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Determination of the physical state of norethindrone acetate containing transdermal drug delivery systems by isothermal microcalorimetry, X-ray diffraction, and optical microscopy

Authors
Journal
European Journal of Pharmaceutics and Biopharmaceutics
0939-6411
Publisher
Elsevier
Publication Date
Volume
57
Issue
2
Identifiers
DOI: 10.1016/s0939-6411(03)00158-9
Keywords
  • Norethindrone Acetate
  • Transdermal Drug Delivery System
  • Crystallisation
  • Microcalorimetry
  • X-Ray Powder Diffraction

Abstract

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°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.

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