Elucidation of process-structure relationships of drug particle-containing polymer composites in melt extrusion processes

• Applicant: Dr. Jan Henrik Finke
• Subject Area: Mechanical Process Engineering ; Pharmacy
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537017158

In the pharmaceutical industry and research, melt extrusion represents an attractive process for the solvent-free production of solid (intermediate) products. With given thermal stability, active ingredients can, for example, be embedded in a water-soluble polymer matrix. Due to intermolecular interactions between the active ingredient and the polymer, it is possible to dissolve the crystalline structure of the active ingredient particles. Since, in particular during further processing of the melt extrudates into individualized dosage forms by means of 3D printing, the highest possible active ingredient loadings are required for the greatest possible flexibility in the dose with simultaneously acceptable and swallowable size, part of the active ingredient remains particulate. However, due to the temperature-dependent solubility, the properties of the drug particles may change during the processes in addition to the usual shear-related effects of (de)agglomeration/aggregation and comminution. Since this behavior has not been sufficiently researched, the overall objective of the research project is to build a population balance model to describe the particle size evolution of dispersed active ingredients in polymer systems and their effect on product properties. To this end, possible influences (formulation, plant, process) will first be investigated by means of statistical experimental design and evaluated in terms of their strength. The three largest influences will then be systematically varied in order to generate fundamental knowledge for the formation of robust models. In addition, the model will be extended to include the influences of a second melting process with deviating size as well as residence time characteristics (3D printing). Since a classical redispersion of the drug particles in aqueous media cannot be applied for size analysis due to the slow dissolution time of the polymer matrix, the analysis of the particle size distributions as the main factor of the product properties will be performed with methods developed in our own preliminary work based on scanning Raman microscopy. As the most important process variable of the formulations, the melt viscosity will be determined by capillary rheology in addition to oscillatory rotational rheology. This data is also used to differentiate dispersion effects of the extruder screw from those of the flow patterns in the nozzle itself. Furthermore, the influences of the disperse loading on the final product properties will be investigated. Finally, the empirical relationships found are to be extended by empirical and mechanistic relationships and equations from the literature and combined in a two-stage population balance model.

• DFG Programme: Research Grants