Subcritical water as a tunable solvent for particle engineering

Abstract

In the research described in this thesis, an environmentally friendly technique for engineering the morphology of particles was developed. Active pharmaceutical ingredients (APIs) were used as model compounds to explore the potential of the new particle engineering technology. APIs were chosen because tuning the size and shape of drug particles can have pharmacokinetic benefits. The new technology used subcritical water (SBCW) as a solvent to dissolve APIs. By rapidly cooling a SBCW-API solution, the dissolved drug was rapidly precipitated, often with a narrow particle size distribution. Furthermore, it was shown that the morphology of the precipitated particles can be changed by altering several process variables. In order to develop a new precipitation technology, fundamental solubility data were required. Solubility data were collected for the model APIs; budesonide, griseofulvin, naproxen and pyrimethamine in SBCW from 100°C to 200°C. To ensure that the solubility results were reliable, data were also collected for anthracene, which were compared to published SBCW solubility data. The solubility of budesonide in SBCW was low. Organic solvents were added to the SBCW-budesonide solution to increase the solubility of the API. A model that correlated the solubility of the solute in SBCW with the dielectric constant of the solvent was developed. Model outputs were within 5% of the experimental solubility values. The solubilities of the APIs were also modelled using a state of the art model available in the published literature. The Modified UNIversal Functional Activity Coefficient (M-UNIFAC) model was used to predict the solubility of budesonide, griseofulvin, naproxen and pyrimethamine in SBCW. It was shown that some of the parameters in literature were not sufficient to describe the data. Model error is reduced significantly when the model parameters were optimized. The potential of the SBCW micronization process to produce particles for drug delivery via inhalation has been assessed. Budesonide was micronized under a model precipitation condition, the suspension of API in water was then spray dried, and the aerodynamic particle size was established using an Anderson Cascade Impactor. It has been shown that, when coupled with an effective drying process, particles suitable for inhalable drug delivery may be produced.