Crystallisation of estradiol containing TDDS determined by isothermal microcalorimetry, X-ray diffraction, and optical microscopy.

ABSTRACT

Transdermal drug delivery systems (TDDS) enable a controlled delivery of drugs to the skin. However, it is still a problem to achieve a stable and prolonged constant drug release. To attain high permeation rates across the skin, the concentrations of the drug dissolved have to be high and often create supersaturated, thermodynamically metastable, or unstable systems that possess a high tendency to crystallise. In the present study, microcalorimetry as well as polarisation microscopy and X-ray powder diffraction (XRPD) were used to characterise the growing crystal germs of estradiol (E2) hemihydrate. Polarisation microscopy enabled the observation of crystals with two different morphologies of E2 in the polymeric acrylic transdermal patch matrix. Crystal formation and growth were also detected by XRPD. The diffraction pattern corresponded to estradiol hemihydrate. The intensity of the observed reflections was proportional to the crystal quantities and increased during storage. A high supersaturation resulted in high peak intensities caused by a high crystallisation rate. Since precipitation is generally accompanied by heat evolution, crystal germ formation, and crystal growth could easily be detected early by isothermal microcalorimetry. Much lower amounts of crystal were detected by this method than with the significantly less sensitive XRPD method. Microscopy was equally sensitive to but much more time-consuming than microcalorimetry.