Hot-melt extrusion is a technology, which is increasingly in use in production of pharmaceuticals to improve water dissolution rate of poorly soluble drugs. Aim of hot-melt extrusion is to amorphize and disperse drug substance in polymer carrier and prevent its recrystallization. Achieving such outcome, depends on thermodynamic and physical properties of used substances, ratio of a drug and polymer in formulation, and process settings at extrusion process. To optimize process variables of melt extrusion with an extruder can be a time and material consuming process. Therefore, the aim of this work is to approach the extrusion process with an extensive preliminary analysis of input materials, construction of their phase diagrams and in silico simulation, using simulating program. With the approach like this, in vivo extrusion experiments lead to more successful outcomes and reduce the amount of material used for process. Through validation experiments, we evaluated the extent to which the theoretical models and simulations can be trusted.
In this work, we assessed two model drugs nifedipine and candesartan cilexetil in two different polymer carriers, Kollidon® VA64 and Soluplus®. Miscibility and solubility are properties that help us predict compatibility and stability of selected drugs and polymers that form an amorphous dispersion. These properties are described by an interaction parameter from the Flory-Huggins theory, which we estimated at two different temperatures and constructed phase diagrams. Considering phase diagrams, the mass ratio of the drug and polymer in extrusion formulation were determined. With the selected ratio of drug and polymer in formulation, we continued with evaluation of their rheological properties and determined an appropriate temperature range for extrusion. After that, we were able to simulate the design of the experiments and study relationships between the process settings and their influence on the process variables, using simulation program Ludovic®. With the help of the design of experiments, based on the results obtained through simulations, we developed models that clearly show the influence of extrusion process parameters within the studied area, on the key variables (temperature, pressure, torque). Obtained results of physical properties, calculated theoretical models, and performed simulations of the process were compared and validated with extrusion process itself. Produced extrudates were analysed by dynamic differential calorimetry and X-ray powder diffraction, and obtained results were compared with the values predicted by the theoretical solubility model.
Based on simple preliminary measurements, theoretical models, and simulations of the process, we believe that we can decide with sufficiently high reliability on the composition of mixture for the preparation of amorphous solid dispersion and determine the melt extrusion parameters that ensure a robust production process and suitable process conditions for the formation of desired amorphous solid dispersion.
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