Exploring Excipient Functionality

This technical forum is part of a special issue on Solid Dosage and Excipients.
Apr 01, 2011
Volume 35

This article is part of PharmTech's supplement "Solid Dosage and Excipients 2011."

Excipients play a vital role in drug formulation. Several leading experts share advances in the field. Stuart C. Porter, PhD, senior director, film coating systems and excipients of global pharmaceutical applications, research and development (R&D), at ISP, provides an overview of solid dispersions as a strategy to improve solubility. Firouz Asgarzadeh, PhD, senior technical manager at Evonik, explains the use of predictive systems in pharmaceutical melt extrusion. Phil Butler, technical sales manager, coatings of pharma ingredients and services at BASF, examines film coatings for taste-masking and moisture-protection applications. Jennifer Trevor, PhD, senior business development manager, Ferro Pfanstiehl Laboratories, explores uses of pharmaceutical sugars.

Solid dispersions overview

Stuart C. Porter, senior director, film coating systems and excipients, global pharmaceutical applications R&D at ISP

It has been estimated that 40–60% of drugs in development have poor bioavailability due to low aqueous solubility, and this is likely to increase in the future with the increased use of combinatorial chemistry in drug discovery targeting lipophilic receptors. Poor bioavailability results in increased development times, decreased efficacy, and increased inter- and intra-patient variability. Thus, improving drug solubility and, hence, bioavailability through formulation and process technology is a formulator's challenge.

Several approaches can be considered for increasing active pharmaceutical ingredient (API) solubility in the gastrointestinal tract (GI), including: particle-size reduction, salt formation, nanoparticles, liquid-filled capsules, conventional formulation techniques with surfactants and/or antinucleating agents, and solid dispersions. The use of solid dispersions/solid solutions in pharmaceutical applications to enhance oral bioavailability was first envisioned in 1961. Only recently, with an increasing number of poorly soluble APIs in development, has interest in using solid dispersions in oral dosage forms gained momentum.

Solid dispersions are molecular (thermodynamically stable solid solutions) and/or colloidal (kinetically stable solid suspensions) dispersions of the amorphous API dispersed in a polymeric matrix. As a result of their morphology and thermodynamic and thermomechanical properties, solid dispersions increase drug surface area, reduce drug crystallinity, and stabilize the system during storage and subsequent administration, in vivo, to inhibit drug recrystallization. Solid dispersions are most practically and most commonly produced in the laboratory through commercial scales via either melt-extrusion or solvent spray-drying process technologies. Each technology for forming a solid dispersion has its advantages and limitations. It has been demonstrated that APIs can be formulated with polymers, such as povidone (e.g., Plasdone, ISP) and copovidone (e.g., Plasdone S-630, ISP) to provide stable solid-dispersions system with excellent shelf-life stability and dramatically enhanced API solubility and bioavailability,

Solubility enhancement, however, does not end with the creation of a suitable solid dispersion of the API. Such a solid dispersion has to be successfully incorporated into the final dosage form. If, for example, the final dosage form is a tablet, the physical stability of the API (in solid dispersion form) has to be maintained throughout the shelf life of that dosage form as well as after ingestion up to the point of drug absorption. Many polymers that are used to create solid dispersions are hydrophilic, and so exposure of the dosage form to environmental moisture can compromise the physical stability of the API, with the result that recrystallization may occur on storage. If the tablet releases the API too quickly on ingestion, especially when drug absorption might be a rate-limiting step, the API may recrystallize in the lumen of the gut before absorption can occur. One remedy, for example, if the API is rapidly released in the stomach, but is not absorbed until after entering the small intestine, may be to delay the release of the API in the stomach with an enteric film coating.

Finally, many oral dosage forms, especially tablets, are likely to be film coated. Because aqueous film coating is the preferred approach today in the global pharmaceutical industry, use of such a process, by potentially adding moisture to the tablet, can again compromise the physical stability of the final product. To mitigate against this risk, one could either employ a non-aqueous coating process (not preferred today) or use a high-solids film coating system (e.g., Advantia Preferred HS Coatings, ISP). By allowing better thermodynamic control of the coating process, the system prevents moisture from penetrating into the tablet core during film coating. Further enhancements could also be achieved by employing a film-coating formulation that exhibits certain moisture-barrier properties.