Enhancement of dissolution, solubility and bioavailability for poorly soluble APIs can be achieved using a number of different approaches
Linkam THMS600 heating and cooling stage with T94 controller and LNP liquid nitrogen
Recent work by a team of researchers at Queen’s University Belfast and University College London has demonstrated a recently developed strategy for the manufacture of a high drug loaded amorphous solid dispersion (HDASD) using a hot-melt extrusion (HME) based platform1.
Enhancement of dissolution, solubility and bioavailability for poorly soluble APIs can be achieved using a number of different approaches, including the formation of an amorphous solid dispersion (ASD).
Many existing ASD polymers only work well at relatively low drug loadings, and, as a result, many ASDs consist of 90% polymer and 10% drug by weight. However, drug loadings of up to 50% by weight, so-called ‘high drug loaded ASD’ (HDASD), have been the focus of study in recent years.
The work, led by Dr Yiwei Tian and Professor Gavin Andrews from the School of Pharmacy, Queens University, Belfast, Northern Ireland, explored the formation of HDASD via a hot-melt extrusion platform. The weak acidic drugs (indomethacin, ibuprofen and naproxen) with amorphous polymeric carrier Eudragit E (EPO) were chosen as suitable combinations for study. Thermodynamic phase diagrams for three HDASD systems were constructed and used to guide the design of the hot-melt extrusion process and the processability and storage stability of HDASDs were further investigated using a range of conventional and advanced analytical techniques.
Dr Tian said: “The solid-state properties of ball-milled samples and the dissolution/melting behaviours of crystalline drug in the polymeric matrix, as a function of temperature, were analysed using small angle/wide angle X-ray scattering.
“The temperature control of the sample was realised by a Linkam stage installed inside the vacuum chamber. The SAXS/WAXS system was calibrated without the need of a standard. The calibration was validated before each measurement using lanthanum hexaboride.
“The WAXS was collected every 60 seconds at exposure time of 30 seconds during the heat-cool-heat cycle. SAXS was also collected on selected samples with 600 seconds of exposure time at key temperature points.”
Dr Tian partnered with Han Wu, Research Lab Manager at the Centre for Nature-Inspired Engineering (CNIE) research facility at University College London, to make the SAXS/WAXS measurements.
The study was able to directly observe the temperature dependences of the X-ray scattering pattern for the crystalline drugs (IND, NPX and IBU) in the presence of a polymeric carrier.
Dr Tian said: ‘The information we collected is particularly useful for the design of hot-melt extrusion processes, where a fully amorphous solid dispersion can be generated at conditions that are significantly lower than the melting point of the crystalline drug, and at much higher drug loadings.”
1. Tian, Y., E. Jacobs, D.S. Jones, C.P. McCoy, H. Wu, G.P. Andrews, The design and development of high drug loading amorphous solid dispersion for hot-melt extrusion platform, International Journal of Pharmaceutics (2020). https://doi.org/10.1016/j.ijpharm.2020.119545
2. Benet, L. Z. The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. J. Pharm. Sci. 102, 34–42 (2013). https://doi.org/10.1002/jps.23359