Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids.

Silvia Cuffini,José Vega-Baudrit,Teodolito Guillén-Girón,Mirtha Navarro-Hoyos,Andrea Araya-Sibaja

doi:10.3390/pharmaceutics11030112

Abstract

Lovastatin (LOV) is a drug used to treat hypercholesterolemia. Recent studies have identified its antioxidant effects and potential use in the treatment of some types of cancer. However, the low bioavailability related to its poor water solubility limits its use in solid oral dosage forms. Therefore, to improve the solubility of LOV three eutectic systems of LOV with the carboxylic acids benzoic (BEN), salicylic (SAL) and cinnamic (CIN) were obtained. Both binary phase and Tammann diagrams were constructed using differential scanning calorimetry (DSC) data of mixtures prepared from 0.1 to 1.0 molar ratios. Binary mixtures and eutectics were prepared by liquid-assisted grinding. The eutectics were further characterized by DSC and powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The LOV-BEN, LOV-SAL and LOV-CIN system formed a eutectic at an LOV mole fraction of 0.19, 0.60 and 0.14, respectively. The systems exhibited improvements in LOV solubility, becoming more soluble by five-fold in the LOV-SAL system and approximately four-fold in the other two systems. Considering that the solubility enhancements and the carboxylic acids used are generally recognized as safe by the U.S. Food and Drug Administration (FDA), the LOV eutectic systems are promising materials to be used in a solubility enhancement strategy for pharmaceutical product formulation.

Highlights

Eutectic mixtures are multicomponent organic materials formed by two or more crystalline solids that are immiscible in the solid state and miscible in the liquid state [1,2]
As expected for eutectic mixtures, a unique endothermic event is observed in Figure 2a–c corresponding to LOV-BEN, LOV-SAL and LOV-CIN eutectic formation, respectively
Binary eutectic mixtures of LOV with benzoic, salicylic and cinnamic carboxylic acids were able to be produced through liquid assisted grinding

Summary

Introduction

Eutectic mixtures are multicomponent organic materials formed by two or more crystalline solids that are immiscible in the solid state and miscible in the liquid state [1,2]. The melting temperature of the eutectic is lower than the melting temperatures of their parent components [5] These systems can be considered as intimately physically blended, with high thermodynamic functions, such as free energy, enthalpy and entropy [6], which provide both solubility and dissolution enhancements [7,8]. Solid dispersion approach has been successfully applied to improve the dissolution rate of LOV using acetylsalicylic acid as coformer [33], which has proved to be a simple strategy to overcome the poor water solubility of this drug. The composition at the eutectic point of LOV and the selected carboxylic acid (BEN, SAL or 2.3.C1.IND)etwearms oinbtaatiinoendobfyMthixetcuornesCtruocmtipoonsoitfiToanmamt tahnenEauntdecbtiincaPryoipnhtase diagrams.

Preparation of Bulk Mixtures at the Eutectic Composition

Characterization of the Eutectic Mixtures

Apparent Solubility

Eutectic Mixture Screening

Solubility Determinations of the Eutectic Systems

Conclusions