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Formulation and process considerations for ethyl cellulose aqueous dispersion in sustained-release applications.
Sustained-release formulations are mainly designed to increase the duration of drug action by providing a gradual and continuous release of a drug substance from its dosage form, and thereby, decrease dosing frequency. The advantages of sustained-release drug delivery include enhanced patient compliance, improved treatment efficacy and a lower incidence of adverse reactions due to a more uniform drug levels in the blood or plasma among others.
Ethyl cellulose polymer has been used as a coating material for oral sustained-release dosage forms since 1985 (1). “Its primary release mechanism is drug diffusion across a water-insoluble membrane,” explained Rina Chokshi, PhD, project leader, controlled release technology, FMC BioPolymer. “Aquacoat ECD is an aqueous colloidal dispersion of ethyl cellulose polymer, which can be used as a moisture barrier as well as in sustained-release and taste-masking applications.”
Ethyl cellulose aqueous dispersion provides a stable, reproducible, pH-independent drug-release profile with similar dissolution profiles in both fed and fasted states (2). “An aqueous dispersion of ethyl cellulose offers various processing advantages over organic ethyl cellulose solution, including reduced coating processing time (higher solid content and low viscosity), avoidance of potential toxicity due to residual solvent, and reduced environmental concerns,” Chokshi told Pharmaceutical Technology.
With ethyl cellulose aqueous dispersion, the desired drug release profile can be achieved by adjusting three critical formulations attributes—plasticizer, pore former concentration, and film thickness. “The plasticizer decreases glass-transition and minimum film-forming temperatures while improving film strength and flexibility,” said Chokshi. “The plasticizer can also affect intrinsic film structure. A water-soluble plasticizer such as triethyl citrate (TEC) produces a more hydrophilic film and faster drug dissolution compared with water-insoluble plasticizers such as dibutyl sebacate (DBS) that retain the film’s hydrophobicity.”
Water-soluble polymers are used as pore formers to create channels in the film that facilitate drug diffusion. “A higher concentration of pore former increases the rate of drug diffusion. On the other hand, a thicker film can be used to slow down the diffusion process,” Chokshi explained.
Coating with an aqueous dispersion poses the challenge of achieving complete film coalescence required to produce a robust dissolution profile and long-term stability. In the case of Aquacoat ECD, the polymer is initially deposited as spheres that fuse or coalesce to form a continuous, dense film as water evaporates during the process. “If polymer particles do not fuse completely during coating, further coalescence may occur during storage, resulting in a denser structure and lower permeability associated with slower drug diffusion rates,” Chokshi noted. “Optimized temperature, time, and humidity are crucial for achieving complete coalescence. A temperature above the minimum film-forming temperature increases macromolecular mobility and facilitates coalescence. Higher humidity also enhances film formation, as water is an efficient plasticizer for many polymers (3).” Various studies have been carried out to optimize time, temperature, and humidity conditions to achieve in-process coalescence; and it has been demonstrated that full film coalescence can be achieved using a fluid-bed process by spraying water and maintaining product temperatures at 55–57 oC for one to two hours (3).
1. M.A. Frohoff-Hulsmann, A. Schmitz, B.C. Lippold, Int. J Pharmaceut. 177 (1) 69-82 (1999).
2. S. Muschert et al., Drug Dev. Industrial Pharmacy 36 (2) 173–179 (2010).
3. S. Muschert et al., Eur. J Pharmaceut. Biopharmaceut. 78 (3) 455-461 (2011).