Using Polymer Technology to Enhance Bioavailability - Pharmaceutical Technology

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Using Polymer Technology to Enhance Bioavailability
The authors review seven polymer classes that can be used to prepare solid-dispersion formulations.

Pharmaceutical Technology
pp. s37-s42

Table ii. Solubility of excipients commonly used in preparing spray-dried dispersions.
Hypromellose has limited solubility with various organic solvents. The polymer is insoluble in dichloromethane, ethanol, acetone, and ether but remain soluble in mixtures of methanol and dichloromethane. Certain grades of hypromellose are soluble in aqueous organic solutions (1). The limited solubility of hypromellose in organic solvents makes it difficult to use in spray-dried dispersions.

Various grades of hypromellose have glass-transition temperatures ranging between 160 C and 210 C but they show significant degradation at temperatures in excess of 250 C (4). Hypromellose is challenging to melt extrude because of its high glass-transition temperature and low degradation temperature. As a result, the polymer has a narrow processing window for hot-melt extrusion. Typically, at least 30% by weight of a plasticizer is required to melt extrude hypromellose (4). However, high levels of plasticizer can help to reduce amorphous solid solution stability. Hypromellose-based solid solutions are also susceptible to high humidity environments (1).

Enteric polymers

Several enteric polymers have been studied for solid-dispersion application, including hypromellose acetate succinates, hypromellose phthalates, cellulose acetate phthalates, and polymethacrylates. Low amounts of these polymers are typically used as coating agents for pharmaceutical application, but manufacturers are conducting extensive toxicology studies to make them suitable for solid-dispersion application. Following compression, these polymers show faster disintegration properties than nonenteric polymers but the API dissolution of these solid-dispersions can be highly pH dependent, thereby affecting permeability and bioavailability.

Hypromellose acetate succinates (HPMCASs). HPMCASs are synthetically modified mixtures of acetic acid and monosuccinic acid esters of hypromellose. HPMCASs are available in three grades (L, M, and H) which correspond to pH-dependent release profiles of low (pH~5), medium (pH~5.5), and high (pH~6.5) pH (5). These synthetically modified natural products are traditionally used as controlled-release agents, enteric-coating agents, film-forming agents, sustained-release agents, and more recently, as solubility enhancing agents. HPMCASs are incompatible with acids, peroxides, and other oxidizing materials (1). In solid-dispersion applications, the aliphatic hydroxyl groups of the natural cellulose and the synthetic 2-hydroxypropoxyl groups are able to donate hydrogen bond to APIs with hydrogen- bond accepting groups. The acetyl and succinyl groups can accept hydrogen bonds from APIs to stabilize the solid dispersion.

HPMCASs are practically insoluble in all organic solvents, but they can form a clear or turbid viscous solution with the addition of acetone, or a mixture of ethanol and dichloromethane (1). The viscous solution is difficult to maneuver in spray-drying applications at the commercial scale, but the process can work with proper solution preparation and spray-drying parameters. HPMCAS polymers have glass-transition temperatures ranging between 120 C and 135 C (6). Limited information is available on onset degradation temperatures. Plasticization by APIs may be necessary to safely melt extrude HPMCAS-based solid dispersions. In spray-drying applications, the high glass-transition temperatures of these polymers aids in producing desired particle size and bulk density powders with good product yield.

Hypromellose phthalates. Hypromellose phthalates are natural cellulose that is synthetically modified to produce partly methyl ethers, 2-hydroxypropyl ethers, and phthalyl esters. Although several different types of hypromellose phthalates are commercially available with molecular weights ranging between 20,000 and 200,000 Da, only two materials (HP-50 and HP-55, where 50 and 55 indicate solubility at pH 5 and 5.5, respectively) are typically used in solid-dispersion technology. Hypromellose phthalates are typically used in oral pharmaceutical formulations as enteric coating materials for tablets, beads, or granules. These polymers are characteristically insoluble in gastric fluid but are swellable and rapidly soluble in the upper intestine. Hypromellose phthalates can be used as coating agents because they do not require the addition of plasticizer or other film formers to produce coatings for oral formulations (1).


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