Equilibration at 37 °C is better than de-aeration/de-gassing of a dissolution medium for reproducible and relevant dissolution testing

It is commonly suggested that a dissolution medium should be de-aerated or de-gassed which presumably helps in reducing the variability in dissolution results. It is to be noted that it is not the presence of air, or gas, in the medium which causes the problem. It is the formation of the bubbles from these gases which may cause the problem. The question is why and how these bubbles are formed. If the source of bubble formation is established and then removed, only then this problem can be addressed.

The source of the bubble formation may be explained as follows: Drug dissolution tests are conducted using media maintained at 37 °C, however, media used are generally stored at room temperature which is lower than 37 °C commonly around 20 °C. Therefore, when a medium is transferred to dissolution vessels/baths and heated up to 37 °C, there is a change in solubility of the dissolved gasses, which are from the air thus de-aeration terminology, from higher to lower solubility. The decrease in solubility of the gasses at higher temperatures causes the dissolved gasses to come out of the medium in the form of tiny bubbles which tend to stick at random to the vessel and spindle surface, and may be to the product itself. However, once the medium is equilibrated at 37 °C the formation of the bubbles stops. Therefore, the answer to the question of why and how the bubbles are formed, is because of a transitory stage during the heating process of the dissolution medium. A simple solution to avoid this problem is to remove the temperature gradient effect, i.e., avoid transferring low temperature medium directly into the dissolution vessels. Therefore, the analysts should heat the medium to 37 °C out side the dissolution vessel or give sufficient time for the medium to equilibrate in a dissolution vessel at 37 °C with moderate stirring.

However, unfortunately, a practice of de-aeration or de-gassing has been introduced to address this problem of bubble formation. It is a practice which does not appear to be well thought out. The practice not only has its practical limitations, but also makes the drug dissolution testing irrelevant and unpredictable. For example:

  1. Physiological environment does not require a de-aerated medium. Obviously, if the results obtained using a de-aerated medium they will not relate well with the physiological characteristics of the product.
  2. The commonly suggested procedure of de-aerating, which is based on heating/vacuum steps, is without a measurable endpoint. Therefore, the de-aerating step will always be variable and unpredictable, thus it will introduce variability in testing.
  3. In addition, no matter how reproducible one tries to be with the de-aeration step, after de-aeration the medium will quickly start equilibrating itself with the atmospheric gasses. Therefore, until this equilibrium is reached, the system will remain unstable and unreliable.
  4. Often media containing detergents such as SLS are difficult, if not impossible, to de-aerate due to excessive foam formation. Therefore, one may not be able to work with de-aerated medium using SLS.

On the other hand, the medium equilibrated at 37 °C within a dissolution apparatus, or external to it such as by keeping in a water bath, provides a simple, stable, reproducible and physiologically relevant alternative.

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