Justin Moser

Development of amorphous solid dispersion formulations of a poorly water-soluble drug, MK-0364.

The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364. The potential solid dispersions would enable an oral solid dosage form as a monotherapy or combination product of MK-0364. Preliminary screening included sample preparation via a solvent casting method, physical characterization, and in vitro dissolution testing. Lead formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying (SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a single phase glass including an amorphous halo when analyzed with X-ray powder diffraction (XRPD), a single glass transition temperature (Tg) measured with differential scanning calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral absorption of MK-0364 from selected HME and SD formulations in monkeys results in marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule reference. Based on the processability, physical characterization, in vitro dissolution, and animal pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based solid dispersion formulations are viable product concepts. The physical stability of both the solid dispersion formulations was also evaluated for 54 weeks under different conditions. The copovidone-based solid dispersion requires protection from moisture.

Practical Considerations for Spray Dried Formulation and Process Development

Amorphous solid dispersion formulations provide a way to improve the bioperformance of poorly water soluble compounds by converting the crystalline drug to a high energy polymer stabilized amorphous state. Spray drying is a mature process with demonstrated production capability from lab to commercial scale for manufacturing amorphous solid dispersions. However, the impact of the drying process on the performance, manufacture, and stability of the drug product is often complex and can impact the chemical and physical stability of the drug, as well as the in vivo performance of the drug product. Physical and chemical properties of the components in the spray dried formulation can be linked to process risks. Analytical technology can build the connection between the process and the components of the formulation by measuring both the process dependent parameters and the product itself. Models can also be used to obtain a fundamental understanding of the system and be predictive of changes across process spaces. The properties of spray dried powder are amenable to multiple drug delivery routes such as oral suspensions and solid oral dosage forms. However, the process and environmental stresses put on the spray dried amorphous solid dispersions bring forth specific technical challenges. This chapter seeks to review the opportunities and failure modes associated with the spray drying process and the downstream fate of amorphous solid dispersions in several drug delivery routes while linking failure modes to the physical and chemical properties of the drug and formulation.

Application of finite inverse gas chromatography in hypromellose acetate succinate-water-acetone systems.

A modification of a GC was developed to investigate both infinitely dilute and finite concentrations of solvents in polymers. Thermodynamic properties of hypromellose acetate succinate (HPMCAS-L)-acetone-water systems are important for the optimization of spray-drying processes used in pharmaceutical manufacturing of solid dispersion formulations. These properties, at temperatures below the glass transition temperature, were investigated using capillary column inverse gas chromatography (CCIGC). Water was much less soluble in the HPMCAS-L than acetone. Experiments were also conducted at infinitely dilute concentrations of one of the solvents in HPMCAS-L that was already saturated with the other solvent. Overall the partitioning of the water was not significantly affected by the presence of either water or acetone in the polymer. The acetone partition coefficient decreased as either acetone or water was added to the HPMCAS-L. A representation of the HPMCAS-L structure in terms of UNIFAC groups has been developed. With these groups, the UNIFAC-vdw-FV model did a reasonable job of predicting the phase equilibria in the binary and ternary systems. The Flory-Huggins correlation with fitted interaction parameters represented the data well.