Pharmaceutical Solid Forms and Formulations for Enhanced Solubility and Dissolution: Cocrystals, Salts, and Crystalline Solid Dispersions

Abstract

This thesis focuses on the development, manufacture, and characterisation of cocrystals and salts and their formulations, to enhance the solubility and dissolution of poorly soluble drugs. Three poorly soluble active pharmaceutical ingredients (APIs), trimethoprim (TMP), dapsone (DAP), and diclofenac acid (DA), were used as model drugs in this study. Salts, cocrystals, and formulations of these three APIs were produced by various pharmaceutical processing technologies, including mechanochemical synthesis, evaporative crystallisation, fluidised bed granulation, hot melt extrusion, and spray drying. With the aid of liquid-assisted ball milling and evaporative crystallisation, ten new salts or cocrystals of TMP were discovered for the first time in our study, of which eight were successfully generated in a physically pure form. The solubility of TMP in simulated intestinal fluid was successfully improved in the salt or cocrystal form. Hot melt extrusion, fluidised bed granulation, and spray drying were proven to be three viable pharmaceutical processing technologies for one step manufacture of a salt or a cocrystal in situ alone or in a formulation. Two continuous manufacturing processes using hot melt extrusion were developed and proven to be feasible for the formation of salt or cocrystal granules (of trimethoprim-succinic acid salt and salt cocrystal). Our study has demonstrated that granules comprising polymer cocrystals (dapsone-polyethylene glycol cocrystals) can be produced in situ by fluidised bed granulation. The polymer cocrystal granules produced by fluidised bed granulation demonstrated superior pharmaceutical properties, including flow properties and tableting properties compared to API and polymer cocrystals prepared by evaporative crystallisation. A physically unstable cocrystal, DA l-proline cocrystal, was successfully produced alone or with polymers by spray drying. The polymer type and loading was shown to affect the physicochemical properties of the powder generated in situ by spray drying. The additional of just 1 wt % polymer to cocrystals has the potential to enhance the cocrystal physical stability and improve API solubility and dissolution characteristics. The improvement in physical stability of the cocrystal was thought to be due to an efficient mixing between polymer and cocrystal at the molecular level provided by spray drying and in situ gelling of polymer. It is hypothesized that polymer chains could undergo gelling in situ and form a physical barrier, preventing cocrystal interaction with water, which contributes to slowing down the water-mediated dissociation.