Cellulose acetate (CA) is a polymeric excipient widely used in pharmaceutical dosage forms for controlled release (1–5) and taste masking (6–8). CA also is one of the most suitable materials to serve as a semipermeable membrane for osmotic drug delivery systems (9–10).
Although osmotic drug delivery systems have many designs and configurations, they generally consist of a tablet core surrounded by a semipermeable membrane (11). When designing an osmotic drug delivery system, many factors could affect the release rate of an active needed to be delivered. Selection and design of the semipermeable membrane remain one of great challenges for formulation scientists.
Knowing the relationship between a formulation and its film properties is crucial for designing a membrane to control release rate. Yuan et al. have investigated the effects of solvent systems (acetone and acetone/water), polyethylene glycol (PEG) molecular weight and level on the properties of CA-free films (12). In that study, water as a cosolvent in the formulation definitely affected morphology, and ultimately, the properties of the films. The films prepared from acetone were transparent, flexible, stronger, but less permeable to water vapor compared with those films containing water as a cosolvent. Meier et al. published similar results when they studied the influence of the plasticizer content and film preparation procedure on the morphology, thermal, and mechanical properties of CA films plasticized with poly(caprolactone triol) (PCL-T) (13). They demonstrated that the addition of water, a nonsolvent, during the membrane-casting process was a simple and effective way to change membrane porosity and consequently the drug-permeation profile. When small quantities of nonsolvent were used to obtain low-porosity membranes, the presence of a plasticizer agent could be used to better modulate drug permeation (14).
Materials and methods
Materials. CA-398-10NF-EP with acetyl content at 39.4% and CA-398-10TG (technical grade) with acetyl content at 40.3% (Eastman Chemical Company, Kingsport, TN) were used in the study. The plasticizer (Pz) investigated was polyethylene glycol 3350 (PEG 3350, Sigma Aldrich, St Louis, MO). High-purity acetone (B&J Brand, Burdick & Jackson, Muskegon, MI) and deionized water (NANOpure water system, Barnstead, Van Nuys, CA) were used as the solvent system. When applying CA onto tablets, the coating formulations were the same as those casting films. The tablets to be coated consisted of 98.5% of POLYOX water-soluble resins with a molecular weight of 5,000,000 (Dow Chemical, Midland, MI), 0.5% of colorant (Sensient Technologies Corp., St. Louis, MO), and 1.0% of magnesium stearate (Mallinckrodt Baker Inc., Phillipsburg, NJ). All of these materials were used as received.
Preparation of model tablets. POLYOX with (molecular weight of 5,000,000), blue dye, and magnesium stearate were blended in a V-blender (The Patterson Kelly Co. Inc, East Stroudsburg, PA) for 3 min with the intensifying bar on for 15 s. The above mixture was then compressed into 250.0-mg tablets on a rotary tablet press (D3B 16 station, Manesty, England) under 200-lb compression force.
CA coated on the model tablets. The CA coating formulations at 6.0% solid level were prepared following the same procedures used to prepare CA-free film except there was no degas step. Table II lists the coating formulations having four repeat points (center point) for CA-398-10NF-EP and one center point for CA-398-10TG based on the same experimental design as the free films.
All of the coating runs, with a target coating weight at 10.0 wt% relative to the tablet weight, were performed in a pan coater (COMPU-LAB, Thomas Engineering, Inc., Hoffman Estates, IL) with one spray gun under the processing conditions indicated in Table III. For each run, 800.0 g of tablets were coated, and all coating runs were repeated at least twice.
Testing of CA-coated tablets. Eight tablets from each coating run were randomly selected and tested in deionized water at 37 °C to determine water uptake using a standard disintegration tester. At selected time intervals, the tested tablets were taken out, gently dried with a tissue, and weighed. The water uptake was calculated using the following equation:
Water uptake at time t =
(tablet weight at time t) – (tablet weight at time 0)
Results and discussion
Acetyl effects on CA-free film properties. CA-398-10TG with acetyl content at 40.3% also was used in the film study to determine how a change in acetyl content over a range of about 1.0% affects film properties. Comparison of the film properties between CA-398-10NF-EP (NF, 39.4% acetyl) and CA- 398-10TG (TG, 40.3% acetyl) suggested that no significant acetyl effect on free-film properties can be observed in the studied range (see Tables IV, V, and VI).
Permeability of CA coating on tablets. CA was coated on model tablets prepared as previously described. The water uptake was measured as a function of time. The water uptake increased linearly with time because of the nature of the POLYOX resin, which will retain water and swell after absorbing water penetrating through the CA film. When the coating film was no longer able to hold the inside pressure, the film ruptured and the experiment was terminated. The slope of the water uptake curve represents water uptake rate (g/min). This value changes with formulation factors such as the plasticizer (Pz) level and water level.
Design expert software (Design Expert V7., Stat-Ease, Inc., Minneapolis, MN) was used to analyze the water uptake data. Based on the data, a model was established to predict water uptake rate. The fitted model is:
Water uptake rate (g/min) =
(3.26145 × 10-3) + (2.90396 × 10-5) ×
PEG – (6.90834 × 10-5) ×
PEG2 – (2.35306 × 10-5) × Water + (1.98277 × 10-6) ×
Water2 + (9.80461 × 10-6) × PEG × Water – (7.15720 ×
10-5 ) × Acetyl
in which PEG is the Pz concentration in the formulation as a percentage (0.00–3.37%); Water is the water concentration in the formulation as a percentage (0.00–10.00%); Acetyl is the percent acetyl content of the CA polymer (39.4–40.3%).
Figure 7 shows water uptake predicted from the model at Pz = 3.00%, Water = 5.00%, Acetyl = 40.3%, and Acetyl = 39.4%. The difference in the water uptakes between the CAs with these two acetyl levels is 5.7%. The difference in water uptake by acetyl content is calculated by the following equation:
When designing a formulation to eliminate the variations from raw materials, it is therefore crucial to understand how formulation factors affect the permeability of the coating film and the release rate
Understanding formulation factor effects on free-film and coating-film properties would provide guidelines for selecting a formulation in the early design stage of developing semipermeable membranes. The results from this study demonstrated that formulation factors such as plasticizer and water level, signifantly affect free-film properties and coating performance. With increasing plasticizer level, the mechanical strength of the free films decreased and the permeability of the films increased. With the interaction of plasticizer and water, the effects on the properties of free films were even greater. Although there were no significant differences in free film properties between CA-398-10NF-EP and CA-398-10TG, the permeability of coating films increased with decreasing acetyl content in CA polymers. The acetyl content over a range of about 1.0% affected permeability of coating films at some degree and the effects were largely dependent on the formulation. With higher plasticizer level and water level in the formulation, the acetyl content only slightly affected the permeability of the coating film. This study demonstrates that it is important to design a robust formulation to reduce the variability of a finished product. It should be realized that besides formulation factors, processing conditions are key controls in ensuring product quality and keeping the release profile of a product in a desirable range.
of a finished product.