An innovative strategy to address recent challenges in the oral administration of poorly soluble drugs is the formulation of amorphous solid dispersions (ASDs), where the drug is dissolved in a highly soluble carrier polymer. Therefore, special knowledge of the drug–polymer phase behavior is essential for an effective product and process design, accelerating the introduction of novel efficacious ASD products. Flory–Huggins theory can be applied to model solubility temperatures of crystalline drugs in carrier polymers over the drug fraction. However, predicted solubility temperatures lack accuracy in cases of strong drug/polymer interactions that are not represented in the Flory–Huggins lattice model. Within this study, a modeling strategy is proposed to improve the predictive power through an extension of the Flory–Huggins interaction parameter by a correlation with the drug fraction. Therefore, the composition dependency of the Flory–Huggins interaction parameter was evaluated experimentally for various drug–polymer formulations that cover a wide variety of drug and polymer characteristics regarding molecular weights, glass transition temperatures and melting temperatures, as well as drug–polymer interactions of different strengths and effects. The extended model was successfully approved for nine exemplary ASD formulations containing the drugs acetaminophen, itraconazole, and griseofulvine, as well as the following polymers: basic butylated methacrylate copolymer, Soluplus^®, and vinylpyrrolidone/vinyl acetate copolymer. A high correlation between the predicted solubility temperatures and experimental and literature data was found, particularly at low drug fractions, since the model accounts for composition dependent drug–polymer interactions.

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over the past decades and focuses on oral dosage forms. A distinction is made between ‘brick-dust’ molecules, which are characterized by high melting points due to the solid-state properties of the substances, and ‘grease-ball’ molecules with high lipophilicity. In general, the discussed strategies are divided into the following three main categories: drug nanoparticles, solid dispersions, and lipid-based formulations.

Hot-melt extrusion is increasingly applied in the pharmaceutical area as a continuous processing technology, used to design custom products by co-processing drugs together with functional excipients. In this context, the residence time and processing temperature during extrusion are critical process parameters for ensuring the highest product qualities, particularly of thermosensitive materials. Within this study, a novel strategy is proposed to predict the residence time distribution and melt temperature during pharmaceutical hot-melt extrusion processes based on experimental data. To do this, an autogenic extrusion mode without external heating and cooling was applied to process three polymers (Plasdone S-630, Soluplus and Eudragit EPO) at different specific feed loads, which were set by the screw speed and the throughput. The residence time distributions were modeled based on a two-compartment approach that couples the behavior of a pipe and a stirred tank. The throughput showed a substantial effect on the residence time, whereas the influence of the screw speed was minor. On the other hand, the melt temperatures during extrusion were mainly affected by the screw speed compared to the influence of the throughput. Finally, the compilation of model parameters for the residence time and the melt temperature within design spaces serve as the basis for an optimized prediction of pharmaceutical hot-melt extrusion processes.

Melt viscosity is an essential property in pharmaceutical processes such as mixing, extrusion, fused deposition modeling, and melt coating. Measuring and modeling of the melt viscosity for drug/polymer mixtures is essential for optimization of the manufacturing process. In this work, the melt viscosity of nine formulations containing the drug substances acetaminophen, itraconazole, and griseofulvin, as well as the pharmaceutical polymers Eudragit EPO, Soluplus, and Plasdone S-630, were analyzed with a rotational and oscillatory rheometer. The shear rate, temperature, and drug fraction were varied systematically to investigate their influence on viscosity. The results for the pure polymers showed typical shear-thinning behavior and are fundamental for modeling with the Carreau and Arrhenius approaches. The investigations of the viscosity of the drug/polymer mixtures resulted in a plasticizing or a filler effect, depending on the type of drug and the phase behavior. A drug shift factor was proposed to model the change in viscosity as a function of the drug fraction. On this basis, a universal model to describe the melt viscosity of drug/polymer mixtures was developed, considering shear rate, temperature, and drug fraction.

The poor solubility of a large number of active pharmaceutical ingredients (APIs) is a major challenge in pharmaceutical research. Therefore, the extrusion of amorphous solid dispersions (ASDs) is one promising approach to enhance the dissolution rate by molecularly dissolve the API in an amorphous carrier polymer. During ASD extrusion, crucial parameters as the dissolution of the API in the carrier polymer need to be monitored. Within this study, a small scale twin screw extruder was coupled with special ColVisTec UV-Vis probes that are characterized by their small dimensions. This setup enables a systematic formulation design and optimization based on in-line monitoring of drug dissolution using small material quantities. In fact, sample quantities of about 5 mg were evaluated for each measurement, representing 50% of the material inside the die. The amount of undissolved drug particles was determined based on the lightness of the extrudates. It was shown that the temperature has a significant effect on the drug dissolution in the polymer. Furthermore, complete drug dissolution were shifted to lower temperatures if higher residence times were applied. Based on the courses of lightness, regime maps were modeled that specify the process conditions where ASDs are successfully manufactured.