Abstract
A validation for the use of model-based melt viscosity in hot-melt extrusion numerical simulations was presented. Here, the melt viscosity of an amorphous solid dispersion (ASD) was calculated by using its glass transition temperature (Tg) and the rheological flow profile of the pure polymeric matrix. All further required physical properties were taken from the pure polymer. For forming the ASDs, four active pharmaceutical ingredients (APIs), that had not been considered in first place to establish the correlation between Tg and melt viscosity were examined. The ASDs were characterized in terms of density, specific heat capacity, melt rheology, API solubility in the polymeric matrix, and deviation from the Couchman–Karasz fit to, identify the influencing factors of the accuracy of the simulation using model-based melt viscosity. Furthermore, the energy consumption of the hot-melt extrusion (HME) experiments, conventional simulation, and simulation using model-based melt viscosity were compared. It was shown, with few exceptions, that the use of model-based melt viscosity in terms of the HME simulation did not reduce the accuracy of the computation outcome. The commercial one-dimensional (1D) simulation software Ludovic® was used to conduct all of the numerical computation. As model excipients, vinylpyrrolidone-vinyl acetate copolymer (COP) in combination with four APIs (celecoxib, loratadine, naproxen, and praziquantel) were investigated to form the ASDs.
Highlights
Nowadays, one of the major challenges in pharmaceutical small molecule formulation development is the increasing number of poorly soluble active pharmaceutical ingredients (APIs) and the respective poor bioavailability
We proposed a procedure to model the melt viscosity of an amorphous solid dispersion (ASD) by using only its glass transition temperature (Tg) and the rheological flow profile of the pure polymeric matrix [20]
We proposed a correlation between Tg and zero-shear viscosity η0 of an amorphous solid dispersion and its use in hot-melt extrusion (HME) simulation [20,21]
Summary
One of the major challenges in pharmaceutical small molecule formulation development is the increasing number of poorly soluble active pharmaceutical ingredients (APIs) and the respective poor bioavailability. HME is a time and API-consuming procedure, especially in early ASD formulation development, as the various process parameters, such as screw speed, throughput, screw configuration, and temperature profile lead to a complex multivariable process, which is challenging to optimize or scale-up [7,8,9]. The main drawback of HME simulation is the need for experimental product input data to conduct computation. In some cases, these data are not easy to access, especially in terms of melt rheology and thermosensitive APIs. the use of simulation for early formulation screening is limited, as the physicochemical characteristics would need to be laboriously measured for every formulation under consideration. As simulation is an inevitable tool to evaluate a potential adiabatic scale-up from small- to large-scale extruders, the above-mentioned drawbacks of HME simulation need to be solved [9]
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