title: Determination of the physical state of norethindrone acetate containing transdermal drug delivery systems by isothermal microcalorimetry, X-ray diffraction, and optical microscopy.
abstract: Transdermal drug delivery systems (TDDS) enable a controlled drug delivery to the skin. The low permeability of the stratum corneum necessitates a high drug concentration of the polymeric matrix and often requires supersaturation. This, however, promotes crystallisation of supersaturated systems. Isothermal microcalorimetry at 25 degrees C, polarisation light microscopy, and X-ray powder diffraction (XRPD) were used to characterise the crystal growth of norethindrone acetate (NEA). The solubility of NEA in the patches determined by these methods is about 4%. The crystallisation process could be measured reliably and with a high accuracy by microcalorimetry and microscopy. XRPD was considerably less sensitive but was the only method allowing a semi-quantitative determination of the amounts of crystals formed. The drug-associated heat measured by microcalorimetry increased proportionally with increasing NEA concentration in the concentration range of 4-10% demonstrating a constant crystallisation rate. At a higher supersaturation, such as 12% drug content, the crystallisation process was accelerated. The application of Johnson-Mehl-Avrami kinetics for the analysis of nucleation and crystal growth of the punched patches indicated a site-saturated nucleation mechanism and a one-dimensional crystal growth. The crystallisation enthalpy of NEA was -22.8+/-2.6 kJ/mol. The most specific method to observe the crystal formation is polarisation light microscopy. However, the microscopic analysis requires much longer storage times than microcalorimetry to detect crystallisation.
authors.affiliation: Institut für Pharmazeutische Technologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Latsch
authors.forename: Torsten
authors.initials: T
authors.lastname: Selzer
authors.forename: Lothar
authors.initials: L
authors.lastname: Fink
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
mesh_terms: D000279:Administration, Cutaneous; D002151:Calorimetry / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D008859:Microscopy, Polarization / Q000379:methods; D009640:Norethindrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry*; D000077563:Norethindrone Acetate; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000077563:Norethindrone Acetate; D009640:Norethindrone