Using Polymer Technology to Enhance Bioavailability

The authors review seven polymer classes that can be used to prepare solid-dispersion formulations.
Sep 01, 2010
Volume 2010 Supplement, Issue 4

The Handbook of Pharmaceutical Excipients lists several generally regarded as safe (GRAS) polymers that have been used in the pharmaceutical industry for decades in a variety of applications. More recently, these polymers have been used in solid-dispersion technology to enhance the solubility of active pharmaceutical ingredients (APIs) to increase bioavailability. These polymers have been used for various purposes, including as binders, fillers, and disintegrants in tablet formulations, enteric coatings, and controlled- and sustained-release matrix systems. Ample stability and safety data demonstrate that these polymers are ideal for solid-dispersion formulations. Further research during the past decade in solid-dispersion technology and process technology has established that stable solid dispersions that enhance solubility can be prepared at commercial scale through spray drying and melt extrusion. This article reviews seven classes of polymers that can be used to prepare solid-dispersion-based formulations. When properly formulated and processed, the result is a polymer-drug matrix, which has excellent shelf-life stability and can improve drug solubility and bioavailability.

These seven polymer types can be grouped into two categories: nonenteric polymers and enteric polymers. Although several of these polymers can increase the dissolution rate of APIs, careful consideration of API permeability properties is necessary when choosing the appropriate polymer. For example, enteric polymers may not be considered useful for APIs with a narrow permeability window, for example. An improperly formulated solid dispersion may enhance the apparent API solubility but not significantly improve API bioavailability.

Nonenteric polymers

Three nonenteric polymers are commonly studied for solid-dispersion technology: copovidone, povidone, and hypromellose. Because these polymers are highly compactable and used at high levels in solid-dispersion, it is often necessary to use disintegrants in the final dosage form to decrease solid-dispersion disintegration times and to prepare immediate-release solid dosage formulations.

Figure 1: Copovidone (FIGURE IS COURTESY OF ISP)
Copovidone. Copovidone is a synthetic polymer of 1-vinyl 2-pyrrolidone and vinyl acetate in a 60:40 ratio. Copovidone has been used in pharmaceutical formulations for decades as a tablet binder and film former. Most commonly, copovidone is used as a binder in direct compression and dry granulation applications. Copovidone is chemically compatible with most organic and inorganic pharmaceutical ingredients (1). For solid-dispersion applications, both monomer units are capable of accepting hydrogen bonds stabilized through carbonyl acetate groups and carbonyl pyrrolidinone groups.

Copovidone is readily soluble in multiple organic solvents, including acetone, dichloromethane, methanol, ethanol, and mixtures, thereby making it ideal for preparing spray-dried dispersions. This copolymer remains chemically and physically stable in various organic solutions for several days. For spray-drying applications, the relatively high glass-transition temperature of copovidone (106 °C) aids in producing desired particle size and bulk-density powders with good product yield. Furthermore, the lower glass-transition temperature of the material as compared with the homopolymer povidone makes it ideal for melt-extrusion processing. Copovidone has been processed in melt-extrusion application at temperatures in excess of 180 °C without visual degradation (2). Typically, plasticizers are not necessary for melt-extruding solid solutions with copovidone but they can be used if necessary. One limitation of copovidone is its hygroscopicity, which can weaken solid-solution stability in humid environments. This concern, however, can be overcome with proper packaging and storage.

Table i. Glass-transition temperatures of excipients commonly used in preparing solid dispersions.
The solubility parameter (δ) of copovidone has been calculated using the Hansen method, the van Krevelen and Hoftyzer method, and the Hoy method at 26.1 MPa½, 21.6 MPa½, 21.9 MPa½, respectively (3). The solubility parameter of the polymer can be compared with the solubility parameter of APIs to determine miscibility for solid dispersion or solid-solution application.

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