Particle Engineering with CO₂-Expanded Solvents: The DELOS Platform

Abstract

Compressed fluids and especially CO₂-expanded solvents (a mixed solvent composed of CO₂ dissolved in an organic solvent) present unique properties for the eco-efficient production of active pharmaceutical ingredients (APIs) with an exceptional control of the operational variables that allow tuning the final properties of the active compounds. The pharmaceutical industry nowadays is facing several challenges, as nearly 40 % of the newly discovered drugs are poorly soluble in water and, hence, present low bioavailability. In addition, there is a huge necessity to move to a more environmentally friendly way of product manufacturing. Therefore, the use of compressed fluid-based technology is a promising solution for the pharmaceutical industry. This chapter provides a general overview covering the properties of compressed fluids (CF), the most used CF-based processes, and a more comprehensive summary of the application of CO₂-expanded solvents for the tailored crystallization of active compounds.

Annexes: Vanishing Point Method

The vanishing point method is based on the observation of the progressive redissolution of a solute C until a complete transparent solution is formed. Such solid is in equilibrium with a saturated phase of itself in a homogeneous mixture between two fluids A and B. The increase of the solvating capacity of A/B binary mixture through the change of its composition provokes the progressive redissolution of the solute, which is completed at what is called the vanishing point. The vanishing point method is an adequate procedure for performing solubility studies either at atmospheric pressure, where A and B are both conventional solvents, or at high pressure, where A and B can be a conventional solvent and a compressed fluid (CF), such as CO₂, respectively (Wubbolts, F.E., Supercritical crystallisation: volatile components as antisolvents, Ph. D. Thesis, Technical UniG.M., Measurement and modelling of the solubility of solids in mixtures of common solvents and compressed gases, Journal of Supercritical Fluids, 32 (2004) 79–87.).

The high-pressure phase analyzer enables to obtain solubility curves of a solute in organic solvent/CO₂ mixtures like those depicted in Fig. 5.A.1, where the CF can present different behaviors with respect to the solution of the solute C in the organic solvent A. Thus, the CF can act as antisolvent (curve 1), cosolvent (curve 2) or can have a synergic behavior with the organic solvent augmenting, as a consequence, the solvating capacity of the mixture organic solvent/CO2 with respect to the pure solvents (curve 3) [7].

Fig.5.A.1

Possible solubility curves of a solute C in an organic solvent/CO₂ mixture of different compositions at constant pressure and temperature. Curve 1: antisolvent behavior of CO₂, curve 2: cosolvent behavior of CO₂, curve 3: synergistic behavior between CO₂ and the organic solvent. The dashed line represents the ideal solubility variation with respect to solvent compositions. Cs = saturation concentration

In curve 1, the addition of CO₂, at constant pressure (Pw) and temperature (Tw), over a saturated solution of the compound C in the organic solvent A provokes the precipitation of such compound presenting, therefore, an antisolvent behavior. In curve 2, there is a range of x_CO2 in which the CF acts as a cosolvent, preventing the precipitation of the solute. This range is defined by the intersection point between the ideal dilution line and the curve corresponding to the real variation of compound C solubility with the composition of the binary mixture organic solvent/CO₂. In the case of curve 3, the addition of CO₂ generates a binary system with a superior solvating power than the organic solvent A due to a synergic effect of the CF and the organic solvent in a range of x_{CO2 .}