flow-through lines and the collection chambers themselves, should be demonstrated by the experiment. It should also be shown that there is no loss of drug through its volatility during the permeation procedure. If volatility is a problem, a quantitative accounting of this must be made. The receptor medium should provide an effective sink for the penetrant. Ideally, it should, at the same time, contain a minimum volume to facilitate analysis because, in general, the more concentrated the drug in the collection medium, the easier the assay procedure. The cell design should allow the receptor fluid to be well mixed and temperature controlled (116).
In vitro systems range in complexity from a simple two-compartment static diffusion cell to multijacketed flow-through cells (111). Although numerous studies using modifications of the various systems described above have been reported (103 - 120), two design types have shown the highest potential for use as standardised, compendial methods. They are the vertical diffusion cells for measurement of percutaneous absorption (i.e., Franz and modified Franz), which require the use of a membrane when measuring drug release and immersion cells for use with the standard USP dissolution apparatus (i.e., the European Pharmacopoeia diffusion cell), which may be used with or without a membrane (116).
1.4.2.1 Franz and modified Franz diffusion cell
Most of the published work on in vitro release from semisolids used vertical Franz-type cells (115). Finite dose techniques and the design of a static one-chambered diffusion cell were described by Franz (121, 122). Shortcomings of the original Franz cells were identified and modifications were proposed to improve adequate solution hydrodynamics, mixing efficiency and temperature control (271). These modifications were employed in this study. The cell body consists of a jacketed glass receptor chamber, 12.5 ml in volume (modified cells exist with slightly different receptor volumes) and a glass sampling port. The membrane is placed horizontally over the receptor chamber, the cell cap is applied over that, and the components are held together with a metal clamp. The test formulation can then be applied to the surface of the membrane through the top of the cell cap, which is open to the atmosphere unless sealed by the user. A study in this laboratory by Pefile et al. (123) showed that the inability to control the evaporation process of the volatile components from the vehicle resulted in erratic drug release from the unoccluded bases with marked variability in drug release rates.
Figure 1.8 Modified Franz diffusion cell (116)
The temperature in the bulk of the receptor medium is maintained by circulating water through a water jacket that surrounds the receptor compartment (223). The entire cell is positioned in a multiple-cell drive unit which drives the magnetic stirrer to agitate the receptor medium at a controlled rate of 100 rpm. The jacketed portions of multiple cells are connected in series with tubing to a circulating temperature-controlled water bath (116).
1.4.2.2 European Pharmacopoeia diffusion cell
An alternate to the Franz diffusion cell is the use of an immersion cell with a standard USP dissolution apparatus. The European Pharmacopoeia diffusion cell, although similar in design and operation to the VanKel enhancer cell and to the Hanson ointment cell (116), has some notable differences. The European Pharmacopoeia diffusion cell is described in detail in the European Pharmacopoeia (124). The diffusion cell consists of a support, a cover and a membrane. The support contains a central depression which acts as the reservoir for the transdermal dosage form. The depth of the central reservoir is 2.6 mm and the diameter 38 mm. The cover has a central aperture with a diameter of 32 mm and a corresponding surface area of 8.03 cm2 through which the topical formulations diffuses. The cover is held firmly in place above the support by four screws extending into the support base.
The diffusion cell is assembled and placed into a cylindrical vessel with the diffusion surface facing upwards and parallel to the horizontal plane. The cylindrical vessel is made from
borosilicate glass or other suitable transparent material, with a hemispherical bottom and a nominal capacity of 1000 ml. The vessel has a flanged upper rim and is fitted with a lid that has a number of openings, one of which is central. The USP dissolution apparatus is
equipped with a motor with a speed regulator capable of maintaining the speed of rotation of the paddle within ± 4% of 100 rpm. The motor is fitted with a stirring element which
consists of a drive shaft and a paddle. The paddle is lowered to a depth corresponding to 10 ± 2 mm above the diffusion cell surface. The temperature of the receptor fluid is
maintained at 32 ± 5 °C. Evaporation is prevented by the fitted lid. Samples are taken from the cylindrical vessel at suitable time intervals (124).
Figure 1.9 European Pharmacopoeia diffusion cell (125)
The diffusion cell is easy to load and most laboratories have a USP dissolution apparatus (115) and it does not have the serious drawback due to the presence of air bubbles at the membrane/liquid interface as commonly observed with the Franz diffusion cells (110).
Fares et al. (115), Liebenberg et al. (105) and Sanghvi et al. (125) compared the rate of drug release from both the Franz cells and the enhancer cells and concluded that once the data is corrected for differing surface area, drug release is nearly superimposable.
CHAPTER TWO
KETOPROFEN MONOGRAPH