Effect of environmental conditions on the crystallization patterns and in vitro release of ibuprofen from drug-in-adhesive acrylic layers

Objectives To examine the effect of different temperature and relative humidity
conditions on the crystallization patterns of ibuprofen in drug-in-adhesive acrylic
layers and to examine the in vitro thermodynamic activity of the layers before and
after storage. Such knowledge can allow prediction of the long-term stability and
performance of the transdermal drug-delivery system (Variankaval et al 1999).
Methods Drug-in-adhesive layers of ibuprofen in an acrylic polymer adhesive
Duro-Tak®-87-4287 (National Adhesive and Starch Corporation, Zutphen,
Netherlands) were prepared in triplicate over a range of ibuprofen concentrations
and examined for the presence of ibuprofen particles immediately after drying,
using a Swift M4000-D microscope (Swift Instruments International) fitted with a
Quodmaster® 100 polarizing (10 ¥) objective. The lowest ibuprofen concentration
at which ibuprofen particles were present in the layer after drying was regarded
as the saturation solubility of ibuprofen in the adhesive. Unsaturated (10 and
20% w/w ibuprofen) drug-in-adhesive layers were then prepared in triplicate for
each concentration and were exposed to three different sets of environmental
conditions; condition A = 1.5 ± 1C and 41 ± 3% relative humidity (RH); condition
B = 20 ± 3C and 41 ± 3% RH; condition C = 20 ± 3C and 61 ± 2% RH.
Temperature and relative humidity were monitored using a temperature/humidity
meter. The layers were examined microscopically twice a week and the time of
initial crystal formation was recorded. Crystal morphology was observed using an
Olympus BH-2 microscope fitted with a camera (AxioCam MRc-ZEISS, UK) and
AxioVision (version 4.4) software. Ibuprofen release from the 10% w/w layers after
preparation and after 14 weeks’ storage was studied using a dissolution test in
phosphate buffer (pH 5.4) at 32C for 6 hours.
Results Crystal nuclei of ibuprofen appeared in the following order: 1 week in
the 20% w/w layers (conditions A and C); 2 weeks in the 20% w/w layers (B);
10 weeks in the 10% w/w layers (B); 12 weeks in the 10% w/w layers (A and C).
Crystal length ranged between 0.5–2.5 mm and 50–200 mm for the 10% and
20% w/w layers, respectively. Plate crystals with smooth edges were formed at
ambient conditions (B) and angular crystals with sharp edges were formed at high
relative humidity (C) and low-temperature conditions (A). The rate of crystal
growth was drug concentration-dependent; 10% w/w < 20% w/w. A dendrite crystal
was also formed, attributed to crystallization of the acrylic polymer. Ibuprofenrelease from the 10% w/w layers was significantly lower (one-way analysis of
variance, P < 0.01) after storage under low temperature (condition A) and high
relative humidity (condition C) compared with the freshly prepared layers.
Conclusions The plate ibuprofen crystals formed after storage of the
drug-in-adhesive layers at ambient conditions did not alter significantly the
in vitro thermodynamic activity of the patches. The sharp-edged angular ibuprofen
crystals formed at low temperature and high relative humidity conditions
significantly decreased the in vitro thermodynamic activity of the patches
compared with the freshly prepared layers.