(279g) Assessing the Solubility of Pharmaceuticals in Supercritical Carbon Dioxide By Using Sublimation Enthalpies
Over the last few years, research has been conducted regarding the use of environmentally friendly technologies for the pharmaceutical industry. In this context, supercritical fluid technologies (mainly with supercritical CO2 (sc-CO2)) can take advantage of their special properties for developing alternatives to different conventional processes. As an example, it is well known the importance of the use of supercritical fluids to extract drugs from seeds or plants, or to obtain non-solvent particles with controlled particle size distribution.
The determination of the solubility of the solid in sc-CO2 must be the first step prior to the use of these processes. In supercritical fluid extraction, this solubility provides information about the limit amount of the compound that can be extracted. On the other hand, the chosen supercritical fluid technique for drug processing (supercritical fluid as a solvent or as an antisolvent) depends strongly on that solubility.
However, the determination of the solubility of the pharmaceuticals in sc-CO2 is not an easy task. Due to the common polarity difference between the drug and the sc-CO2, the solubility is usually between 10-5-10-8. That means that a small difference in solid purity, or in the protocol can provide high deviations. Moreover, depending on the methodology, experimental differences around one order of magnitude can be obtained. Due to the previous reasons, discrepancies are often observed between experimental solubility data for the same drug.
The previous facts point out the importance of the development of consistency tests to assess the solubility data of highly polar compounds in sc-CO2. So far, Méndez Santiago and Teja test is the most used option, although it needs at least three different studies to distinguish the data accuracy. Other theoretical tools, such as cubic equations of state or semiempirical models need adjustable parameters, and consequently they cannot be used for that aim.
An empirical analysis of the solubility of solids in sc-CO2 has been performed in this work by using only a group contribution method to estimate the sublimation enthalpy of the solid, and by defining a modified enhancement factor. After studying more than 2300 solubility data of pharmaceuticals in sc-CO2 at different temperatures, polar solids with similar sublimation enthalpies and at similar experimental conditions showed similar solubility behaviour in terms of the previously proposed modified enhancement factor. Based on these results, several equations to estimate that modified enhancement factor (depending only on the sublimation enthalpies) at different temperatures have been defined, providing with an average absolute relative deviation of less than 5%.
Therefore, by knowing only the molecular structure of the compound (as long as there is a group contribution method to calculate the sublimation enthalpies), those equations can be used as a helpful tool to identify if the experimental solubility data follow the usual solubility tendency, and as a consequence their accuracy.