RESUMO
The inclusions in a typical transdermal drug delivery system (TDS) containing estradiol drug were characterized using microscopic, spectroscopic and thermal analytical techniques. Optical and scanning electron microscopy were used to determine the locations and morphologies of the crystals in the matrix. Two different types of crystals randomly distributed laterally inside the patch were observed. Solid aggregates were found surrounding needle-like inclusions. Optical imaging through the thickness of the patch and SEM sections of the patch revealed that these inclusions were found to occupy a single layer inside the adhesive matrix. No inclusions were observed either in the backing-matrix interface or the matrix-liner interface. The inclusions exhibited a wide range of sizes. The thickness of the crystals as determined by SEM ranged from 10-14 microm. Out of the four crystal forms of estradiol, two of which are solvates (EA and EM) and the other two are anhydrous (EC and ED). Forms EC and ED did not exhibit significant differences in the spectra. Thermal analysis revealed that this was due to the highly unstable nature of ED and its tendency to either convert spontaneously to EC or occur in mixtures with it. The Raman spectrum of the aggregates in the patch showed peaks that seemed characteristic of at least two different forms of estradiol. Only one of these forms is a completely hydrogen bonded system and therefore, was concluded to be estradiol hemihydrate. A splitting of the C17-O peak at 1284 cm(-1) and 1294 cm(-1) was attributed to the existence of at least two types of crystal forms - one that exhibits hydrogen bonding and one that does not. DSC on different concentrations of estradiol in acrylic adhesive showed a clear endotherm for 14 wt % estradiol and apparent endotherms for lower concentrations. The absence of crystallization exotherms is due to the extremely slow kinetics of crystals growth in the polymeric patch.
RESUMO
Transdermal drug delivery systems are pharmaceutical products that can deliver controlled doses of drugs from polymeric patches applied on the human skin. The long-term stability of these patches is a critical issue relative to their performance in delivering drugs at a constant rate. Where a drug has been dissolved in the polymeric adhesive patch, crystallization has been reported in several systems. This study uses a variety of characterization tools to determine the physical and chemical nature of the precipitates formed in situ in estradiol patches. Optical microscopy revealed that crystals were formed in a single layer inside the adhesive matrix and that there were two distinctly different morphologies: needle-like crystals and aggregates around the needles. From IR measurements it was evident that estradiol probably was present in more than one crystal form in these patches. Raman microscopy showed that the needle-like crystals contain the adhesive component and the aggregates some modified crystal form of estradiol, indicating that in addition to the drug, the polymeric adhesive also crystallizes during storage.
