Applications of KinetiSol® Dispersing for the production of plasticizer free amorphous solid dispersions

Thermal manufacturing methods for the production of solid dispersions frequently require the addition of a plasticizer in order to achieve requisite molten material flow properties when processed by unit operations such as hot melt extrusion. KinetiSol® Dispersing, a rapid high energy thermal manufacturing process, was investigated for the ability to produce amorphous solid dispersions without the aid of a plasticizer. For this study itraconazole was used as a model active ingredient, while Eudragit® L100-55 and Carbomer 974P were used as model solid dispersion carriers. Triethyl citrate (TEC) was used as necessary as a model plasticizer. Compositions prepared by KinetiSol® Dispersing and hot melt extrusion were evaluated for solid state properties, supersaturated in vitro dissolution behavior under pH change conditions and accelerated stability performance. Results showed that both manufacturing processes were capable of producing amorphous solid dispersions, however compositions produced by hot melt extrusion required the presence of TEC and yielded a glass transition temperature (Tg) of approximately 54 °C. Plasticized and unplasticized compositions were successfully produced by KinetiSol® Dispersing, with plasticizer free solid dispersions exhibiting a Tg of approximately 101 °C. Supersaturated in vitro dissolution testing revealed a significantly higher dissolution rate of plasticized material which was attributed to the pore forming behavior of TEC during the acidic phase of testing. A further contribution to release may also have been provided by the greater diffusivity in the plasticized polymer. X-ray diffraction testing revealed that under accelerated stability conditions, plasticized compositions exhibited partial recrystallization, while plasticizer free materials remained amorphous throughout the 6-month testing period. These results demonstrated that KinetiSol® Dispersing could be used for the production of amorphous solid dispersions without the aid of a plasticizer and illustrated the enhanced solid state stability that can be achieved by producing solid dispersions with higher glass transition temperatures.