A comparison between pure active pharmaceutical ingredients and therapeutic deep eutectic solvents: Solubility and permeability studies

Abstract

THEDES, so called therapeutic deep eutectic solvents are here defined as a mixture of two components, which at a particular molar composition become liquid at room temperature and in which one of them is an active pharmaceutical ingredient (API). In this work, THEDES based on menthol complexed with three different APIs, ibuprofen (ibu), BA (BA) and phenylacetic acid (PA), were prepared. The interactions between the components that constitute the THEDES were studied by NMR, confirming that the eutectic system is formed by H-bonds between menthol and the API. The mobility of the THEDES components was studied by PFGSE NMR spectroscopy. It was determined that the self-diffusion of the species followed the same behavior as observed previously for ionic liquids, in which the components migrate via jumping between voids in the suprastructure created by punctual thermal fluctuations. The solubility and permeability of the systems in an isotonic solution was evaluated and a comparison with the pure APIs was established through diffusion and permeability studies carried out in a Franz cell. The solubility of the APIs when in the THEDES system can be improved up to 12 fold, namely for the system containing ibu. Furthermore, for this system the permeability was calculated to be 14×10cm/s representing a 3 fold increase in comparison with the pure API. With the exception of the systems containing PA an increase in the solubility, coupled with an increase in permeability was observed. In this work, we hence demonstrate the efficiency of THEDES as a new formulation for the enhancement of the bioavailability of APIs by changing the physical state of the molecules from a solid dosage to a liquid system.

Insights into the Nature of Eutectic and Deep Eutectic Mixtures

“…Other mixtures of dl-menthol with caprylic, capric and lauric acids were also proposed as hydrophobic DES and used to extract neonicotinoids from diluted aqueous solutions [35]. Duarte et al [36] proposed a DES composed of menthol and three different APIs: ibuprofen, BA, and phenylacetic acid, and demonstrated their efficiency in the enhancement of the solubility, permeability and thus, bioavailability of APIs by changing the physical state of the pure components. From another perspective, menthol:flurbiprofen was suggested as a DES to avoid menthol crystallization and allow the estimation of its glass transition temperature [37].…”

A Novel Binary Supercooled Liquid Formulation for Transdermal Drug Delivery

“…DES is a liquid consisting of two or more solid compounds of hydrogen donor and acceptor and has lower melting point than room temperature. 4,5) It offers several advantages such as increasing solubility and circumventing polymorphism. In addition, DES could be used for transdermal formulation of drugs without vehicle, with efficient transdermal drug permeation.…”

Organic Salts Based on Isoniazid Drug: Synthesis, Bioavailability and Cytotoxicity Studies

“…The permeability ( P ) of the isoniazid and organic salts with isoniazid was calculated following Equation (1): where C t is the concentration in the receptor compartment at time t , C 0 is the initial concentration in the donor compartment, V is the volume in two compartments, and A is the effective area of permeation. The permeability coefficient can be calculated from the slope of the curve –(V/2A)*ln(1 − 2C t /C 0 ) versus t (cm s −1 ) [ 31 , 32 , 33 , 34 ].…”