Metrolab Blog

Dissolution Media Degassing

All dissolution media should be degassed before it is placed in the dissolution vessel. Incorrectly prepared media can cause results that are either too great or too small. High results can occur when the bubbles adhere to the surface of the tablet particles, increase their buoyancy, and raise them to a higher part of the vessel where the media flow is quicker. Lower results can occur if the bubbles adhere to the surface of the basket or the tablet forming a physical barrier between the tablet and the media.
If a liquid is left to stand in air, they will form a natural equilibrium over a period of time so that a portion of the gas is dissolved in the liquid. The volume of dissolved gas is dependent on the temperature of the media and the pressure of the gas. Unlike the behaviour with solids the saturation level of gases decreases with temperature. The equilibrium value of oxygen in water drops from 8.74mg/l at 22°C to 7.73mg/l at 37°C (130% of the value at room temperature). Therefore if the media is heated it becomes supersaturated with air and air bubbles will form.
The effects on a dissolution rate can be significant, particularly with prednisone tablets. In some test results the rate of dissolution was higher by more than 30% when all the dissolved gases were removed. There is a linear relationship between the amount of dissolved gas and the rate of dissolution and a lot of low failures may be caused by the effects of unwanted gases in the media.
The release of gases from the media can be prevented if the level of gas is reduced before heating — to avoid possible problems a value at least 5% below saturation at the test temperature should be provided.
Typically the deaeration is measured by volume of dissolved oxygen present in the media as it is easy to measure directly with sensitive electrodes and has a virtually pH independent solubility in water. Oxygen is much easier to measure than nitrogen and the relationship between the level of air and that of oxygen is well correlated. It is important that the level of oxygen is always given an absolute value in parts per million (ppm). Values that are given as a percentage of dissolved air are not sufficient as these are dependent on the temperature of the media. When using an oxygen meter it is important that the media being prepared is water as an additive such as acid or buffer may adversely affect the reading.

Methods of Degassing
There are various methods of degassing media — helium sparging, warming, and subsequent filtering and vacuum degassing are the most popular. The method suggested in the USP is to heat the media to 45°C then filter it through a 0.45µm filter under vacuum and stirred for about 5 minutes before being placed directly into the dissolution vessel (the paddles/ baskets should be switched off until the analysis is ready to start). At no time must the temperature be allowed to drop below 37°C. This method of degassing has been shown to reduce the level of dissolved gases by about 85% which is enough to ensure that the air will not affect the dissolution results.

Helium sparging can be effective but is costly to use for large volumes, as it requires a constant supply of helium gas to continually bubble through the media. It degasses the liquid by absorbing the gases that are dissolved in the media into the helium bubbles and carrying them out of solution. One of the major problems with this method is that the media can become saturated with helium which causes similar problems to be saturated with air and it is difficult to measure the amount of helium in the liquid.
Heating and filtering the media is fairly reliable and is the method described in USP 23 (it actually specifies heating to 45 °C, followed by filtration through a 0.45µm filter membrane). This will remove about 85% of the dissolved oxygen, although the media then has to be cooled before the dissolution test which gives it time to reaerate.
Vacuum degassing can remove more than 95% of the dissolved gas and if the media is held under vacuum (as it is in the Dosaprep) then it will not be able to reaerate before it is placed in the dissolution vessel.
Other common laboratory methods of degassing such as sonication or membrane degassing are not practical for degassing the large volumes required for dissolution testing and are more suited for HPLC.

Reaerating Media
If the media is left to stand in the air it will reaerate over a period of several hours. The rate of reaeration is largely dependent on the temperature of the media and its agitation. Media that is stirred by a paddle has a reaeration rate of ~3mg/l over 120 minutes. This compares to ~2mg/l for 100rpm paddles and 1.5mg/l for media that is left to stand. It is important to fill the vessels carefully — if the liquid is slowly transferred to the vessel, without splashing, the level of air will increase by around 0.5mg/l. If it is just splashed in it will increase by roughly double this value.
The speed of reaeration slows as it approaches saturation level and should not form bubbles for the duration of the test.

Degassing Media with Surfactants
Degassing media that contains surfactants can be difficult as the degassing process inevitably causes bubbles which will create a significant amount of foam. This foam can interfere with volumetric measurements and will also attach to the basket as it is placed into the media. There are three popular procedures that can be used:

  1. The best method is to use a tank or a degasser where the media is withdrawn from the bottom. In this way all the foam remains at the top of the liquid and is not transferred to the vessels.
  2. It is possible to blow the foam off with a gentle stream of air. This method should be done before the media is transferred to the vessel so that it does not affect the volume.
  3. If you don’t have the ability to do that, a couple of drops of methanol or ethyl ether can be used. The solvent should only be used if it is allowed within your internal SOPs.