Solid dispersions (overview) section references

1. J.D. Moser et al., Am. Pharma Review, 11 (6), 68–73, 2008.

2. K. Sekiguchi and N. Obi, Chem. Pharm. Bull. 9 (11), 866–872 (1961).

Solid dispersion formulation development using predictive approaches Firouz Asgarzadeh, PhD, senior techical manager at Evonik

Solid dispersion formulations offer effective solutions to the problem of the growing number of poorly soluble drugs (i.e., Biopharmaceutics Classification Scheme (BCS) Class II and IV) in the current pharmaceutical company pipelines. Crystalline drug molecules are converted and stabilized in the amorphous state by the polymeric matrix. Depending upon polymer–drug miscibility, the final product is either a single-phase solid solution with molecular level mixing of the drug molecule or a multiphase matrix containing dispersions of fine particles of crystalline drug within the polymer matrix or a combination thereof. To achieve stable, single-phase solid solutions, selection of polymer–drug combinations with high affinity and appropriate drug-loadings (below saturation concentration) are essential in successful formulation development. Empirical and/or systematic approaches are applied to help with this selection.

Empirical approaches. Empirical trial-and-error methodologies have extensively been used to identify polymer–drug pairs and saturation concentrations in solid-dispersion formulation development. In the empirical approach, binary or ternary blends of drug and polymers, possibly in combination with solublizers, are mixed at several drug loadings. Blends are transformed into solid dispersions via solvent techniques (e.g., film casting, spray-drying, coprecipitation, and freeze-drying) or heating techniques (e.g., comelting, modulated differenetial scanning calorimetry (mDSC), and extrusion). Finally, these prototype formulations are analyzed for stability and amorphous structure content using physicochemical methods (X-ray diffraction, DSC, atomic force microscopy, Raman specroscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance, assay/degradation products, and/or dissolution). In the second stage of product development, promising formulations are put on accelerated stability to further refine the selection. Considering the number of available polymers for solid–solution preparation and unknown saturation drug loadings for each drug and polymer combinations, numerous empirical trials are needed to identify appropriate concentrations and miscible polymer–drug pairs. Depending upon available drug supplies and resources, such empirical approaches may not be acceptable due to the cost and too long development-time requirements.

To reduce the development cost and to accelerate empirical screening time, high throughput screening (HTS) tools, such as 96-well plate formats with in-tube film casting coupled with in-tube dissolution testing have been developed. These tools can screen hundreds of formulations in a matter of a few weeks. Of course, these HTS tools address the time constraint with empirical approaches. However, to select appropriate combinations, an in-depth understanding of structure–properties relations for drug and polymeric matrix is essential through systematic approaches.

Systematic approaches. Systematic approaches to formulation development of solid dispersions can potentially reduce the number of experiments significantly. In such methods, rather than relying on random mixing of drug and polymers, the initial formulations in the screening studies are selected based upon drug–polymer physicochemical properties, such as solubility parameters, hydrogen bonding, and thermal indicators (e.g., glass-transition or melting temperatures).

One is MemFis (Melt Extrusion Modeling and Formulation Information System, Evonik Pharma Polymers). The system allows pharmaceutical formulators systematic screening of formulations and processing conditions at early stages of solid-dispersion product development to save material and development costs. As the name implies, MemFis has two parts. Formulation Information System uses well- established polymer and organic chemistry group contribution theories to estimate Hansen solubility parameters of drug molecules and polymers. In MemFis calculations, more than 50 chemical group contributions and effects of polar forces (e.g., dipole moments) as well as 40 different hydrogen-bonds on solubility parameters are considered.