Solubility and modeling of telmisartan in binary solvent mixtures of dichloromethane and (methanol, ethanol, n-propanol, or n-butanol) and its application to the preparation of nanoparticles using the supercritical antisolvent technique

Abstract

In this study, the mole-fraction solubility data for telmisartan in dichloromethane + primary alcohol (methanol, ethanol, n-propanol or n-butanol) mixtures were measured at five different temperatures by employing a solid-liquid equilibrium using the shake-flask technique. In addition, the melting temperature and enthalpy of telmisartan were determined by differential scanning calorimetry, while powder X-ray diffraction analysis was used to evaluate the crystal form of telmisartan obtained before and after the solubility experiments. The solid state characterization confirmed no transformation of telmisartan into polymorphs. The solvent synergistic effect was observed in all binary mixtures. In particular, the telmisartan solubility in the mass fraction values of dichloromethane (w) of 0.8 at 298.15 K was found to be approximately 90.77 and 4.98 times higher than that in pure methanol and pure dichloromethane, respectively. The experimental solubility data for telmisartan were correlated and fitted to the van't Hoff, modified Apelblat, simplified CNIBS/R-K, Jouyban-Acree, Jouyban-Acree-van't Hoff, Jouyban-Acree-Apelblat, Ma, and Sun models. The thermodynamic parameters, such as the dissolution enthalpy (∆H°), Gibbs free energy (∆G°), and dissolution entropy (∆S°), confirmed that the dissolution of telmisartan in the mixtures was an endothermic process. Furthermore, dichloromethane and primary alcohol mixtures (w = 0.8) were used as the solvent in the preparation of telmisartan nanoparticles using the supercritical antisolvent (SAS) technique. The smallest particle size (630.8 nm) of the telmisartan nanoparticle obtained from a solvent mixture of dichloromethane and methanol was obtained. Results confirmed that the solubility data and estimated equations for telmisartan in the dichloromethane + primary alcohol mixtures with a strong synergistic solvation are useful in research and development for the purification and preparation of nanoparticles as well as in future studies on telmisartan to design and develop dosage forms.