Publications

In vitro release properties of etonogestrel and ethinyl estradiol from a contraceptive vaginal ring
J.A.H. van Laarhoven, M.A.B. Kruft, H. Vromans
The release properties of steroids from a combined contraceptive vaginal ring have been investigated. The product design is based on a coaxial fiber consisting of two types of polyethylene vinylacetate copolymers. Inside the core of the fiber, two steroids are present in a molecularly dissolved state. In order to design a controlled release system with specified release characteristics, values of diffusion coefficient and solubility are required. These data can either be determined during pre-formulation studies on e.g. polymeric flat films or from in-vitro release measurements of the actual coaxial fibers. It can be concluded from this study that polyethylene vinylacetate copolymers exhibit suitable properties to develop a controlled release system with the two steroids etonogestrel and ethinyl estradiol. It has been found that the permeability data obtained in the pre-formulation studies are useful in semi-quantitative terms, but deviate from the permeability data found from the in-vitro release of coaxial fibers. This is most likely due to differences in the polymeric structure of films and coaxial fibers. As a consequence, further studies should be initiated to evaluate the relationship between the manufacturing process and the resulting polymeric structure. It has also been found that the solubility and release of etonogestrel are influenced by the concentration of ethinyl estradiol. By investigating this phenomenon by thermoanalysis, it was shown that the steroids form an eutectic. The lower melting point of the steroids results in an increase in solubility and hence in altered permeability properties.

Effect of supersaturation and crystallization phenomena on the release properties of a controlled release device based on EVA copolymer
J.A.H. van Laarhoven, M.A.B. Kruft, H. Vromans
This study describes the influence of steroid concentration, manufacturing and storage on the release properties of etonogestrel from polyethylene vinylacetate (EVA) based coaxial fibers. Coaxial fibers were manufactured by extrusion technology. As a consequence of the high extrusion temperatures large amounts of etonogestrel dissolve in the polymeric melt. Since the release from the coaxial fibers is directly proportional to the concentration gradient over the membrane, the amount of dissolved drug that recrystallizes upon cooling is of crucial importance. Therefore crystallization kinetics were studied using thermal analysis and hot stage microscopy. It was found that if the amount of etonogestrel is below a critical nucleation concentration at room temperature, the dissolved steroid remains in a supersaturated state. If on the other hand the amount of dissolved steroid is just above the critical nucleation concentration, the supersaturated steroid recrystallizes very slowly. It is concluded that the release of etonogestrel from an extruded coaxial fiber is a result of a complicated set of parameters, where, respectively process conditions, concentration of etonogestrel and both time and temperature of storage are of importance.

Influence of Spinline Stress on Release Properties of a Coaxial Controlled Release Device Based on EVA Polymers
Hans van Laarhoven, Jan Veurink, Marc-Anton Kruft, Herman Vromans
Purpose. To investigate the influence of the extrusion parameters on the polymeric structure and release properties of polyethylene vinyl acetate (EVA) coaxial fibers, used for controlled release of steroids.
Methods. Coaxial fibers were prepared under various extrusion conditions. Both spinline stress and release properties were determined. The polymeric structure of the membrane was investigated with wide angle X-ray scattering (WAXS).
Results. Upon leaving the spinneret, the polymeric fiber exhibits a large die swell. As a consequence, it is necessary to apply a force to draw the fiber to its desired diameter. A larger drawing force is needed at lower extrusion temperature, at a smaller air gap, or at a higher spinning velocity. It was found that the release rate of a steroid from the coaxial fiber increases, when the fibers are prepared at a higher spinline stress. X-ray measurements reveal that at higher spinline stress, the crystalline volume fraction of the membrane decreases. As a result of a decreasing crystallinity, the permeability of the polymer increases.
Conclusions. It is demonstrated that the extrusion parameters and spinline stress have a significant influence on the polymeric structure of the membrane and hence the release properties. Higher spinline stress results in a higher release rate.

Effect of process induced changes in membrane morphology of a coaxial controlled release device
J.A.H. van Laarhoven, M. Ypma, H. Vromans
This study discusses a coaxial controlled release system based on EVA polymers which is manufactured by means of a melt spinning process. In a previous study it was shown that the process conditions of the melt spinning process exhibit a pronounced effect on the release properties of the coaxial fibers, which is attributed to variations in the polymeric morphology of the membrane. In the present study it is demonstrated that these changes in the polymeric structure of the membrane also have a significant influence on the mechanical properties of the coaxial fiber. After leaving the spinneret it is necessary to apply a drawing force to  elongate the fiber to its desired dimensions. The elongation of the fiber not only takes place in the air gap but also to some extend in a cooling bath. The major part of the exerted stress during elongation is due  to the membrane. Transmission electron microscopy (TEM) confirms differences in the polymeric morphology of the membrane. An increasing spinline stress results in a polymeric morphology of the membrane that characterized by a lamellar stacked structure where the lamellae are orientated perpendicular to the fiber axis.

Temperature effects on the release properties of a coaxial controlled release device based on EVA polymers.
J.A.H. van Laarhoven, H. Vromans
Coaxial controlled release systems were prepared by means of a co-extrusion process using various grades of polyethylene vinyl acetate (EVA) copolymers. EVA polymers are semicrystalline. The polymeric structure and permeability properties of these polymers can be adapted by varying the vinyl acetate content. The polymeric structure is however also influenced by the manufacturing method and the storage conditions.
This study investigates the influence of temperature on the release properties of EVA. It is demonstrated that the release rate of etonogestrel increases when the coaxial fibers are stored at elevated temperatures or are cooled down more slowly during manufacturing. The changes are shown to be related with the size of the crystalline and amorphous domains. The cooling rate of a membrane diminishes in radial direction. As a consequence, permeability of a membrane is not constant but increases in the radial direction. It was found that the influence of temperature on permeability of EVA decreases at lower vinyl acetate content. In fact, this is a logical consequence of the lower crystallinity of these polymers.

The influence of the extrusion parameters on release and mechanical properties of a coaxial controlled release device based on EVA copolymer
J.A.H. van Laarhoven, H. Vromans^,b
This paper describes the influence of the process parameters on the permeability and mechanical properties of a coaxial controlled release device based on polyethylene vinyl acetate (EVA) copolymers. This device is prepared by means of a co-extrusion process where two EVA copolymers are melted and finally elongated into a coaxial fiber. The force needed to elongate the fiber is dependent on the process conditions applied. It was found that these process conditions have a significant influence on the final permeability properties of the coaxial fiber. The release rate of a drug from the coaxial fiber increases, if the fibers are manufactured at lower extrusion temperatures and smaller air gaps (distance between die and water surface). Furthermore a relation is demonstrated between the release properties of the fiber and mechanical properties (the elongation at break).

A study on water permeation through rubber closures of injection vials
H. Vromans, J.A.H. van Laarhoven
Freeze-dried products are highly hygroscopic. Because of their reactivity with water, they must be adequately protected against the uptake of moisture. In the vial presentation, the rubber closure forms the critical barrier. Water absorption and desorption profiles indicate that the rate-controlling water diffusion coefficient is concentration dependent. From these curves the diffusion coefficients can be estimated. Real time penetration experiments were compared with the absorption curves. From this it can be concluded that rubbers with a low permeability are often able to take up significant amounts of water. The rate at which saturation is achieved is an indication of the diffusion coefficient. Therefore, this reveals an elegant way of discriminating between the quality of rubbers. On the basis of the experimental results, it is possible to evaluate the water protection capacity of rubber closures. Quantitative permeation through the rubbers is, however, highly unpredictable because of the concentration dependency of the diffusion coefficient.