Abstract
The aim of this work is to investigate the solubility enhancement of mefenamic acid (MA), a non-steroidal anti-inflammatory agent, by formation of stable amorphous ternary system (MA, polyvinylpyrrolidone (PVP), β-cyclodextrin (β-CD)) compared to the binary system (MA, β-CD). Firstly, on the basis of the molecular docking simulation and job’s plot results, three methods were adopted for the preparation of the binary inclusion complexes at the ratio of 2:1 of MA:β-CD, namely solvent co-evaporation (CE), kneading (KN) and physical mixture (PM). However, in order to decrease tendency to self-assembly of cyclodextrins and form aggregates in aqueous media, each binary system was co-milled at ambient temperature in presence of different ratios of a highly water-soluble polymer (PVP). These complexes were characterized using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), nuclear magnetic resonance (1H- and 13C-NMR) spectroscopy and scanning electron microscopy (SEM) techniques. The release of the drug from the diverse formulations was also investigated by means of UV-VIS spectroscopy. Finally anti-inflammatory and anti-nociceptive activities were performed. The results showed that the solubility of MA in water from ternary complexes was significantly improved.
Highlights
Physicochemical properties and ADME (Absorption, Distribution, Metabolism, Elimination) parameters of a drug substance are essential to ensure the accessibility to its target(s).Only the free part of the drug substance diffuses in tissues from the blood and can access to the active binding site of the desired target.Among all parameters to control for a successful treatment, an acceptable level of drug substance solubility is required.In the case of low solubility drug substances, inclusion complexes with β-CD can be an interesting alternative to facilitate drug administration.To increase complexation and to optimize solubilization, addition of small quantities of a suitable hydrophilic polymer to a drug:β-CD system is very favorable.Mefenamic acid (MA) and its physicochemistry
The aim of this work is to investigate the solubility enhancement of mefenamic acid (MA), a non-steroidal anti-inflammatory agent, by formation of stable amorphous ternary system (MA, polyvinylpyrrolidone (PVP), β-cyclodextrin (β-CD)) compared to the binary system (MA, β-CD)
The results showed that the solubility of MA in water from ternary complexes was significantly improved
Summary
Physicochemical properties and ADME (Absorption, Distribution, Metabolism, Elimination) parameters of a drug substance are essential to ensure the accessibility to its target(s).Only the free part of the drug substance diffuses in tissues from the blood and can access to the active binding site of the desired target.Among all parameters to control for a successful treatment, an acceptable level of drug substance solubility is required.In the case of low solubility drug substances, inclusion complexes with β-CD can be an interesting alternative to facilitate drug administration.To increase complexation and to optimize solubilization, addition of small quantities of a suitable hydrophilic polymer to a drug:β-CD system is very favorable.Mefenamic acid (MA) and its physicochemistry. Physicochemical properties and ADME (Absorption, Distribution, Metabolism, Elimination) parameters of a drug substance are essential to ensure the accessibility to its target(s). The free part of the drug substance diffuses in tissues from the blood and can access to the active binding site of the desired target. Among all parameters to control for a successful treatment, an acceptable level of drug substance solubility is required. In the case of low solubility drug substances, inclusion complexes with β-CD can be an interesting alternative to facilitate drug administration. Hydrophobic (brown) and hydrophilic (blue) surface areas of MA, β-CD and MA:β-CD binary inclusion complexes (CÅ, cubic Ångströms). Hydrophilic area increases upon formation of IC1 ((2:1) MA:β-CD). Higher polar surface area of the supramolecular inclusion complex improved the MA solubility MA molecule in the primary complex enhances the stability (further hydrogen electrostatic interaction and improved filling of the β-CD cavity)
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