Complex amorphous solid dispersions with delayed drug release promoting supersaturation maintenance in the gastrointestinal tract

In the field of drug development many new active pharmaceutical ingredients (APIs) face the issue of having a poor solubility in water, limiting their uptake in the gastrointestinal (GI) tract after oral administration. One of the formulation strategies that has become increasingly popular in the past decades, is an amorphous solid dispersion. In this formulation, the API is molecularly dispersed in an inert carrier which causes it to have a higher solubility than its crystalline form due to lack of long range ordering. Throughout the years of formulation research, this carrier was often a water-soluble polymer. This type of carrier guarantees a rapid drug release, leading to a fast increase in drug concentration in the GI tract. A downside of this rapid increase in drug concentration, is the risk for precipitation of the drug which causes the ASD to lose its benefit of improved solubility. An alternative system which is proposed in this PhD, is the use of an insoluble or slowly dissolving polymer to install a slower drug release via diffusion with the benefit that the improved solubility can be maintained for a longer period of time. The insoluble carriers that are investigated in this work are poly(2-hydroxyethyl methacrylate), poly(2-oxazolines) and ethyl cellulose. Since drug release is dictated by a diffusion mechanism, porosity of the formulation is expected to influence the drug's release profile. Therefor, an additional component called a porosity increasing agent is incorporated in the formulation to investigate the effect of an altered porosity. Next to that the porosity increasing agent, which is a water-soluble polymer, can also act as a precipitation inhibitor. The overarching goal of this PhD project is to combine all these different elements into one particle. This is attained via spray drying, a solvent-based manufacturing technique which can be applied on an industrial scale. After preparation, all formulations are subjected to a detailed solid state analysis by investigating them with modulated differential scanning calorimetry, X-ray powder diffraction, solid-state nuclear magnetic resonance spectroscopy and thermogravimetric analysis. Finally, pharmaceutical performance of the ASDs is also tested via dissolution studies in acidic and neutral media.

Publication year:2021

Accessibility:Open