(M1030-11-76) Correlation between Material Properties, Extrusion Processing Conditions and Permeability of Etonogestrel in Polyethylene Vinyl Acetate Films

Purpose: Polyethylene vinyl acetate (EVA) is a biocompatible, non-biodegradable and semicrystalline copolymer that has been widely used for long-acting implants. (1) The mechanisms of drug release of EVA implants consist of drug dissolution and diffusion through EVA. The kinetic of diffusion is defined by drug permeability in EVA, which is impacted by EVA material and structural properties. EVA implants are manufactured by hot melt extrusion. During extrusion, EVA is subjected to heating, cooling, and drawing forces, all of which can impact the crystal structures of EVA, including crystallinity, crystal size and crystal orientation, and consequently the drug permeability in EVA. The objective of this study was to investigate the effect of raw material properties and processing conditions on the permeability of etonogestrel in EVA using free film as a model. The results from this study can be used to guide the investigation of the effect of manufacturing process conditions on drug release properties of implant.

Methods: EVA films were prepared using a Randcastle single screw extruder. EVA 12.0 (12.0 wt.% VA content) and EVA 15.8 (15.8 wt.% VA content) pellets were cryo-milled and blended at predetermined ratios to prepare 7 grades of EVA blends with VA contents ranging from 12.0 wt.% to 15.0 wt.% at intervals of 0.5 wt.%, which were subsequently extruded into films. It was reported that EVA matrix with higher molecular weight EVA rendered slower drug release. (2) Permeability of EVA 12.0 films with three melt indexes, 0.8 g/10 mins, 3.0 g/10 mins and 10 g/10 mins, were compared. Higher melt index is equivalent to lower molecular weight. EVA 15.8 pellets were extruded into films at different cooling rates and relative draw down ratios (DDR), which are calculated by: Relative DDR / Reference DDR (set to 1) = (R_{relative DDR X} l_{reference DDR}) / (R_{reference DDR} /l_{relative DDR}) where R is extrusion output rate (g/min) and l is film thickness after drawn down (µm). Subsequently, the flux of etonogestrel through different EVA films at 37 °C and lag time were measured using a PermeGear Side-by-Side diffusion cell setup. (3) Permeability is given by: P = (dM_t/dt) X l / A where P is permeability (g/cm/s), M_t is accumulative drug amount (g) in receptor side, l is film thickness and A is effective diffusion area (cm²). Diffusivity is calculated using time lag method (3): D = l² / (6 * t) where D is diffusivity (cm²/s) and t is lag time (s). Solubility of etonogestrel in EVA is calculated using: C_s = P / D Where C_s is drug solubility in EVA (g/cm³). Finally, the enthalpy of melting and glass transition temperature of EVA films were measured by differential scanning calorimetry. The crystallinity of EVA film is calculated based on:

C = ΔH_EVA / ΔH_(100%) *100% where C is wt. % crystallinity, ΔH_EVA is heat of melting of EVA film (J/g) and ΔH_100% is heat of melting of the 100% crystalline polyethylene (293.6 J/g).

Results: Every 0.5% increase in VA content resulted in 8% increase in permeability (Figure 1). The increase in permeability is attributed to lower crystallinity (Table 1), which result in increased solubility and diffusivity (Figure 2). When VA content increased from 12.0% to 15.0%, solubility increased by 30% and diffusivity increased by 18% (Figure 2). The increases in solubility and diffusivity were caused by greater portion of amorphous region and less constraining effect of rigid crystalline region of polyethylene, respectively. Shown in Figure 3, the permeability difference between low (0.8 g/10 mins), medium (3.0 g/10 mins) and high melt index (10 g/10 mins) EVA films was not statistically significant (p = 0.08). EVA 15.8 film extruded at higher cooling rate was transparent with higher permeability while film extruded at lower cooling rate was hazy with lower permeability (Figure 4). The difference in physical appearance is due to different size of crystal spherulite. The permeability of film was only 30% higher even when DDR was 7-folds higher (Figure 5).

Conclusion: Etonogestrel permeability in EVA films with different VA contents, molecular weights, and processing conditions were measured using a diffusion cell apparatus. Higher VA content resulted in higher permeability. Over the tested VA contents ranged from 12.0 to 15.0 wt.%, every 0.5% increase in VA content resulted in 8% increase in permeability. The increase in the permeability was attributed to lower crystallinity, which resulted in the increase in solubility and diffusivity. Solubility was more sensitive to the change of VA content than diffusivity. Molecular weight had limited impact on permeability. Permeability was not sensitive to change of draw down ratio for EVA 15.8, which is in agreement with literature (4) that drug release of implants made with higher VA content EVA is less sensitive to elongation effect. EVA 15.8 film is more transparent with higher permeability if processed under higher cooling rate.

References: 1. Schneider C, Langer R, Loveday D, Hair D. Applications of ethylene vinyl acetate copolymers (EVA) in drug delivery systems. Journal of Controlled Release. 2017;262:284-95.
2. Hsu TT-P, Langer R. Polymers for the controlled release of macromolecules: Effect of molecular weight of ethylene-vinyl acetate copolymer. Journal of Biomedical Materials Research. 1985;19(4):445-60.
3. Lee EK, Lonsdale H, Baker R, Drioli E, Bresnahan P. Transport of steroids in poly (etherurethane) and poly (ethylene vinyl acetate) membranes. Journal of membrane science. 1985;24(2):125-43.
4. Laarhoven JAHv. Physical-chemical aspects of a coaxial sustained release device based on Poly-EVA: Utrecht University; 2005.

Acknowledgements: This work was supported by the Broad Agency Announcement (BAA) Contract # 75F40122C00019 from the U.S. Food and Drug Administration (FDA). The content reflects the views of the authors and should not be construed to present FDA’s views or policies. The authors would like to thank Jeffrey Haley from Celanese for providing EVA and suggestions on study design.

Figure 1. Effect of VA content on permeability of etonogestrel in EVA films at 37C (error bars: SD, N = 3)
Figure 2. Effect of VA content on solubility and diffusivity of etonogestrel in EVA films at 37C (error bars: SD, N = 3)
Table 1. DSC measured crystallinity and Tg of EVA 12.0, 13.5 and 15.0 films

Figure 3. Effect of molecular weight on permeability of etonogestrel in EVA 12.0 film at 37C (error bars: SD, N=3)

Figure 4. Effect of cooling rate on permeability of etonogestrel in EVA 15.8 at 37C (error bars: SD, n=3)
Figure 5. Effect of draw down ratio on permeability of etonogestrel in EVA 15.8 film at 37C (error bars: SD, n=3)