Table 1.

Summary of Approaches to Investigate the Effects of Heat on TDS.

Approach	Experiment	Purpose
In vitro permeation test (IVPT)	Fentanyl TDS, seven heating protocols and control (no heat), Franz diffusion cell, skin, different sampling protocols Protocol 1: no heat (32 °C); Protocols 2 and 3: heat for 1 h at 11–12 h and 18–19 h, respectively, with TDS removal at 19 h; Protocol 4: heat from 6 to 72 h; Protocol 5: heat from 24 to 72 h; Protocol 6: heat from 48 to 72 h; Protocol 7: heat from 6 to 7 h, 18–19 h, and then 48–72 h; Protocol 8: heat from 0 to 72 h	Identify the IVPT experimental conditions for assessing heat effects on TDS and skin permeation of fentanyl Protocol 1: baseline control condition; Protocols 2 and 3: short heat exposure effect mimicking those in a recent study21; Protocol 4: sustained heat exposure when the flux begins to reach its peak in the baseline profile (6 h time point); Protocol 5: sustained heat exposure after the flux begins to decrease from its peak in the baseline profile (24 h time point); Protocol 6: heat effect after a significant portion of the drug has been depleted from the TDS; Protocol 7: multiple heat application scenarios for the comparison of the short heat exposure between 6 and 7 h and sustained heat exposure from 6 to 72 h (vs. Protocol 4) and the effect of prior heat exposure at 6–7 h on subsequent heat exposures at 18–19 h (vs. Protocol 3) and heat exposures at 6–7 h and 18–19 h on subsequent exposure at 48–72 h (vs. Protocol 6); Protocol 8: sustained heat effect at the start of TDS application (including the lag time phase) for comparison to other heat exposures
In vitro release testing (IVRT)	Fentanyl TDS, one heating protocol and control (heat from 0 to 72 h and no heat), Franz diffusion cell, filter membrane Dye solution, one heating protocol and control, Franz diffusion cell, filter membrane	Examine heat effects on drug release from TDS in Franz diffusion cell using IVRT Verify the effect of aqueous boundary layer (ABL) in Franz diffusion cell
Dissolution test	Fentanyl TDS, one heating protocol and control (heat from 0 to 24 h and no heat), 20-mL vial	Examine heat effects on drug release from TDS with minimal ABL in a vial as dissolution chamber (vs. Franz diffusion cell)
Steady-state permeability test	Fentanyl solution, 32 °C and 42 °C for 12 h, side-by-side diffusion cell, skin	Determine skin permeability for fentanyl and calculate activation energy