior of a homologous series of isoxazolyl-naphthoquinone derivatives, which exhibit important biological activity, were studied. Their pK(a) values were determined spectrophotometrically as well as from their pH-solubility profiles. Also, the molar aqueous solubility of these compounds was estimated with the equations developed by Yalkowsky and Valvani using the data of their melting points and octanol/water partition coefficients.

Preparation and Characterization of Solid Complexes of Naphtoquinone and Hydroxypropyl-b-Cyclodextrin

The formation of an inclusion compound between a naphthoquinone derivative (I) and HP-s-CD was studied in solid state by X-ray diffractometry, DSC, and IR.

Solvent effects on the chemical shifts of halogenated derivatives of diphenyl sulphone, dibenzothiophene and dibenzothiophene 5,5-dioxide

The 1H NMR spectra of the title compounds were recorded in [2H6]DMSO and CDCl3 solvents and analysed using the LAOCOON-3 program. A different degree of shielding of the two protons ortho to the halogen atoms was observed in the tricyclic compounds. The sign and the magnitude of this differential shielding depends on both the halogen substituent and the solvent. Models for the solute–solvent interactions are suggested, and it is proposed that both mesomeric and steric effects contribute to the observed NMR results.

Solid state characterization of potential protozoocidal agents: aminoisoxazolylnaphthoquinones

Abstract As part of their preformulation evaluation, four in vitro protozoocidal 3,4-dimethyl-5-isoxazolylnaphthoquinones (ANQ-1–4) were investigated by differential scanning calorimetry (DSC), simultaneous differential thermal analysis–thermogravimetry–derivative thermogravimetry (DTA–TG–DTG), and Fourier transform infrared spectroscopy (FTIR). X-ray powder diffractometry (XRPD), thermomicroscopy and polarized light microscopy were used as an aid to interpret the thermoanalytical curves. The study demonstrated that the compounds are crystalline solids, unaffected by oxygen, safely manipulated at room temperature (RT) and also at higher temperatures as solids; however, all decompose exothermically at about their mp. Polycrystalline mixtures or undesirable solvates were not detected. All the compounds are insoluble in water and n-hexane and slightly soluble in ethanol, indicating that all are candidates to improve their solubilities in order to avoid formulation problems.

High Performance Liquid Chromatography of Isoxazolyl-Naphthoquinones: A Comparison Between Experimental and Theoretical Lipophilicity

An RP-HPLC procedure was developed for determining the lipophilicity of a series of isoxazolyl-naphthoquinones which possess antibacterial, trypanosidal and antineoplasic activity. The experimental results were compared with theoretical log P values, and it was found that there was a good relationship between the two methods, except for very lipophilic compounds.

Synthesis and Characterization of New Naphthoquinonic Derivatives Containing the Pyrazole Ring: Pyrazolylnaphthoquinones

The reaction of 3-aminopyrazole (1) with 1,2-naphthoquinone-4-sulfonic acid sodium salt (2) was studied in different aqueous media. The novel pyrazolylnaphthoquinones synthesized were physical and spectroscopically characterized, including 2D NMR spectroscopy (HETCOR). The possible reaction mechanism is proposed.

Development and validation of a reversed phase HPLC method for quantitative analysis of bis-isoxazolylnaphthoquinone

The goal of this study was to determine the kinetic parameters involved in the decomposition of 2-(5-methyl-4-isoxazolylamino)-N-(5-methyl-4-isoxazolyl)-1,4-naphthoquinone-4-imine (1) in aqueous solution and to identify the main degradation products. An isocratic HPLC assay was used to study the degradation rate of 1. The products of hydrolysis were identified by comparison of their retention times with those of authentic samples. The amount of 1 and the two degradation products resulting from storage of 1 in various buffer solutions was followed in function of time by a reversed-phase HPLC stability-indicating method. The observed degradation rates followed pseudo-first-order kinetics at constant pH, temperature and ionic strength. The logk-pH-profile was constructed at 35 degrees C from the first-order rate constants obtained from studies at pH values ranging from 0.88 to 10.80 (mu=0.5 M). Hydrolysis in the acidic and alkaline media resulted in the formation of two degradation products in each case. The pH-rate profile of 1 in buffer solution was adequately described using a four-term rate equation. The obtained pH-rate profile indicated specific acid-base catalysis with a region of maximum stability between pH 6.40 and 7.40 which can be adequate for formulations of 1.

Determination of the Formation Constant of the Inclusion Complex from a Naphthoquinone

Inclusion complexation of 1 with HP-β-CD or HP-β-CD:PVP K30 in aqueous solution was spectroscopically studied and the formation constant for a 1:1 complex was determined from these measurements.