Tuesday, March 31, 2009

Formulation Effects on the Thermomechanical Properties and Permeability of Free Films and Coating Films: Characterization of Cellulose Acetate Films

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).

In general, as the acetyl content in CA increases, the CA film permeability decreases, solvent resistance increases, and the glass transition temperature increases (15). However, for the small variation within the specification of CA-398-10NF-EP, no study has been found to address the effect of the acetyl content on CA film properties. Although free film properties would provide insights for predicting permeability of the films, applying CA polymer onto a substrate is a final step to ensure the release profile as designed. The objectives of this study were to investigate the acetyl content in CA polymer on the film properties, particularly the permeability of free films and coating films, and to study the effects of plasticizer level (polyethylene glycol 3350) and water level on the properties of fre

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 CA-free films. The CA-free films were prepared using a solvent evaporation method. PEG 3350 was dissolved in water for 1.5 h, then most of needed acetone was added to the PEG/water solution. CA was gradually added to the solvent system under stirring. After all CA was added, stirring continued for another 2 h to allow CA to dissolve completely. The remaining needed acetone was added to the above mixture, followed by stirring for 30 min. After the CA solution was degassed for about 3 h, the solution was ready to be used to cast films. The film-cast method and procedures can be found in reference (12). The film formulations were developed based on an experiment design; the design space was that water varied from 0.0–10.0% and the ratio of Pz to polymer varied from 0.00 to 0.29. There were three repeated points (center point) for CA-398-10NF-EP and one center point for CA-398-10TG. The design was constrained with water, which must be in the formulation whenever Pz is present. Table I lists all of the free films prepared. Characterization of CA-free films. The prepared films were characterized, and film properties such as film morphology, glass transition temperature, oxidative and thermal stability, mechanical strength and elongation, contact angle, and water vapor transmission rate were determined according to the methods described in a previous article (12).

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

Table IV: Cellulose acetate (CA)-free film properties with 0.00% plasticizer (Pz) and 0.00% water in formulations.
CA-free film properties. Effects of plasticizer and water level on CA-free film properties. The CA-free films were opaque, except for the two films that didn't include water in the formulation, which were transparent. Previous studies concluded that water in the film formulation affects the morphology of the film (13, 16). Film properties results are organized in Tables IV, V, and VI according to the water content in the formulations.

Table V: Cellulose acetate (CA)-free film properties with 5.00% water in the formulations.
Modulated differential scanning calorimetry (MDSC) data show that glass-transition temperature (Tg) changed from 191 °C without the Pz and water in the formulation to 185 °C with the most Pz and the highest water level in the studied range. The small change suggests that PEG 3350 is not a very effective plasticizer for CA films in the studied range. This result is consistent with a previous study (12).

Table VI: Cellulose acetate (CA)-free film properties with 10.00 % water in the formulations.
The value of T10 (°C, N2 purge), at which temperature 10% of the sample weight is lost, represents the thermal stability of the films. The value of T10 (°C, air purge) represents the oxidative stability of the films. Thermogravimetric analysis (TGA) results indicated that Pz and water level didn't have significant influence on the thermal and oxidative stability of the films because the temperatures didn't vary greatly with increasing Pz and water level.

Figure 1: Mechanical strength of cellulose acetate (CA)-free films changes with plasticizer (Pz) and water level. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
Figure 1 shows the mechanical strength of the CA-free films as it varies with water and Pz level. It is clear that PEG 3350 and water level influence mechanical strength significantly and that PEG 3350 level has the major effect. With increasing PEG level, the films weakened, which was expected because a plasticizer increases polymer chain mobility and decreases mechanical strength. Water functions as a weak plasticizer, so that the film mechanical strength decreased with increasing amount of water in the formulations.

Figure 2: Scanning electron microscopy (SEM) images of the cellulose acetate film without Pz and water. Left: surface image; right: cross-section image.
The significant mechanical strength decrease may also be contributed by the morphology of the films. Figures 2–5 show the scanning electron microscope images of the CA-free films. With increasing Pz level and water level in the formulations, the number and size of the pinholes increased significantly.

Figure 3: SEM images of the cellulose acetate films with 5.00% water in the formulations. Top: surface images; bottom: cross-section images. Left: 0.00% Pz; middle: 1.67% Pz; right: 3.37% Pz.
The percentage of elongation reflects the extent to which the films can be stretched, so that it represents the flexibility of a film. Because a plasticizer increases polymer chain mobility, one would expect Pz level would increase the flexibility of the free films, which increases percent elongation. However, data listed in Tables VI, V, and VI show that the film was more flexible when no Pz and water existed, and not much difference with Pz and water change. This further suggests that PEG 3350 is not an effective plasticizer for the films in the studied range and that bigger and more numerous pinholes with increasing Pz and water made the films less stretchable.

Figure 4: SEM images of the CA films with 10.00% water in the formulations. Top: surface images; bottom: cross-section images. Left: 0.00% Pz; middle: 1.67% Pz; right: 3.37% Pz.
The wettability of a film is represented by the contact angle. A small angle means the film has better wettability. In general, it is known that films plasticized with hydrophilic plasticizer have increased wettability, and the films plasticized with hydrophobic plasticizer have decreased wettability. The data in tables IV, V and VI show that PEG and water level did not affect the wettability of the films in the studied range.

Figure 5: Water vapor transmission rates of CA-free films changes with Pz and water level.
Permeability of a film is a key factor to consider when designing a film formulation. Water vapor transmission rate (WVTR) is a commonly used measurement to determine the permeability of a film. Figure 5 shows the WVTR of CA films changes with Pz and water level. It is not surprising that PEG 3350 alone did not affect WVTR significantly. As discussed previously in this article, PEG 3350 is not a very effective plasticizer for CA in the studied range. However, with the interaction of water and PEG 3350, WVTR increased with PEG 3350 and water level, and significantly increased when water was more than 5% in the formulations. This result can be explained by the morphologies of the films. SEM images show that the number and size of pinholes increased greatly with water and PEG 3350 level (see Figures 2–4).

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 6: Water uptake rate changes with Pz and water level.
The fitted model indicates that an increase in Pz level in the formulation increases water uptake rate, which is also true for water level. PEG is the major influencing factor (see Figure 6).

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:

Figure 7: Predicted acetyl effects on water uptake at Pz = 3.00% and water = 5.00%.
Difference in water uptake (%) = (water uptake at acetyl = 39.4%) – (water uptake at acetyl = 40.3%) / (water uptake at acetyl = 39.4%) × 100%

Table VII: Water uptake difference between the CAs with two levels of acetyl content (39.4% and 40.3%).
Acetyl effects on the water uptake decreases significantly with increasing Pz and water in the formulations. Table VII lists the difference in water uptake by acetyl content, assuming the coating processing conditions are controlled precisely the same.

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.

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