Use of isothermal heat conduction microcalorimetry, X-ray diffraction, and optical microscopy for characterisation of crystals grown in steroid combination-containing transdermal drug delivery systems

Abstract

The combined application of the steroids estradiol (E2) hemihydrate and norethindrone acetate (NEA) is desirable for hormone replacement therapy. Transdermal drug delivery systems (TDDS) enable a controlled delivery of these drugs to the skin. However, in order to attain high skin permeation rates the concentration of the dissolved drugs in the TDDSs has to be high. This often results in supersaturated systems with a high crystallisation tendency. The combination of NEA and E2-hemihydrate in the acrylic matrix of patches yields crystals that are different from single drug systems. A new crystal phase showing additional X-ray powder diffraction peaks and a new feather-like crystal shape appeared. The crystal formation was considerably accelerated and enhanced by increasing E2 contents in the patches. The new crystal phase seems to be kinetically favoured compared with crystals appearing from pure E2-hemihydrate or NEA. A crystallisation enthalpy of −7.9±0.95 kJ/mol in the matrix containing a 1:3 mixture of E2-hemihydrate and NEA was determined by isothermal microcalorimetry. The crystallisation rate increased with higher drug concentrations. In addition, the influence of patch pre-treatment at 80°C prior to storage on crystallisation was investigated. This treatment enabled a slight reduction of the crystallisation in the TDDSs. Microcalorimetry enabled the classification of various additives according to their influence on the crystallisation process.